CONGENITAL MALFORMATIONS - … · Dandy-Walker Malformation 67 Barbara K. Burton vii For more...

CONGENITAL MALFORMATIONS

http://dx.doi.org/10.1036/0071471898

� NOTICE

Medicine is an ever-changing science. As new research and clinical experience broaden ourknowledge, changes in treatment and drug therapy are required. The authors and the publisher ofthis work have checked with sources believed to be reliable in their efforts to provide informationthat is complete and generally in accord with the standards accepted at the time of publication.However, in view of the possibility of human error or changes in medical sciences, neither the au-thors nor the publisher nor any other party who has been involved in the preparation or publi-cation of this work warrants that the information contained herein is in every respect accurate orcomplete, and they disclaim all responsibility for any errors or omissions or for the resultsobtained from use of the information contained in this work. Readers are encouraged to con-firm the information contained herein with other sources. For example and in particular, readersare advised to check the product information sheet included in the package of each drug theyplan to administer to be certain that the information contained in this work is accurate and thatchanges have not been made in the recommended dose or in the contraindications for admin-istration. This recommendation is of particular importance in connection with new or infrequentlyused drugs.

CONGENITALMALFORMATIONS

Evidence-Based Evaluationand Management

Editors

PRAVEEN KUMAR, MBBS, DCH, MD, FAAPAssociate Professor of Pediatrics

Feinberg School of MedicineNorthwestern University

Children’s Memorial Hospital and Northwestern Memorial HospitalChicago, Illinois

and

BARBARA K. BURTON, MDProfessor of Pediatrics

Feinberg School of MedicineNorthwestern University

Children’s Memorial HospitalChicago, Illinois

New York Chicago San Francisco Lisbon London Madrid Mexico CityMilan New Delhi San Juan Seoul Singapore Sydney Toronto

http://dx.doi.org/10.1036/0071471898

Copyright © 2008 by The McGraw-Hill Companies, Inc. All rights reserved. Manufactured in the United States of America. Except aspermitted under the United States Copyright Act of 1976, no part of this publication may be reproduced or distributed in any form orby any means, or stored in a database or retrieval system, without the prior written permission of the publisher.

0-07-159356-X

The material in this eBook also appears in the print version of this title: 0-07-147189-8.

All trademarks are trademarks of their respective owners. Rather than put a trademark symbol after every occurrence of a trademarkedname, we use names in an editorial fashion only, and to the benefit of the trademark owner, with no intention of infringement of thetrademark. Where such designations appear in this book, they have been printed with initial caps.

McGraw-Hill eBooks are available at special quantity discounts to use as premiums and sales promotions, or for use in corporate training programs. For more information, please contact George Hoare, Special Sales, at [email protected] or (212) 904-4069.

TERMS OF USE

This is a copyrighted work and The McGraw-Hill Companies, Inc. (“McGraw-Hill”) and its licensors reserve all rights in and to thework. Use of this work is subject to these terms. Except as permitted under the Copyright Act of 1976 and the right to store and retrieveone copy of the work, you may not decompile, disassemble, reverse engineer, reproduce, modify, create derivative works based upon,transmit, distribute, disseminate, sell, publish or sublicense the work or any part of it without McGraw-Hill’s prior consent. You mayuse the work for your own noncommercial and personal use; any other use of the work is strictly prohibited. Your right to use the workmay be terminated if you fail to comply with these terms.

THE WORK IS PROVIDED “AS IS.” McGRAW-HILL AND ITS LICENSORS MAKE NO GUARANTEES OR WARRANTIESAS TO THE ACCURACY, ADEQUACY OR COMPLETENESS OF OR RESULTS TO BE OBTAINED FROM USING THEWORK, INCLUDING ANY INFORMATION THAT CAN BE ACCESSED THROUGH THE WORK VIA HYPERLINK OR OTHERWISE, AND EXPRESSLY DISCLAIM ANY WARRANTY, EXPRESS OR IMPLIED, INCLUDING BUT NOT LIMITEDTO IMPLIED WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE. McGraw-Hill and its licensors do not warrant or guarantee that the functions contained in the work will meet your requirements or that its operation will beuninterrupted or error free. Neither McGraw-Hill nor its licensors shall be liable to you or anyone else for any inaccuracy, error oromission, regardless of cause, in the work or for any damages resulting therefrom. McGraw-Hill has no responsibility for the contentof any information accessed through the work. Under no circumstances shall McGraw-Hill and/or its licensors be liable for any indirect, incidental, special, punitive, consequential or similar damages that result from the use of or inability to use the work, even ifany of them has been advised of the possibility of such damages. This limitation of liability shall apply to any claim or cause whatsoever whether such claim or cause arises in contract, tort or otherwise.

DOI: 10.1036/0071471898

http://dx.doi.org/10.1036/0071471898

We dedicate this book to all infants with congenital malformations, their parents,and their families.

This page intentionally left blank

Contents

Contributors xiii

Preface xv

PART I

General Considerations / 1

01. Dysmorphology 3Praveen Kumar

02. Assessment of an Infant with a Congenital Malformation 13Barbara K. Burton

03. Genetic Counseling: Principles and Practices 21Katherine H. Kim

Part II

Central Nervous System Malformations / 39

14. Spina Bifida 41Barbara K. Burton

5. Anencephaly 51Barbara K. Burton

6. Encephalocele 53Barbara K. Burton

7. Holoprosencephaly 57Barbara K. Burton

8. Hydrocephalus 61Barbara K. Burton

9. Dandy-Walker Malformation 67Barbara K. Burton

vii

For more information about this title, click here

http://dx.doi.org/10.1036/0071471898

viii CONTENTS

10. Chiari Malformations 71Barbara K. Burton

11. Agenesis of the Corpus Callosum 77Barbara K. Burton

12. Craniosynostosis 83Barbara K. Burton

Part III

Craniofacial Malformations / 91

13. Cleft Lip and Palate 93Brad Angle

14. Micrognathia 101Brad Angle

15. Congenital Anomalies Associated with Facial Asymmetry 105Brad Angle

16. Ear Anomalies 111Brad Angle

17. Choanal Atresia 117Brad Angle

18. Coloboma 121Brad Angle

19. Cataract 125Brad Angle

Part IV

Respiratory Malformations / 133

20. Congenital High Airway Obstruction Syndrome 135Sandra B. Cadichon

21. Pulmonary Agenesis 139Sandra B. Cadichon

22. Pulmonary Hypoplasia 143Sandra B. Cadichon

23. Congenital Cystic Adenomatoid Malformations 147Sandra B. Cadichon

24. Congenital Diaphragmatic Hernia 151Sandra B. Cadichon

25. Congenital Hydrothorax 159Sandra B. Cadichon

26. Congenital Pulmonary Lymphangiectasia 165Sandra B. Cadichon

Part V

Cardiac Malformations / 171

27. Septal Defects 173Barbara K. Burton

28. Conotruncal Heart Defects 183Amy Wu

29. Right Ventricular Outflow Tract Obstructive Defects 193Barbara K. Burton

30. Left Ventricular Outflow Tract Obstructive Defects 199Barbara K. Burton

31. Dextrocardia 205Barbara K. Burton

32. Cardiomyopathy 209Barbara K. Burton

Part VI

Gastrointestinal Malformations / 215

33. Esophageal Atresia and Tracheoesophageal Fistula 217Praveen Kumar

34. Duodenal Atresia 223Praveen Kumar

35. Anorectal Malformations 227Praveen Kumar

CONTENTS ix

x CONTENTS

36. Hirschsprung Disease 233Praveen Kumar

37. Omphalocele 241Praveen Kumar

38. Gastroschisis 247Praveen Kumar

Part VII

Renal Malformations / 251

39. Renal Agenesis 253Praveen Kumar

40. Horseshoe Kidney 261Praveen Kumar

41. Renal Cystic Diseases 265Praveen Kumar

42. Posterior Urethral Valves 277Praveen Kumar

Part VIII

Skeletal Malformations / 283

43. Polydactyly 285Praveen Kumar

44. Syndactyly 293Praveen Kumar

45. Limb Reduction Defects 299Praveen Kumar

46. Skeletal Dysplasias 307Praveen Kumar

47. Arthrogryposis 321Praveen Kumar

CONTENTS xi

Part IX

Miscellaneous Malformations / 331

48. Single Umbilical Artery 333Praveen Kumar

49. Sacral Dimple and Other Cutaneous Markers of Occult Spinal Dysraphism 339Praveen Kumar

50. Hemihyperplasia and Overgrowth Disorders 347Praveen Kumar

51. Cystic Hygroma 355Praveen Kumar

Glossary of Genetic Terms 363

Web Resources 375

Index 379


Contributors

Brad Angle, MDAssociate Professor of PediatricsFeinberg School of MedicineNorthwestern UniversityChildren’s Memorial HospitalChicago, Illinois

Barbara K. Burton, MDProfessor of PediatricsFeinberg School of MedicineNorthwestern University’s Children’s Memorial HospitalChicago, Illinois

Sandra B. Cadichon, MDAssistant Professor of PediatricsFeinberg School of MedicineNorthwestern UniversityChildren’s Memorial Hospital and Northwestern

Memorial HospitalChicago, Illinois

Katherine H. Kim, MSInstructor, Department of PediatricsFeinberg School of MedicineNorthwestern UniversityChildren’s Memorial HospitalChicago, Illinois

Praveen Kumar, MBBS, DCH, MD, FAAPAssociate Professor of PediatricsFeinberg School of MedicineNorthwestern UniversityChildren’s Memorial Hospital and Northwestern

Memorial HospitalChicago, Illinois

Amy Wu, MDPediatric Cardiology FellowDepartment of CardiologyThe Willis J. Potts Children’s Heart CenterChildren’s Memorial HospitalChicago, Illinois

xiii

Copyright © 2008 by The McGraw-Hill Companies, Inc. Click here for terms of use.


Preface

Based on a World Health Organization (WHO)report, about 3 million fetuses and infants areborn each year with major congenital malfor-mations. Furthermore, congenital malformationsaccount for nearly 500,000 deaths worldwideeach year. Several large population-based studiesplace the incidence of major malformations atabout 2–3% of all live births; among still births,the prevalence of major congenital malforma-tions is even higher. However, individual con-genital malformations are seen only infrequentlyby the individual practitioner. This book is in-tended to serve as a quick reference for medicalstudents, residents, fellows, nurse practitioners,and practicing clinicians in the fields of pedi-atrics, family practice, genetics, and obstetrics.

The main objectives of this book are to pro-vide the most current information on commonmajor congenital malformations in a concise andeasy-to-read format and to provide evidence-based guidelines for evaluation and management

of these infants. The first three chapters providea broad overview of dysmorphology, assess-ment of an infant with congenital malformation,and guiding principles of genetic counseling.The rest of the chapters are devoted to the com-monly encountered congenital malformationsfrom different organ systems. The structure of thisbook was conceived to provide information in aconcise but clear and easy-to-read format. Forexample, the list of associated syndromes is notexhaustive but includes syndromes most likely tobe seen in association with a particular congeni-tal malformation. We hope that this format andthe content will be helpful in achieving our goals.

We are greatly indebted to all individualswhose hard work and commitment made thisproject possible. We would especially liketo thank all contributors and our editors atMcGraw-Hill, Jim Shanahan and Anne Sydor,for their patience and expert guidance through-out this project.

xv



Part I

General Considerations



The word dysmorphology is derived by combining

three Greek words (dys—bad or disordered;

morph—shape or structure; and ology—

the study or science of). Dorland’s Medical

Dictionary defines dysmorphology as a branch

of clinical genetics concerned with the study

of structural defects, especially congenital

malformations.

Chapter 1

DysmorphologyPRAVEEN KUMAR

3

� EPIDEMIOLOGY OF BIRTHDEFECTS

Congenital malformations or birth defects are com-mon among all races, cultures, and socioeconomicstrata. Birth defects can be isolated abnormalitiesor part of a syndrome and continue to be an im-portant cause of neonatal and infant morbidityand mortality. Based on a World Health Organi-zation (WHO) report, about 3 million fetusesand infants are born each year with major con-genital malformations; congenital malformationsaccounted for an estimated 495,000 deaths world-wide in 1997.1 Several large population-basedstudies place the incidence of major malforma-tions at about 2–3% of all live births.2–6 Table 1-1describes the relative frequencies of congenitalmalformations for different major organ systemsat birth. An approximately equal number of ad-ditional major anomalies are diagnosed later inlife. Of all congenital malformations diagnosedby the end of first year of life, nearly 60% areidentified in the first month and about 80% by

the end of 3 months.7 The prevalence of majorcongenital malformations is even higher amongstillbirths with a significant birth defect reportedin 15–20% of all stillbirths.

With the introduction of prenatal ultrasoundin obstetric care, many major congenital mal-formations are diagnosed prenatally, allowingparents to have the option of terminating thepregnancy. Termination of pregnancy for fetalmalformations rose from 23 to 47 per 10,000births between 1985 and 2000.8 The same studyalso reported that the diagnostic accuracy ofprenatal ultrasound exceeds 90% for anencephalyand for abdominal wall defects but is still lessthan 70% for diaphragmatic hernia, bladder outletobstruction, and many major skeletal defects.8

Similarly, many cardiac defects diagnosed in thefirst year of life remain unsuspected before or atbirth. Several recent reports on secular trends inthe prevalence of congenital malformationsfrom Europe, Canada, and Asia have also shownthat prenatal diagnosis rates and pregnancy ter-minations have gradually increased over the last


two decades but the overall total prevalence ofmajor malformations has been unchanged.8–10

Other studies have reported a gradual declinein the total prevalence of nonchromosomal andan increase in chromosomal anomalies.11,12 Noconsistent evidence of seasonality has been re-ported for common birth defect groups.13

A higher overall rate of birth defects is reportedin males and black infants.14,15 Another studyfrom the UK reported a higher risk of congenitalanomalies of nonchromosomal origin with in-creasing socioeconomic deprivation and specu-lated that this increase in risk was probably re-lated to differences in nutritional factors, lifestyle,environment and occupational exposures, ac-cess to healthcare, maternal age, and ethnicity.16

However, more research is necessary to confirmthese findings and to better understand thereasons for the increased risk of congenitalmalformations with increasing socioeconomicdeprivation, if any.

Detailed information from population-basedstudies on the incidence and prevalence of mi-nor malformations is limited, less reliable, andless accurate because of difficulties and incon-sistencies in definitions, identification, docu-mentation, and reporting of these non–life-threatening birth defects. The incidence ofminor malformations has been reported to varyfrom about 7% to as much as 41% among new-born infants. In addition, the majority of birthdefect registries collect data only on congenitalanomalies diagnosed before, at, or soon afterbirth; few collect data on cases diagnosed from

birth to the age of 1 year. However, many mi-nor malformations of internal organs are diag-nosed later in life, if at all.

Contribution of Birth Defects toInfant Mortality

Congenital malformations are an important causeof infant death, both in absolute terms and as aproportion of all infant deaths, in both the de-veloped and developing world. Although onlya small percentage of all newborns, 2–3%, areborn with a major congenital malformation, con-genital malformations account for nearly 20% ofall infant deaths in developed countries. Basedon WHO data from 36 countries from differentcontinents, overall infant mortality decreasedon average 68.8% from 1950 to 1994 but infantmortality attributable to congenital anomaliesdecreased only 33.4%. Infant mortality attribut-able to congenital anomalies was higher in de-veloping countries than in developed countriesbut as a proportion of all deaths, infant mortal-ity attributable to congenital anomalies washigher in developed countries.1 The data fromthe United States and Canada show that infantdeaths caused by major congenital malforma-tions have decreased significantly over the lastseveral decades but birth defects remain theleading cause of infant death and account fornearly 20% of all infant deaths in these coun-tries.15,17 Birth defects are the leading cause ofdeath among whites, Native Americans, andAsian Americans in the United States but the in-fant mortality rate related to birth defects forblack infants is higher than the correspondingrates for infants of other races.15

Very few studies have addressed the survivaldata beyond infancy for children born with con-genital anomalies. A recent report concludedthat the overall relative risk of mortality washigher in children with congenital malforma-tions compared to children without congenitalmalformations, and this risk of mortality washighest during the second year of life and re-mained high through the end of the sixth year.18

4 PART I GENERAL CONSIDERATIONS

� TABLE 1-1 Incidence of Major Malformationsin Human Organs at Birth

Organ Incidence of Malformation

Brain 10:1000Heart 8:1000Kidneys 4:1000Limbs 2:1000All other 6:1000Total 30:1000

Almost 15–30% of all pediatric hospitalizationsin the United States are related to birth defects,and approximately $8 billion is spent annuallyto provide medical and rehabilitative care for af-fected children in the United States alone.19

� EMBRYOLOGY OF BIRTHDEFECTS

Since all congenital anomalies are a result ofaberrant structural development before birth,basic understanding of normal and abnormalembryogenesis and fetal development is impor-tant for clinicians providing care for these in-fants. Prenatal development can be divided intothree time periods: the preembryonic period orimplantation stage, extending from the time offertilization to the end of the second week of ges-tation; the embryonic stage, from the beginning

of the third week to the end of the eighth week;and the fetal stage, from the ninth week untilbirth (Fig. 1-1).20 The preembryonic stage startswith the fertilization and formation of the zygotewhich transforms into a blastocyst by the end ofthe first week. Characterized by the presence ofpluripotent cells and rapid cell proliferation, im-plantation of the blastocyst is complete by theend of the second week. The presence of thesepluripotent cells is also responsible for the “allor none” effect of teratogens during this period.An environmental insult during this period willeither kill the embryo or produce no harm if theembryo survives.

The embryonic stage is the time of primarytissue differentiation and formation of definitiveorgans. During the third week of gestation, it startswith the formation of primitive streak, notochord,and three germ layers from which all embryonictissues and organs develop. During the following

CHAPTER 1 DYSMORPHOLOGY 5

Central Nervous System

Ear

Eyes

U.Limb

L.Limb

Teeth

Palate

External Genitalia

Functional Defects and Minor MalformationsMajor MalformationsDeath

Lip

Heart

Fertilization toBilaminar disc

Formation

Pre-organogenesis

1 2 3 4 5 6 7 8 9 10 11 12 20 38

Embryonic Period(weeks)

Fetal Period(weeks)

Figure 1-1. Susceptibility to teratogenesis for different organ systems. Solid bar indicates highlysensitive periods. (Reprinted with permission from Clayton-Smith J, Donnai D. Human Malforma-tions. In: Rimoin DL, Connor JM, Pyeritz RE, eds. Emery and Rimoin’s principles and practice of med-ical genetics Vol I. 3rd ed. New York; Edinburgh: Churchill Livingstone; 1997:383–94.)20

five weeks, from the fourth to the eighth week,all major organs and systems of the body formfrom the three germ layers and assume their fi-nal positions. By the end of this stage, the ap-pearance of embryo changes to a distinctly hu-man form. Because all essential external andinternal structures are formed during this period,this is the most critical and vulnerable period ofdevelopment (Fig. 1-1). The majority of majorcongenital malformations are a result of alter-ation in normal development during this stage.

The remainder of gestation is primarily a pe-riod of growth in size and is characterized byrapid body growth and differentiation of tissuesand organ systems. During this period, the fetusis less vulnerable to teratogenic effects of vari-ous agents but these agents may still interferewith growth and development of organs suchas brain and eyes during the fetal period.

� ETIOLOGY OF BIRTH DEFECTS

The branch of medicine concerned with thestudy of abnormal prenatal development is ter-atology and includes the study of causes andpathogenesis of birth defects. The causes of con-genital anomalies are divided into four broadcategories; genetic, environmental, multifactor-ial, and unknown. Initially, as many as 50–60%of all congenital anomalies were considered tohave an unknown etiology but with recent ad-vances in genetics, the etiology of many syn-dromes is being identified. Based on earlier data,a genetic cause was considered to be responsi-ble in as many as 10–30% of all birth defects,environmental factors in 5–10%, multifactorialinheritance in 20–35%, and unknown causeswere responsible in 30–45% of the cases.5,19,21,22

However, more recent data indicate that the eti-ology of a congenital malformation is unknownin about 17% of the cases.7

Genetic factors are responsible for a largemajority of congenital malformations with knowncauses and play an important role in disordersof multifactorial inheritance. A chromosomalabnormality occurs in 1 of 170 liveborn infants.

Among chromosomally abnormal neonates, one-third have an extra sex chromosome, one-fourthhave trisomy of an autosome, and the remaininghave an aberration of chromosomal structuresuch as a deletion or translocation.23 However,a significant majority of these infants have no phe-notypic manifestations at birth. Earlier studies re-ported that nearly 10% of infants with lethal mul-tiple congenital malformations have abnormalcytogenetic studies.23 However, this proportionis likely to be much higher today with advancesin genetics. A chromosomal abnormality leadingto a congenital malformation can be either nu-merical or structural. The examples of numericalabnormalities of chromosomes include Downsyndrome (trisomy 21) and Turner syndrome(45 XO monosomy). The examples of structuralchromosomal abnormalities include transloca-tions, deletions, microdeletions, duplications, orinversions. With better understanding of the hu-man genome and improved techniques in mole-cular cytogenetics, more and more structuralchromosomal abnormalities are being identifiedas a cause of congenital anomalies previouslyconsidered to be of unknown etiology.

Environmental factors also play an impor-tant role in the etiopathogenesis of many con-genital malformations. Maternal exposure to cer-tain environmental agents can lead to disruptionof the normal developmental process and resultin both minor and major congenital anomalies.These agents with a potential to induce a struc-tural anatomic anomaly in a developing fetusare termed teratogens (Greek: teratos [monster]and gen [producing]). Table 1-2 summarizessome common examples of teratogens in dif-ferent categories and the associated congenitalmalformations. The exact mechanisms by whicheach teratogen induces anomalies are not clearlyknown but include altered gene expression, his-togenesis, cell migration and differentiation,apoptosis, protein or nucleic acid synthesis andfunction, or supply of energy. The risk of hav-ing a congenital anomaly after exposure to ateratogenic agent depends on the nature andthe dose of the agent, timing and duration ofexposure, presence of concurrent exposures,


and the genetic susceptibility of the embryo. Itis likely that the interactions between genes andenvironmental factors are responsible for mostbirth defects related to teratogenic exposures.

Classification of CongenitalAnomalies

Although all congenital malformations are a resultof an aberrant structural development, the under-lying cause/mechanism, extent of maldevelop-ment, consequences, and the risks of recurrence

are variable. Congenital anomalies can be clas-sified either based on timing of insult, underly-ing histological changes, or based on its med-ical and social consequences.

A. Classification based on timing of insult.Congenital anomalies can be placed into thefollowing three categories on the basis ofdevelopmental stage during which the aber-ration in development took place.1. Malformation. A malformation is a mor-

phologic defect of an organ, part of anorgan, or a region of the body due to


� TABLE 1-2 Common Teratogens and Associated Anomalies

Vulnerable Period Associated Congenital Anomalies

Teratogen DrugsAntihypertensive 13th week-term Hypocalvaria, renal failure, pulmonary

ACE inhibitors hypoplasia, deathAnticonvulsants

Phenytoin 18–60 days Cleft lip/palate, congenital heart defect,hypoplasia of nails

Valproic acid 18–60 days Hypertelorism, hyperconvex nails, septo-optic dysplasia, cleft lip/palate, limbdefects, microcephaly

Retinoids 18–60 days CNS/ear defects, cleft lip/palate, heartdefects, eye anomalies

AnticoagulantsWarfarin 6–9 weeks Nasal hypoplasia, eye anomalies,

hypoplastic phalangesAndrogens 2–24 weeks Genital tract abnormalities

InfectionsRubella First trimester Cataract, microcephaly, microopthalmia,

heart defectsVaricella zoster 8–20 weeks Microcephaly, limb hypoplasia, cutaneous

scars

Maternal DisordersDiabetes First trimester Neural tube defects, cardiac defects,

caudal regression syndromePhenylketonuria Mainly first trimester IUGR, microcephaly, dysmorphic features,

maxillary and mandibular hypoplasia,cardiac defects, cleft lip/palate

MiscellaneousAlcohol First trimester Microcephaly, maxillary hypoplasia,

heart defects

CNS, central nervous system; IUGR, intrauterine growth retardation; ACE, angiotensin-converting enzyme.

an intrinsically abnormal developmentalprocess. They usually result from abnor-mal processes during the period of em-bryogenesis and have usually occurredby eighth week of gestation with the ex-ception of some anomalies of brain, gen-italia, and teeth. Since malformations ariseduring this early stage of development,an affected structure can have a configu-ration ranging from complete absence toincomplete formation. The examples ofmalformations in this category include re-nal agenesis and neural tube defects. Mal-formations are caused by genetic or envi-ronmental influences or by a combinationof the two.

2. Disruption. Disruptions result from theextrinsic breakdown of or an interferencewith an originally normal developmentalprocess, and the resulting anomaly can in-clude an organ, part of an organ, or a largerregion of the body. Congenital abnormal-ities secondary to disruption commonlyaffect several different tissue types andthe structural damage does not conformto the boundaries imposed by embryonicdevelopment. A disruption is never in-herited but inherited factors can predis-pose to and influence the developmentof a disruption. An anomaly secondary todisruption can be caused by mechanicalforces, ischemia, hemorrhage, or adhe-sions of denuded tissues and occur dur-ing or after organogenesis. An exampleof congenital anomaly caused by disrup-tion is the amniotic band sequence.

3. Deformation. Deformational anomaliesare produced by aberrant mechanicalforces that distort otherwise normal struc-tures. These anomalies occur after organo-genesis, frequently involve musculoskeletaltissues and have no obligatory defects inorganogenesis. Common causes of defor-mation are structural abnormalities of theuterus such as fibroids, bicornuate uterus,multiple gestation, and oligohydramnios.

Deformations can be reversible after birthdepending on the duration and extentof deformation prior to birth.

Thus, both deformations and disruptions af-fect previously normally developed structureswith no intrinsic tissue abnormality. These anom-alies are unlikely to have a genetic basis, are oftennot associated with cognitive deficits, and havea low recurrence risk.

B. Classification based on underlying his-tological changes. Certain anomalies havea well-defined alteration in underlying cellu-lar and tissue development which can beascertained by histologic analyses and clin-ical presentation. The understanding ofthese processes can help in explaining thepathogenesis of several common congenitalmalformations.1. Aplasia. Aplasia indicates absence of cel-

lular proliferation leading to absence ofan organ or morphologic feature such asrenal agenesis.

2. Hypoplasia. This term refers to insuffi-cient or decreased cell proliferation, re-sulting in undergrowth of an organ ormorphologic feature such as pulmonaryhypoplasia.

3. Hyperplasia. Hyperplasia means exces-sive proliferation of cells and overgrowthof an organ or morphologic feature.

The terms hypo- or hyperplasia are usedwhen there is either decrease or increase in anumber of otherwise normal cells. Any alter-ation in normal cellular proliferation leads todysplasia.

4. Dysplasia. Dysplasia refers to abnormalcellular organization or histogenesis withina specific tissue type throughout the bodysuch as Marfan syndrome, congenital ecto-dermal dysplasia, and skeletal dysplasias.Most dysplasias are genetically determined;unlike other mechanisms of congenital


malformations, most dysplastic conditionshave a continuing course and can leadto continued deterioration of functionduring life.

C. Clinical classification of birth defects1. Single system defects. These defects

constitute the largest group of birth de-fects and are characterized by involve-ment of either a single organ system oronly a local region of the body such ascleft lip/palate and congenital heart de-fects. These anomalies usually have a mul-tifactorial etiology and the recurrence riskis often low.

2. Multiple malformation syndrome. Theterm “syndrome” (Greek: running together)is used if a combination of congenitalmalformations occurs repeatedly in a con-sistent pattern and usually implies a com-mon etiology, similar natural history, anda known recurrence risk. However, therecan be marked variability in phenotypicpresentation in different patients with thesame syndrome and the etiology may re-main unknown in many cases.

3. Associations. Association includes clini-cal entities in which two or more con-genital anomalies occur together moreoften than expected by chance alone andhave no well-defined etiology. The linkamong these anomalies is not as strongand consistent as among anomalies ina syndrome. A common example of anassociation is the VACTERL associationwhich includes vertebral, anal, cardiac,tracheoesophageal, renal, and limb anom-alies. The awareness of these associationscan prompt a clinician to look for otherdefects when one component of an as-sociation is noted. These conditions usu-ally have a low recurrence risk and theprognosis depends on the number ofmalformations and severity of each un-derlying defect present in an individualcase.

4. Sequences. The term sequence impliesthat a single primary anomaly or mechan-ical factor initiates a series of events thatlead to multiple anomalies of the same orseparated organ systems and/or body ar-eas. A common example is the Potter se-quence in which primary abnormality ofrenal agenesis leads to oligohydramnios,limb deformities, flat facies, and pulmonaryhypoplasia. The underlying etiologies formost sequences are unknown and the re-currence risk is usually low.

5. Complexes. The term complex is usedto describe a set of morphologic defectsthat share a common or adjacent regionduring embryogenesis, for example,hemifacial microsomia. These defects arealso referred to as polytopic field defects.Lack of nutrients and oxygen secondaryto aberration of blood vessel formation inearly embryogenesis as well as direct me-chanical forces have been identified asa cause of many recognized complexes.

D. Classification of birth defects based onmedical consequences. Based on the med-ical consequences, a congenital malforma-tion can be classified as either major or minor.1. Major malformations. Major malforma-

tions are anatomic abnormalities which aresevere enough to reduce life expectancyor compromise normal function such asneural tube defects, renal agenesis, etc.Major malformations can be further di-vided into lethal or severe malformations.A malformation is considered lethal if itcauses stillbirth or infant death in morethan 50% of cases.7 The remaining majormalformations are life-threatening with-out medical intervention and are consid-ered severe.

2. Minor malformations. Minor malforma-tions are structural alterations which eitherrequire no treatment or can be treated eas-ily and have no permanent consequencefor normal life expectancy. The distinction


between minor malformation and a nor-mal variant is often arbitrary and is pri-marily based on the frequency of a findingin general population. A normal variantusually occurs in 4% or more of the pop-ulation as compared to minor malforma-tions which are present in less than 4% ofthe normal population. It is common forisolated minor anomalies to be familial.Minor malformations are most frequent inareas of complex and variable featuressuch as the face and distal extremities.Minor malformations are relatively frequentand a higher incidence may be notedamong premature infants and infants withintrauterine growth retardation. In general,minor malformations are more subtle, havelow validity of diagnoses, and are not re-ported consistently. They are neverthelesssignificant as they may be an indicationof the presence of a major malformationand may also provide critical clues to thediagnosis. The risk of having a major mal-formation increases with the number ofassociated minor malformations. It is es-timated that infants with three or moreminor defects have a 20–90% risk ofa major malformation; those with two mi-nor defects have 7–11% risk; those withone minor defect have a 3–4% risk com-pared to infants with no minor malforma-tions who have a 1–2% risk of a majormalformation.2,3 Some of this variabilityin risk is probably related to variability indefinition, documentation, and validity ofminor malformation diagnoses in differentstudies.

E. Etiological classification of birth defects.In order to achieve consistency among vari-ous studies, a new hierarchical system ofclassification was proposed recently.24 Thisnew classification system divides all congeni-tal malformations into the following eight cat-egories based on etiology: (1) Chromosome(C): for microscopically visible, unbalanced

chromosome abnormalities such as Trisomies;(2) Microdeletion (MD): for all submicro-scopic chromosome abnormalities includingmicrodeletions, uniparental disomy, and im-printing mutations such as 22q11 deletion(DiGeorge syndrome) and 15q11 dele-tion (Prader-Willi or Angelman syndrome);(3) Teratogen (T): for known teratogens andprenatal infections such as fetal alcohol syn-drome and congenital cytomegalovirus(CMV) infection; (4) New dominant (ND):for new dominant mutations such as achon-droplasia, Apert syndrome; (5) Familial (F):for familial disorders not included as a newdominant such as tuberous sclerosis, fragileX syndrome; (6) Syndrome (S): for recog-nized nonfamilial, nonchromosomal syn-dromes such as Kabuki syndrome; (7) Isolated(I): for isolated anomalies not included inone of the above categories such as gas-troschisis, isolated cleft lip; and (8) Multiple(M): for unrelated anomalies from more thanone system with no unifying diagnosis suchas VACTERL and MURCS. This classificationsystem would allow cases to be classified toone category only, the highest in the list ofcategories applicable.

In summary, congenital anomalies are animportant cause of morbidity and mortality bothin the perinatal period and later in life, and de-spite a considerable decline in the prevalenceof some types of congenital malformations,around 2–3% of all births are still associatedwith a major congenital malformation. A betterunderstanding of the etiology and pathogenesisof these defects has led to several preventionstrategies over the years. Rubella immunizationand avoidance of teratogenic drugs in women ofreproductive age, use of folic acid supple-mentation and maintenance of euglycemia indiabetic patients during the periconceptionperiod, premarital and preconception geneticcounseling to couples at risk of certain geneticdisorders, and screening for Down syndromein presence of advanced maternal age are a few


examples of very effective and successful strate-gies to prevent congenital malformations ina newborn.

REFERENCES

1. Rosano A, Botto LD, Botting B, et al. Infant mor-tality and congenital anomalies from 1950 to 1994:an international perspective. J Epidemiol Commu-nity Health. Sep 2000;54(9):660–6.

2. Leppig KA, Werler MM, Cann CI, et al. Predictivevalue of minor anomalies. I. Association withmajor malformations. J Pediatr. Apr 1987;110(4):531–7.

3. Marden PM, Smith DW, McDonald MJ. Congenitalanomalies in the newborn infant, including minorvariations. A study of 4,412 babies by surface ex-amination for anomalies and buccal smear for sexchromatin. J Pediatr. Mar 1964;64:357–71.

4. Mattos TC, Giugliani R, Haase HB. Congenital mal-formations detected in 731 autopsies of childrenaged 0 to 14 years. Teratology. Jun 1987;35(3):305–7.

5. Nelson K, Holmes LB. Malformations due to pre-sumed spontaneous mutations in newborn infants.N Engl J Med. Jan 1989;320(1):19–23.

6. Van Regemorter N, Dodion J, Druart C, et al. Con-genital malformations in 10,000 consecutive birthsin a university hospital: need for genetic counselingand prenatal diagnosis. J Pediatr. Mar 1984;104(3):386–90.

7. Czeizel AE. First 25 years of the Hungarian con-genital abnormality registry. Teratology. May 1997;55(5):299–305.

8. Richmond S, Atkins J. A population-based study ofthe prenatal diagnosis of congenital malformationover 16 years. BJOG. Oct 2005;112(10):1349–57.

9. De Vigan C, Khoshnood B, Lhomme A, et al. Preva-lence and prenatal diagnosis of congenital malfor-mations in the Parisian population: twenty years ofsurveillance by the Paris Registry of congenital mal-formations. J Gynecol Obstet Biol Reprod (Paris).Feb 2005;34(1 Pt 1):8–16.

10. Tan KH, Tan TY, Tan J, et al. Birth defects in Sin-gapore: 1994-2000. Singapore Med J. Oct 2005;46(10):545–52.

11. Dastgiri S, Stone DH, Le-Ha C, et al. Prevalenceand secular trend of congenital anomalies in Glas-gow, UK. Arch Dis Child. 2002;86(4):257–63.

12. Rankin J, Pattenden S, Abramsky L, et al. Preva-lence of congenital anomalies in five British re-gions, 1991-99. Arch Dis Child Fetal Neonatal Ed.2005;90(5):F374–9.

13. Siffel C, Alverson CJ, Correa A. Analysis of sea-sonal variation of birth defects in Atlanta. BirthDefects Res A Clin Mol Teratol. Oct 2005;73(10):655–62.

14. Dryden R. Birth defects recognized in 10,000 ba-bies born consecutively in Port Moresby GeneralHospital, Papua New Guinea. P N G Med J. Mar1997;40(1):4–13.

15. Petrini J, Damus K, Russell R, et al. Contribution ofbirth defects to infant mortality in the United States.Teratology. 2002;66(1):S3–6.

16. Vrijheid M, Dolk H, Stone D, et al. Socioeconomicinequalities in risk of congenital anomaly. Arch DisChild. May 2000;82(5):349–52.

17. Wen SW, Liu S, Joseph KS, et al. Patterns of infantmortality caused by major congenital anomalies.Teratology. May 2000;61(5):342–6.

18. Berger KH, Zhu BP, Copeland G. Mortality through-out early childhood for Michigan children bornwith congenital anomalies, 1992-1998. Birth De-fects Res A Clin Mol Teratol. Sep 2003;67(9):656–61.

19. Hobbs CA, Cleves MA, Simmons CJ. Genetic epi-demiology and congenital malformations: from thechromosome to the crib. Arch Pediatr Adolesc Med.Apr 2002;156(4):315–20.

20. Clayton-Smith Jill DD. Human Malformations. In:Rimoin DL, Connor JM, Pyeritz RE, et al, eds. Emeryand Rimoin’s principles and practice of medicalgenetics Vol I. 3rd ed. New York; Edinburgh:Churchill Livingstone; 1997:383–94.

21. Holmes LB. Current concepts in genetics. Congen-ital malformations. N Engl J Med. Jul 1976;295(4):204–7.

22. Brent RL. Environmental causes of human congen-ital malformations: the pediatrician’s role in dealingwith these complex clinical problems caused bya multiplicity of environmental and genetic factors.Pediatrics. Apr 2004;113(4):957–68.

23. McLean S. Congenital Anomalies. In: Avery GB,Fletcher MA, MacDonald MG, eds. Neonatology :pathophysiology and management of the newborn.5th ed. New York: Lippincott Williams & Wilkins;1999:839–58.

24. Wellesley D, Boyd P, Dolk H, et al. An aetiologicalclassification of birth defects for epidemiologicalresearch. J Med Genet. Jan 2005;42(1):54–7.



Chapter 2

Assessment of an Infant witha Congenital Malformation

BARBARA K. BURTON

13

� INTRODUCTION

The primary goals of the assessment of the in-fant with a congenital anomaly or anomalies areto establish a diagnosis, identify any associatedabnormalities, develop a treatment plan and as-sess prognosis, if possible, so that parents canbe provided with accurate information regard-ing their child’s future health and developmentand with genetic counseling that is essential totheir future family planning. Critical componentsof the assessment include the history and phys-ical examination, use of appropriate references,and selective use of genetic testing.

� HISTORY

A detailed prenatal history is critical in the eval-uation of any infant with congenital malforma-tions. Was there a history of any maternal illnesssuch as diabetes mellitus that increases the riskof birth defects? Exposure to prescription med-ications, illicit drugs, and alcohol should be ex-plored. The age of the parents may be of signif-icance. Advanced maternal age may increase theindex of suspicion for a chromosome anomalyor a disorder resulting from maternal uniparental

disomy such as Prader-Willi syndrome. If ad-vanced maternal age is a factor, it is importantto determine if genetic testing was performedprenatally by amniocentesis or chorionic villussampling. In any pregnancy, an inquiry shouldbe made as to whether genetic testing was per-formed for any other reason, such as increasedrisk for chromosome anomalies or neural tubedefects on maternal serum screening. If oligo-hydramnios or polyhydramnios was presentduring pregnancy, this may be an importantfinding. Oligohydramnios can be the explana-tion for fetal deformations associated with in-trauterine constraint or may suggest the pres-ence of urinary tract malformations. In contrast,polyhydramnios may be a clue to underlyingneurologic deficits with impaired swallowing orto gastrointestinal malformations such as in-testinal atresias. The birth presentation is signif-icant in that breech presentation is more likelyto be associated with neurologic impairment inthe infant with inability to achieve a normalcephalic presentation.

The family history is of obvious significancein evaluating an infant with congenital anom-alies. Attention should be paid not only to otherfamily members with similar anomalies but toa history of previous pregnancy losses which


could suggest the possibility of a chromosomeabnormality in the family and to any history ofconsanguinity which would suggest the possi-bility of an autosomal recessive disorder. Minordysmorphic features or unusual characteristicscan at times represent benign familial charac-teristics so examination of the parents for suchfeatures, or simply asking the parents aboutthese findings, can be helpful in sorting out theirsignificance. Some caution should be used inassuming the fact that a dysmorphic infant re-sembles a parent is always reassuring, sincemany dysmorphic syndromes are dominantlyinherited and a parent may be unaware that heor she is affected. A classic example of this isNoonan syndrome. An undiagnosed parent maybe short with a broad neck and low set ears butno significant medical problems, yet can givebirth to a child with much more serious con-cerns such as hypertrophic cardiomyopathy.

� PHYSICAL EXAMINATION

In an infant who is noted to have a congenitalmalformation, either major or minor, a detailed

physical examination is critical to determine ifthere are additional anomalies. The significanceof multiple malformations is clearly differentfrom that of a single isolated malformation. Theexamination should begin with careful mea-surements of length, weight, and head circum-ference since findings of intrauterine growth re-tardation (IUGR), microcephaly, or macrocephalycould be of great significance. Efforts should bemade to systematically assess facial features andall other organ systems. If dysmorphic featuresare noted, they should be described as preciselyas possible. In circumstances in which struc-tures appear abnormally large or small, graphsor charts representing a compilation of normativedata are often available against which individualmeasurements can be compared1,2 so obtainingmeasurements may be desirable.

Special mention should be made of the sig-nificance of minor anomalies, usually defined asdysmorphic features or unusual findings of mini-mal or no functional or cosmetic significance. Ex-amples of minor anomalies are seen in Figs. 2-1to 2-5. A single minor anomaly is found in ap-proximately 14% of all newborns and is not asso-ciated with an increased risk of associated major


Figure 2-1. Inner epicanthal folds, in this case in a patient with Down syndrome.

malformations.3 Three or more minor anomaliesare found in only 0.5% of newborns, however,4

and in various series are associated with a risk ofmajor malformations between 19.6% and 90%.3–5

Therefore, any infant with three or more minoranomalies should be carefully assessed for majormalformations, using techniques such as echocar-diography and abdominal ultrasound, since many

such malformations cannot be appreciated byphysical examination alone.

The presence of certain anomalies in an in-fant should always trigger an assessment forother specific congenital anomalies. For exam-ple, an infant with two or more of the findingsassociated with the VACTERL association shouldbe assessed for all of the other components ofthis association using techniques such as echocar-diography, renal ultrasonography, and vertebral

CHAPTER 2 ASSESSMENT OF AN INFANT WITH A CONGENITAL MALFORMATION 15

Figure 2-2. Brushfield spots, seen in 20%of normal newborns but 80% of newbornswith Down syndrome.

Figure 2-3. Minor anomalies of the handtypical of Down syndrome including a simiancrease and clinodactyly of the fifth finger.A unilateral simian crease is found in 4% ofnormal newborns with a bilateral simiancrease in 1%.

Figure 2-4. Preauricular pit, a minor anomalythat is commonly familial. (Used with permissionfrom Carl Kuschel, MD)

Figure 2-5. Sacral dimple, in this case abovethe gluteal fold and accompanied by cutaneoushyperpigmentation. (Used with permission fromCarl Kuschel, MD)

radiographs. Similarly, an infant with choanalatresia and an ocular coloboma should be as-sessed for other components of CHARGE syn-drome such as cardiac defects or hearing loss.Numerous similar examples could be cited andare discussed in individual chapters of the bookin the discussion of individual malformations.

� LABORATORY EVALUATION

Cytogenetic Testing

Cytogenetic testing is indicated in any infantwith multiple congenital anomalies suggestiveof a specific chromosomal abnormality or in aninfant with multiple abnormalities or neurologicdysfunction of undetermined etiology. Chromo-some analysis is typically performed on periph-eral blood but can also be performed on cul-tured skin fibroblasts or on bone marrow. Inrare circumstances, there may be an indicationto analyze more than one tissue to rule out chro-mosomal mosaicism. Certain chromosomal ab-normalities, such as tetrasomy 12p associatedwith the Pallister-Killian syndrome, may fre-quently escape detection in peripheral blood.Therefore, infants with clinical findings sugges-tive of this disorder who have a normal periph-eral blood karyotype should be studied withchromosome analysis in cultured skin fibrob-lasts. The same is true for infants with congeni-tal anomalies accompanied by linear or whorledhyper- or hypopigmentation of the skin, a find-ing referred to in the literature by a variety ofterms including hypomelanosis of Ito and pig-mentary mosaicism. Infants with these findingstypically have chromosomal mosaicism which isoften detected only in skin.

If conventional cytogenetic analysis fails toreveal an abnormality in an infant suspected ofhaving a chromosomal abnormality, microarrayanalysis, also referred to as comparative ge-nomic hybridization, can be considered. Thismicrochip technique utilizes hundreds of DNAprobes for the subtelomeric regions of all

23 pairs of chromosomes and other loci scat-tered along the lengths of the chromosomes todetect submicroscopic deletions and duplica-tions as small as 80–100 kb in size. If a specificsubmicroscopic chromosome deletion syn-drome is suspected, such as the 22q11 deletionsyndrome or Williams syndrome, a specific FISH(fluorescence in-situ hybridization) test for thatindividual disorder can be ordered. In that case,a single fluorescently labeled DNA probe fora specific chromosomal locus is utilized to deter-mine the presence of that region on each of twopaired chromosomes (Figs. 2-6 and 2-7).

Molecular Testing

Molecular testing to define specific mutations inindividual genes is being used with increasingfrequency to diagnose multiple malformationsyndromes. When using molecular testing asa diagnostic tool, however, it is essential to un-derstand its limitations. In many cases in whichone or more genes have been linked to a par-ticular disorder, mutations are not detected in100% of cases. Indeed, the detection rate can besignificantly lower than this. Therefore, althoughpositive test results may confirm a diagnosis, theconverse is often not the case. One disorder forwhich molecular testing is often helpful is Noo-nan syndrome, which may present in the new-born with many diverse signs and symptoms in-cluding hydrops fetalis, thrombocytopenia,dysmorphic facial features, pulmonic stenosis,hypertrophic cardiomyopathy, or any combina-tion of these. Approximately 50% of affected in-dividuals have a mutation in the gene PTPN116

while a smaller percentage of patients have amutation in either KRAS or SOS1.7 A significantpercentage of patients do not have a detectablemutation in either of these genes, so negativemolecular testing does not rule out the diagnosis.Another disorder for which molecular testing ishelpful is CHARGE syndrome, recently found tobe associated with mutations in the CHD7 genein 58–71% of patients with this disorder.8,9



Figure 2-6. FISH (fluorescence in-situ hybridization) testing for the 22q11 syndrome. Negativetest results showing a positive signal for the 22q11 probe and the control probe on both copiesof the #22 chromosome.

Figure 2-7. FISH (fluorescence in-situ hybridization) testing for the 22q11 syndrome. Positivetest results showing a positive signal for the 22q11 probe and the control probe on one #22chromosome but only a signal for the control probe on the other #22 chromosome.

In patients with several of the cardinal featuresof the disorder, identification of a CHD7 muta-tion provides a definitive diagnosis and allowsfor appropriate anticipatory guidance and ge-netic counseling to families that would be muchmore difficult otherwise.

Biochemical Testing

Biochemical testing may be helpful in evaluatinginfants with specific malformations or patterns ofmalformations but, like molecular testing, needsto be targeted to a specific diagnosis. There area few inherited metabolic disorders that producemalformations in multiple organ systems as aresult of far-reaching metabolic effects on earlyfetal development. An excellent example of thisis the Smith-Lemli-Opitz syndrome which repre-sents a defect in cholesterol biosynthesis and isassociated with low levels of total serum choles-terol and marked elevations of the cholesterolprecursor 7-dehydrocholesterol. In its severeform, this disorder is associated with dysmorphicfacial features, cleft palate, syndactyly, poly-dactyly, genital anomalies, and mental retarda-tion. Another example is Zellweger syndrome,associated with multiple peroxisomal enzymedeficiencies as a result of a defect in peroxisomalassembly. Patients with this disorder have a char-acteristic pattern of multiple minor dysmorphicfeatures including a large fontanel, tall forehead,epicanthal folds, Brushfield spots, antevertednares, excess skin folds on the nape of the neck,simian creases, and camptodactyly. Cardiac sep-tal defects may be present and there is alwaysprofound hypotonia. Because many of the find-ings superficially resemble those seen in Downsyndrome, the latter disorder may be initially con-sidered. Other inborn errors of metabolism thatare more typically associated with a “metabolicpresentation” are known to be linked to specificcongenital malformations, reflecting the effect ofthe metabolic derangement in utero. An exampleof this is the fact that approximately 40% of infantswith nonketotic hyperglycinemia, who typically

present with a neonatal encephalopathy, are alsofound to have agenesis of the corpus callosum.Infants with pyruvate dehydrogenase or otherdisorders associated with congenital lactic acido-sis often have dysmorphic facial features resem-bling those observed in association with fetal al-cohol syndrome. Patients with the severe form ofglutaric aciduria type II, while presenting withsevere metabolic acidosis, hypoglycemia, andhyperammonemia, also often exhibit dysmorphicfeatures including hypospadias, cystic kidneys,and abnormal facial features. The setting of hy-drops fetalis is another circumstance in whichbiochemical testing can be helpful. While thereare many nongenetic causes of hydrops, the dif-ferential diagnosis of nonimmune hydrops in-cludes both multiple malformation syndromessuch as chromosomal abnormalities and Noonansyndrome and storage disorders such as infantileGaucher disease, congenital disorders of glyco-sylation, GM1 gangliosidosis, sialidosis, and mu-colipidosis II (I-cell disease), among others.

Follow-up

In some cases in which an infant is identified ashaving multiple congenital malformations, a spe-cific diagnosis cannot be established in the im-mediate neonatal period despite appropriate clin-ical evaluation and testing. In these cases, follow-upshould be arranged with a clinical geneticist. Itmay be possible to establish a diagnosis at a latertime as more information comes to light throughfollowup of the infant’s growth and developmentand medical progress. The appearance of a nor-mal child changes very significantly over time andthe same is true of the dysmorphic features asso-ciated with many malformation syndromes. A di-agnosis that was not recognizable in a newbornmay become apparent in an older infant or tod-dler. Follow-up is equally important for childrenwith an established diagnosis of a genetic disor-der or birth defect syndrome since there are oftenassociated medical concerns for which periodicsurveillance is important. For some disorders,


specific health supervision guidelines have beenpublished by the American Academy of Pediatricsor various disease-specific organizations and canbe helpful in patient management.

REFERENCES

1. Saul RA, Geer JS, Seaver LH, et al. Growth Refer-ences: Third Trimester to Adulthood. GreenwoodGenetic Center: Greenwood, SC; 1998.

2. Hall JG, Froster-Iskenius UG, Allanson JE. Hand-book of Normal Physical Measurements. OxfordUniversity Press: Oxford; 1989.

3. Marden PM, Smith DW, McDonald MJ. Congenitalanomalies in the newborn infant, including minorvariations. A study of 4,412 babies by surface ex-amination for anomalies and buccal smear for sexchromatin. J Pediatr. 1964;64:357–71.

4. Mehes K, Mestyan J, Knoch V, et al. Minor malforma-tion in the neonate. Helv Pediatr Acta. 1973;28:477–83.

5. Leppig KA, Werler MM, Cann CI, et al. Predictivevalue of minor anomalies: association with majormalformations. J Pediatr. 1987;1120:531–7.

6. Jongmans M, Sistermans EA, Rikken A, et al. Geno-typic and phenotypic characterization of Noonansyndrome: new data and review of the literature.Am J Med Genet. 2005;A 134:165–70.

7. Tartaglia M, Pennacchio LA, Zhao C, et al. Gain-of-function SOS1 mutations cause a distinctive form ofNooman syndrome Nat Genet. 2007;39:75–9.

8. Lalani SR, Safiullah AM, Fernbach SD, et al. Spec-trum of CHD7 mutations in 110 individuals withCHARGE syndrome and genotype-phenotype cor-relation. Am J Hum Genet. 2006;78:303–14.

9. Aramaki M, Udaka T, Kosaki R, et al. Phenotypicspectrum of CHARGE syndrome with CHD7 muta-tions. J Pediatr. 2006;148:410–4.



Chapter 3

Genetic Counseling: Principlesand Practices

KATHERINE H. KIM

21

Genetic counseling is the process of educating

patients and family members on the natural

history, management, inheritance, and risk of

genetic conditions. It is an integral part in the

delivery of clinical genetic services. The goal of

genetic counseling is to help patients and fam-

ily members understand and cope with the im-

plications of a genetic diagnosis so that they

can make informed medical and personal

decisions.

� DEFINITION

In 1975, The American Society of Human Genet-ics (ASHG) adapted a definition of genetic coun-seling, which has essentially held true throughthe quickly evolving field of genetic medicine.

Genetic counseling is a communication processwhich deals with the human problems associ-ated with the occurrence or risk of occurrenceof a genetic disorder in a family. This processinvolves an attempt by one or more appropri-ately trained persons to help the individual orfamily to: (1) comprehend the medical factsincluding the diagnosis, probable course orthe disorder, and the available management,(2) appreciate the way heredity contributes to thedisorder and the risk of recurrence in specified

relatives, (3) understand the alternative fordealing with the risk of recurrence, (4) choosea course of action which seems to them ap-propriate in view of their risk, their family goals,and their ethical and religious standards andact in accordance with that decision, and (5) tomake the best possible adjustment to the dis-order in an affected family member and/or tothe risk of recurrence of that disorder.1

This definition illustrates the complexity ofthis process and some of the deviations from thetraditional delivery of medicine. The need forthis process has also resulted in the creation of aunique healthcare profession in which individu-als are specifically trained as genetic counselorsto work along with physicians in the delivery ofgenetic health services.


� PRINCIPLES AND PRACTICES

The educational goal of genetic counseling is tocommunicate the complex genetic information tothe patient and family members using a languagethat is familiar and understandable. A typical edu-cational session includes (1) discussing the testresults and how the diagnosis was established;(2) reviewing the natural history of the disorderand the likely prognosis; (3) addressing the med-ical management and treatment options, includingpossible research and experimental opportunities;(4) discussing the inheritance of the disorder, riskof recurrence and potential risks for relevantfamily members; and (5) exploring the repro-duction options, including the availability ofprenatal diagnosis and preimplantation geneticdiagnosis. Most geneticists and genetic coun-selors believe that all relevant informationshould be disclosed to the patient.2 This is basedon the belief that patients and family membersshould have autonomy in making medical de-cisions, especially in relation to reproductiveoptions and uptake of prenatal testing. The in-formation is also conveyed in a manner that issensitive to the patient’s cultural and religiousbeliefs.

In genetic counseling, discussing the inheri-tance of genetic conditions and assessing riskoften expands beyond the affected person.A genetic diagnosis in one person can implyrisks for other family members, and practitionersoften make recommendations for genetic test-ing and screening of relevant family membersbased on a patient’s diagnosis. This can some-times be challenging since the information hasto be communicated without violating the indi-vidual’s right to privacy. The patient may greatlybenefit from the practitioner’s guidance andhelp in communicating relevant genetic infor-mation to family members at risk.

The third and fourth aspects of the ASHGdefinition focus on the reproductive implica-tions and options for patients and families. Theseprinciples exemplify the primary differencebetween genetic counseling and the traditional

delivery of medicine.3 Geneticists and geneticcounselors present information in a nondirec-tive manner so that the patient has autonomy inmaking reproductive decisions. In contrast tothe traditional method of practitioners makingrecommendations, genetic counseling focuseson communicating the relevant information re-garding reproductive options and facilitatingthe decision-making process.3 It is however, im-possible and sometimes counterproductive tobe completely nondirective and facilitating thedecision-making process sometimes involvesguidance from the practitioner.

Lastly, the principles of genetic counselingare not just to educate patients and familymembers but to help them cope with the im-plications of a genetic diagnosis. Helping pa-tients and family members accept and copewith a genetic condition involves understandingthe patient’s cultural and religious beliefs andeducational and socioeconomic background2

and communicating in a manner that is sen-sitive to the person’s experiences and beliefs.The practitioner can provide resources andreferrals to support groups and empower indi-viduals to make their own medical decisions tohelp patients successfully cope with their ge-netic disorder. Conveying empathy and ac-knowledgement of the patient’s experience andfeelings can have a positive impact on the patient’sability to cope.

� MODES OF INHERITANCE ANDASSESSMENT OF RISK

Genetic disorders, excluding chromosome anom-alies, can be characterized into three main cate-gories, single gene (mendelian), mitochondrial,and complex conditions. Once a genetic diag-nosis is established, counseling the patient andfamilies on the risks of a genetic disorder aredependent on the category and known mode ofinheritance of the condition. The risk can alsobe modified by the penetrance and expressivityof the condition.


Single Gene Disorders

Humans have approximately 20,000–25,000 codinggenes. Over 10,100 genes with a known sequencehave been identified at the time this chapter waswritten according to the Online Mendelian Inher-itance in Man (OMIM). Only a small percentage ofidentified genes have a recognized disease phe-notype associated with mutations in these genes.For many genetic conditions in which the causativegene has not yet been identified, the mode of in-heritance is based on pattern of occurrence of thedisorder in affected families. Single gene disordersare typically classified as either autosomal or sex-linked and dominant or recessive.4

Autosomal Dominant InheritanceAn autosomal dominant disorder is a conditionin which the disease state is expressed when amutation is present in one copy of the genepair. The condition can equally affect both malesand females and can be transmitted from parentto child. A typical pedigree (Fig. 3-1) of a fam-ily with achondroplasia, a common autosomal

dominant disorder caused by mutations in thefibroblast growth factor receptor 3 (FGFR3)gene, reveals multiple affected individuals pre-sent in multiple generations with expressionand transmission of the condition independentof the sex of the individual. The risk that an af-fected individual can have a child with the samedisorder is 50% with each pregnancy.

In some autosomal dominant conditions, ifan individual has mutations in both gene copiesfor the disorder, the phenotype is more severe.In achondroplasia, if both parents have the con-dition, there is a 25% risk with each pregnancythat the infant will inherit FGFR3 mutations fromboth parents. Infants with two achondroplasiagene mutations have a perinatal lethal pheno-type similar to what is observed in thanatophoricdysplasia and die shortly after birth due to res-piratory insufficiency.

In the majority of autosomal dominant con-ditions, unaffected parents of a child with a denovo autosomal dominant condition will rarelyhave a second affected child. The risk of recur-rence is generally estimated at ≤1%. In some au-tosomal dominant disorders, however, the risk ofrecurrence can be increased due to observanceof germline mosaicism. Germline mosaicism isdefined as an individual having the presence oftwo of more genetically different types ofgermline cells, resulting from mutation duringthe proliferation and differentiation of thegermline.4 Therefore, recurrence of an autoso-mal dominant disorder to unaffected parents isobserved because one parent is producing germcells that carry the gene mutation for the disor-der. Osteogenesis imperfecta (OI) type II, a peri-natal lethal form of a group of autosomal domi-nant type I collagen disorders, is one of the firstdisorders in which the occurrence of germlinemosaicism was demonstrated. The estimated riskof recurrence for OI type II for a couple with oneaffected child is approximately 6%.5

Autosomal Recessive InheritanceAutosomal recessive disorders are defined asconditions in which the disease state is expressed

CHAPTER 3 GENETIC COUNSELING: PRINCIPLES AND PRACTICES 23

Figure 3-1. A typical pedigree of an autoso-mal dominant condition.Pedigree symbols: � male, � female, � affectedmale, • affected female

when mutations are present in both copies ofthe gene. An individual with an autosomal re-cessive disorder generally inherits a gene muta-tion from each parent. The parents are referredto as being carriers for the condition, havingone gene copy with a disease causing mutationand one unaltered gene copy. For the majorityof autosomal recessive conditions, carriers donot manifest features of the condition. In a typi-cal pedigree (Fig. 3-2) for an autosomal recessivedisorder like cystic fibrosis, males and femalesare equally affected and there is generally nodirect parent to child transmission of the disor-der. For the majority of autosomal recessive dis-orders, population screening is not availableand the presence of carriers goes unrecognized

in the family until the first affected child isborn. With each pregnancy, carrier couples havea 25% risk of having an affected child, 50% risk ofhaving a child who is a carrier, and a 25% riskof having a child who is not a carrier and notaffected with the disorder.

Parents who are consanguineous have anincreased risk of having a child with an autoso-mal recessive disorder and first cousin unionshave an overall 1.7–2.8% increased risk abovethe general population risk to have a child witha major congenital anomaly.6 Genetic screeningrecommendations for consanguineous unionsinclude: (1) detailed family history, (2) carrierscreening for appropriate genetic disorders basedon the couple’s ethnicity, (3) high-resolution fetal


Figure 3-2. A typical pedigree of an autosomal recessive condition.

ultrasound in the second trimester, (4) expandednewborn screen by tandem mass spectrometryfor metabolic disorders, and (5) newborn screen-ing for hearing.6

Sex-Linked ConditionsDisorders that involve mutations in genes lo-cated on the X sex chromosome are referred toas X-linked disorders. They can be either dom-inant or recessive. Pedigrees of families withX-linked conditions can be distinguished fromautosomal dominant or recessive conditions be-cause transmission of the condition differs be-tween males and females. Because normal maleshave one copy of the X chromosome and femaleshave two copies, females undergo inactivationof one of their X chromosomes to maintain equalgene dosage between the sexes. The principle ofX inactivation is referred to as the Lyon hypoth-esis. Inactivation of one of the X sex chromo-somes occurs early in embryogenesis, generallyrandomly determined, and permanent, with allsubsequent cells derived from the original cellhaving the same X sex chromosome inactivated.There are areas of the X sex chromosome, how-ever, that never become inactivated, and thesesegments are referred to as pseudoautosomalregions.

Only a few disorders are inherited in anX-linked dominant pattern. In disorders likeX-linked hypophosphatemic rickets, both malesand females express the disease state if a genemutation is present. The risk of transmitting thedisorder, however, differs based on the sex ofthe individual (Fig. 3-3). Affected males cannottransmit the condition to their sons but all oftheir daughters will be affected. Affected femaleshave a 50% risk with each pregnancy of havingan affected child, regardless of whether thechild is male or female. In conditions like in-continentia pigmenti type 2 and X-linked chon-drodysplasia punctata, the condition is generallyconsidered lethal in males and therefore, onlyaffected females may be observed in the family(Fig. 3-4). With each pregnancy, affected femaleshave a 25% risk of having an affected daughter,

25% risk of having an unaffected daughter, 25%risk of having an unaffected son, and 25% riskof having an affected son. The affected male in-fant may be miscarried, stillborn, or expire shortlyafter birth.

In X-linked recessive disorders, males whohave a gene mutation express the disease statebut females who have one gene mutation aregenerally carriers and may not manifest fea-tures of the disorder. Females who have muta-tions in both gene copies will be affected. The


Figure 3-4. A typical pedigree of an X-linkedlethal dominant condition.

Figure 3-3. A typical pedigree of an X-linkeddominant condition.

pedigree (Fig. 3-5) for typical X-linked reces-sive disorders, such as Duchenne or Beckermuscular dystrophy (DMD/BMD) or ornithinetranscarbamylase (OTC) deficiency, can be read-ily recognized based on the presence of no maleto male transmission of the disorder and typicallyonly males are affected in the family. With eachpregnancy, female carriers have a 25% risk ofhaving an affected son, 25% risk of having an un-affected son, 25% risk of having a daughter whois a carrier, and a 25% risk of having a daughterwho is not a carrier. For affected males, all theirdaughters will be carriers and a gene copy isgenerally not transmitted to their sons.

In some conditions, female carriers of X-linkedrecessive disorders can exhibit features of thecondition. This is generally felt to be due toskewed X inactivation, with the X chromosomethat has the normal gene copy inactivated inmore tissues than the X chromosome with thegene mutation. In conditions such as Fabry dis-ease, there is a high number of manifesting car-rier females who have severe enough symptoms

to require enzyme replacement therapy. In fragileX syndrome, women who are carriers can exhibitlearning disabilities, social immaturity, and pre-mature ovarian failure.

Disorders that are due to genes located onthe Y sex chromosome are rare. At the time thischapter was written, only two disorders withknown genes on the Y chromosome and fourdisorders suspected of Y-linked inheritancewere reported on the OMIM. A Y-linked disor-der will be readily recognized since only maleswill be affected and the condition can only betransmitted from father to son (Fig. 3-6).

For conditions that are due to mutations ingenes in the pseudoautosomal regions of X andY, the pattern of inheritance will be similar tothat observed on autosomal disorders.

Mitochondrial Disorders

The mitochondria are unique organelles in thehuman cell because it has its own genome and a


Figure 3-5. A typical pedigree of an X-linked recessive condition.

single cell generally has >1000 copies of the mito-chondrial genome dispersed in >100 mitochondria.The mitochondrial genome is a circular chromo-some approximately 165 kb in size and contains37 genes.4 The encoded proteins are involved inoxidative phosphorylation. The majority of pro-teins required for normal mitochondrial function,however, are encoded in the nuclear DNA andtherefore, mitochondrial disorders are also asso-ciated with mendelian inheritance.

Mitochondrial DNA (mtDNA) disorders areunique in that they are associated with maternalinheritance only. A mature oocyte is felt to have>100,000 copies of the mitochondrial genomewhile sperm contain very few. A child, there-fore, inherits the mitochondrial genome fromthe mother and not from the father. Mutationsand deletions in the mitochondrial DNA havebeen identified to cause several disorders, suchas mitochondrial encephalopathy and ragged redfibers (MERRF) and mitochondrial encephalopa-thy, lactic acidosis, and stroke-like episodes(MELAS). A typical pedigree (Fig. 3-7) is char-acterized by the presence of both affected malesand females but no transmission of the disorder

through affected males. The number of mito-chondrial genome copies with a mutation canvary in a given somatic cell or mature oocyte.Most cells contain a mixture of both normal andmutated mtDNA. The severity in manifestationsof the disorder is felt to be due to the percent-age of mutated mtDNA to normal mtDNA invarious tissues.4 Therefore, an affected motherhas up to 100% risk of passing on the conditionto her child.

Complex Disorders

Disorders in which a combination of genetic andenvironmental factors is involved in the manifes-tation of the disease state are referred to as com-plex or multifactorial disorders. Multifactorialdisorders, such as isolated congenital heart defects,isolated cleft lip and/or palate, diabetes mellitus,and hypertension, can be observed to aggregatein a family but not follow a clear mendelian modeof inheritance. The genes underlying the complexdisorder are transmitted following the mendelianprinciples but the disease state occurs when the


Figure 3-7. A typical pedigree of an mtDNAdisorder.Figure 3-6. A typical pedigree of a Y-linked

condition.

combination of predisposing gene mutations andother environmental factors are present or en-countered.3 Risks for these disorders are gener-ally based on empiric data and depend upon thegiven population, number of affected familymembers, and the degree of relationship to theaffected family members. The risk increases if thenumber, of affected family members increases,if the manifestation of the disorder is more se-vere and if the affected member is of the lesscommonly affected sex.3 The empiric risks willvary based on the specific disorder, but for manycomplex disorders a couple who has had oneaffected child has a 2–6% risk of recurrence inanother pregnancy.

Penetrance and Expressivity

Risks for genetic disorders can be modified bypenetrance or expressivity. Penetrance is de-fined as the proportion of individuals with a genemutation for a known condition that manifestany features of the disorder. If some individualswith a gene mutation have no clinical featuresof the disorder, the disorder is stated to have re-duced penetrance. If all individuals who havethe gene mutation manifest features of the con-dition, the condition is stated to have full pene-trance. Reduced penetrance can therefore alterthe risks that a person manifests features of thecondition, but the risks of transmitting the genemutation do not vary from the principles ofmendelian inheritance and segregation of genes.Expressivity is defined as the extent to which anindividual manifests features of the disorder.Thus, expressivity describes the variability andlevel of severity of the disorder in a given af-fected person.

Estimation of Risk When a SpecificDiagnosis Is Unknown

One of the most challenging aspects of geneticcounseling is discussing recurrence risks with

parents when a specific diagnosis for theirchild’s findings is not evident. The risk of re-currence is then estimated based on the clinicalpresentation, known family history, and exclu-sion of possible etiologies, such as chromosomeanomalies. In general, for a couple who has hadone affected child, a negative family history ofsimilar findings, and no known consanguinity,the risk of recurrence is estimated at a range of≤1% up to 25%. This range would account for thepossibility that the condition is associated withde novo autosomal dominant, autosomal reces-sive or multifactorial inheritance. If consanguin-ity is known, the parents are generally quoted arecurrence risk of 25% due to the increased prob-ability of shared alleles in consanguineousunions. If more than one affected family memberis known, the risk should be determined on themost likely mode of inheritance that would ex-plain the pattern of affected family members. Forexample, if only males are observed affected inthe family, and women are the connecting mem-bers between the affected male relatives; themost likely possibility is an X-linked recessivepattern of inheritance. If the parents have hadat least two affected children, the most likelymode of inheritance is autosomal recessive andthe couple should be quoted a 25% risk of re-currence. Parents should always be counseledthat this is an estimated risk and that the exactrisk of recurrence is unknown without a spe-cific diagnosis and known mode of inheritanceassociated with the disorder.

� GENETIC SCREENING ANDPRENATAL DIAGNOSIS

Carrier Screening

The prevalence of some genetic disorders variesby ethnic group and populations due to factorssuch as the founder effect and genetic drift. Cur-rent practices of standard care recommendscreening for carrier status of certain geneticdisorders given a person’s ethnicity. Due to the


heterogeneity of the population in the UnitedStates, it can be difficult to assess the exact riskfor couples who have diverse ethnic back-grounds. The counseling is further complicatedby a decrease in the test’s detection rate withheterogeneity of one’s ethnic background. Ob-taining the patient’s ethnicity, however, is an es-sential element of obtaining the family history,and appropriate carrier screening should thenbe offered to individuals preconceptionally oras early as possible in pregnancy.

Several genetic disorders are known to occurwith higher frequency in the Ashkenazi (EasternEuropean) Jewish population. Highly reliabletesting for detection of carriers is now availablefor 12 disorders (Table 3-1). All the conditionsare inherited in an autosomal recessive pattern.There is no clear consensus on recommenda-tions for screening. Currently, the AmericanCollege of Obstetrics and Gynecology (ACOG)recommends carrier screening for cystic fibrosis,familial dysautonomia, Tay-Sachs disease, andCanavan disease for couples of Ashkenazi Jew-ish descent. At least one member of the coupleshould be tested with appropriate screening ofhis or her partner if one person is a carrier for acondition. Ideally, both members of the coupleshould be tested prior to a pregnancy. In manylarge cities in the United States, preconceptionscreening programs targeted toward individualsof reproductive age are available through Jewishcommunity centers and medical institutions. Ide-ally, carrier status should be identified prior topregnancy so that couples can receive appropri-ate genetic counseling in a timely manner toconsider all options for prenatal diagnosis.

Individuals of African, Chinese, SoutheastAsian, Indian, Indonesian, Mediterranean, andMiddle Eastern descent have a higher carrier fre-quency of sickle-cell disease and related hemo-globinopathies, a-thalassemia, and b-thalassemia.Individuals of Hispanic descent from countriesthat were highly populated by individuals fromAfrica also have a higher carrier frequency ofthese disorders. Approximately 1/12 AfricanAmericans are carriers for hemoglobin S trait,

1/50 African Americans are carriers for hemo-globin C trait, and 1/65 African Americans are car-riers for b-thalassemia. Individuals of SoutheastAsian descent have the highest carrier frequen-cies of a-thalassemia and Greek Americans havethe highest carrier frequency for b-thalassemia.The best method of detecting carriers for sickle-cell disease and variants and b-thalassemia is byassessing the hemoglobin, MCV, and MCH levelsand performing hemoglobin electrophoresis witha quantitative HbA2. The carrier status can be fur-ther confirmed by genetic testing. Detecting carri-ers for a-thalassemia can be more challengingsince hemoglobin levels may not be decreasedand the hemoglobin electrophoresis is generallynormal for a-thalassemia carriers. The bestmethod of carrier screening for a-thalassemia isby direct genetic testing. Individuals in the high-est risk ethnic populations, like Southeast Asian,or those with a positive family history should di-rectly be offered genetic testing to determinecarrier status. Hemoglobinopathies and tha-lassemias are autosomal recessive disorders andprenatal diagnosis is available.

Screening for Genetic Disorders inthe Fetus

Assessing risk for certain genetic conditions hasbecome a routine aspect of prenatal care. Thesemethods of screening are designed to adjust theperson’s baseline risk and are not considereddiagnostic tools. Positive screen results shouldlead to referrals for genetic counseling and con-sideration or prenatal diagnostic testing.

Since the 1970s, maternal serum screening inthe second trimester has been utilized as an ef-fective tool to assess risks for open neural tubedefect (ONTD), Down syndrome, trisomy 18, andTurner syndrome. The traditional maternal serumscreen (also referred to as the triple screen) in-volves assessment of maternal a-fetoprotein(AFP), human chorionic gonadotropin (hCG),and unconjugated estriol (uE3) between 15 and20 weeks gestation, with optimal time of screening



� TABLE 3-1 Genetic Disorders Common in the Ashkenazi Jewish Population

Carrier DetectionDisorder Clinical Features Frequency Rate

Bloom A chromosome instability syndrome characterized 1/100 97–98%syndrome by small size, possible developmental delay

and mental retardation, recurrent infections,and predisposition to cancers. One commonmutation accounts for 97% of mutant alleles inthe population.

Canavan A progressive neurodegenerative disorder with 1/38 97%disease onset of symptoms at 3–6 months of age and

death in the first decade of life. Significantdemyelination of the brain seen on MRI. Threecommon mutations in the aspartoacylcase(ASA) gene present in the population.

Cystic fibrosis A defect in the chloride ion channel resulting in 1/25 >95%progressive pulmonary disease, gastrointestinaldysfunction, pancreatic insufficiency, andinfertility.

Factor XI A defect in plasma thromboplastin increasing risk 1/8–1/10deficiency for prolonged bleeding after surgery, dental

extractions, and with menstrual periods.Spontaneous bleeding is rare.

Familial A degenerative disorder of the sensory and 1/30 >95%dysautonomia autonomic systems characterized by absent

deep tendon reflexes and fungiform papillaeon the tongue, and alacrima. Two commonmutations known.

Fanconi anemia A genetically heterogenous condition due to 1/89 95%type C defects in DNA repair. One mutation in the

FANCC gene is present in the AshkenaziJewish population. The condition ischaracterized by thrombocytopenia orleukopenia leading to bone marrow failure,congenital anomalies such as absent thumbs,and increased risk for malignancies.

Gaucher Onset of symptoms is in children or 1/10 95%disease adults with hepatosplenomegaly, anemia, type I osteopenia, and severe bone crises. Type 1 has

no neurological involvement, unlike types 2 and 3, which are not increased in frequency in the Ashkenazi Jewish population.

Mucolipidosis IV A neurodegenerative lysosomal storage disorder 1/100 95%with wide clinical severity. Two commonmutations present in the population.

at 16–18 weeks gestation. The risk for ONTD isdetermined by the level of the AFP, and by us-ing a value of ≥2.0 MoM (multiples of the me-dian) as a positive test result, the serum screenhas a >85% detection rate for ONTDs and a 1–2%false positive rate. All three serum markers areused to assess risks for Down syndrome, trisomy18, and Turner syndrome. By using a value of≥1/270 risk for a positive test result, the triplescreen has a 60–65% detection rate for Downsyndrome with a 5–6% false positive rate.7 In thelate 1990s, inhibin A was added to the mater-nal serum screen panel in some laboratories toincrease the detection rate for Down syndrome.The “Quad” screen has a detection rate of 81%for Down syndrome with a false positive rateof 5%.8

The most recent advances in screening in-volve first trimester measurement of the fetalnuchal translucency for assessment of Downsyndrome. Combined first trimester screeninginvolves measuring the fetal nuchal translucency

and assessing maternal pregnancy-associatedplasma protein (PAPP-A) and free-β hCG levelsbetween 11 and 13 weeks gestation to calculatea risk for Down syndrome. The first trimesterscreen does not assess risk for ONTDs or othertrisomy disorders. The overall detection rate forDown syndrome is 87% at 11 weeks gestation,85% at 12 weeks gestation, and 82% at 13 weeksgestation, with a 5% false positive rate.8

A fully integrated screen approach for as-sessing Down syndrome risk is also available.The integrated screen involves assessing anoverall risk for Down syndrome by using the in-formation obtained from the combined firsttrimester screen and the second trimester quadserum screen. The woman will undergo the firsttrimester fetal nuchal translucency and serumscreen and then undergo a second trimesterquad serum screen at the appropriate times inpregnancy. A risk for Down syndrome will beprovided to the woman in the second trimesterafter the information from the first trimester


� TABLE 3-1 Genetic Disorders Common in the Ashkenazi Jewish Population (Continued)

Carrier DetectionDisorder Clinical Features Frequency Rate

Niemann-Pick A heterogenous group of lysosomal storage 1/70 95%disease disorders associated with hepatosplenomegaly,

neurological problems, and ocular anomalies.Three common mutations in type A and onecommon mutation in type B present in thepopulation.

Nonclassical Mild form of the defect in cortisol synthesis which 1/3 95%adrenal results in overproduction of androgens. Nohyperplasia effect on males. Females present in puberty

with severe acne, excess facial and body hair,menstrual irregularities, and advanced bone age.

Nonsyndromic Nonprogressive mild to profound sensorineural 1/20–1/25 >95%hearing loss hearing loss due to mutations in connexin-26.

Two common mutations in this gene arepresent in the population.

Tay-Sachs A progressive, neurodegenerative, lysosomal 1/26–1/30 95%disease storage disorder due to accumulation of GM2

gangliosides in the neurons. Death occurs by2–4 years of age.

screen is incorporated with the information pro-vided by the second trimester screen to calcu-late one overall risk for Down syndrome. Theintegrated screen is reported to have a 96% de-tection rate for Down syndrome with a 5% falsepositive rate.8 If a patient, however, has a signif-icantly increased risk based on the first trimestercombined screen or observance of an increasednuchal translucency, she should be offered theoption of chorionic villus sampling, instead ofwaiting for an amniocentesis in the secondtrimester. Studies have now shown that evenwith normal chromosome analysis, if a fetus hasan increased nuchal translucency measurementof 3.5 mm in the first trimester, there is a signif-icant increased risk for other congenital anom-alies, such as cardiovascular defects, other singlegene disorders such as Noonan syndrome,Smith-Lemli-Opitz syndrome, spinal muscularatrophy, and poor pregnancy outcome.9 Therisk increases exponentially with measurementsabove 3.5 mm. The majority of anomalies asso-ciated with an increased nuchal translucencycan be detected by a fetal echocardiogram anddetailed fetal ultrasound at 18–22 weeks gesta-tion. If these screens are normal and a chromo-some abnormality has been excluded, the riskfor adverse outcome or developmental delay isnot significantly increased.9 However, a new-born infant with a history of an increased nuchaltranslucency in pregnancy should have a care-ful assessment for other possible single genedisorders.

Methods of Prenatal Diagnosis

Amniocentesis and chorionic villus sampling(CVS) are two methods of prenatal diagnosisthat are being routinely offered to couples. Bothmethods can be used to detect chromosome ab-normalities and single gene disorders with equalsensitivity and accuracy of results (>99%). Chro-mosome analysis (Figs. 3-8 and 3-9) is generallyperformed on cultured amniocytes or villi witha 1.5–2 week turnaround time for results. In

the majority of laboratories, fluorescence insitu hybridization (FISH) studies are performedon direct cells for a quick analysis of commonaneuploidy disorders: trisomy 21, trisomy 18,trisomy 13, and sex chromosome conditions. TheFISH results are typically available in 2–3 days.

Amniocentesis has been available since the1970s for the detection of chromosome abnor-malities. Traditionally, ultrasound-guided amnio-centesis (Fig. 3-10) is performed after 15 weeksgestation and the risk of fetal loss is 0.5–1.0%.Various centers may quote a risk specific to theircenter’s experience, but the national reportedloss rate as recommended by the Centers for Dis-ease Control and Prevention is 0.5%. In additionto the standard chromosome analysis or testingfor single gene disorders, a-fetoprotein can bemeasured in the amniotic fluid between 15 and22 weeks gestation to assess risk for ONTDs.This cannot be measured in CVS tissue.

Early amniocentesis is performed between13 and 15 weeks gestation but associated witha higher risk of fetal loss and leakage of amni-otic fluid. A significant increased risk for talipesequinovarus (club foot) has also been observedwith early amniocentesis, especially if leakageof amniotic fluid is present. Given these find-ings, the American College of Obstetricians andGynecologists does not recommend early am-niocentesis as a method of prenatal diagnosis.

Chorionic villus sampling (Fig. 3-11) has beenreadily available since the mid 1980s as a methodof detecting chromosome abnormalities and sin-gle gene disorders in the fetus. The majority ofcases are performed transcervically with the useof ultrasound guidance and a catheter between10 and 12 weeks gestation. If the placental villicannot be obtained transcervically, a transab-dominal CVS can be performed using a needle.The WHO-sponsored registry10 monitoring thesafety of CVS reported a fetal loss rate similarto that observed in early amniocentesis. Con-troversy remains regarding the risk of CVS-associated fetal anomalies such as limb reductiondefects. In the 1990s, several centers reporteda clustering of limb reduction defects in infants


following CVS procedures. The WHO-sponsoredregistry10 on CVS safety reported no increasedobservance of fetal limb reduction defects andsimilar results were reported by several other mul-ticenter clinical trials.11 Recently, one center hasreported an increased risk of absence of the tip ofthe third finger associated with CVS.12 The risk ofCVS-associated limb defects appears to be smallbut real and is estimated to be 1 in 3000.

A potential complication of CVS that is theobservance of mosaic chromosome results in ap-proximately 1% of CVS samples. In the majorityof cases, the chromosome mosaicism is con-fined to the placenta and the fetus likely hasnormal chromosomes. The patient is generally

offered amniocentesis to further assess the pos-sibility of a chromosome abnormality in the fe-tus. If the results are normal, the most likely out-come is for a normal infant. Couples, however,should be counseled that amniocentesis cannever definitively rule out all levels of mosaicismand that a possible risk for adverse outcome ex-ists since the tissues that are present in amnio-cytes are limited. A newborn infant who has hada mosaic result on either CVS or amniocentesisshould have blood chromosome analysis andexamination for possible anomalies.

Since the 1980s, fetal blood sampling or cor-docentesis has been an available method ofprenatal diagnosis and a vehicle for fetal therapy.


1 2 3 4 5

1211109876

13 14 15 16 17 18

SexChromosomes

22212019

Figure 3-8. 46,XY, a normal male karyotype. (Printed with permission from the Cytogenetics Lab-oratory at Children’s Memorial Hospital.)

Fetal blood sampling is performed after 18 weeksgestation using ultrasound guidance to insert aneedle into the umbilical vein or artery, gener-ally near the insertion of the cord into the pla-centa or fetus or directly into the fetal hepaticvein. Fetal blood sampling can be offered forrapid chromosome analysis, diagnosis of blooddisorders when direct gene testing is not avail-able, and for fetal infections.13 Fetal blood sam-pling can also be used for treatments such astransfusion of blood components or direct de-livery of medications to the fetus. The risk ofmiscarriage is higher than CVS or amniocentesisand is estimated at 1–2%.

With the technological advances in ultra-sound and magnetic resonance imaging (MRI),fetal ultrasound, fetal echocardiography, and fetalMRI are now readily available tools in the diag-

nosis of structural abnormalities in the fetus. Ul-trasound has been used for decades to monitorfetal size and growth, movement, position, andamniotic fluid levels in pregnancy. With the ad-vances in technology, equipment, and skill ofthe sonographer, ultrasound has become theprimary method of visualizing the fetal anatomyand detecting structural abnormalities in the fe-tus. The majority of the fetal anatomy can bewell visualized by 18 weeks gestation and de-fects such as anencephaly can be visualized by14 weeks gestation. A detailed fetal anatomyscreen is recommended for couples who havehad a previous child with a structural defector have a higher risk based on personal or familyhistory. Ultrasound can also be used to screenfor features associated with fetal aneuploidyand can be used for follow-up after abnormal


1 2 3 4 5

1211109876

13

19 20 21 22 SexChromosomes

14 15 16 17 18

Figure 3-9. A trisomy 21 karyotype, 47,XY +21. (Printed with permission from the CytogeneticsLaboratory at Children’s Memorial Hospital.)


Figure 3-10. Amniocentesis. (Printed with permission from the Greenwood Genetics Center.)

Figure 3-11. Chorionic villous sampling. (Printed with permission from the Greenwood GeneticsCenter.)

maternal serum screen results.13 A detailed fetalultrasound can detect approximately 90–95% ofONTDs and anencephaly and should be offeredin pregnancy following an elevated a-fetoproteinlevel on the serum screen. Ultrasound cannotbe used to diagnose chromosome anomaliesbut can be helpful in adjusting risk for fetal ane-uploidy by screening for features (choroidsplexus cysts, echogenic bowl, cystic hygroma,and so on) known to be associated with an in-creased risk. For genetic conditions associatedwith multiple malformations in which directDNA testing is not available, fetal ultrasound canbe used as a method of screening for recurrencein a subsequent pregnancy for conditions suchas the short-rib polydactyly syndromes, whichare associated with autosomal recessive inheritancebut for which the genetic defects are unknown.A detailed or high resolution fetal ultrasoundcan be performed by sonographers with expertisein screening for skeletal abnormalities that arevisible by the mid-second trimester.

Congenital heart defects are among themost common birth defects, with an incidenceof 8 per 1000 live births.14 Fetal echocardiogramswith Doppler performed after 20 weeks gesta-tion can detect the majority of structural cardio-vascular defects and rhythm abnormalities. Theearly detection of fetal cardiovascular defects al-lows for better management during the preg-nancy and during the perinatal period, promptscreening for potential chromosome abnormal-ities and other structural anomalies in the fetus,and better education and preparation of the par-ents. According to the American Academy ofPediatrics, Committee on Genetics, fetal echocar-diography should be considered when (1) a car-diac defect is suspected on a routine ultrasoundexam; (2) an extracardiac structural defect hasbeen identified by ultrasound; (3) positive fam-ily history of a cardiovascular or rhythm defect;(4) chromosome abnormality or genetic disor-der associated with cardiac defects is suspectedin the fetus; (5) maternal disease associated withincreased risk for cardiac defects in the fetus,such as maternal diabetes or phenylketonuria

(PKU); (6) known prenatal exposure to a ter-atogenic agent; (7) fetal arrhythmia has beendetected on examination.13

With advances in ultrafast MRI technologyovercoming distortion of images by fetal motionartifact, MRI has become a more prevalent toolfor the detailed characterization of structural ab-normalities in pregnancy. Fetal MRI has beenmost helpful in delineating central nervous sys-tem abnormalities15 allowing for a more accu-rate diagnosis and prognosis of the infant. FetalMRI can also be used in the second trimester tobetter characterize abnormalities in fetal vascu-lature, thorax, abdomen, and pelvis.15 MRI canbe helpful in visualizing fetal anatomy whenoligohydramnios is present, making ultrasounddifficult. Fetal MRI is not recommended in thefirst trimester13 and should be offered to coupleswhen a structural defect is suspected on ultra-sound that could be better characterized by MRI.

Lastly, preimplantation genetic diagnosis(PGD) has become an important alternative totraditional methods of prenatal diagnosis of ge-netic disorders. PGD is defined as a method ofanalyzing the chromosomal or genetic makeupof an embryo obtained by in vitro fertilization(IVF) techniques.16 Once a diagnosis is estab-lished, embryos can be transferred to the woman’suterus for a successful pregnancy. PGD was firstused to determine the sex of embryos for cou-ples at risk of having a child with an X-linkedcondition. Since then, PGD has been used forthe diagnosis of chromosome aneuploidy andtranslocations, over 100 single gene disorders,and for HLA typing for a potential stem celldonor match relative.16 Currently there are threemethods of genetic testing of an embryo, earlyembryo biopsy, polar body extraction, andblastocyst-stage biopsy.16 Early embryo biopsyinvolves removing one or two blastomeres fromthe embryo on the third day after IVF. The cellscan then be used for single cell FISH for certainchromosome anomalies or polymerase chainreaction (PCR)-based DNA analysis for single genedisorders. The blastocyst-stage biopsy involvesthe laser-guided removal of several cells from the


trophectoderm layer of the blastocyst approxi-mately 5 or 6 days after IVF. The advantage of theblastocyst-stage biopsy is that more cells can beobtained from the embryo, improving the accu-racy of the diagnosis compared to early embryobiopsy.16 In the polar body method, polar bod-ies from the product of meiosis I and II are re-moved for genetic testing. This method can onlyprovide information on the genetic material con-tributed by the mother. Therefore, it can be usedfor diagnosis of chromosome translocations car-ried by the mother, chromosome aneuploidy de-rived from the mother, and autosomal dominantconditions in which the mother is the affectedparent. It can also be used for autosomal reces-sive conditions but only tests for the presence ofthe mutation in the gene contributed by themother and not the father. PGD has become a vi-able alternative for couples who have difficultyin electing to terminate an affected pregnancyidentified by traditional methods of prenatal di-agnosis or who are in need of HLA matching.With advances in genetic testing techniques, PGDwill become more widely available; however, thecurrent methods do not allow for the broad di-agnosis of chromosome conditions and geneticdisorders as in amniocentesis or CVS. The cost,limitations and technical complexity of PGDmake it unlikely to replace traditional methods ofprenatal diagnosis in the near future.

� CONCLUSIONS

Genetic counseling is an integral part of pro-viding good medical care for patients and fam-ilies receiving a diagnosis of a genetic disorder.This chapter is designed to provide insight intothe complexities of the genetic counselingprocess and to assist medical professionals inhelping families understand and cope with theimplications of a genetic diagnosis. As the ASHGdefinition implies, the scope of genetic coun-seling expands beyond an explanation of factsand risks. The goal of genetic counseling is toempower patients and their families through

education, resources, and support so that theymay understand, accept, and cope with theirgenetic disorder and make informed medicaland personal decisions.

REFERENCES

1. American Society of Human Genetics Ad Hoc Com-mittee on Genetic Counseling. Genetic counseling.Am J Hum Genet. 1975;27:240–2.

2. Walker AP. The practice of genetic counseling. In:Baker DL, Schuette JL, Ulhmann WR, eds. A Guideto Genetic Counseling, 1st ed. New York, Wiley-Liss. 1998;p 5–9.

3. Jorde LB, Carey JC, White RL. Medical Genetics.St. Louis, Mosby; 1995.

4. Nussbaum RL, McInnes RR, Willard HF. Thompson& Thompson: Genetics in Medicine. 6th ed. Philadel-phia, WB Saunders Company; 2001.

5. Byers PH, Tsipouras P, Bonadio JF, et al. Perinatallethal osteogenesis imperfecta (OI type II): a bio-chemically heterogeneous disorder usually due tonew mutations in the genes for type I collagen.Am J Hum Genet. 1988;42:237–48.

6. Bennett RL, Motulsky AG, Bittles A, et al. GeneticCounseling and Screening of Consanguineous Cou-ples and Their Offspring: Recommendations of theNational Society of Genetic Counselors. J GenetCouns. 2002;11:97–119.

7. Haddow JE, Palomaki GE, Knight GT, et al. Pre-natal screening for Down syndrome with use ofmaternal serum markers. N Engl J Med. 1992;327:588–93.

8. Malone FD, Canick JA, Ball RH, et al. First-trimesteror second-trimester screening, or both, for Down’ssyndrome. N Engl J Med. 2005;353:2001–11.

9. Souka AP, von Kaisenberg CS, Hyett JA, et al. In-creased nuchal translucency with normal kary-otype. Am J Obstet Gynecol. 2005;192:1005–21.

10. WHO/PAHO Consultation on CVS. Evaluation ofchorionic villus sampling safety. Prenat Diagn.1999;19:97–9.

11. Brambati B, Tului L. Chorionic villus sampling andamniocentesis. Curr Opin Obstet Gynecol. 2005;17:197–201.

12. Golden CM, Ryan LM, Holmes LB. Chorionicvillus sampling: a distinctive teratogeniceffect on fingers? Birth Defects Res (Part A).2003;67:557–62.


13. Cunniff C. Committee on genetics. Prenatal screen-ing and diagnosis for pediatricians. Pediatrics.2004;114:889–94.

14. Friedman AH, Copel JA, Kleinman CS. Fetal echocar-diography and fetal cardiology: indications, diagnosisand management. Semin Perinatol. 1993;17:76–88.

15. De Wilde JP, Rivers AW, Price DL. A review of thecurrent use of magnetic resonance imaging in preg-nancy and safety implications for the fetus. ProgBiophys Mol Biol. 2005;87:335–53.

16. Brick DP, Lau EC. Preimplantation genetic diagnosis.Pediatr Clin North Am. 2006;54:559–77.


Part II

Central Nervous SystemMalformations



Chapter 4

Spina BifidaBARBARA K. BURTON

41

� INTRODUCTION

Myelomeningocele is a congenital malforma-tion involving protrusion of neural tissue andmembranes through the vertebral arches intoan open lesion or sac somewhere along thespine. A similar defect involving the meningesonly is referred to as a meningocele. Both le-sions are referred to by the terms open spinabifida and open neural tube defect if there isno overlying skin covering. If there is a completeskin covering, the lesion is referred to as closedspina bifida or a closed neural tube defect. Bothlesions are associated with an underlying bonydefect in the spine and represent failure of nor-mal closure of the neural tube during early em-bryonic development. Approximately 90% ofcases of open spina bifida are myelomeningoce-les and all of these have neurologic involvementresulting from damage to the exposed neural tis-sue. The remaining 10% are meningoceles andmay not be associated with a neurologic deficit.Approximately 70% of myelomeningoceles are inthe lumbar or lumbosacral region with the re-mainder distributed in the cervical, thoracic, andsacral regions. This chapter will review meningo-cele, myelomeningocele, open spina bifida, spinabifida occulta, occult spinal dysraphism, andopen neural tube defects.

� EPIDEMIOLOGY/ETIOLOGY

The epidemiology of open neural tube defectshas been extensively studied and there is evi-dence for an important role of both genetic andenvironmental factors in the occurrence of thesebirth defects. There are major geographic, so-cioeconomic, and racial differences in the inci-dence of the defects and variations in birthprevalence have been documented over time. Ingeneral, the highest incidence of neural tube de-fects in the world is thought to occur in North-ern Ireland and South Wales where the incidenceof anencephaly is 6.7 per 1000 and the incidenceof spina bifida is 4.1 per 1000.1 In North Amer-ica, the incidence generally decreases from eastto west and in any given area, is highest amongHispanics, lowest in blacks and Asians, and in-termediate in non-Hispanic Caucasians.2 An av-erage prevalence in the United States of about1 per 1000 births is frequently quoted. There isa significant excess of females among fetuses andinfants with open neural tube defects, greaterfor anencephaly than for spina bifida and en-cephaloceles. Birth defect monitoring programsworldwide have documented a downward trendin the birth prevalence of all open neural tubedefects that predates both prenatal diagnosis ofthese malformations and efforts to fortify the diet


of women of child-bearing age with folic acid.A more recent dramatic decline in western soci-eties may reflect the latter effort.3 Analysis ofsecular data in the United States reveals that theincidence of open neural tube defects was in-creasing in the early 1900s, and reached a peakin the early 1930s before beginning to decline.A lesser peak occurred in the early 1950s andagain in the early 1960s, interrupting the otherwisesteady decline in prevalence. No explanationhas been brought forth to explain this temporalphenomenon. The only exception to this obser-vation has been in South America and SouthAfrica where no decline in prevalence has beendemonstrated.

A relative folic acid deficiency has emergedas the single most important environmental fac-tor associated with the occurrence of openneural tube defects. The term relative is usedbecause most mothers of infants with neuraltube defects have serum and/or red blood cellfolate levels within the normal range althoughas a group they are lower than in mothers ofhealthy infants. Furthermore, there is now evi-dence that up to 70% of nonsyndromic neuraltube defects can be prevented by periconcep-tional folic acid supplementation continuedthrough the period of neural tube closure.4 Thedose that is recommended for women in thegeneral population is 0.4 mg per day which istypically included in most multivitamin prepa-rations but is often not achieved in a typicalWestern diet. Therefore, fortification of foodswith folic acid has been recommended and ac-complished in several countries. The reason forthe reduced folic acid levels observed in moth-ers of infants with neural tube defects is un-clear. Variation in methylene-tetrahydrofolatereductase activity may play a role.5

Other environmental variables that affect riskof neural tube defects include a number of ter-atogens that have been linked to an increasedincidence of these malformations. Perhaps themost significant of these is maternal diabetesmellitus. Diabetic women face a risk of neuraltube defects that is up to 20 times greater than

the general population risk; this can be reducedby achieving tight glycemic control prior to con-ception and maintaining it throughout the firsttrimester of pregnancy. Several anticonvulsantdrugs, including carbamazepine and valproicacid, are also associated with an increased riskof neural tube defects. Valproic acid appears tohave a propensity for causing lumbosacral de-fects. Maternal hyperthermia has been impli-cated as a causative factor in neural tube defectsand this is likely a risk factor when the fever ishigh (>39°C) and prolonged (>24 hours).

The nature of the genetic contribution toneural tube defects is unclear. While it was oncegenerally believed that most nonsyndromic neuraltube defects were multifactorial in origin, mean-ing both genetic and environmental factors playa role, this is no longer uniformly accepted. Mul-tifactorial, multigenic, and monogenic models allhave their proponents, and multiple mechanismsmay exist to explain the disorder in different fam-ilies. There are clearly two broad categories ofnonsyndromic neural tube defects, those that arefolate-preventable and those that are not, and theetiology of the two may be entirely different. Inaddition, there are some families in which pedi-gree analysis suggests a single gene mode of trans-mission, such as X-linked recessive or autosomaldominant. In the majority of families, however,this is not the case. In this larger group, one ob-serves a recurrence risk in siblings that is greaterthan in the general population and is typicallygreater in areas of high incidence than in areas oflow incidence. An increased risk of recurrence isalso observed in second- and third-degree rela-tives of probands with the risk higher among ma-ternal than paternal relatives.

� EMBRYOLOGY

Myelomeningoceles and meningoceles both rep-resent failure of closure of some segment of therostral portion of the neural tube. The process ofneural tube closure begins approximately 18 daysfollowing ovulation and is complete by 28 days

42 PART II CENTRAL NERVOUS SYSTEM MALFORMATIONS

(Fig. 4-1). It has been hypothesized that allmyelomeningoceles begin as myeloschisis withthe uncovered neural plate exposed. Over time,this degenerates and there is epithelializationof the surface of the lesion. The anterior sub-arachnoid space fills with fluid and pushes the

neural elements outward, to the surface of whatappears to be a sac-like lesion. Although theremay be complete destruction of a segment ofspinal cord, the nerves remain where they exitfrom the spine, indicating that the cord was oncepresent at the site of the defect.

CHAPTER 4 SPINA BIFIDA 43

Neural Fold

Neural Groove Neural Crest

Somite

Notochord

Neural Crest

Neural Tube

SurfaceEctoderm

Mesoderm

Yolk Sac

B

A

C

Anencephaly

Craniorachischisis Open Spina Bifida

CranialNeuropore

NeuralFold

NeuralGroove

Iniencephaly

Encephalocele

Closed Spina Bifida

CaudalNeuropore

Somite

A B

Figure 4-1. Features of neural tube development and neural tube defects. Panel A shows a cross section of the rostral end of the embryo at approximately 3 weeks

after conception, showing the neural groove in the process of closing. Panel B shows a crosssection of the middle portion of the embryo after the neural tube has closed. The neural tube,which will develop into the spinal cord, is now covered by surface ectoderm (which will laterbecome skin). The mesoderm will form the bony spine. Panel C shows the features of the maintypes of neural tube defects. The diagram in the center is a dorsal view of a developing em-bryo, showing a neural tube that is closed in the center but still open at the cranial and caudalends. The dotted lines marked A and B refer to the cross sections shown in panels A and B.

Anencephaly, spina bifida and encephalocele are described in this chapter and in Chapters5 and 6. Craniorachischisis, a rare defect, is characterized by anencephaly accompanied by acontiguous bony defect of the spine and exposure of neural tissue. Iniencephaly, another raredefect, is associated with dysraphism in the occipital region and severe retroflexion of the neck.(Reprinted with permission from Botto LD, Moore CA, Khoury MJ, et al. Neural tube defects. NewEngl J Med. 1999;341:1509–19.)

� CLINICAL PRESENTATION

The diagnosis of a myelomeningocele or meningo-cele is readily made either on a prenatal ultra-sound or at birth when the lesion is noted on theinfant’s back. Meningoceles are often, but not al-ways, covered by normal skin. In the case of thetypical myelomeningocele, neurologic impairmentis usually evident at birth and varies with the leveland extent of the lesion. Positional foot deformi-ties, dislocated hips and knee, and hip contrac-tures may be present as a result of decreased fetalmovement in utero. Hydrocephalus is present inapproximately 90% of infants with lumbar andlumbosacral myelomeningoceles and is often pre-sent before an abnormal increase in the head cir-cumference is noted. It is less often associatedwith cervical, thoracic, and sacral lesions. TheChiari II malformation is uniformly associated withmyelomeningocele and other central nervous sys-tem (CNS) lesions, such as aqueductal stenosisand heterotopias, can be observed.

The terms spina bifida occulta and occultaspinal dysraphism refer to the situation in whichthere is an abnormal tethering of the spinal cordconus to a neighboring structure with failure ofclosure of two or more vertebral arches, often inassociation with abnormal neurologic findings andwith a cutaneous or subcutaneous marker such asa tuft of hair, hemangioma, or lipoma. This lesionis part of the neural tube defect spectrum and isgenerally considered to have the same genetic im-plications as open spina bifida or myelomeningo-cele. Sometimes, the term spina bifida occulta isused incorrectly to describe the incompleteossification of the posterior vertebral laminae,commonly L5 or S1, in a healthy individual. Thisbenign lesion, found in up to 20% of normaladults, is of no clinical or genetic significance. It isoften discovered coincidentally on radiographs.

� EVALUATION

MRI of the brain is the best tool for delineatingthe intracranial anatomy while a CT scan of the

spine is helpful in outlining the extent of the ver-tebral abnormalities. Although myelomeningo-cele is readily diagnosed at birth, the prenataldiagnosis is more challenging despite the nowwidespread use of ultrasonography and mater-nal serum α-fetoprotein (MSAFP) screening inmany parts of the world. MSAFP is elevated inthe midtrimester in approximately 80% ofwomen carrying a fetus with open spina bifida.In the vast majority of cases, experienced ultra-sonographers in high risk centers should be ableto delineate the lesion on targeted ultrasoundexamination. Amniotic fluid α-fetoprotein andacetylcholinesterase determinations can providedefinitive confirmation of the presence of a de-fect. It should be noted that there is markedvariability in the detection rate for spina bifidaby ultrasonography reported among ultrasoundcenters and some of the variability may be ex-plained by gestational age and operators skill.The defects are often not detected on examina-tions performed for routine indications. How-ever, in a patient at high risk for an open neuraltube defect because of an MSAFP elevation, andparticularly in a patient who has undergone am-niocentesis and has an elevated amniotic fluid AFPand positive acetylcholinesterase, it is essentialthat every effort be made to identify the defectby imaging techniques. This is necessary in or-der to provide the patient with the informationneeded to make an informed decision aboutwhether to continue the pregnancy. MRI of thefetus has been used in some cases but is notclearly superior to ultrasonography in outliningthe nature of the defect.

A number of ultrasound markers have beendemonstrated to be helpful in the prenatal di-agnosis of spina bifida. In imaging the spine, onsagittal view, there are two parallel lines repre-senting the dorsal neural arches, which con-verge at the sacrum. In spina bifida, the dorsalline and overlying soft tissue are absent. Oncoronal view, two lines are seen when the trans-ducer is in a dorsal position and these may beseen to spread when spina bifida is present.1

Additional helpful intracranial markers of fetal


spina bifida include the so-called lemon sign(Fig. 4-2) and the banana sign (Fig. 4-3) notedin 98% and 69% of fetuses with spina bifida im-aged prior to 24 weeks gestation, respectively.

� ASSOCIATED MALFORMATIONSAND SYNDROMES

Of infants with a myelomeningocele not knownto have a chromosome anomaly, approximately18.8% have at least one other malformation. Themost commonly reported anomalies in threelarge registry series are reported in Table 4-1.6

Chromosome anomalies are uncommon ininfants with neural tube defects, occurring in lessthan 10% of fetuses detected in the midtrimesterand an even lower percentage of liveborn in-fants. Trisomy 18 and structural chromosome ab-normalities (deletions/duplications) are the mostcommonly observed abnormalities and shouldbe associated with other findings that suggest theneed for chromosome analysis. The syndromesmost commonly associated with neural tube de-fects are listed in Table 4-2. In some cases, a dis-order may be associated with any type of neuraltube defect—anencephaly, spina bifida, or en-cephalocele. If a condition is specifically associ-ated with one particular type of defect, this isnoted in the table.

� MANAGEMENT AND PROGNOSIS

Treatment of the patient with myelomeningo-cele requires a multidisciplinary approach tothe many complex problems resulting from thisdevastating birth defect. Most spinal defects canbe treated by the neurosurgeon in the neona-tal period by primary closure and this is typi-cally performed soon after birth. In infants with


Figure 4-2. Cranial ultrasound of a fetus withspina bifida demonstrating the typical bilateralfrontal scalloping of the cranium, referred toas the lemon sign. (Used with permission fromWilliam Grobman, MD, Dept. of Obstetrics andGynecology, Northwestern University’s FeinbergSchool of Medicine.)

Figure 4-3. Another of the typical ultrasoundmarkers of fetal spina bifida. The arrow de-notes the cerebellar compression and abnor-mal alignment referred to as the banana sign.(Used with permission from William Grobman, MD,Dept. of Obstetrics and Gynecology, NorthwesternUniversity’s Feinberg School of Medicine.)

� TABLE 4-1 Associated Malformations in anInfant with Spina Bifida

Cardiac defects 3.7%Anal atresia 2.4%Renal anomalies 2.1%Abdominal wall defects 1.8%Facial clefts 1.4%Anophthalmia/microphthalmia 1.2%Limb reduction defects 1.1%

hydrocephalus, shunt placement may be per-formed simultaneously or during a subsequentsurgery. Early complications that may be ob-served include shunt infection or malfunctionand symptoms related to the Chiari II malfor-mation. These are discussed in more detail inChap. 8 but include cranial nerve dysfunction,

swallowing problems, and respiratory stridorand can progress rapidly to death if posteriorfossa decompression is not performed. Strabis-mus and nystagmus are also common findings.

Later complications of a myelomeningocelecan include growth of an accompanying lipomawhich may compress the spinal cord, affecting


� TABLE 4-2 Syndromes Associated with Anencephaly or Spina Bifida (NOTE: Unless otherwiseindicated, an entry may be associated with either spina bifida or anencephaly.)

Syndrome Other Clinical Findings Etiology

Acrocallosal syndrome Postaxial polydactyly; duplicated great Autosomal recessive(Schinzel syndrome) toe; macrocephaly; agenesis of

corpus callosum; mental retardation(Anencephaly)

Amniotic band syndrome Secondary disruption of skull and facial Amnion disruption(Amnion disruption structures; facial clefts; amputation-sequence) type limb defects

(Disrupted cranium may resembleanencephaly)

CHILD syndrome Unilateral limb defects ranging from X-linked dominantabsence of a limb to hypoplasia, NSDNL, Xq28webbing, or contractures; unilateralichthyosiform skin lesions; cardiacdefects(Myelomeningocele)

Chromosome anomalies, Multiple minor and major anomalies in Trisomies (esp. 18),various various organ systems triploidy, tetraploidy,

deletions, duplicationsMaternal diabetic Caudal regression, including sacral Abnormal maternal

embryopathy agenesis; congenital heart defects; glucose metabolismcardiomyopathy; proximal focalfemoral deficiency; holoprosencephaly

Pentalogy of Cantrell Abdominal wall defect; sternal defect; Unknowndeficient anterior diaphragm anddiaphragmatic pericardium; heartdefects; CNS anomalies

Valproic acid embryopathy Brachycephaly; dysmorphic Valproic acid exposurefacies; developmental delay in utero(Myelomeningocele)

Vitamin A embryopathy Microtia/anotia; dysmorphic facies; Excess vitamin Aheart defects; limb defects; exposure in uteromultiple CNS malformations

Waardenburg syndrome, White forelock; widely spaced eyes; Autosomal dominanttype I heterochromia irides; hearing loss PAX3, 2q25

(Myelomeningocele)

function, or tethering of the cord resulting fromscarring or failure of development of the conusmedullaris. In patients with low level lesions,this can lead to local pain and progression of anascending motor deficit. Syringomyelia occursin many patients with spina bifida and may besymptomatic, leading to upper limb, neck, orshoulder weakness, often in association withlower cranial nerve dysfunction. This may beassociated with progressive scoliosis above thelevel of the spinal defect. Repeated neurosurgi-cal procedures may be necessary to addresssome of these complications.

Patients with lower level lesions are morelikely to walk, and at an earlier age, than thosewith higher level lesions, but some initial ambu-lators eventually return to wheelchairs becauseof problems posed by weight gain, cord tether-ing, and other factors. Whether in braces or awheelchair, patients are always prone to pres-sure sores because of lack of sensation. Similarly,young children exploring their environment areat risk of injury, particularly from burns.

A major problem for patients withmyelomeningocele relates to their lower urinarytract dysfunction and rectal incontinence. In thepast, the natural history of the disorder was thatmany patients developed end stage renal diseaseby early adult life as a result of stasis and chronicurinary tract infections. Standard therapy now in-volves the use of clean intermittent catheteriza-tion to manage the neurogenic bladder, which issuccessful in many, but not all, patients. This maybe combined with oral anticholinergic agents. Inpatients whose urinary incontinence is not suc-cessfully managed medically, a variety of surgicalapproaches have been described and are in use.The rectal incontinence associated with spina bi-fida is typically treated with a regimen of boweltraining using a routine of regularly scheduledbowel emptying and is successful in most cases.As many as 80% of patients with myelomeningo-cele develop a latex allergy resulting from multi-ple diagnostic and surgical exposures.7 Theyshould be treated in a latex-free environment frombirth to avoid this complication.

A limited number of centers have devel-oped expertise with fetal surgery for surgicalclosure of myelomeningocele in utero follow-ing the prenatal diagnosis of this birth defect.The impetus for intervention prenatally wasbased on the hypothesis that there was pro-gressive damage to the exposed neural tissue,supplemented by the observation that manyaffected fetuses were noted to have leg move-ment in utero, which was often no longer pre-sent at the time of birth. Evidence accumulatingto date suggests that prenatal surgical closuredecreases the need for postnatal shunting forhydrocephalus and may result in improved legfunction.8,9 However, it clearly results in a sig-nificant increase in obstetrical complicationsincluding oligohydramnios, premature ruptureof the membranes, and preterm delivery. Thereis no evidence of improved urinary tract func-tion and there are insufficient data to commenton long-term intellectual outcome or motorfunction.

Although survival statistics and the risk ofvarious complications varies considerably in dif-ferent series and may vary as a function of theaggressiveness of postnatal management, somegeneralizations can be reached and are usefulin counseling parents of a fetus or newborn di-agnosed with a myelomeningocele. Approxi-mately 10–15% of infants with spina bifida arestillborn.10 Infants who are born alive withoutassociated anomalies have about an 87% chanceof living to be 1 year of age and a 75% chanceof surviving into adult life.11 Eighty-five percentwill require shunting for hydrocephalus, 95%will require at least one shunt revision, and over30% will require surgery for a tethered cord re-lease.12 Close to 50% will develop scoliosis withmost of them requiring spinal fusion; one quar-ter will have at least one seizure. More than 80%will have bladder and bowel continence ade-quate for socialization; 70% will have an IQ of80 or above.13 Late deterioration in motor andrenal function will be a common occurrence.Lifelong comprehensive care by multiple spe-cialists will be a necessity.


� GENETIC COUNSELING

The genetic counseling provided to parents ofan infant with myelomeningocele or any otheropen neural tube defect will vary depending ona number of factors including family history andthe background incidence of open neural tubedefects in the local population. Initially, ofcourse, it should be determined by physical ex-amination and, if necessary, by laboratory testing,that the defect is not part of a broader malforma-tion syndrome associated with a chromosomeanomaly or a known mendelian pattern of in-heritance. If the defect is isolated, then the fam-ily history should be explored to rule out thepossibility that one is dealing with one of theunusual examples of single gene transmissionof isolated neural tube defects. If pedigree analy-sis is consistent with either X-linked recessive orautosomal dominant transmission, then appro-priate counseling for these modes of inheritanceshould be provided. Since this is a distinctly un-usual situation, consultation with a geneticistwould be highly recommended.

If there is only a single case in the family,then the parents will be at increased risk in fu-ture pregnancies for having another affectedchild as compared to couples in the generalpopulation. In general, the higher the back-ground risk in the population, the higher therisk of recurrence. Couples who have had a fe-tus or infant with any type of neural tube defectare at risk in future pregnancies for having a re-currence of any type of neural tube defect—inother words, a couple who first had a fetus withanencephaly may have a baby with spina bifidain a subsequent pregnancy. Therefore, counsel-ing of such couples should include a discussionof the full spectrum of neural tube defects. Thereare some families in which risk appears to berestricted to one type of defect and there is aslight tendency to recurrence of the same typeof defect in most families but there are manyexamples of families in which both spina bifidaand anencephaly occur. Specific recurrence riskfigures are difficult to quote because of the

significant variability observed between variouspopulation groups. In general, they tend to bein the range of 1–5% after a single affected in-fant. They are significantly higher if there aretwo affected siblings. Physicians are encouragedto seek out information on recurrence risks spe-cific to the local population prior to providinggenetic counseling to families in their practices.

In addition to discussing the risk of recur-rence, all women who have previously had aninfant with a neural tube defect should be ad-vised to take an increased dose of folic acid inthe periconceptional period for the preventionof neural tube defects in future pregnancies.The dose that is recommended is 4.0 mg perday which is 10 times higher than the dose rec-ommended for the general population. Thisshould be initiated before conception is at-tempted and continued through at least the first6 weeks of pregnancy. All women of child-bearing potential who are sexually active, butdo not have a prior history of neural tube de-fects, should receive 0.4 mg per day of folic acideither through the diet or in multivitamin formfor the prevention of neural tube defects.

Patients who have previously had a childwith a neural tube defect should be offeredprenatal diagnosis in all future pregnancies.Anencephaly may be detectable in many casesby ultrasonography as early as the late firsttrimester. MSAFP is elevated at 16–18 weeks ges-tation in about 80% of open neural tube defectsincluding 75–80% of cases of spina bifida and95–100% of cases of anencephaly. Most coupleswho have previously had a child with a neuraltube defect will not want to rely on MSAFP alonein subsequent pregnancies. This should be com-bined with high-resolution-targeted ultrasonog-raphy to image the fetal spine and intracranialstructures. Amniocentesis to measure AFP in theamniotic fluid may also be considered by couplesat high risk. If amniotic fluid AFP is elevated, anacetylcholinesterase determination should beperformed. An elevated amniotic fluid AFP withpositive acetylcholinesterase, in the absence offetal blood contamination, is definitive evidence


of the presence of an open fetal defect. If it has notpreviously been visualized by ultrasonography,every effort should be made following amniocen-tesis to image the defect so that appropriate coun-seling can be provided to the family.

REFERENCES

1. Stevenson AC, Johnston HA, Stewart MA, et al.Congenital malformations: a report of a study ofseries of consecutive births in 24 centres. BullWorld Health Organ. 1966;34(suppl):9–127.

2. Mitchell LE. Epidemiology of neural tube defects.Amer J Med Genet Part C (Semin Med Genet).2005;135C:88–94.

3. Rosano A, Smithells D, Cacciani L, et al. Time trendsin neural tube defects prevalence in relation to pre-vention strategies: an international study. J EpidemiolCommunity Health. 1999;53:630–5.

4. Czeizel AE, Dudas I. Prevention of the first oc-currence of neural-tube defects by periconcep-tional vitamin supplementation. N Engl J Med.1992;327:1832–5.

5. Botto LD, Yang Q. 5,10-methylenetetrahydrofolatereductase gene variants and congenital anomalies:a HuGE review. Am J Epidemiol. 2000;151:862–77.

6. Kallen B, Robert E, Harris J. Associated malfor-mations in infants and fetuses with upper orlower neural tube defects. Teratology. 1998;57:56–63.

7. Mazon A, Nieto A, Linana JJ, et al. Latex sensiti-zation in children with spina bifida: follow upcomparative study after two years. Ann AllergyAsthma Immunol. 2000;84:207–10.

8. Bruner JP, Tulipan N, Paschall RL, et al. Fetalsurgery for myelomeningocele and the incidenceof shunt-dependent hydrocephalus. JAMA. 1999;282:1819–25.

9. Patricolo M, Noia G, Pomini F, et al. Fetalsurgery for spina bifida aperta: to be or not to be?Eur J Pediatr Surg. 2002;12(1):S22-4.

10. Preis K, Swiatkowska-Freund M, JanczewskaI. Spina bifida—a follow-up study of neonatesborn from 1991 to 2001. J Perinat Med. 2005;33:353–6.

11. Wong LC, Paulozzi LJ. Survival of infants withspina bifida: a population study, 1979–1994. Pae-diatr Perinat Epidemiol. 2001;15:374–8.

12. Bowman RG, McLone DG, Grant JA, et al. Spinabifida: a 25-year prospective. Pediatr Neurosurg.2001;34:114–20.

13. Oakeshott P, Hunt GM. Long-term outcome inopen spina bifida. Br J Gen Pract. 2003;53:632–6.



Chapter 5

AnencephalyBARBARA K. BURTON

51

� INTRODUCTION

Anencephaly is the complete or partial absenceof the brain resulting from failure of closure ofthe cephalic portion of the neural tube whichleads to protrusion of the unenclosed brainthrough the defective skull covering and subse-quent degeneration. It is readily detected pre-natally by ultrasound and, given the frequencywith which prenatal ultrasound is currentlyused, most cases are now diagnosed prior tobirth. If not identified prenatally, it is immedi-ately apparent at birth.


The epidemiology of open neural tube defects isdiscussed in the chapter on spina bifida (Chap. 4).The neural groove and folds in the human em-bryo can first be seen by day 18 of developmentand have begun to fuse by day 22. The cephalicneural tube closes in a bidirectional fashion byday 24 (see Fig. 4-1 in Chap. 4 on spina bifida).In the case of an open neural tube defect in thecephalic region, closure proceeds normally be-low the level interrupted by the defect. As a re-sult of the defect, there is eversion of the cephalicneural tube and absence of the cranium. Theneural tissue may undergo some overgrowth and

vascular proliferation but, over time, the exposedtissue is subject to secondary destruction and formsa spongy mass of connective tissue and vasculartissue referred to as the cerebrovasculosa. In abouttwo-thirds of cases, there is complete absence ofthe brain and skull covering while in the remain-ing one-third, there is partial skull formation withthe cerebrovasculosa protruding through a mid-line defect.

Many pregnancies affected with anencephalyare electively terminated prior to the end of themidtrimester following prenatal diagnosis of thedefect. Polyhydramnios is a common complica-tion of affected pregnancies. Approximately 50%of anencephalic infants in continuing pregnan-cies are stillborn while the remainder die withinthe first 48 hours of life.


Of anencephalic infants without a known chro-mosome anomaly, approximately 25% have atleast one associated anomaly.1 The most com-monly observed anomalies are listed in Table 5-1.In general, the syndromes associated with anen-cephaly are the same as those associated withany type of open neural tube defect and arelisted in Table 4-2 in Chap. 4 on spina bifida.


� EVALUATION AND TREATMENT

The infant with anencephaly should be care-fully examined for the presence of other anom-alies that could influence the genetic counselingprovided to the parents. If other malformationsare present, chromosome analysis should beobtained. Aggressive treatment, such as intuba-tion, resuscitation, and artificial ventilation ofthe affected infant is not warranted because of

the dismal prognosis. In the past, anencephalicinfants have served in a number of cases as or-gan donors but this practice has largely beenabandoned in recent years. Difficulties in defin-ing brain death in these infants and the gener-ally poor quality of the organs by the time theywere harvested have been the major obstaclesto successful donation.

� GENETIC COUNSELING ANDPRENATAL DIAGNOSIS

This is discussed in the chapter on spina bifida(Chap. 4).

REFERENCES

1. Kallen B, Robert E, Harris J. Associated malforma-tions in infants and fetuses with upper or lowerneural tube defects. Teratology. 1998;57:56–63.


� TABLE 5-1 Associated Malformations in anInfant with Anencephaly

Facial clefts 8.3%Anotia/microtia 3.1%Cardiac defects 3.0%Limb reduction defects 2.2%Abdominal wall defects 1.7%

Chapter 6

EncephaloceleBARBARA K. BURTON

53

� INTRODUCTION

An encephalocele is a herniation of brain andmeninges through a defect in the skull. It is typ-ically covered by skin (closed defect) or a thinlayer of epithelium (open defect). In rare cases,only meninges may protrude through the cra-nial defect, in which case the lesion is referred toas a cranial meningocele. An encephalocele maybe present anywhere along the midline of thecranium, from the nasal septum to the base of theocciput. Approximately 75% of encephalocelesare in the occipital region.

� EPIDEMIOLOGY/EMBRYOLOGY

Encephaloceles are within the spectrum of neuraltube defects. They are much less common thaneither anencephaly or spina bifida, occurring inan estimated 1 in 5000 to 10,000 births. The epi-demiology and embryology of neural tube de-fects is discussed in Chap. 4 on spina bifida.

� CLINICAL PRESENTATION ANDEVALUATION

In most cases, the lesion will be grossly appar-ent on physical examination after birth. The sizeof an encephalocele can range from very smallto larger than the head. In most cases, an en-cephalocele can be distinguished clinically fromother cranial lesions such as cephalohematomas,cysts, or cystic hygromas. If there is any doubt,the bony defect can be visualized by skull radi-ographs. Frontal encephaloceles are often ac-companied by hypertelorism and a bifid foreheadand may protrude into the orbit, causing a defor-mity of the eye. Nasal encephaloceles may pre-sent as a facial mass. In all cases, neuroimaging bycomputed tomography (CT) scan or magnetic res-onance imaging (MRI) should be performed todefine the contents of the extracranial sac and toassess the intracranial structures for the presenceof associated anomalies.

Encephaloceles are frequently identified pre-natally by ultrasonography. In these cases, it is


critically important to carefully examine the fetusfor associated anomalies and to consider amnio-centesis for fetal chromosome analysis. Amnioticfluid α-fetoprotein (AFAFP) is often not elevatedin the presence of a fetal encephalocele so anormal AFAFP level should not be viewed as ev-idence against the presence of such a defect.


A large percentage of fetuses and infants withencephaloceles have associated anomalies. Thecommon malformations seen in infants with anencephalocele and a normal chromosomeanalysis are presented in Table 6-1.1 It shouldbe noted that encephalocele, cystic kidneys,and polydactyly are all features of the autoso-mal recessive Meckel-Gruber syndrome, a dis-order that accounts for a significant percentageof infants with encephalocele and other anom-alies. Syndromes associated with encephaloce-les are listed in Table 6-2.


In planning treatment for the infant with an en-cephalocele, the primary factors to consider arethe presence of associated anomalies, includ-ing intracranial anomalies, and the contents ofthe lesion itself. Large lesions containing occip-ital or parietal cortex tend to have the worst

prognosis for survival and for intellectual out-come, with most of the infants who do surviveexhibiting very limited developmental progress.2

Additional poor prognostic indicators are theassociated findings of absent corpus callosum,holoprosencephaly, or microcephaly. In con-trast, infants with cranial meningoceles or withencephaloceles containing only glial nodulesmay do very well following surgical closure.3

Similarly, nasal encephaloceles are associatedwith a more favorable prognosis than occipitalor parietal encephaloceles with only 20–25% ofaffected infants exhibiting severe disabilities.

Predicting prognosis following the prenataldiagnosis of an encephalocele is often difficultbecause of the high incidence of associatedanomalies. Over 50% of fetuses identified as hav-ing an encephalocele in the midtrimester of preg-nancy are found to have associated anomalies.Some of these have chromosome anomalies, suchas trisomy 13 or 18, or a recognizable single genedisorder, such as the Meckel-Gruber syndrome.In the apparently isolated lesions, an effort shouldbe made to determine if the sac contains signifi-cant brain tissue prior to counseling the familyregarding the prognosis for the infant.


In an infant with an encephalocele and otheranomalies, every effort should be made to es-tablish a specific diagnosis so that appropriategenetic counseling can be provided to the fam-ily. Chromosome analysis should be obtained.Autopsy should be strongly encouraged for in-fants who do not survive to look for findingssuch as cystic kidneys, which may lead to a di-agnosis of Meckel-Gruber syndrome with an au-tosomal recessive mode of inheritance, and a25% risk of recurrence in future pregnancies. Inthe case of isolated encephaloceles, the geneticcounseling is the same as for other isolatedneural tube defects and is covered in Chap. 4on spina bifida.


� TABLE 6-1 Associated Malformations in anInfant with Encephalocele

Facial clefts 14.6%Anophthalmia/microphthalmia 8.5%Cardiac defects 7.4%Cystic kidneys 6.1%Limb reduction defects 5.8%Polydactyly 5.2%

CHAPTER 6 ENCEPHALOCELE 55

� TABLE 6-2 Syndromes Associated with Encephaloceles

Syndromes Other Clinical Findings Etiology

Amniotic band syndrome Irregular disruption of skull and Amnion disruption(Amnion disruption sequence) facial structures; facial clefts;

limb and digital constrictionsand amputation-type defects

Apert syndrome Craniosynostosis; syndactyly Autosomal dominantboth hands and both feet FGFR2, 10q26

Chromosome anomalies Multiple minor and major Trisomies (13, 18);anomalies in various organ deletions, duplicationssystems

Dyssegmental dysplasia Skeletal dysplasia with very Autosomal recessive(Silverman-Handmaker) short limbs; oral clefts; HSPG2, 1p36.1

stillborn or early neonatal perlecandeath

Fraser syndrome Syndactyly; eyelid fusion; Autosomal recessiveabnormal ears; laryngeal FRAS1, 4q21anomalies; renal FREM2, 13q13.3agenesis/dysgenesis;abnormal genitalia; mentalretardation

Frontonasal dysplasia Widow’s peak; hypertelorism; Sporadic, occasionallybroad or bifid nose; median autosomal dominantcleft lip; variable mentalretardation(Frontonasal encephalocele)

Meckel-Gruber syndrome Microphthalmia; cleft lip/palate; Autosomal recessivecystic kidneys; polydactyly 8q24

11q1317q23

MURCS association Short stature; cervicothoracic Unknownvertebral defects; absence ofproximal 2/3 of vagina anduterus; renal agenesisor ectopia

Pallister-Hall syndrome Dysmorphic facies; cleft palate; Autosomal dominantpolydactyly; syndactyly; renal GLI3, 7p13anomalies; anal atresia;hypothalamic hamartoma

Roberts SC-phocomelia Microcephaly; growth failure;syndrome cleft lip/palate; limb deficiency;

mental retardationWalker-Warburg syndrome Lissencephaly; cerebellar Autosomal recessive

malformations; retinal dysplasia, POM1, 9q34.1microphthalmia; congenital POM2, 14q24.3muscular dystrophy FCMD, 9q3.1

REFERENCES

1. Kallen B, Robert E, Harris J. Associated malfor-mations in infants and fetuses with upper orlower neural tube defects. Teratology. 1998;57:56–63.

2. Simpson DA, David J, White J. Cephaloceles: treat-ment outcome, and antenatal diagnosis. Neurosurgery.1994;15:14–21.

3. Brown MS, Sheridan-Pereira M. Outlook for the childwith a cephalocele. Pediatrics. 1992;90:914–9.


Chapter 7

HoloprosencephalyBARBARA K. BURTON

57

� INTRODUCTION

Holoprosencephaly is a severe structural mal-formation of the brain in which the developingforebrain fails to divide into two separate hemi-spheres and ventricles. It can be further subdi-vided into alobar holoprosencephaly in whichthere is a single ventricle and no separation ofthe cerebral hemispheres; semilobar holopros-encephaly in which the left and right frontaland parietal lobes are fused and the interhemi-spheric fissure is only present posteriorly; andlobar holoprosencephaly in which most of thehemispheres and lateral ventricles are sepa-rate but the ventral portions of the frontal lobesare fused.


Holoprosencephaly is one of the most commondevelopmental defects of the forebrain and mayoccur as frequently as 1 in 250 pregnancies, but alarge majority of these fetuses do not survive todelivery. The defect occurs with an incidence of1 in 10,000 to 1 in 20,000 live births. Between 25%and 50% of all infants with holoprosencephalyare found to have a chromosomal abnormality,and this should be the first consideration in anyinfant with this malformation. The most commonchromosomal abnormality identified is trisomy

13 but a large number of numerical and struc-tural chromosome abnormalities have been re-ported in association with holoprosencephaly.Maternal diabetes is an important nongeneticcause of holoprosencephaly with diabetic moth-ers having an overall risk of approximately 1%of having an affected infant. This is 20 timeshigher than the general population risk. Theremay be other teratogenic causes of this malfor-mation but none have yet been conclusivelyidentified in humans.

Most cases of nonsyndromic holoprosen-cephaly are probably genetically determinedwith five autosomal dominant genes for the dis-order having thus far been identified.1 Mutationsin these five genes account for approximately50% of familial cases and less than 10% of spo-radic cases of nonsyndromic holoprosencephaly(Table 7-1). A number of other candidate geneshave also been identified. Of significance is thefact that expression of all five of the genes thusfar identified is highly variable and all exhibitincomplete penetrance with approximately one-third of gene carriers having normal intelligenceand no clinical manifestations whatsoever. Indi-vidual family members who do exhibit clinicalmanifestations may have obvious holoprosen-cephaly or much more subtle findings such asocular hypotelorism, a single maxillary incisoror midline cleft lip with no central nervous sys-tem (CNS) findings.2



The diagnosis of holoprosencephaly at birth istypically suspected on the basis of the character-istic facial findings which can range from cyclopiawith a proboscis above the eye at the most severeend of the spectrum to hypotelorism with a me-dian cleft lip in less severely affected infants(Fig. 7-1). There is some correlation betweenthe severity of the facial abnormalities and thetype of holoprosencephaly with cyclopia andcebocephaly (the finding of a single nostril nose)virtually always predicting alobar holoprosen-cephaly. Semilobar and lobar holoprosen-cephaly are more commonly associated with aflat nose (often with the nares opening onto thelip or anterior palate), ocular hypotelorism, anda median or bilateral cleft lip.

In patients without any facial dysmorphol-ogy, the diagnosis of a CNS malformation is usu-ally suspected later in infancy on the basis ofdevelopmental delay or seizures. Once the di-agnosis is suspected, either immediately afterbirth or at a later time, it can be confirmed byneuroimaging, preferably by magnetic reso-nance imaging (MRI). This will also identify anyassociated CNS anomalies.


Holoprosencephaly is accompanied by the char-acteristic pattern of facial anomalies in about80% of affected individuals. Although infants with

chromosome anomalies are likely to have ab-normalities in other organ systems, these are notalways immediately apparent. Therefore, chro-mosome analysis should be obtained on everyinfant with holoprosencephaly. Holoprosen-cephaly not associated with a chromosomeanomaly can be further subdivided into syn-dromic and nonsyndromic forms. Holoprosen-cephaly has been reported in association with alarge number of multiple malformation syn-dromes, most of which are rare. In many ofthese disorders, holoprosencephaly is an incon-stant or occasional finding. Therefore, it is pru-dent to seek consultation with a geneticist inany infant with holoprosencephaly and multiplemalformations who has a normal karyotype sincethe differential diagnosis may be quite complex.


� TABLE 7-1 Autosomal Dominant Genesfor Holoprosencephaly (% of Patients withMutations in the Gene)

FamilialGene Locus Cases De Novo Cases

SHH 7q36 30–40% <5%ZIC2 13q32 5% <2%SIX3 2p21 1–2% RareTGIF 18p11.3 1–2% RarePTCH 9q22.3 Rare Rare

Figure 7-1. Patient with semilobar holopros-encephaly exhibiting the typical facial charac-teristics of the disorder. Note the findings ofhypotelorism, a flat nose, and median cleft lip.

� EVALUATION

The evaluation of the infant with holoprosen-cephaly should include the following:

1. Neuroimaging, preferably by MRI, to definethe defect and identify any associated CNSanomalies.

2. Detailed physical examination to identifyany associated anomalies outside the CNS.

3. Careful prenatal and family history to excludematernal diabetes as a cause and to explorethe history for findings that would suggestpossible autosomal dominant inheritance.

4. Chromosome analysis; if normal, considermicroarray analysis (comparative genomichybridization) to identify submicroscopicdeletions or duplications.

5. In nonsyndromic cases, particularly if familyhistory is suggestive of autosomal dominanttransmission, obtain DNA analysis for muta-tions in the five genes listed in Table 7-1.Over time, clinical testing may become avail-able for additional genes.


Developmental delay is observed in all infantswith holoprosencephaly with the degree of delaycorrelating with the severity of the CNS malfor-mation.3 Infants with alobar holoprosencephalytypically do not exhibit any developmentalprogress and only 20% survive beyond the firstyear of life. In contrast, approximately 50% ofinfants with lobar or semilobar holoprosen-cephaly survive 1 year and most develop a so-cial smile. Seizures are extremely common andpanhypopituitarism may be observed as a resultof pituitary dysgenesis. There is often evidenceof brain stem and hypothalamic dysfunctionwith temperature, heart rate, and respiratory in-stability. Difficulties in coordinating suck andswallowing may lead to significant feeding prob-lems and aspiration, which may be com-pounded if a cleft lip and palate is present.

There is no specific treatment for the brainmalformation. In some children, hydrocephalusmay develop and this can be treated with ashunt procedure. Consideration can be given torepair of cleft lip and palate in infants who sur-vive beyond 1 year of age. Otherwise, treatmentis essentially symptomatic for complicationsof the disorder including anticonvulsants forseizures, hormone replacement therapy forpituitary insufficiency, if present, and nutritionalsupport.


Prior to genetic counseling, every effort shouldbe made to determine if the holoprosencephalyis syndromic or nonsyndromic and, if syn-dromic, to establish a specific diagnosis. If achromosomal abnormality or multiple malfor-mation syndrome is diagnosed, then the geneticcounseling will be determined by the counsel-ing appropriate for that disorder.

In the case of nonsyndromic holoprosen-cephaly in an infant with normal chromosomes,the family history must be carefully explored indetail for subtle findings that might suggest thatthere are other family members carrying an auto-somal dominant gene for the disorder beforethe assumption is made that a case is isolated.Findings in relatives that may be significant in-clude single maxillary incisor, microcephaly,anosmia, cleft lip, pituitary insufficiency, hy-potelorism, or developmental delay. If the par-ent of an infant with holoprosencephaly exhibitsfindings suggesting that he or she carries a disease-causing mutation, or if a parent is shown to carrya mutation by DNA analysis, then there is a50% risk to subsequent siblings of inheritingthe mutation. Taking into account the incom-plete penetrance and variable expressivity of allof the dominant holoprosencephaly genes, therisk to subsequent siblings for various outcomeshas been shown to be 20% for holoprosen-cephaly, 15% for minor manifestations, and 15%for a normal phenotype (silent gene carrier).

CHAPTER 7 HOLOPROSENCEPHALY 59

If the family history is completely unremark-able in a sporadic case of holoprosencephaly,the risk of recurrence is likely relatively low.Some cases may represent new mutations ofautosomal dominant genes. The recurrence riskis always greater than that faced by couples inthe general population, however, because ofthe possibility of gonadal mosaicism for a dom-inant gene mutation or because of the possibilitythat a parent could be a nonexpressing carrier ofa dominant gene. High resolution ultrasonogra-phy should be offered in subsequent pregnan-cies for examination of the intracranial anatomyand facial structures. Alobar holoprosencephalyshould be easily detectable in the midtrimesterof pregnancy by ultrasonography.4 Semilobarand lobar holoprosencephaly cannot be reli-ably detected by prenatal ultrasound examination,although the accompanying facial anomaliesmay be detected. If a previous child with

holoprosencephaly has had a chromosomeanomaly, then prenatal chromosome analysis,by chorionic villus sampling or amniocentesis,should be offered.

REFERENCES

1. Muenke M and Gropman A. HoloprosencephalyOverview. Available at: http://www.genetests.org.Accessed March 11, 2006.

2. Hehr U, Gross C, Diebold U, et al. Wide phenotypicvariability in families with holoprosencephaly and asonic hedgehog mutation. Eur J Pediatr. 2004;163:347–52.

3. Hahn JS, Plawner LL. Evaluation and managementof children with holoprosencephaly. Pediatr Neurol.2004;31:79–88.

4. Joo GJ, Beke A, Papp C, et al. Prenatal diagnosis,phenotypic and obstetric characteristics of holo-prosencephaly. Fetal Diagn Ther. 2005;20:161–6.


http://www.genetests.org

Chapter 8

HydrocephalusBARBARA K. BURTON

61

� INTRODUCTION

Hydrocephalus is a condition associated withan increase in the volume of the ventricularcavities in the brain relative to the cerebralparenchyma. The discussion in this chapter willfocus on true hydrocephalus, usually associatedwith increased intracranial pressure, resultingfrom either obstruction to the normal flow of cere-brospinal fluid or fluid production that exceedsthe resorptive mechanisms. It will not include adiscussion of “hydrocephalus ex vacuo” in whichenlarged ventricles are observed as a result ofcerebral atrophy. A distinction should also bemade between hydrocephalus and both hydra-nencephaly, in which the brain is replaced by afluid-filled sac covered with meninges, and poren-cephaly in which there are one or more fluid-filled cysts which may be contiguous with theventricular system.


The incidence of isolated congenital hydro-cephalus, not associated with spina bifida is ap-proximately 0.5 per 1000 births.1 No significantdifferences in incidence have been documentedamong various ethnic groups. It is a very het-erogeneous disorder with multiple etiologies.Many cases are felt to be nongenetic in origin,

resulting from posthemorrhagic or postinflam-matory changes in the brain. The origin of thedisorder can be prenatal, perinatal, or even post-natal. In preterm infants, intracranial hemor-rhage is a major cause. In a small percentage ofpatients, specific etiologic agents, such as toxo-plasmosis, can be identified. In other cases, aspecific single gene mutation can be demon-strated as the basis for the disorder. The bestknown example of this is the syndrome ofX-linked aqueductal stenosis, also known asX-linked hydrocephalus-MASA spectrum, whichresults from mutations in the LICAM gene atXq28.2 This is a highly variable disorder withfindings ranging from mental retardation withouthydrocephalus to severe prenatal hydrocephalusleading to stillbirth. Indeed the term MASA isan acronym for Mental retardation, Adductedthumbs, Shuffling gait, and Aphasia. About 25%of affected patients have the associated findingof adducted thumbs which can be a useful diag-nostic marker. Unfortunately, the mental retarda-tion associated with the disorder is an intrinsicfeature that is present even if the patient isshunted early. The incidence of this syndromeis estimated to be approximately 1 in 30,000 births.It may account for as many as 25% of cases ofaqueductal stenosis in males. Other forms ofisolated hydrocephalus may rarely have a singlegene basis but most of these are rare. ExcludingX-linked aqueductal stenosis, most cases of


nonsyndromic isolated hydrocephalus are spo-radic and of unknown, presumably nongenetic,etiology.


Increased use of ultrasound in pregnancy has re-sulted in increased numbers of fetuses being di-agnosed with ventriculomegaly. It is importantto recognize that the finding of ventriculomegalyin utero is not equivalent to a diagnosis of con-genital hydrocephalus. Mild to moderate in uteroventriculomegaly is often nonprogressive andwill not require treatment postnatally. Further-more, ventriculomegaly in utero may be a re-flection of other central nervous system (CNS)malformations, such as neuronal migration de-fects, and the prognosis may be quite differentthan that associated with isolated hydrocephalus.Caution should always be used in making pre-dictions about treatment or prognosis prior tobirth. In attempting to establish a diagnosis ofhydrocephalus prenatally by ultrasound, how-ever, a number of helpful ultrasound parametershave been identified. There may be significantventricular dilatation and parenchymal compres-sion before there is an increase in the biparietaldiameter. Therefore, the diagnosis typically restson intracranial measurements, including com-parison of the lateral ventricle to hemisphere ra-tio (LV/H), evidence of separation of the choroidplexus from the ventricular wall, and an increasein the ventricular diameter.

Postnatally hydrocephalus is characterizedby an increasing head circumference that crossespercentiles on the growth chart. Serial head cir-cumference measurements are very important.The fontanelle may be tense or bulging withwidened cranial sutures. Neurologic findingssuch as loss of upward gaze, the “setting sunsign” (in which there is downward displacementof the eyes with the sclera visible above the iris),neck rigidity, irritability, or abnormal reflexesmay be observed. Many affected infants have noabnormal neurologic findings, however.


The most common anomaly associated with hy-drocephalus is open spina bifida (myelomeningo-cele). This has been addressed in Chap. 4. It mayalso be observed in association with the Dandy-Walker malformation which is discussed inChap. 9. Most cases of congenital hydrocephalusare either isolated, associated with open spinabifida, or occur in preterm infants secondary tointracranial hemorrhage. However, hydro-cephalus can occur as a component of a numberof different multiple malformation syndromesand can be a manifestation of intrauterine infec-tion. Therefore, the infant should be carefullyexamined for any evidence of associatedanomalies or abnormal findings in other or-gan systems. A list of some of the most commonsyndromes associated with congenital hydro-cephalus is provided in Table 8-1.

� EVALUATION

The following evaluation is recommended if afetus is identified to have ventriculomegaly ona prenatal ultrasound:

1. Serial imaging to assess for progression2. Careful assessment for associated anomalies

within and outside the CNS3. Amniocentesis for fetal karyotype and testing

for cytomegalovirus (CMV) and toxoplasmosis4. Consider fetal magnetic resonance imaging

(MRI), if available

After birth, routine skull radiographs, al-though not usually necessary, will show splayedsutures, thinning of the calvarium, flattening ofthe cranial base and, in long-standing cases,digital impressions. The diagnosis can be estab-lished by ultrasonography, cranial tomography,or MRI. This will usually also help to distinguishthe various subtypes of hydrocephalus, basedon the anatomy observed. The most common


CHAPTER 8 HYDROCEPHALUS 63

� TABLE 8-1 Syndromes Associated with Hydrocephalus

Syndrome Other Features Etiology

Achondroplasia Skeletal dysplasia with proximal Autosomal dominantlimb shortening; prominent FGFR3 geneforehead; depressed nasal bridge; 4p16.3large head. Findings can be subtlein the neonate.

Amniotic band syndrome Facial clefts; amputation type defects Amnion disruption withof limbs or digits, often accompanied mechanical disruptionby annular constrictions. of fetal structures by

amnion adhesion orfibrous amnioticbands

Cytomegalovirus Intrauterine growth retardation; microcephaly; Cytomegalovirusinfection, congenital deafness; chorioretinitis infection in utero

MASA syndrome Mental retardation; adducted thumbs; X-linked recessiveagenesis of corpus callosum; spastic LICAM geneparalysis; increased incidence of stillbirth Xq28

Microphthalmia—linear Microphthalmia; linear dermal aplasia Chromosome deletionskin defects syndrome of head and neck; septum pellucidum del Xp22.3 lethal in

cyst; absent corpus callosum malesNoonan syndrome Short stature; ptosis; hypertelorism; Autosomal dominant

low set/abnormal ears; short/webbed PTPN11neck; pectus excavatum; dysplastic 12q24.1 (50% of cases)pulmonic valve; hypertrophic SOS1 or KRAScardiomyopathy; mild mentalretardation in 25%

Oral-facial-digital Median cleft/notched lip; multiple oral X-linked dominant,syndrome, type I frenula; lobulated tongue; short fingers male lethal

with syndactyly; porencephaly; hypoplastic Xp22.3-p22.2cerebellar vermis; Dandy-Walker cyst;agenesis of corpus callosum

Oral-facial-digital Short stature; hypertelorism; bifid nasal tip; Autosomal recessivesyndrome, type II cleft tongue; cleft palate; short fingers

with syndactyly; polydactyly; agenesis ofcorpus callosum

Toxoplasmosis, Intrauterine growth retardation; intracranial Prenatal infection withcongenital calcifications; chorioretinitis; deafness toxoplasma gondii

Triploidy Severe intrauterine growth retardation; Chromosome anomalysyndactyly; congenital heart defects 69, XXY or 69, XXX

VATER or VACTERL Vertebral anomalies; anal atresia; cardiac Sporadic; etiologysyndrome defects; tracheo-esophageal fistula; unknown

renal anomalies; limb defectsWalker-Warburg Agyria; Dandy-Walker malformation; Autosomal recessive

syndrome cerebellar hypoplasia; encephalocele; POMT1, 9q34.1retinal dysplasia; corneal opacities; POMT2, 14q24.3elevated CK; myopathy Fukutin, 9q31;

multiple other genesto be identified

broad categories, aqueductal stenosis and com-municating hydrocephalus, are about equallycommon in most series of neonates, each ac-counting for 35–40% of cases. Less common en-tities include aplasia of the foramen of Monro,which can produce unilateral hydrocephalus,and stenosis of the third ventricle. AssociatedCNS malformations may also be detected byneuroimaging in infants with hydrocephalus, al-tering both the diagnosis and prognosis.

In addition to these neuroimaging studies,all infants with congenitial hydrocephalusshould have the following workup to identifythe etiology and to plan an adequate follow-up:

1. Eye examination for choreoretinitis, retinaldysplasia, or other abnormalities

2. Hearing assessment3. Chromosome analysis, if associated anom-

alies are present4. Evaluation for toxoplasmosis and CMV, if

indicated5. Consider genetic testing for mutations in LI-

CAM if male with aqueductal stenosis


The treatment and prognosis for patients withhydrocephalus depends, to a certain extent, onthe age at diagnosis, the etiology of the disorder,and whether there are any associated anomalies.Before attempting to predict prognosis for fe-tuses diagnosed in utero, it is essential to at-tempt to determine if there are any associatedanomalies. The presence of associated anom-alies, especially within the CNS, is a very poorprognostic indicator. Sequential imaging studiesmay be necessary. MRI, if available, can now beof value in assessing the CNS for associatedanomalies not readily seen on ultrasound. It hasbeen shown that up to 15% of infants who werefelt on prenatal ultrasound to have sonographi-cally isolated ventriculomegaly have at least oneadditional CNS anomaly detected at the time ofbirth, many of which may be detected by MRI.

In general, patients with mild, nonprogressiveventriculomegaly in utero have a more favorableprognosis than those with more severe abnor-malities, although the outcome is not guaranteedto be normal.3 For those patients with progres-sive hydrocephalus, particularly those diagnosedprior to 32 weeks gestation, the outcome is gen-erally poor. This observation led to the hypothe-sis several decades ago that there might be a rolefor intrauterine shunting in the treatment of hy-drocephalus diagnosed prenatally. The resultswere uniformly poor4 and this was largely aban-doned in the late 1980s. Currently, early deliveryfor postnatal shunting is considered in somecases, balancing the risks of prematurity againstthe risks of progressive hydrocephalus. Shuntingis the standard neurosurgical treatment for thedisorder. A discussion of the various types ofshunt procedures, specific indications for shuntplacement, and shunt complications is beyondthe scope of this discussion. The most commonshunt procedure used in most centers is the ven-triculoperiotoneal shunt.

Of children whose hydrocephalus has a pre-natal onset, 24% are stillborn and 17% die in theneonatal period.5 Of those surviving at the age of10 years, only 28% have an IQ within the normalrange. Predictors of a better outcome includelack of associated malformations, lack of shuntmalfunctions and infections, and aqueductalstenosis not due to a LICAM mutation or to tox-oplasmosis. In a recent series of all infants withisolated hydrocephalus of either prenatal orpostnatal onset followed to 10 years of age,there was a 5% overall mortality and 46% hadmental retardation, 31% cerebral palsy, and 31%epilepsy%.1


If a specific diagnosis of a malformation syn-drome, single gene disorder (such as X-linkedhydrocephalus secondary to a LICAM gene mu-tation) or teratogenic syndrome has been es-tablished in a patient with hydrocephalus, then


appropriate genetic counseling should be pro-vided for that disorder and prenatal diagnosisshould be discussed, if applicable. In most othercases, empiric recurrence risk counseling willneed to be given. Estimated risks for variouscategories of patients are given in Table 8-2. Inaddition to discussing the risk of recurrence,parents should be offered sequential high reso-lution ultrasound in future pregnancies. Thegestational age at which hydrocephalus devel-ops is highly variable, however, so parentsshould clearly understand that normal findingsin the second trimester when pregnancy termi-nation is an option do not in any way precludethe development of hydrocephalus at a latertime in gestation.

REFERENCES

1. Persson EK, Hagberg G, Uvebrant P. Hydrocephalusprevalence and outcome in a population-based co-hort of children born in 1989-1998. Acta Paediatr.2005;94:726–32.

2. Weller S, Gartner J. Genetic and clinical aspects ofX-linked hydrocephalus (L1) disease): mutations inthe LICAM gene Hum Mutat. 2001;18:1–12.

3. Goldstein I, Copel JA, Makhoul IR. Mild cerebralventriculomegaly in fetuses: characteristics and out-come. Fetal Diagn Ther. 2005;20:281–4.

4. Von Koch CS, Gupta N, Sutton LN, et al. In uterosurgery for hydrocephalus. Childs Nerv Syst.2003;19:574–86.

5. Stein SC, Feldman JG, Apfel S, et al. The epidemiol-ogy of congenital hydrocephalus. A study in Brooklyn,N.Y. 1968-1976. Childs Brain. 1981;8:253–62.

CHAPTER 8 HYDROCEPHALUS 65

� TABLE 8-2 Recurrence Risk for Siblings of an Infant with Congenital Hydrocephalus

Proband Recurrence Risk for Siblings

Male with aqueductal stenosis 12% for male siblings; 6% for females for hydrocephalus

Female with any type of hydrocephalus 2% for male or female siblings for hydrocephalusor male with communicates hydrocephalus


Chapter 9

Dandy-Walker MalformationBARBARA K. BURTON

67

� INTRODUCTION

The Dandy-Walker malformation is a central ner-vous system (CNS) malformation defined by atriad of findings including hypoplasia or absenceof the cerebellar vermis with upward rotation ofthe vermis; an enlarged posterior fossa with up-ward displacement of the falx, lateral sinuses, andtorcular; and cystic dilatation of the fourth ventri-cle that is in communication with a thin-walledretrocerebellar cyst that is formed by the roofof the fourth ventricle. There is wide variabilityin the findings. Some patients exhibit hypoplasiaof the vermis and/or smaller cysts with a normalposterior fossa. These findings are often referredto as a “Dandy-Walker variant.” Hydrocephalus istypically not present in fetuses with the Dandy-Walker malformation in utero but it frequentlydevelops as a secondary complication postnatally.


Estimates of the prevalence of the Dandy-Walkermalformation among live births vary from about1 in 25,0001 to about 1 in 50002, depending onthe population studied and the method of ascer-tainment. The disorder is etiologically diverse andhas been reported in many different mendelian,

teratogenic, and chromosomal syndromes. Recentwork has implicated heterozygous loss of thegenes ZIC1 and ZIC4 in cases of isolated Dandy-Walker malformation.3 A mouse model has beendeveloped. Inborn errors of metabolism thathave been associated with Dandy-Walker mal-formation include 3-methyl-glutaconic aciduria,which is typically associated with metabolic aci-dosis and abnormal urine organic acids, andcongenital disorders of glycosylation (CDG syn-dromes) which may exhibit variable features in-cluding abnormal fat distribution, retinopathy,renal tubulopathy, and elevated transaminases.


The diagnosis of the Dandy-Walker malformationis often made in utero by ultrasound examinationwhich demonstrates the characteristic intracranialfindings. In infants who are not ascertained pre-natally, macrocephaly, with a prominent occiput,is often present at birth. Patients are typically di-agnosed with the development of signs and symp-toms of hydrocephalus including increasing headcircumference, bulging fontanelle, irritability, andocular signs, such as upward and lateral gazepalsy, nystagmus, and strabismus. Cerebellar dys-function is uncommon in infancy.



The majority of patients with Dandy-Walker mal-formation have associated CNS anomalies andthese should be carefully sought. The most com-mon is agenesis of the corpus callosum. Ex-tracranial malformations are also very common.Among those most frequently noted are facialhemangiomas, cardiovascular defects, and digi-tal anomalies.

Each affected infant with the Dandy-Walkermalformation must be carefully examined to de-termine the extent of any associated anomaliesand to determine if a unifying diagnosis can beestablished. The Dandy-Walker malformation orvariant has occasionally been reported in asso-ciation with a very large number of differentsyndromes. However, it is a common feature ofonly a few. These are listed in Table 9-1. Seealso Fig. 9-1. If a diagnosis cannot be readily es-tablished in an infant, consultation with a ge-neticist should be obtained as there are many

other conditions, not on this list, that might beconsidered.

� EVALUATION

The following evaluation is recommended if afetus is identified to have Dandy-Walker mal-formation or variant on ultrasonography:

1. Careful assessment for any associated anomalies2. Amniocentesis for fetal karyotype3. Fetal echocardiogram

After birth, diagnosis is confirmed by neu-roimaging. It can usually be established by ei-ther computerized tomography or magnetic res-onance imaging (MRI), but MRI is probably thepreferred method to show the status of the cere-bellar vermis. It is essential that good sagittaland axial views at the level of the fourth ventri-cle be obtained (Fig. 9-2). A recommended eval-uation plan for all infants with the Dandy-Walkermalformation should include:


� TABLE 9-1 Syndromes Commonly Associated with Dandy-Walker Malformation


3 C syndrome Growth retardation; cardiac defects; Autosomal recessive(Ritscher-Schinzel large fontanel; hypertelorism;syndrome) downslanting palpebral fissures

Chromosome anomalies, Highly variable—minor and major Chromosome deletions,various malformations in any organ duplications, trisomies,

system triploidyPHACE syndrome Acronym for Posterior fossa Unknown, female

abnormalities; facial and/or predominancesubglottic Hemangiomas; Arterialabnormalities including coarctationof the aorta; Cardiac defects; andEye defects includingmicrophthalmia

Walker-Warburg syndrome Lissencephaly; retinal dysplasia; other Autosomal recessiveeye anomalies; encephalocele; POMT1, 9q34.1myopathy; elevated CK; growth failure POMT2, 14q24.3

Fukutin, 9q31;multiple other genes

1. MRI with sagittal and axial views of thefourth ventricle to confirm the diagnosis,delineate the anatomy, and detect any asso-ciated CNS anomalies

2. Eye examination3. Echocardiogram4. Karyotype if any associated anomalies are

noted5. Neurosurgical consultation


The outcome for infants with the Dandy-Walkermalformation varies widely, largely as a func-tion of associated malformations and underly-ing diagnosis. Overall mortality for patients withthe disorder is in the range of 27%2 with mostdeaths attributable to associated malformations,uncontrolled hydrocephalus, shunt malfunctionor infection. Sudden death has been reported ina number of cases and it has been suggestedthat this may be due to brain stem ischemia.4

Many surviving patients are developmentallydelayed and ultimately mentally retarded butthose without associated anomalies clearly ap-pear to have a better prognosis than those with

CHAPTER 9 DANDY-WALKER MALFORMATION 69

Figure 9-1. Infant with Walker-Warburgsyndrome, an autosomal recessive disorderfrequently associated with Dandy-Walker mal-formation. Note the dressing over the scalpcovering a posterior encephalocele. This infantalso had retinal dysplasia, anterior chamberanomalies with congenital glaucoma, a cleftlip and palate, hypotonia, and an elevatedcreatine kinase level consistent with congenitalmuscular dystrophy.

Figure 9-2. Sagittal MRI scan showing Dandy-Walker malformation with upward deviation ofthe cerebellar vermis and posterior fossa cyst.In this case, the cerebellar vermis is relativelywell-developed whereas many patients withDandy-Walker malformations have significantcerebellar hypoplasia with only remnants ob-served on MRI. (Used with permission fromAlexander G. Bassuk, MD, PhD, Dept. of Pediatrics,Northwestern University’s Feinberg School ofMedicine.)

other CNS anomalies or broader malforma-tion syndromes, with up to 50% of the for-mer in some series having normal development.A cerebellum that is not only small but also dys-genetic may be a poor prognostic indicator.5

Unfortunately there is a paucity of long-termoutcome data on well-categorized survivingchildren. Cerebellar dysfunction is an additionalfinding that is present in up to half of all sur-vivors as they grow older.

When the Dandy-Walker malformation orvariant is diagnosed in utero, it is even more dif-ficult to make predictions regarding outcome. Itcan be extremely difficult to ascertain the extentof associated CNS or extracranial malformationspresent prior to birth. If available, fetal MRI canbe very useful in this regard. If not, serial ultra-sonography should be employed. Amniocente-sis should be offered for determination of thefetal karyotype since there is a significant risk ofchromosomal abnormality in the fetus. Parentsshould be counseled of the range of possibleoutcomes. There has been no clear differencedemonstrated in outcome between patients withDandy-Walker malformation and the Dandy-Walker variant.

Treatment for the Dandy-Walker malforma-tion is directed toward control of the hydro-cephalus that frequently develops as a sec-ondary complication. A variety of different shuntprocedures are utilized and the complica-tions are the same as in infants with isolatedhydrocephalus.


If the diagnosis of a specific chromosome anom-aly or malformation syndrome has been estab-lished in a patient with the Dandy-Walker syn-drome, appropriate genetic counseling for thatdisorder should be provided, with discussion ofprenatal diagnosis as applicable. In the case ofpatients with isolated Dandy-Walker malforma-tion with no family history of the disorder, em-piric recurrence risk counseling must be pro-vided. The estimated risk of recurrence in afuture pregnancy in these cases is in the rangeof 1–5%. Parents should be offered high resolu-tion ultrasonography in future pregnancies.

REFERENCES

1. Osenbach RK, Menezes AH. Diagnosis and manage-ment of the Dandy-Walker malformation: 30 years ofexperience. Pediatr Neurosurg. 1992;18:179–89.

2. Parisi MA, Dobyns WB. Human malformations of themidbrain and hindbrain: review and proposed clas-sification scheme. Mol Genet Metab. 2003;80:36–53.

3. Grinberg I, Northrup H, Ardinger H, et al. Het-erozygous deletion of the linked genes ZIC1 andZIC4 is involved in Dandy-Walker malformation.Nat Genet. 2004;10:1053–5.

4. Elterman RD, Bodensteiner JB, Barnard JJ. Suddenunexpected death in patients with Dandy-Walkermalformation. J Child Neurol. 1995;10:382–4.

5. Klein O, Pierre-Kahn A, Boddaert N, et al. Dandy-Walker malformation: prenatal diagnosis and prog-nosis. Childs Nerv Syst. 2003;19:484–9.


Chapter 10

Chiari MalformationsBARBARA K. BURTON

71

� INTRODUCTION

Chiari malformations are defined by caudal dis-placement and herniation of cerebellar structuresinto the cervical canal. The two most commontypes are type I, which is a congenital or ac-quired anomaly that involves caudal displace-ment of the cerebellar tonsils but not the brainstem, cerebellar vermis, or fourth ventricle intothe cervical canal. The level is rarely below C2and there is no association with spina bifida. Theposterior fossa is small and hydrocephalus oc-curs in less than 10% but an associated syrinxis common. In type II, also referred to as theArnold-Chiari malformation, the cerebellar vermis,tonsils, medulla, and/or fourth ventricle are dis-placed caudally into the cervical canal. There isa virtual 100% association with meningomyelo-cele and hydrocephalus, and other central ner-vous system (CNS) anomalies are common. Chiaritype III and IV malformations are extremely rareand will not be considered here. The term Chiaritype 1.5 is occasionally used to refer to a Chiaritype II malformation occurring in the very rareinfant who does not have a myelomeningocele.


The prevalence of the Chiari I malformation inthe population has been difficult to ascertain

because of the number of affected individualswho remain asymptomatic. In two large seriesof unselected magnetic resonance imaging(MRI) studies in the United States, a frequencyof 0.55% and 0.77% was observed.1,2 A lowerrate was noted in a Japanese series.3 The Chiari Iis more common in females than in males, withthe female:male ratio ranging from 3:2 to 3:1.The pathogenesis of the defect is not well un-derstood, but it has been suggested that it maybe the result of a primary defect in para-axialmesoderm, resulting in a decreased size of theposterior fossa.

The epidemiology of Chiari II malforma-tions essentially parallels the epidemiology ofopen neural tube defects and is discussed inChap. 4. The prevailing theory on the patho-genesis of the Chiari II malformation holdsthat it is the result of cerebrospinal fluid (CSF)leakage from the myelomeningocele at thetime of early failure of closure of the neuraltube.4 This in turn leads to relative collapseof the fourth ventricle at a time when closureof the neural tube normally leads to distention ofthe posterior fossa, which then has importantsecondary “mechanical induction” effectsthroughout the CNS. The absence of these in-duction forces explains the often-observedabnormalities in cranial nerve nuclei, hetero-topias, and other anomalies associated withspina bifida.



The Chiari I malformation is rarely diagnosed inthe neonatal period unless it is associated with abroader malformation syndrome that leads toneuroimaging. Patients with an isolated Chiari Itypically appear normal in early infancy and thediagnosis is not established until early adult life. Atthe time of diagnosis, it is sometimes recognized,however, that patients have had lifelong symp-toms including headache and clumsiness. Whenthe diagnosis is established, the most commonpresenting symptoms are headache and neck pain,although a wide variety of signs and symptomscan be observed.5 Symptoms in Chiari I are gen-erally felt to be the result of direct cerebellarcompromise, compression of the brain stem andcranial nerves, and syrinx-associated central cordsyndrome. In addition to head and neck pain,other symptoms that can be observed includeblurred vision or photophobia, dizziness, tinnitus,decreased hearing, dysphagia, numbness, andweakness. Some patients present with apnea, pos-sibly related to respiratory center dysfunction, orto vocal cord paralysis, and these patients may beat increased risk for postoperative complications.When the diagnosis of a Chiari I malformation issuspected, it can be confirmed by MRI (Fig. 10-1).

It has been estimated that approximately57% of pediatric patients with a Chiari I areasymptomatic. Of those who have symptoms,63% have pain, 26% numbness, 19% weakness,16% incoordination, 18% cranial nerve abnor-malities, 28% central cord signs, and 13% cere-bellar signs.6 Scoliosis is an important finding asit is indicative of the presence of syringomyelia.7

The Chiari type II malformation (orArnold-Chiari malformation) has associatedmyelomeningocele in all cases and essentiallynever occurs in its absence. Less than 20% ofChiari II malformations produce symptoms and,when they do, they usually occur prior to3 months of age. The Chiari II malformation is theleading cause of death in infants with spina bi-fida under the age of 2 years.8 Symptoms beginto appear following closure of the spinal defect

and are the result of brain stem dysfunction re-sulting from the small posterior fossa with down-ward displacement of the hindbrain into thecervical canal, obstructing the flow of CSF intothe fourth ventricle. The lower cranial nerves arecompressed as they exit the cranium and are atrisk for necrosis. Symptomatic infants presentwith dysphonia, stridor, difficulty in swallowing,and vocal cord dysfunction. Sleep apnea is com-mon and glossopharyngeal dysfunction leads toan increased risk of aspiration. Vagal nerve dys-function results in respiratory compromise andsudden death. There is no correlation betweenthe level of the myelomeningocele and the riskof a symptomatic Chiari II malformation.


There are no anomalies commonly associated withChiari I malformations. Hydrocephalus occurs inless than 10% of cases. Other CNS anomalies are


Figure 10-1. Sagittal MRI of a patient with aChiari I malformation showing the herniation ofthe cerebellar tonsils through an enlargedforamen magnum. (Used with permission fromAlexander G. Bassuk, MD, PhD, Dept. of Pedi-atrics, Northwestern University University’sFeinberg School of Medicine.)

uncommon. Syringomyelia and scoliosis are com-mon secondary consequences of the defect butdo not represent primary associated defects. In-telligence is typically normal in patients with thenonsyndromic form of the disorder. Since theChiari II malformation uniformly accompaniesspina bifida, the associated anomalies are thesame as those listed for spina bifida (Chap. 4).

The syndromes most commonly associatedwith the Chiari I malformation are listed inTable 10-1. Those associated with the Chiari IImalformation are the same as those associated

with open neural tube defects and are listed inTable 4-2 in Chap. 4.

� EVALUATION

MRI is the best imaging technique for demon-strating the anatomic abnormalities associated witha Chiari II malformation. The caudal displacementof the posterior fossa contents into the cervicalcanal is difficult to detect by computed tomog-raphy (CT) scan so, when using this technique,

CHAPTER 10 CHIARI MALFORMATIONS 73

� TABLE 10-1 Syndromes Associated with Chiari Malformation

Syndrome Other Findings Etiology

Apert syndrome Craniosynostosis; soft tissue and bony Autosomal dominantsyndactyly of fingers and toes; mental FGFR2, 10q26retardation (50%)

Beare-Stevenson Craniosynostosis; mental retardation; Autosomal dominantsyndrome cutis gyrata and acanthosis nigricans; FGFR2, 10q26

midface hypoplasia; abnormal ears;bifid scrotum

Crouzon syndrome Craniosynostosis; proptosis; strabismus; Autosomal dominantprognathism FGFR2, 10q26

FG syndrome Macrocephaly; hypotonia; developmental X-linked recessivedelay; agenesis of corpus callosum;gastrointestinal disorders

Hajdu-Cheney Short stature; coarse facies; prominent Autosomal dominantsyndrome eyebrows and eyelashes; Wormian

bones; short neck; short digitsand nails; progressive kyphoscoliosis

Klippel-Feil anomaly Fused or abnormal cervical vertebrae; Usually sporadic;or sequence webbed neck; cranial nerve palsies; occasionally autosomal

scoliosis; deafness; rib defects; dominantSprengel anomaly; cardiac and renalanomalies

Neurofibromatosis type I Multiple café au lait spots; multiple Autosomal dominantsubcutaneous neurofibromas; iris Lisch Neurofibrominnodules; increased risk of CNS tumors 17q11.2including optic pathway gliomas

Williams syndrome Developmental delay; supravalvular aortic Submicroscopicstenosis; unusual facies; short stature; chromosome deletionhypercalcemia 7q11.23

Velocardiofacial syndrome Conotruncal cardiac defects; thymic Submicroscopic(22q11 deletion hypoplasia; cleft palate; velopharyngeal chromosome deletionsyndrome) insufficiency; hypocalcemia; mildly 22q11.2

dysmorphic facial features

other characteristic findings should be reliedupon for diagnosis. These include a lacunar skull,concave petrous pyramids with a posterior sur-face groove, hypoplasia of the falx and tento-rium, and an abnormal quadrigeminal plate witha spectrum of collicular fusion and midbrainbreaking that indents the midline cerebellum andmay come to overlie the pons. The fourth ven-tricle is generally invisible, flattened, or small andthere is poor visualization of the basal cisternae.Recommended evaluation for the patient with aChiari I or II malformation is as follows:

1. MRI.2. Neurosurgical consultation..3. In the case of Chiari II, all of the same as-

sessments recommended for infants withspina bifida are also indicated.


The primary objective of surgical treatment ofpatients with symptomatic Chiari I malformationis decompression of the posterior fossa with thegoals of equalizing intracranial and intraspinalpressure, restoring the posterior fossa sub-arachnoid space, relieving brain stem pressure,eliminating the syrinx, and resolving signs andsymptoms. The most common surgical approachused in pediatric patients has involved a limitedcraniectomy with C1 laminectomy. A less com-mon approach has been to reduce the obstructionat the foramen magnum by cerebellar tonsillec-tomy. The resected tonsillar tissue has shownatrophy and gliosis and presumably has littlefunctional importance. Overall, most pediatric sur-gical series have shown resolution of symptoms inover 80% of patients.6 Patients whose symptomshave been of short duration have generally had abetter prognosis than those with long-standingsymptoms. Symptoms can recur after initial reso-lution so long-term follow-up is necessary.

There is general agreement that treatment isnot indicated for patients with Chiari I malforma-tions who are asymptomatic. The natural history

of the disorder is unclear but there certainly ap-pear to be some individuals who never developsymptoms.

The prognosis for infants with a Chiari IImalformation who become symptomatic is notas good as it is for those with the Chiari I. Manyexperience acute neurologic deterioration anddie. Others may respond initially to surgical in-tervention but later have a recurrence of symp-toms and deteriorate. This may reflect a moreextensive CNS dysgenesis in some of these pa-tients or there may be brain stem hemorrhagesecondary to the acute brain stem compression.More recent surgical series have shown somepromising results with C1 laminectomy or duro-plasty with release of adhesions and reestab-lishment of flow from the fourth ventricle. Inone such series, 80% of patients had resolutionof symptoms at 1 year of age.9 However, by4 years of age, close to 50% had recurrence ofsymptoms requiring a second operation.


A genetic component to the nonsyndromicChiari I malformation is suggested by the fact thatthis malformation has been reported in a numberof sibling pairs.10 The specific genetic mechanismhas not been established and empiric recurrencerisk data for use in genetic counseling have notbeen published in the literature. Parents of anaffected child should be counseled that their riskof having a second affected child is greater thanthe risk faced by couples in the general popula-tion. A specific recurrence risk cannot be quotedat this time. The same advice should be given toan individual with the Chiari I malformation re-garding his or her risk of having an affectedchild. Level II ultrasound examination should beoffered during pregnancy for assessment of thefetal intracranial anatomy. However, the patientshould be advised that normal findings will notrule out a Chiari I malformation. Genetic coun-seling for couples with a child with a Chiari IIwill be the same as that provided to any other


couple with a child with an open neural tubedefect. This is covered in detail in Chap. 4.

REFERENCES

1. Elster AD, Chen MY. Chiari I malformations: clini-cal and radiologic reappraisal. Radiology. 1992;183:347–53.

2. Meadows J, Kraut M, Guarnieri M, et al. Asympto-matic Chiari type I malformations identified onmagnetic resonance imaging. J Neurosurg. 2000;92:920–6.

3. Furuya K, Sano K, Segawa H, et al. Symptomatictonsillar ectopia. J Neurol Neurosurg Psychiatry.1998;64:221–6.

4. McLone DG, Dias MS. The Chiari II malformation:cause and impact. Childs Nerv Syst. 2003;19:540–50.

5. Milhorat TH, Chou MW, Trinidad EM, et al. Chiari Imalformation redefined: clinical and radiographic

findings for 364 symptomatic patients. Neuro-surgery. 1999;44:1005–7.

6. Tubbs RS, McGirt MJ, Oakes WJ. Surgical experi-ence in 130 pediatric patients with Chiari I malfor-mations. J Neurosurg. 2003;99:291–6.

7. Steinbok P. Clinical features of Chiari I malforma-tions. Childs Nerv Syst. 2004;20:329–31.

8. Hudgins RJ, Boydston WR. Bone regrowth and re-currence of symptoms following decompression inthe infant with Chiari II malformation. Pediatr Neu-rosurg. 1995;23:323–7.

9. Teo C, Parker EC, Aureli S, et al. The Chiari II mal-formation: a surgical series. Pediatr Neurosurgery.1997;27:223–9.

10. Mavinkurre GG, Sciubba D, Amundson E, et al.Familial Chiari type I malformation withsyringomyelia in two siblings: case report andreview of the literature. Childs Nerv Syst. 2005;21:955–9.

CHAPTER 10 CHIARI MALFORMATIONS 75


Chapter 11

Agenesis of the CorpusCallosumBARBARA K. BURTON

77

� INTRODUCTION

Agenesis of the corpus callosum is the failure ofthe callosal commissural fibers to cross the mid-line and form the major connection betweenthe two cerebral hemispheres. There are twoprimary types of agenesis of the corpus callo-sum. In the first type, the callosal axons developand move toward the midline but do not cross.This results in the formation of the longitudi-nally oriented bundles of Probst that are locatedmedial to the lateral ventricles in patients withthis disorder and are pathognomonic of the de-fect. In the second type, the commissural axonsor their cell bodies fail to form and never ap-proach the midline. This is considerably lesscommon and usually associated with syndromicforms of agenesis of the corpus callosum.


The true incidence of agenesis of the corpus cal-losum is difficult to determine because many iso-lated cases may be asymptomatic. The incidencein autopsy series is reported to be 1 in 20,000.1

Among pediatric patients referred for magneticresonance imaging (MRI) because of neurologic

abnormalities, the incidence is 1 in 100 orgreater.2 The defect is more common in malesthan in females with a sex ratio approaching 2:1.

The etiology of agenesis of the corpus cal-losum is extremely heterogeneous. Its occurrencehas been well-documented in the fetal alcoholsyndrome3 and other teratogenic causes such asmaternal diabetes and infectious agents havebeen suggested in isolated case reports. Inbornerrors of metabolism are an important causeof agenesis of the corpus callosum and mayrepresent up to 4% of all cases.4 Perhaps thebest known metabolic disorder associated withthis malformation is nonketotic hyperglycine-mia, a condition typically associated with aneonatal encephalopathy. As many as 40% ofpatients with this disorder may have callosalagenesis, reflecting the fact that metabolic de-rangements may begin in early prenatal life, af-fecting fetal development. Another significantgroup of metabolic disorders associated withagenesis of the corpus callosum is the group ofdefects in pyruvate metabolism including pyru-vate dehydrogenase and pyruvate carboxylasedeficiencies. These disorders are typically asso-ciated with lactic acidosis and it is of interest that,in some cases, they are also associated with dys-morphic facial features similar to those observed


in infants with fetal alcohol syndrome. Agenesisof the corpus callosum may also be observed ininfants with congenital lactic acidosis secondaryto mitochondrial respiratory chain defects. Othermetabolic disorders in which it may be observedinclude mupolysaccharidoses, mucolipidoses,Zellweger syndrome, and Lowe syndrome.

Isolated agenesis of the corpus callosumwhich cannot be linked to any teratogenic causeand is not a component of a generalized mal-formation syndrome nor associated with a meta-bolic disorder is generally a sporadic occurrence.However, familial cases have been reported bothin siblings and in parents of affected individu-als. In addition to genes for some of the multi-ple malformation syndromes listed in Table 11-1,two genes which are of importance in geneti-cally determined forms of agenesis of the cor-pus callosum have been identified. One of theseis the LICAM gene on the X chromosome whichis also responsible for X-linked hydrocephalussecondary to aqueductal stenosis.5 Mutations inthis gene may lead to a wide range of effects onthe central nervous system, including isolatedagenesis of the corpus callosum or callosal age-nesis in conjunction with other malformations.The second gene is the SLC12A6 gene, which ismutated in patients with Andermann syndrome,a disorder which occurs with high frequency inthe Charlevoix and Saguenay-Lac-St. Jean re-gion of Quebec. In addition to agenesis of thecorpus callosum, patients with this autosomalrecessive disorder have a progressive hereditaryneuropathy.6 Clinical testing is available for mu-tations in both LICAM and SLC12A6.


It is generally believed that the presenting find-ings in patients with agenesis of the corpus cal-losum are the result of associated anomalies andthat isolated agenesis of the corpus callosum isasymptomatic. This conclusion is based onthe observation that many clinically normalindividuals have been found at autopsy or on

neuroimaging for indications such as headacheto have agenesis of the corpus callosum. In-creasingly, patients with agenesis of the corpuscallosum are being identified at birth because offindings noted on prenatal ultrasonography.Dysmorphic facial features may be present withthe most commonly observed facial featuresbeing hypertelorism and a broad nose. Macro-cephaly and microcephaly both occur with in-creased frequency. If not identified at birth, thediagnosis usually follows neuroimaging ob-tained for evaluation of developmental delay orseizures later in infancy. Other neurologic find-ings are common including poor coordination,spasticity, quadriparesis, or hemiparesis. MRI isthe best modality for establishing the diagnosisof agenesis of the corpus callosum and for de-lineating the associated anomalies of the centralnervous system (CNS). (Fig. 11.1)

Prenatal diagnosis of agenesis of the corpuscallosum by ultrasonography cannot be reliablyaccomplished prior to 20 weeks gestation. Find-ings suggestive of agenesis of the corpus callo-sum include ventriculomegaly, a high position ofthe third ventricle, and failure to visualize thecavum septum pellucidum. Agenesis of the cor-pus callosum occurs in up to 10% of cases of mildventriculomegaly noted in utero but is less com-mon among cases of severe ventriculomegaly.


A large percentage of patients with agenesis ofthe corpus callosum have associated anomalies.Certainly all of those detected on the basis ofclinical signs and symptoms have associatedanomalies since isolated callosal agenesis isasymptomatic. It is more difficult to determinewhat fraction of fetuses with agenesis of thecorpus callosum detected in utero have associ-ated anomalies. Despite careful serial ultrasoundexaminations, some of the associated abnor-malities cannot be visualized by prenatal ultra-sound. Therefore an anomaly that may appear


CHAPTER 11 AGENESIS OF THE CORPUS CALLOSUM 79

� TABLE 11-1 Syndromes Commonly Associated with Agenesis of the Corpus Callosum

Syndrome Other Clinical Features Etiology

Acrocallosal syndrome Macrocephaly; large fontanel; Autosomal recessiveshort neck; polydactyly; mental 12p13.3–p11.2retardation

Aicardi syndrome Chorioretinal lacunae; infantile X-linked dominant,spasms; polymicrogyria; lethal in malehypoplastic cerebellar vermis Xp22

Cerebro-oculo-facio-skeletal Microcephaly; cataracts; Autosomal recessive(COFS) syndrome contractures; severe postnatal

growth and developmentalretardation

Chromosome anomalies Major and minor anomalies in Trisomies (18,13),multiple organ systems deletions, duplications

FG syndrome Hypotonia; anal anomalies; small X-linked recessiveears; broad thumbs and great Xq12–q21.3toes may be heterogeneous

Fetal alcohol syndrome Intrauterine growth retardation; Prenatal alcoholmicrocephaly; short palpebral exposurefissures; simple philtrum;nail hypoplasia

Fryns syndrome Coarse facies; hirsutism; Autosomal recessivediaphragmatic hernia;hypoplastic distal phalangesand nails

Miller-Dieker syndrome Lissencephaly; seizures; Submicroscopicmicrocephaly; anteverted chromosome deletionnares; cryptorchidism 17p13.3

Mowat-Wilson syndrome Microcephaly; hypotonia; Autosomal dominantHirschsprung disease; large ZFHX1B, 22q22nose; cardiac defects

Neu-Laxova syndrome Intrauterine growth retardation; Autosomal recessiveedema; very abnormal facieswith proptosis, sloping foreheadand flat nose; microcephaly;syndactyly; pterygia;ichthyosis

Proud syndrome Microcephaly; seizures; coarse X-linked dominantfacies; contractures; tapering ARX, Xp22.13fingers; porencephaly;urogenital anomalies

Septo-optic dysplasia Optic nerve hypoplasia; absence Sporadic in most cases;of septum pellucidum; pituitary some due to mutations ininsufficiency HESX1, 3p21.2–p21.1

(Continued)

isolated in utero can turn out to be part of abroader syndrome. A summary of malforma-tions associated with agenesis of the corpus cal-losum is listed in Table 11-2.7

The available data indicate that approxi-mately 15% of patients with agenesis of the cor-pus callosum have a chromosomal abnormality.In addition to the usual trisomies 13 and 18 andstructural abnormalities such as deletions and

duplications, trisomy 8 mosaicism should bementioned since this is an abnormality that ap-pears with some frequency in series of patientswith agenesis of the corpus callosum and willusually be missed by blood karyotype alone. Ifthis diagnosis is suspected and blood chromo-somes are normal, chromosomes should be an-alyzed in skin fibroblasts.

Approximately 15% of patients with agene-sis of the corpus callosum have normal chro-mosomes but have multiple malformations thatfall into the spectrum of a recognizable multiplemalformation syndrome. The most common of


� TABLE 11-1 Syndromes Commonly Associated with Agenesis of the Corpus Callosum (Continued)


Toriello-Carey syndrome Hypotonia; short palpebral fissures; Autosomal recessivecleft palate; micrognathia;cardiac defects

Walker-Warburg syndrome Lissencephaly; retinal dysplasia; Autosomal recessiveother eye anomalies; POMT1, 9q34.1hydrocephalus; encephalocele; POMT2, 14q24.3congenital muscular dystrophy Fukutin, 9q31with elevated CK FKRP, 19q13.3

� TABLE 11-2 Associated Malformations in anInfant with Agenesis of Corpus Callosum

Other CNS Anomalies (any) 44%Hydrocephalus 23%Heterotopias/polymicrogyria 23%Cysts—Porencephalic, 23%

Dandy-Walker, otherMicrocephaly 15%Microgyria 6%Lissencephaly 3%Pachygyria 2%

Craniofacial Anomalies 29%Hypertelorism 20%

Cardiac Anomalies 13%

GI Anomalies 8%

Urinary Tract Anomalies 20%

GI, gastrointestinal

Figure 11-1. Sagittal MRI scan showing ab-sence of the corpus callosum. (Used with per-mission from Alexander G. Bassuk, MD, PhD.,Dept. of Pediatrics, Northwestern University’sFeinberg School of Medicine.)

these are listed in Table 11-1. There are manyother multiple malformation syndromes, notlisted in the table, in which agenesis of the cor-pus callosum can be an occasional feature.Therefore, consultation with a clinical geneticistis recommended in complex cases.

� EVALUATION

The following studies should be obtained onany infant with agenesis of the corpus callosum:

1. MRI of the brain—to confirm the presenceof the defect and to detect and define anyassociated CNS malformations

2. Careful physical examination to identify anyassociated major or minor birth defects ordysmorphic features

3. Ophthalmologic examination—this is par-ticularly important in female infants to lookfor the chorioretinal lacunae seen in Aicardisyndrome

4. Blood chromosome analysis5. Ultrasound evaluation of the urinary tract6. Echocardiogram


The treatment for infants with agenesis of thecorpus callosum is directed at any associatedanomalies for which treatment may be indi-cated. Similarly, the prognosis is dependent onthe overall diagnosis and on the prognosis forthat condition or, if there is no specific diagno-sis established, the prognosis for the anomaliesidentified. The outcome is generally not favorablefor symptomatic patients who have neurologicabnormalities in early infancy. Of all patients withagenesis of the corpus callosum, mental retar-dation of some degree is found in approximately83%.8,9 About half of all patients develop seizuresand over a third have findings consistent withcerebral palsy.9 Factors predictive of a poor out-come include microcephaly or findings of cere-bral dysgenesis on MRI.


Genetic counseling for families of patients withagenesis of the corpus callosum is dependent onthe underlying diagnosis. If a diagnosis cannotbe established and the patient has multiple mal-formations, a clinical geneticist should be con-sulted since there are many single gene disordersin which agenesis of the corpus callosum can bean occasional feature. Some of these can be in-herited in an autosomal recessive or autosomaldominant pattern so a specific diagnosis wouldbe important prior to future family planning.

If the patient has isolated agenesis of the cor-pus callosum with no evidence of a metabolicdisorder, then counseling can be provided in thepostnatal setting. The prognosis may be goodfor the infant once associated anomalies havebeen ruled out and there is room for cautiousoptimism. This reassurance can only be givenpostnatally, however, and only after a thoroughevaluation since some of the syndromes mostcommonly associated with agenesis of the cor-pus callosum, like Aicardi syndrome, would notbe expected to be associated with any additionalfindings on prenatal ultrasonography. Parents ofan asymptomatic normal infant are rarely tooconcerned about recurrence risks except for thefact that they may again be confronted by ab-normal ultrasound findings should they have arecurrence. Since familial cases have been re-ported, recurrence risks are higher than thosefaced by couples in the general population. Em-piric recurrence risk data are not available; anestimated risk of 5% would seem reasonable.

REFERENCES

1. Hunter, Alaidair GW. Agenesis of the corpus callo-sum, In: RE Stevenson and JG Hall, eds. HumanMalformations and Related Anomalies. 2nd ed.New York: Oxford University Press; 2006:581–604.

2. Chacko A, Koul R, Sankhla DK. Corpus callosumagenesis. Saudi Med J. 2001;22:22–5.

3. Bookstein FL, Sampson PD, Connor PD, et al. Mid-line corpus callosum is a neuroanatomical focus offetal alcohol damage. Anat Rec. 2002;269:162–74.

CHAPTER 11 AGENESIS OF THE CORPUS CALLOSUM 81

4. Goodyear PW, Bannister CM, Russell S, et al. Out-come in prenatally diagnosed fetal agenesis of thecorpus callosum. Fetal Diagn Ther. 2001;16:139–45.

5. Fransen E, Van Camp G, Vits L, et al. L1-associateddiseases: clinical geneticists divide, molecular ge-neticists unite. Hum Mol Genet. 1997;6:1625–32.

6. Howard H, Mount DB, Rochfort D, et al. The K-Clcotransporter KCC3 is mutant in a severe peripheralneuropathy associated with agenesis of the corpuscallosum. Nat Genet. 2002;32:384–92.

7. Jeret JS, Serur D, Wisniewski KE, et al. Clinico-pathological findings associated with agenesis of thecorpus callosum. Brain Dev. 1987;9:255–64.

8. Bedeschi MF, Bonaglia MC, Grasso R, et al. Agene-sis of the corpus callosum: clinical and genetic studyin 63 young patients. Pediatr Neurol. 2006;34:186–93.

9. Shevell MI. Clinical and diagnostic profile of agene-sis of the corpus callosum. J Child Neurol. 2002;17:896–900.


Chapter 12

CraniosynostosisBARBARA K. BURTON

83

� INTRODUCTION

Craniosynostosis is the premature fusion of oneor more cranial sutures, typically resulting in anabnormal head shape. Plagiocephaly is a non-specific term used to describe an asymmetrichead shape, which can be the result either ofcertain types of craniosynostosis or of nonsyn-ostotic deformation or molding. It is criticallyimportant to distinguish between the two sincethe treatment is different. Deformational plagio-cephaly has become increasingly common asinfants are routinely placed in the supine posi-tion for sleep to reduce the incidence of suddeninfant death syndrome, and may develop a pref-erence to sleep on one side, leading to flatten-ing of the head on that side.1


The incidence of craniosynostosis is 1 in 2500 births.Sagittal synostosis is the most common type,representing approximately 50–60% of all cases.It is three to four times more common in malesthan in females and only 6% of cases are familial.The frequency of twinning is increased (4.8%)and most twin pairs are discordant, suggestingthat fetal crowding and intrauterine constraintmay play a role in the etiology of this type ofcraniosynostosis. Aberrant fetal lie is another

factor that has been theorized to play a role inproducing abnormal mechanical forces on thefetal head that may lead to sagittal and otherforms of craniosynostosis.

Coronal craniosynostosis is the second mostcommon type, accounting for 20–30% of cases.It is also the type that is most likely to be ge-netically determined. Bilateral cases are morecommon than unilateral and coronal synostosisis more common in females than in males (sexratio 1:2). Coronal synostosis is more frequentlyassociated with other malformations than issagittal synostosis and is more often familial.When familial (and not a component of a spe-cific malformation syndrome), it is inherited inan autosomal dominant pattern with incompletepenetrance. Mutations in several different fi-broblast growth factor receptor (FGFR) genesand in a gene for a transcription factor that reg-ulates their function (TWIST1) have been shownto be important causes of coronal craniosynos-tosis, both in patients with isolated synostosisand in various craniosynostosis syndromes(Table 12-1).2

Multiple suture synostosis (the cloverleafskull anomaly) is very often genetically deter-mined and often associated with a definablegene mutation. Metopic craniosynostosis ac-counts for 10–20% of cases of craniosynostosisand, like sagittal synostosis, is more common inmales than in females and is infrequently familial.



� TABLE 12-1 Craniosynostosis Syndromes Associated with Mutations in FGFR and TWIST1 Genes

MutationSutures Detection

Disorder Involved Other Features Gene Rate

Muenke syndrome Unilateral or Some family members FGFR3 100%bilateral may have macrocephalycoronal only without

craniosynostosisCrouzon syndrome Bicoronal or No extracranial manifestations; FGFR2 50–60%

cloverleaf difficult to distinguish fromskull isolated coronal

craniosynostosis in absenceof a family history. Progressivehydrocephalus is common.

Crouzon syndrome Bicoronal or Acanthosis nigricans FGFR3 100%with acanthosis cloverleafnigricans skull

Jackson-Weiss Bicoronal or Broad and medially deviated FGFR2 Unknownsyndrome cloverleaf great toes with normal hands

skullApert syndrome Bicoronal or Syndactyly both hands and both FGFR2 99%

cloverleaf feet; cardiac defects in 10%;skull mental retardation more

common than in most ofthe other forms of craniosynostosis (50%)

Pfeiffer syndrome Bicoronal or Broad, medially deviated thumbs FGFR1 67%cloverleaf and great toes; variable ((1–2%)skull syndactyly and brachydactyly. FGFR2

(98–99%)Beare-Stevenson Bicoronal or Cutis gyrata and acanthosis FGFR2 Unknown

syndrome cloverleaf nigricans; abnormal ears;skull natal teeth; bifid scrotum

Isolated familial Unilateral or None FGFR2 100%coronal bilateralsynostosis coronal

Saethre-Chotzen Unilateral or Minor dysmorphic facial TWIST1 70%syndrome bilateral features including ptosis;

coronal ear anomalies; cleft palate;common but cutaneous syndactyly;ANY sutures brachydactylycan be involvedincludingsagittal

As an isolated finding, it is primarily of cosmeticsignificance. Isolated lambdoidal synostosis isthe least common type, representing less than10% of cases with a male predominance andmost cases sporadically occurring.

All forms of craniosynostosis can occur asan isolated anomaly or as part of a broader mal-formation syndrome. Craniosynostosis can beassociated with a wide range of chromosomeanomalies, including deletions, duplications,and triploidy. In addition to the dominantly in-herited craniosynostosis syndromes typically as-sociated with coronal craniosynostosis, there area number of multiple malformation syndromeswith varying patterns of inheritance that can beassociated with craniosynostosis of a variety oftypes. Some of these are listed in Table 12-2.

Craniosynostosis can also occur as a sec-ondary finding in a wide variety of different dis-orders. These include metabolic disorders suchas the mucopolysaccharidoses, mucolipidoses,and rickets, and hematologic disorders such asthalassemia. It has been reported in associationwith several teratogenic syndromes including

those related to exposure to diphenylhydantoin,retinoic acid, valproic acid, and cyclophosphamide.Sutures may fuse prematurely in infants withmicrocephaly but, in this instance, the headshape is typically symmetrical so there shouldbe no confusion as to which defect is primary.


The diagnosis of craniosynostosis is typicallysuspected shortly after birth on the basis of theabnormal head shape. The shape of the headwill vary depending on the suture or sutures in-volved. Premature fusion of the sagittal suturerestricts growth of the head in the lateral direc-tion and as a result the head is elongated in theanteroposterior (AP) dimension with a promi-nent forehead and occiput. This head shape isreferred to as scaphocephaly or dolichocephaly.There may be a palpable ridge over the poste-rior aspect of the suture. In contrast, the pre-mature fusion of both coronal sutures results ina decreased AP diameter to the skull and a high,

CHAPTER 12 CRANIOSYNOSTOSIS 85

� TABLE 12-2 Syndromes Associated with Craniosynostosis (Excluding those Associated withMutations in FGFR and TWIST1)


Antley-Bixler Choanal atresia; cardiac defect; ambiguous Autosomal recessivegenitalia; joint synostosis; multiple POR, 7q11.2fractures

Baller-Gerold Absent thumbs; radial aplasia; growth Autosomal recessivedeficiency RECQL4, 8q24.3

Carpenter Ear anomalies; cardiac defects; genital Autosomal recessivedefects; polydactyly

Chromosome anomalies Major and minor anomalies in multiple Deletions, duplications,organ systems triploidy

Gorlin-Chaudhry-Moss Hirsutism; deafness; microphthalmia; Autosomal recessivehigh-arched palate; short stature

Opitz C Trigonocephaly (metopic synostosis only); Unknowndysmorphic facies; hypotonia

Shprintzen-Goldberg Proptosis; hypertelorism; arachnodactyly; Unknown in most casesmarfanoid habitus Autosomal dominant

FBN1, 15q21.1(a few cases)

wide forehead. This skull shape is referred to asbrachycephaly (Fig. 12-1 A and B). If only onecoronal suture is fused, the head shape and facewill be asymmetrical, or plagiocephalic, withflattening of the forehead and elevation of theeyebrow on the involved side. Combined fu-sion of both coronal and sagittal sutures leadsto a very tall pointed skull shape referred to asacrocephaly. In extreme cases of multiple su-ture synostosis, the cloverleaf skull appearanceor Kleeblattschadel anomaly is observed with allsutures fused and brain growth progressingthrough the open anterior and parietal foram-ina. This is frequently accompanied by signs ofincreased intracranial pressure, such as optic at-rophy, proptosis, and visual loss. Premature fusion

of the metopic suture leads to a triangularshaped skull, referred to as trigonocephaly. Iso-lated lambdoidal craniosynostosis is uncommonbut results in a trapezoidal head shape with lit-tle change in the facial appearance.

� EVALUATION

When the diagnosis of craniosynostosis is clearon clinical grounds, as is often the case, directreferral to a plastic surgeon or neurosurgeon(ideally in a multidisciplinary craniofacial center)may be the best first step since early surgery willbe warranted in many cases. Three-dimensionalcomputed tomography (3-D CT) scanning of the


Figure 12-1. Infant with bilateral coronal craniosynostosis. Note the decreased anteroposte-rior diameter to the skull and the high broad forehead.

craniofacial structures will need to be obtainedpreoperatively and it may be best to defer or-dering the testing until the patient has had a sur-gical evaluation. If there is a question about thediagnosis, then it may be necessary to obtain thestudies earlier. Plain skull radiographs can behelpful but are not always able to distinguishoverlapping sutures from synostotic ones.

Distinguishing craniosynostosis from defor-mational plagiocephaly can usually be accom-plished on clinical grounds. Although it oftendoes not develop until later, deformational pla-giocephaly can be present at birth if the fetushas been compressed unevenly in utero duringlate fetal life. It often accompanies torticollis, inwhich the sternocleidomastoid muscle is shorteror tighter on one side of the neck, causing thehead to tilt toward the affected muscle. Thisleads the infant to preferentially turn the headto one side when placed in a supine positionfor sleep, progressively leading to flattening ofthe head. Physical therapy and repositioningare usually successful in managing this problemwith cranial orthotics reserved for the most se-vere cases.

The evaluation of the patient with a clinicaldiagnosis of craniosynostosis should include thefollowing:

1. Careful physical examination to determinethe presence or absence of other associatedanomalies. Particular attention should be paidto the extremities since many of the geneti-cally determined craniosynostosis syndromesare associated with syndactyly, brachydactyly,or abnormalities of the digits such as broad ormedially deviated thumbs or great toes.

2. 3-D CT scan of the craniofacial structures.In some cases, this may be deferred untilsurgical consultation is obtained since it isoften preferable to obtain this study nearthe time of corrective surgery. If there is asevere deformity, neuroimaging should beobtained immediately since hydrocephalusmight be present. This should also be donein any patient who obviously has syndromic

craniosynostosis because of the high inci-dence of hydrocephalus accompanying con-ditions like Apert and Pfeiffer syndromes.

3. Referral to a multidisciplinary craniofacialcenter if available; otherwise referral to aplastic surgeon, neurosurgeon, or both

4. Ophthalmologic consultation if bicoronal ormultiple suture involvement is present or thereis suspicion of increased intracranial pressure.

5. Testing for mutations in FGFR genes andTWIST1 (Table 12-1) in patients with unilat-eral or bilateral coronal synostosis or multi-ple suture involvement. The utility of this inpatients with sagittal synostosis is a subjectof debate but an occasional patient will befound to have a mutation.

6. Blood for chromosome analysis in any pa-tient with craniosynostosis and multipleanomalies. If normal, consider telomericFISH or microarray analysis.


The treatment of craniosynostosis is primarilysurgical with the goal of restoring normal cran-iofacial shape and growth. In the case of singlesuture synostosis, the brain typically has enoughroom to grow without the patient suffering neu-rologic damage, but at the expense of causingsignificant craniofacial deformity. With multiplesuture involvement, particularly both coronaland sagittal, brain growth is impaired and a va-riety of neurologic and ophthalmologic compli-cations may ensue if treatment does not proceedin a timely fashion. Depending on the severityof the condition, surgery may be performed inthe first few weeks or months of life or later inthe first year of life. Most patients with involve-ment of a single suture are successfully treatedwith a single operation. Approximately 10%require a second operation.3,4 Repeat surgeryis required more commonly in patients withsyndromic craniosynostosis (27%) than inthose with nonsyndromic forms of the disorder(5–6%).


A variety of surgical techniques are in use.Most involve removing the aberrant portion ofthe bony calvarium from the underlying dura,including the area surrounding the synostoticsutures. The new bony calvarium and suturesusually reform normally within 5–8 weeks. Sur-gical complications are uncommon. In one largeseries 87.5% of patients were considered to havean adequate craniofacial appearance followingsurgery.3 The long-term outcome for patientswith syndromic forms of craniosynostosis variesdepending on the specific diagnosis. Some dis-orders, such as Apert and Pfeiffer syndrome, arecommonly associated with mental retardationwhich may be unrelated to the craniosynostosisand its treatment. Hydrocephalus is also a muchmore common accompaniment of the syndromicforms of the disorder, occurring in at least 40%of patients with Crouzon, Apert, and Pfeiffersyndromes.5 In contrast, it is rarely observed innonsyndromic craniosynostosis. Patients withnonsyndromic craniosynostosis appear to be atincreased risk of speech, cognitive and behav-ioral abnormalities with increasing age with 49%of patients manifesting some problems in theseareas at 6 years of age.6 There is no evidencethat these problems are relative to the timing ofsurgery. Indeed, there is no convincing evidencethat surgical treatment impacts the cognitive out-come of patients with single suture synostosis atall. In these patients, surgery is primarily of cos-metic benefit.


Genetic counseling for families of patients withcraniosynostosis will be dependent on the spe-cific diagnosis. If a mutation is identified in anFGFR gene or TWIST, then parents can be testedto determine if they carry the same mutation. Ifa parent carries a mutation in one of these au-tosomal dominant genes, then there is a 50%risk in each pregnancy of transmitting the geneto the child. The specific phenotype will de-pend on the diagnosis in the index case and the

nature of the mutation. For example, a parentwith Apert syndrome has a 50% risk of having achild with Apert syndrome only and the gene isfully penetrant. He or she is not at risk for hav-ing a child with any of the other craniosynosto-sis syndromes. The same is true for a parentwith a TWIST mutation and the Saethre-Chotzensyndrome, although that disorder is associatedwith a phenotype that is considerably more vari-able than is Apert syndrome. In some cases, therisk of craniosynostosis in a subsequent childmay be considerably less than 50%, even if theparent carries the mutation; because of issuesrelated to reduced penetrance in disorders likenonsyndromic coronal synostosis and Muenkesyndrome. If a newborn is found to have an au-tosomal dominant new mutation with neitherparent being a carrier, then the risk in futurepregnancies is 1%. Prenatal diagnosis shouldstill be offered by amniocentesis or chori-onic villus sampling since either techniquecan be combined with DNA analysis to de-tect the causative mutation in either familial orde novo cases in which a specific mutation hasbeen detected. This should be combined withultrasonography to visualize the craniofacialstructures.

In the case of isolated single suture synosto-sis with no definable mutation, and no other as-sociated malformations, a multifactorial etiologyis most likely. Although nongenetic factors suchas intrauterine constraint may play a role, thereis an increased risk in siblings, suggesting thatgenetic predisposition may also be a factor.Parents should be counseled that they are at in-creased risk in future pregnancies when com-pared with couples in the general population.Recurrence risks after a single case are typicallyin the range of 5% or less. When recurrencesoccur, the same suture is most commonly butnot invariably involved. There are examples offamilies with one child with sagittal synostosisand another with coronal synostosis. Prenatalultrasonography for visualization of the cranio-facial structures should be offered in futurepregnancies.


REFERENCES

1. Little TR, Saba NM, Kelly KM. On the current inci-dence of deformational plagiocephaly: an estima-tion based on prospective registration at a singlecenter. Semin Pediatr Neurol. 2004;11:301–4.

2. Robin NH and Falk MJ. FGFR-Related Craniosynosto-sis Syndromes. Available at: http://www.genetests.org.Accessed on Jan 9, 2006.

3. McCarthy JG, Glasberg SB, Cutting CB, et al. Twenty-year experience with early surgery for craniosynos-tosis: I. Isolated craniofacial synostosis—results andunsolved problems. Plast Reconstr Surg. 1995;96:272–83.

4. Williams JK, Cohen SR, Burstein FD, et al. A longi-tudinal, statistical study of reoperation rates in cran-iosynostosis. Plast Reconstr Surg. 1997;100:305–10.

5. Collmann H, Sorensen N, Krauss J. Hydrocephalusin craniosynostosis: a review. Childs Nerv Syst. 2005;21:902–12.

6. Becker DB, Petersen JD, Kane AA, et al. Speech,cognitive, and behavioral outcomes in nonsyn-dromic craniosynostosis. Plast Reconstr Surg. 2005;116:400–7.


http://www.genetests.org


Part III

CraniofacialMalformations



Chapter 13

Cleft Lip and PalateBRAD ANGLE

93

� INTRODUCTION

Orofacial clefts (cleft lip [CL], cleft palate [CP])are among the most common of all major birthdefects. CL may occur either in association withCP or in the absence of CP, and is generally re-ferred to as “cleft lip with or without cleft palate”(CL/P). CL/P is etiologically and genetically dis-tinct from CP, which typically occurs without as-sociated CL. CL/P and CP may occur as isolatedcongenital anomalies (nonsyndromic orofacialclefts) or as components of genetic disorders orsyndromes.


The overall incidence of CL with or without cleftpalate is approximately 1/1000, ranging from1/500 to 1/2500 in different populations, vary-ing with geographic location, ethnic group, andsocioeconomic conditions.1 CL may be unilat-eral (80%) or bilateral (20%) and when unilat-eral, it is more common on the left side (70%).Approximately 85% of cases of bilateral CL and70% of unilateral CL are associated with CP. Theincidence of isolated CP is approximately 1 in25002 and Robin sequence occurs in approxi-mately 1 in 14,000 live births.3

Both genetic and environmental factors arethought to play important roles in the causation

of orofacial clefts (multifactorial inheritance). Itis likely that there are multiple genes that mayplay a role in cleft malformations. In addition tosingle gene disorders that cause syndromicforms of orofacial clefts, it has been estimatedthat at least six genes, and possibly many more,could be involved in the development of non-syndromic orofacial clefts.4,5 It has been sug-gested that causation does not involve “majorgenes” but rather the combination of many genes,each conferring only a small risk, in conjunctionwith a significant environmental component.6

Results of a number of studies suggest that in-volvement of the pathways of folate metabolismmay play a role in the etiology of orofacial clefts.5

Some studies have suggested that women with aspecific mutation (C677T) in the methylenete-trahydrofolate reductase (MTHFR) gene have anincreased risk of having an offspring with anorofacial cleft.7,8

Many epidemiological studies have demon-strated a relation between specific environmen-tal factors and teratogens and the developmentof orofacial clefts. Environmental factors such ascigarette smoking appear to play a role in theoccurrence of these malformations.5 Alcohol usein pregnancy increases the risk of CL/P but notCP only.9 The anticonvulsants phenytoin andvalproic acid are associated with an increasedrisk for a variety of congenital anomalies includ-ing orofacial clefts.10 It is unclear whether CP


occurring in association with CL results from me-chanical deformation or from genes or environ-mental factors that affect development of boththe lip and palate.

� EMBRYOLOGY

Between the fourth and eighth week of embry-ologic development, the upper lip and palateform from the migration and connection of threebilateral processes (nasomedial, nasolateral, max-illary) derived from cells of neural crest origin.Clefting occurs when there is failure of fusion ordiminished mesenchymal penetration betweenthese migrating embryological processes.

The embryology of CL and CP is for the mostpart distinct. CL is a unilateral or bilateral gap inthe upper lip and jaw, which form during thethird through seventh week of embryonic de-velopment. CP is a gap in the hard or soft palate,which forms from the 5th through 12th weeksof development. CP may result from defectivegrowth of the palatine shelves or failure of ele-vation or fusion of the shelves. In some cases,hypoplasia of the mandibular area prior to 9 weeksof development may allow the tongue to beposteriorly located, impairing the closure of theposterior palatal shelves and resulting in theformation of a U-shaped CP (Robin sequence—see later).

� ASSOCIATED ANOMALIES ANDSYNDROMES

Cleft Lip with or withoutCleft Palate

Approximately 70% of cases of CL with or with-out CP occur as isolated abnormalities (nonsyn-dromic CL/P) and 30% as part of more than300 multiple malformation syndromes, chromo-some abnormalities, teratogenic conditions, andinherited single-gene disorders.3 Some of themore common genetic disorders and syndromes

in which CL/P frequently occur are listed inTable 13-1.

Among the most common single-gene dis-orders associated with CL/P, Van der Woudesyndrome (VWS) is an autosomal dominant dis-order caused by mutations in the IRFG gene. In-dividuals with VWS have congenital lower lipfistulae (pits) or sometimes small mounds (usu-ally bilateral), CL, or CP, each alone or in anycombination of the three anomalies (Fig. 13-1).

Orofacial clefts are a frequent occurrence ina number of ectodermal dysplasia syndromes.

94 PART III CRANIOFACIAL MALFORMATIONS

� TABLE 13-1 Genetic Disorders Associatedwith Cleft Lip with or without Cleft Palate

Amnion rupture sequenceCrouzon syndromeDeletion 4p syndromeEctrodactyly-ectodermal dysplasia (EEC)

syndromeFetal alcohol syndromeFetal hydantoin syndromeFetal valproate syndromeFryns syndromeHay-Wells ectodermal dysplasiaOral-facial-digital syndromeTrisomy 13Van der Woude syndrome

Figure 13-1. Pits in lower lip of individual withVan der Woude syndrome. (Used with permis-sion from Dr. Jeffrey Murray, University of Iowa.)

These disorders involve abnormalities of thehair, teeth, and skin. Some ectodermal dys-plasias also are associated with congenital limbanomalies involving absence of fingers or toes(ectrodactyly/split hands and feet). Mutationsin the TP63 gene cause the ectrodactyly, ecto-dermal dysplasia, and cleft lip/palate (EEC)syndrome and Hay-Wells anklyoblepharon-ectodermal dysplasia–clefting (AEC) syndrome.

CL with or without palate may occur in a vari-ety of chromosome abnormalities, particularly inassociation with partial deletion of the short armof chromosome 4. Deletion 4p syndrome (4p- orWolf-Hirschhorn syndrome) is characterized byocular hypertelorism, broad or beaked nose, mi-crocephaly, low-set ears, and CL and/or CP.

While the vast majority of CL malformationsare lateral clefts, median or midline clefts (throughthe center of the upper lip) are very rare and rep-resent approximately 0.5% of all CL defects. Me-dian CL may occur as an isolated anomaly or aspart of a number of malformation syndromes.The most common disorders associated with amedian CL are holoprosencephaly, Trisomy 13,and oral-facial-digital (OFD) syndrome.

Holoprosencephaly is a malformation inwhich impaired cleavage of the embryonic fore-brain is the major feature. Typical craniofacialfeatures include hypertelorism, various degreesof abnormal nasal development, and occasionalmedian CL. Infants with Trisomy 13 may haveholoprosencephaly and/or median CL.

Oral-Facial-Digital type 1 syndrome is anX-linked dominant disorder affecting mainlyfemales, which is characterized by multiplefrenuli between the buccal mucous membraneand alveolar ridge, median CL and/or CP, lobu-lated or bifid tongue, and a variety of digitalanomalies including asymmetric digits, syn-dactyly, and polydactyly.

As previously mentioned, a number of ter-atogens may cause CL/P including alcohol,phenytoin, and valproic acid. Each of theseteratogens is associated with characteristiccraniofacial features and a variety of congeni-tal anomalies most commonly including digital

abnormalities, congenital heart defects, and gen-itourinary anomalies.

Cleft Palate

Approximately 15–50% of infants with CP withoutCL have additional congenital abnormalities andthere are a number of specific genetic disordersin which CP is a frequent finding (Table 13-2).

One of the disorders most frequently associ-ated with CP is the 22q11.2 deletion syndrome.This syndrome is caused by a submicroscopicdeletion of chromosome 22 detected by fluo-rescence in situ hybridization (FISH). With anincidence of 1/4000, 22q11.2 deletion syndromeis the most common chromosome microdele-tion syndrome and one of the most common ofall recognized genetic disorders. The most fre-quently observed features of this disorder in-clude congenital heart defects, particularlyconotruncal defects (tetralogy of Fallot, inter-rupted aortic arch, ventricular septal defect),palatal abnormalities (CP, abnormal velopha-ryngeal musculature and function), hypocal-cemia, immune deficiency, and characteristic fa-cial features (Table 13-3).

The 22q11.2 deletion syndrome includes thephenotypes previously described as DiGeorgesyndrome (heart defects, hypocalcemia, absentor hypoplastic thymus) and velocardiofacial

CHAPTER 13 CLEFT LIP AND PALATE 95

� TABLE 13-2 Genetic Disorders Associatedwith Cleft Palate

22q11.2 deletion syndrome and otherchromosome abnormalities

Fetal alcohol syndromeHay-Wells ectodermal dysplasiaKniest dysplasiaOto-Palato-digital syndromeRobin sequenceSpondyloepiphyseal dysplasia congenitaStickler syndromeTreacher Collins syndromeVan der Woude syndrome

syndrome (VCFS). More than 95% of individualswith typical clinical features of 22q11.2 deletionwill have detectable deletions by FISH testing.A small number of individuals with the 22q11.2phenotype have a deletion of chromosome 10p13.

The 22q11.2 deletion syndrome is inherited inan autosomal dominant fashion. Approximately90% of affected individuals have a de novo (new)deletion and 10% have an inherited deletion froma parent. Offspring of affected individuals have a50% chance of inheriting the deletion.

The combination of CP (frequently U-shaped),micrognathia (small mandible), and glossopto-sis (tongue retroposition into the pharyngealairway resulting in variable degrees of obstruc-tion and respiratory distress) was first describedby Pierre Robin in 192311 and is referred to asPierre Robin syndrome or Robin sequence.While the classic definition of Robin sequencerequires the presence of all three findings, var-ious authors have advocated other definitions

allowing for the presence of only two findings,most commonly micrognathia and CP withoutglossoptosis.12

Robin sequence often occurs as an isolatedcondition in otherwise normal individuals, but itmay also occur with additional nonspecific con-genital anomalies or as one feature in more than40 genetic disorders.13 In one study, Robin se-quence occurred as an isolated finding in 48% ofcases, with additional anomalies in 17% of cases,and as part of an identifiable syndrome in 35%of cases.14 The most common genetic disordersassociated with Robin sequence are 22q11.2deletion syndrome, Stickler syndrome, andTreacher Collins syndrome (see Micrognathia).

Stickler syndrome is an autosomal dominantconnective tissue disorder caused by mutations inone of the three collagen genes (COL2A1,COL11A1, and COL11A2). The most commonfeatures include ocular findings (myopia, cataract,retinal detachment), hearing loss (conductive and


� TABLE 13-3 Clinical Features of 22q11.2 Deletion Syndrome

Findings % Affected

Congenital heart defects (total) 74%Tetralogy of Fallot 22%Interrupted aortic arch 15%Ventricular septal defect 13%Truncus arteriosus 7%Other 17%

Palatal abnormalities (total) 69%Overt cleft palate 11%Other 58%

Immune defects 77%Hypocalcemia 50%Renal anomalies 37%Characteristic facial features Majority

Minor ear anomaliesProminent noseNarrow palpebral fissuresRetruded mandibleFlattened malar area

Slender fingers 63%Feeding problems 30%Learning problems 90%

sensorineural), midfacial underdevelopment, andCP or Robin sequence. A mild spondyloepiphy-seal dysplasia or early arthritis may develop dur-ing later childhood and adulthood.

CP may be a finding in a number of skeletaldysplasias and conditions with digital anomalies.Spondyloepiphyseal dysplasia congenita andKniest dysplasia are autosomal dominant skele-tal disorders characterized by disproportionateshort stature with vertebral and long bone ab-normalities and variable non-skeletal anomaliesincluding CP. Oto-Palatal-Digital syndrome is anX-linked disorder associated with deafness, broaddistal digits with short nails, and CP.

� EVALUATION

The evaluation of an infant with an orofacial cleftrequires a detailed family and prenatal history andphysical examination. A family history of orofacialclefts and/or lip pits may suggest the possibility of

a heritable form of clefting such as Van der Woudesyndrome. A prenatal history of maternal alcoholuse or treatment with anticonvulsant medicationsshould prompt an evaluation for other anomaliesassociated with exposure to these teratogens.

An approach to the evaluation of CL/P is il-lustrated in Fig. 13-2. In the cases of apparentisolated CL/P without other anomalies, dysmor-phic features, or known teratogenic exposures,no additional evaluation or testing may be indi-cated. Chromosome analysis should be obtainedin any infant with additional congenital anom-alies or dysmorphic features. Evaluation for spe-cific syndromes associated with CL/P should bepursued based upon the clinical findings.

The general approach to the evaluation of aninfant with CP is similar to that of an infant withCL/P with some additional considerations (Fig.13-3). Due to the frequency and phenotypic vari-ability of 22q11.2 deletion syndrome, FISH test-ing should be considered in any infant with a CP,including an infant with an isolated CP.


CL/P

Lip Pits or Family History ofPits and CL

No Other Anomalies orDysmorphic Features

Other Anomalies and/orDysmorphic Features

Van der Woude Syndrome Isolated CL/P

Abnormal Karyotype

Trisomy 13Deletion 4p Syndrome

Other ChromosomeAbnormalities

Normal Karyotype

Evaluate forSpecific SyndromesBased Upon Clinical

Findings

Obtain Chromosome Analysis

Figure 13-2. Algorithm for evaluation of an infant with cleft lip with or without cleft palate.

The diagnosis of 22q11.2 deletion should beparticularly considered in infants with a CP and acongenital heart defect (with or without hypocal-cemia), and in infants with Robin sequence. All in-fants with a confirmed diagnosis of 22q11.2 dele-tion should have particular baseline diagnostictests and evaluations (Table 13-4) and long-termmultidisciplinary follow-up. Any infant with Robinsequence in which 22q11.2 deletion syndrome hasbeen excluded should have a baseline ophthal-mology exam and hearing screening to evaluatefor abnormalities associated with Stickler syn-drome. Molecular testing is available for confir-mation of a suspected diagnosis.


The clinical management of orofacial clefts re-quires a multidisciplinary approach involving cran-iofacial surgeons, dentists, orthodontists, speechtherapists, otolaryngologists and clinical geneticists.Surgical repair of CL is usually performed at 2–3months of age while repair of CP is typically per-

formed at 8–12 months of age. Infants with CP areat risk for recurrent otitis media and conductivehearing loss and should be monitored accordingly.

GENETIC COUNSELINGSusceptibility to nonsyndromic CL/P and CPlikely involves a combination of many genesand environmental components. Relatives of pa-tients with nonsyndromic CL/P and CP are at anincreased risk of recurrence with the risk (in


CP

No Other Anomalies Isolated Robin Sequence

Fish for 22q11.2 Deletion Fish for 22q11.2 Deletion

AbnormalNormal

22q11.2 DeletionIsolatedCP

Normal

Eye ExamHearing Screen

Abnormal:Stickler Syndrome

Normal:Isolated CP

Abnormal:22q.11 Deletion

Other ChromosomeAbnormalities

CP or Robin Sequence +Other Anomalies

Chromosome AnalysisFish for 22q11.2 Deletion

Normal:Evaluatefor Other

Syndromes

Figure 13-3. Algorithm for evaluation for an infant with cleft palate.

� TABLE 13-4 Evaluation of Infant with22q11.2 Deletion Syndrome

EchocardiogramRenal ultrasoundCalcium levelImmunology evaluation including quantitative

and qualitative T and B cell studiesHearing screeningFeeding evaluation if cleft present or

symptoms of feeding problemsEvaluation for early intervention services

during first few months of life

cases of CL/P) declining as the degree of rela-tionship decreases (Table 13-5). In addition, therecurrence risk of CL/P varies based upon theseverity of the defect, with the greatest risk oc-curring when the abnormality is bilateral withCP and lower when there is only CL (Table 13-5). Recurrence risks for syndromic forms of CLand CP are based upon the inheritance pattern ofthe specific disorder. Parental FISH testing shouldbe offered for any infant diagnosed with 22q11.2deletion syndrome to identify a potentially mildlyaffected and previously undiagnosed parent.

The use of multivitamins with folic acid iscurrently recommended for all women of re-productive age to reduce the risk of neural tubedefects in offspring and there is now evidencefrom some studies that women taking multivit-amins containing folic acid in early pregnancymay also be at lower risk of having childrenwith orofacial clefts.5 However, other studieshave found no evidence that folic acid is in-volved in preventing orofacial clefts, and the is-sue remains unresolved.6

REFERENCES

1. Bender PL. Genetics of cleft lip and palate. J Pedi-atr Nurs. 2000;15:242–9.

2. Natsume N, Kawai T, Kohama G, et al. Incidenceof cleft lip or palate in 30,338 Japanese babies bornbetween 1994 and 1995. Br J Oral Maxillfac Surg.2000;38:605–7.

3. Printzlau A, Andersen M. Pierre-Robin sequencein Denmark: a retrospective population-based

epidemiological study. Cleft Palate CraniofacJ. 2004;41:47–52.

4. Farrell M, Holder S. Familial recurrence-patternanalysis of cleft lip with or without cleft palate.Am J Med Genet. 1992;50:270–7.

5. Carinci F, Pezzetti F, Scapoli L, et al. Recent devel-opments in orofacial cleft genetics. J CraniofacSurg. 2003;14:130–43.

6. Spritz R. The genetics and epigenetics of orofacialclefts. Curr Opin Pediatr. 2001;13:556–60.

7. Mills JL, Kirke PN, Molloy AM, et al. Methylenete-trahydrofolate reductase thermolabile variant andoral clefts. AM J Med Genet. 1999;86:71–4.

8. Martinelli M, Scapoli L, Pezzetti F, et al. C677T vari-ant form at the MTHFR gene and CL/P: a risk fac-tors for mothers? Am J Med Genet. 2001;98:357–60.

9. Munger RG, Romitti PA, Daack-Hirsch S, et al. Ma-ternal alcohol use and risk of orofacial cleft birthdefects. Teratology. 1996;54:2–33.

10. Azarbayjani F, Danielsson BR. Phenytoin-inducedcleft palate: evidence for embryonic cardiac brad-yarrhythmia due to inhibition of delayed rectifierK+ channels resulting in hypoxia-reoxygenationdamage. Teratology. 2001;63:152–60.

11. Robin P. La chute de la base de la langue consid-érée comme une nouvelle cause de gene dans larespiration naso-pharyngienne. Bull Acad NatlMed. 1923;89:37–41.

12. Cohen MM. Craniofacial disorders. In: Rimoin DL,Connor JM, Pyeritz RE, et al., eds. Principles andPractice of Medical Genetics. 4th ed. New York,Churchill Livingstone; 2002:3714.

13. Cohen MM. The Child with Multiple Birth Defects.New York, Oxford University Press; 1997.

14. Holder-Espinasse M, Abadie V, Cormier-Daire V, etal. Pierre Robin sequence: a series of 117 consecu-tive cases. J Pediatr. 2001;139:588–90.


� TABLE 13-5 Recurrence Risks for Nonsyndromic Cleft Lip and Cleft Palate

Cleft Lip with or without Cleft Palate Isolated Cleft PalateRelationship to Index Case (%) (%)

Sibs (overall risk) 4.0 1.8Bilateral cleft lip and palate 5.7Unilateral cleft lip and palate 4.2Unilateral cleft lip alone 2.5

Children 4.3 3Second-degree relatives 0.6Third-degree relatives 0.3General population 0.1 0.04


Chapter 14

MicrognathiaBRAD ANGLE

101

� INTRODUCTION

Micrognathia refers to the appearance of a smalljaw caused by mandibular hypoplasia (Fig. 14-1).Congenital mandibular hypoplasia is a com-mon craniofacial anomaly and is highly vari-able in its clinical presentation and etiology. It mayoccur as an asymptomatic isolated minor craniofa-cial difference or as a severe abnormality causingsignificant medical complications, often with asso-ciated anomalies and syndromes.

� ETIOLOGY/EMBRYOLOGY

Congenital mandibular hypoplasia may be clas-sified as either deformational or malformational.A deformation is an abnormal form, shape, orposition of a body part caused by extrinsic me-chanical forces affecting the development ofotherwise normal tissue.1 Some cases of con-genital mandibular hypoplasia may be the re-sult of deformation caused by intrauterine con-straint. Other cases of congenital mandibularhypoplasia are malformations resulting from aprimary intrinsic growth disturbance.

The cartilages and bones of the mandibularskeleton form from embryonic neural crest cellsthat originate in the mid- and hindbrain regionsof the neural folds. Mandibular developmentbegins early in the fourth week of gestation, as

neural crest cells migrate into the future headand neck region to initiate branchial arch for-mation. The first branchial arch develops twoelevations, the mandibular and maxillary promi-nences. The mandibular prominence forms themandible, and the maxillary prominence formsthe maxilla, zygoma, and squamous portion ofthe temporal bone.

Mandibular hypoplasia is believed to resultfrom insufficient or defective neural crest pro-duction or migration into the first branchial archduring the fourth week.2 Derivatives of the defi-cient ectomesenchyme (specifically the zygomatic,maxillary, and mandibular bones) are hypoplastic,accounting for the typical facies found in thecommon craniofacial syndromes associated withmicrognathia.


While mandibular hypoplasia may occur as anisolated congenital anomaly, many infants withthis finding have associated syndromes. More than60 syndromes having mandibular hypoplasia as acomponent have been described.3

The most common disorder associated withmandibular hypoplasia is oculo-auriculo-vertebral(OAV) spectrum (see Chap. 15). The next mostcommon conditions are Treacher Collins syndrome


(TCS) (mandibulofacial dysostosis) and Robinsequence (see Chap. 13). Mandibular hypopla-sia is also frequently observed in infants withchromosome abnormalities. TCS is a craniofacialdisorder characterized by hypoplasia of the zygo-matic bones and mandible, external ear abnormal-ities (absent, small, malformed), coloboma of thelower eyelid, absence of lower eyelashes, cleftpalate, and conductive hearing loss. TCS is in-herited in an autosomal dominant manner. Morethan 90% of affected individuals have mutationsin the TCOF1 gene, which is the only gene cur-rently known to be associated with TCS. Ap-proximately 60% of individuals have the disor-der as a result of a new (de novo) mutation inthis gene.

Nager syndrome is an autosomal recessivedisorder with craniofacial features similar to TCSand, in addition, is also associated with limb

defects (most commonly hypoplastic or absentthumbs and radial bones).

� DIAGNOSIS AND EVALUATION

Identification of micrognathia in an infant requiresa careful examination for additional craniofacialabnormalities and other congenital anomalies.The presence or absence of other craniofacialfeatures and/or cleft palate can be helpful insuggesting the most likely associated disordersand directing further evaluation as illustrated inFig. 14-2. In cases of some suspected syndromes(e.g., 22q11 deletion), confirmation by genetictesting may be possible. However, diagnosis ofmany disorders associated with micrognathiacan only be made on a clinical basis.


The degree of mandibular hypoplasia is quitevariable and, when severe can lead to significantfunctional issues at birth. The majority of infantsborn with micrognathia are either asymptomaticor can be treated conservatively by prone posi-tioning with anticipation of catch-up mandibulargrowth.4 With severe mandibular hypoplasia,obstruction at the hypopharynx occurs becauseof the retroposition of the base of the tongueinto the posterior pharyngeal airway. This maycause severe respiratory obstruction with fre-quent hypoxic events and resultant poor feed-ing. These infants may require more immediateand aggressive intervention, including endotra-cheal intubation.

Until recently, tracheostomy has traditionallybeen the most common treatment option for in-fants with severe upper airway obstruction. A newadvancement in the treatment of children withcongenital mandibular hypoplasia and signifi-cant upper airway obstruction is mandibular dis-traction osteogenesis. Distraction osteogenesis isa surgical procedure which involves lengthen-ing of the jaw through new bone growth madeacross a bony cut (osteotomy). The objective ofmandibular distraction osteogenesis is to ad-vance the tongue base anteriorly via its muscularattachments to the distracted mandible, thus


Figure 14-1. Infant with micrognathia.(Reprinted from Denny A and Christian A. Newtechniques for airway correction in neonateswith severe Pierre Robin sequence. J Pediatr.147:97–101. Copyright 2005, with permissionfrom Elsevier.)

pulling the tongue out of the hypopharynx andrelieving upper airway obstruction. This procedurehas proven to be highly successful in neonateswith severe micrognathia.5

Some, but not all, patients may outgrow theirmicrognathia without intervention. Infants withdeformational hypoplasia have the best progno-sis because of the mandibular growth potentialthat is present once the deforming forces havebeen removed. The natural history of mandibulargrowth in patients with isolated Robin sequenceis typically one of continued development, aswell. Micrognathia associated with more com-plex conditions such as OAV spectrum and TCSis more likely to persist over time.3,6


In cases of infants who have isolated mildmandibular hypoplasia with subsequent self-correction, the most likely etiology is intrauterine

constraint and the recurrence risk appears to below. Severe, isolated mandibular hypoplasia re-quiring aggressive interventions (e.g., tra-cheostomy, mandibular distraction osteogene-sis) is most likely a result of an intrinsicmalformational process of unknown etiology.The recurrence risk in these cases is unknown.The recurrence risk for infants with identifiedsyndromes is dependent on the inheritance pat-tern of the specific disorder.

REFERENCES

1. Spranger J, Benirschke, Hall JG, et al. Errors of mor-phogenesis: concepts and terms. Recommendationsof an international working group. J Pediatr.1982;100:160.

2. Sperber GH. Craniofacial Development. London,BC Decker Inc; 2001:127–38.

3. Singh DJ, Bartlett SP. Congenital mandibular hy-poplasia: analysis and classification. J CraniofacSurg. 2005;16:291–300.

CHAPTER 14 MICROGNATHIA 103

Micrognathia

Isolated Micrognathia

IntrinsicMandibularHypoplasia

Other Anomalies

Cleft Palate

Evaluate forRobin Sequence

SignificantCraniofacial

Findings

Primary CraniofacialDisorders: Treacher

Collins, OAVSpectrum, and Others

IntrauterineConstraint

SignificantNoncraniofacial

Anomalies

Other Syndromes andChromosomeAbnormalities

Figure 14-2. Algorithm for identifying causes of mandibular hypoplasia.

4. Caoette-Laberge L, Bayet B, Larocque Y. The PierreRobin sequence: a review of 125 cases and evolu-tion of treatment modalities. Plast Reconstr Surg.1994;93:934–42.

5. Mandell DL, Yellon RF, Bradley JP, et al. Mandibulardistraction for micrognathia and severe upper air-way obstruction. Arch Otolaryngol Head Neck Surg.2004;130:344–8.

6. Sidman JD, Sampson D, Templeton B. Distractionosteogenesis of the mandible for airway obstructionin children. Laryngoscope. 2001;111:1137–46.


Chapter 15

Congenital AnomaliesAssociated with Facial

AsymmetryBRAD ANGLE

105

� INTRODUCTION

Facial asymmetry is often noted shortly afterbirth. If the face is symmetric at rest but asym-metric during grimacing or crying, the possibilityof asymmetric crying facies should be suspected.The finding of facial asymmetry at rest with oneside of the face appearing smaller than the other(hemifacial microsomia) is suggestive of morecomplex craniofacial malformations and fur-ther evaluation for other disorders should bepursued.

� ASYMMETRIC CRYING FACIES

Asymmetric crying facies refers to the finding inan infant whose face appears symmetrical atrest and asymmetric while crying as the mouthis pulled downward on one side while not mov-ing on the other side (Fig. 15-1). The cause offacial asymmetry in this disorder is congenitalabsence or hypoplasia of the depressor angulioris muscle (DAOM) at the corner of the mouthon the side that does not move downward.1

This may be an isolated abnormality or associated

with various cardiovascular, craniofacial, mus-culoskeletal, or genitourinary anomalies.

� ETIOLOGY AND INCIDENCE

The orofacial muscles are the first to develop inthe body and arise from the second pharyngealpouch between the eighth and ninth weeks ofembryonic development. The DAOM originatesfrom the oblique line of the mandible and ex-tends upward medially to the orbicularis oris,blending into the fibers of the opposite side, at-taching to skin and mucous membrane of thelower lip. It draws the lower corner of the lipdownward and laterally. Innervations derivefrom the buccal and mandibular branches of thefacial nerve. Aplasia or hypoplasia of DAOM re-sults in the lack of downward movement of thelip on the affected side. The underlying causeof failure of muscle development is unknown.

The frequency of asymmetric crying faciesranges from 1 in 160 to 1 in 350 neonates.2,3

There is an unequal sex distribution with a male-to-female ratio of 2:1,4 and left-sided defectspredominate.4,5



Cayler6 reported an association between hy-poplasia of DAOM and congenital heart diseaseand coined the term “cardiofacial syndrome.”A number of retrospective studies have found avery high frequency of additional anomalies(45–70%), including a high incidence of heartdefects (44%) and ear or other craniofacialanomalies (48%), as well as skeletal (22%) andgenitourinary tract (24%) anomalies.4,7 However,prospective studies suggest that hypoplasia ofDAOM is an isolated finding in most cases butmay be associated with other congenital anom-alies, particularly cardiovascular anomalies.3,8

The greater occurrence of additional anomaliesin retrospective studies may result from selectionbias. Asymmetric crying facies has been reportedin a number of individuals with 22q11 deletionsyndrome, most of whom have associated car-diac defects.9

� EVALUATION

The diagnosis of asymmetric crying facies maybe suspected when the face is symmetrical atrest but while crying one corner of the mouthdoes not move downward and outward sym-metrically with the other. Palpable thinning ofthe lateral portion of the lower lip is usuallypresent on the affected side.

Hypoplasia of DAOM must be differentiatedfrom a seventh cranial nerve palsy of traumaticor congenital origin. Seventh nerve palsy maybe associated with abnormalities of eye closure,forehead wrinkling, or other cranial nerve palsiessuch as sixth nerve palsy (Moebius syndrome).Forehead wrinkling, eye closure and tearing aresymmetrical in infants with hypoplasia of DAOM.

Careful physical examination with particularattention to the craniofacial features and cardio-vascular exam is warranted. An echocardiogramshould be considered in view of the associationwith congenital heart defects. Other screening


A B

Figure 15-1. A. Facial symmetry at rest. B. On crying, the right corner of the infant’s mouth isdrawn downward while the left corner does not move due to hypoplasia of DOAM on left side,resulting in asymmetric crying facies. (Reprinted with permission from Caksen H. Indian Pediatrics.2000;37:1385.)

evaluations, including renal ultrasound andskeletal x-rays should be considered if there areany abnormalities of the musculoskeletal sys-tem or genitalia on physical examination.

� PROGNOSIS

Hypoplasia of DAOM does not interfere withsucking or smiling and does not cause drooling.The asymmetry usually improves with age asother facial muscles dominate facial expressionbut may persist into adulthood.


The observation of affected first-degree rela-tives in some families has suggested possibleautosomal dominant inheritance with variableexpressivity, but most cases of asymmetric cry-ing facies likely have a complex multifactorialcause with a low recurrence risk.

� HEMIFACIAL MICROSOMIA ANDOCULO-AURICULO-VERTEBRALSPECTRUM

Facial asymmetry noted at birth may reflect un-derdevelopment of the facial bones and/or softtissue on one side. Various abnormalities of eardevelopment frequently accompany this abnor-mality. In the 1960s, the term hemifacial micro-somia was used to define this condition whichaffects mainly aural, oral, and mandibular de-velopment.10 The occurrence of these featureswith the additional finding of epibulbar der-moid tumors of the eye and, in some cases,vertebral abnormalities was designated as Gold-enhar syndrome.11 Subsequently, the term oculo-auriculo-vertebral (OAV) spectrum has beenused to encompass the variable phenotypes ofthis complex.10

The major features of OAV spectrum includefacial asymmetry, maxillary, zygomatic, and

mandibular hypoplasia (especially the ramus andcondyle), microtia to absence of the pinna, preau-ricular tags and sinuses, atretic auditory canal andmiddle ear anomalies, and vertebral anomalies(Fig. 15-2). Vertebral anomalies occur in up to60% of individuals, including hypoplastic orfused vertebrae and hemivertebrae, and mostcommonly involve the cervical region. Oculardefects include epibulbar dermoid tumors in35% of cases, iris colobomata, microphthalmia,and other ocular findings.12 Hearing loss iscommon, including both conductive and

CHAPTER 15 CONGENITAL ANOMALIES ASSOCIATED WITH FACIAL ASYMMETRY 107

Figure 15-2. Note facial asymmetry with hy-poplasia of the malar and mandibular regionsand small, malformed auricle. (Reprinted withpermission from Farraris S, Silengo M, Ponzone A,et al. Goldenhar anomaly in one of triplets derivedfrom in vitro fertilization. Am J Med Genet.1999;84:167–8. Reprinted with permission of Wiley-Liss Inc., a subsidiary of John Wiley & Sons, Inc.)

sensorineural types. The disorder varies frommild to severe, and involvement is usually uni-lateral (70%) with right sided preponderance.

� ETIOLOGY AND INCIDENCE

The incidence of OAV spectrum is approxi-mately 1/3000–1/5600 live births with a male pre-ponderance of 3:2.13 Embryologically, the OAVdefects have been described as defects of devel-opment of the first and second branchial arches.The first pair of arches are involved in the for-mation of facial bones (maxilla, zygoma,mandible, and ear ossicles), related muscles andligaments, and cranial nerves V and VII. How-ever, this mechanism does not explain theanomalies of the brain, heart, kidneys, or spinethat are commonly associated with the cranio-facial anomalies (see below). It has been sug-gested that the OAV spectrum is a disorder ofblastogenesis and the developing midline, oc-curring during the first 4 weeks of embryonicdevelopment.14

OAV appears to be an etiologically het-erogenous disorder. Teratogenic effects havebeen identified as this condition has been notedin infants of diabetic mothers, in fetal alcoholsyndrome, and in infants exposed to retinoicacid. In addition, multiple chromosome abnor-malities have been identified in infants with fea-tures of the OAV spectrum.

� ASSOCIATED MALFORMATIONS

In addition to craniofacial and vertebral abnor-malities, visceral anomalies including cardiac(5–30%) and renal defects may occur in the OAVspectrum. The most common cardiac defects areventricular septal defect and patent ductus arte-riosus. Renal anomalies include renal agenesis,ectopic or fused kidneys, vesicoureteral reflux,ureteropelvic junction obstruction, and multicys-tic dysplastic kidneys. A wide range of centralnervous system (CNS) defects occur occasionally,including hydrocephalus, Chiari malformation,and agenesis of the corpus callosum.

� EVALUATION

A detailed prenatal history should be obtainedto identify any maternal drug exposures or dia-betes mellitus. Because of the complexity of thisspectrum, infants with craniofacial features of OAVspectrum should undergo a systematic search forassociated skeletal or visceral malformations, aswell as hearing and ophthalmologic evaluations(Table 15-1). In addition, chromosome analysis iswarranted to exclude the possibility of a chromo-some abnormality as a cause of the congenitalanomalies.

� PROGNOSIS

Plastic surgery may be warranted in cases with se-vere facial deformities or ear anomalies. Hearingevaluations in early infancy are important to iden-tify any significant hearing loss. Most individualshave normal intelligence in the absence of majorCNS anomalies or a chromosome abnormality.


Most cases of OAV spectrum are sporadic, butfamilial instances with apparent autosomal dom-inant inheritance with variable expressivity havebeen reported. As the disorder is most likely ge-netically and etiologically heterogeneous, theempiric recurrence risk is about 2–3%.


� TABLE 15-1 Recommended DiagnosticStudies for Evaluation of Oculo-Auriculo-Vertebral Spectrum

EchocardiogramRenal ultrasoundVertebral x-raysCNS imaging (if abnormal neurological

findings)Hearing evaluationOphthalmology evaluationChromosome analysis

REFERENCES

1. Nelson KB, Eng GD. Congenital hypoplasia of thedepressor anguli oris muscle: differentiation fromcongenital facial palsy. J Pediatr. 1972;81:16–20.

2. Singhi S, Singhi, Lall KB. Congenital asymmetriccrying facies. Clin Pediatr. 1980;19:673–8.

3. Lahat E, Heyman E, Barkay A, et al. Asymmetriccrying facies and associated congenital anomalies:Prospective study and review of the literature.J Child Neurol. 2000;15:808–10.

4. Lin D, Huang F, Lin S, et al. Frequency of associ-ated anomalies in congenital hypoplasia of de-pressor anguli oris muscle: a study of 50 patients.Am J Med Genet. 1997;71:215–8.

5. Pape KE, Pickering D. Asymmetric crying facies:An index of other congenital anomalies. J Pediatr.1972;81:21–30.

6. Cayler GG. Cardiofacial syndrome. Arch Dis Child.1969;44:69–75.

7. Caksen H, Odabas D, Tuncer O, et al. A review of35 cases of asymmetric crying facies. Genet Couns.2004;15:159–65.

8. Alexiou D, Manolidis C, Papaevangellou G, et al.Frequency of other malformations in congenitalhypoplasia of depressor anguli oris muscle syn-drome. Arch Dis Child. 1976;51:890–3.

9. Stewart HS, Clayton Smith J. Two patients withasymmetric crying facies, normal cardiovascularsystems and deletion of chromosome 22q11. ClinDsymorphol. 1997;6:165–9.

10. Gorlin RJ, Cohen MM, Hennekam RCM. Syndromesof the Head and Neck. 4th ed. New York, OxfordUniversity Press; 2001:790–9.

11. Goldenhar M. Associations malformatives de l’oeilet de l’oreille. J Genet Hum. 1952;1:243.

12. Mansour AM, Wang F, Henkind P, et al. Ocularfindings in the facioauriculovertebral sequence(Goldenhar-Gorlin syndrome). Am J Ophthalmol.1985;100:555–9.

13. Grabb WC. The first and second branchial archsyndrome. Plast Reconstr Surg. 1965;36:485–508.

14. Opitz JM. Blastogenesis and the “primary field” inhuman development. In: Opitz JM, Paul NW, eds.Blastogenesis: Normal and Abnormal. New York,Wiley-Liss; 1993:3–37.

CHAPTER 15 CONGENITAL ANOMALIES ASSOCIATED WITH FACIAL ASYMMETRY 109


Chapter 16

Ear AnomaliesBRAD ANGLE

111

� INTRODUCTION

Abnormalities in the size, shape, structure, andposition of the external ear are common findingsin newborn infants. External ear anomalies maybe minor deformational abnormalities of no seri-ous medical consequence or may be significantstructural abnormalities associated with anom-alies of the middle and inner ear, hearing loss, orother congenital defects and genetic syndromes.Recognition of ear anomalies in a newborn mayrepresent an important clue in the diagnosis ofan underlying genetic disorder or syndrome.


External ear anomalies of all types, includingdeformations from fetal constraint, occur in al-most 20% of all newborn infants.1 Ear pits andtags are the most common nondeformationalminor ear anomalies, occurring with a frequencyof 5–6 per 1000 live births.2

Most minor ear anomalies at birth representdeformations caused by altered mechanical forcesaffecting the development of otherwise normaltissue. The most common cause of the deforma-tion is uterine constraint. Intrauterine constraintcan result in flattening of the ears leading to theappearance of large ears. Asymmetric ear sizemay be the result of torticollis, which causes

head positioning on one side and enlargementof one ear.

The most common minor structural earanomalies are preauricular tags and pits. Preau-ricular tags (Fig. 16-1), which often contain acore cartilage, appear to represent accessoryhillocks. Preauricular pits (Fig. 16-2) are smalldepressions which may be familial and are twiceas common in females as in males and morecommon in blacks than whites.3

Severe malformations of the auricle rangefrom microtia (small, underdeveloped, abnor-mally shaped ear) (Fig. 16-3) to anotia (completeabsence of auricular tissue). These malforma-tions may be caused by developmental anom-alies of the branchial arches which contribute toboth external ear and middle ear structures. Ap-proximately 85% of children with unilateral mi-crotia have ipsilateral hearing loss and 15% havecontralateral hearing loss. Low placement andposteriorly rotated positioning of the auricleoften go together and usually represent a lag inmorphogenesis, since the auricle is normally inthat position in early fetal life.

� EMBRYOLOGY

The external ear develops in the neck region assix auricular hillocks (swellings) surroundingthe first pharyngeal groove that forms the ex-ternal acoustic meatus. Differential growth and


fusion of the hillocks by the end of the eighthweek of gestation produces the characteristicshape of the auricle. The auricle and externalacoustic meatus appear to migrate up the sideof the developing face from their original cervi-cal location to reach their normal position bythe fourth month post conception, largely dueto lower facial and mandibular growth.4


External ear anomalies occur as frequent findingsin over 100 genetic disorders and syndromes, mul-tiple chromosome abnormalities, and in infants

with diabetic embryopathy.4 Some of the mostcommon disorders are listed in Table 16-1.

Noonan syndrome is one of the common mul-tiple congenital anomaly syndromes (incidenceof 1 in 1000–2500) associated with external earanomalies. Noonan syndrome is an autosomaldominant disorder characterized by short stature,congenital heart defect (frequently pulmonicstenosis), broad or webbed neck, developmen-tal delay, and characteristic facies. Typical facialfeatures include hypertelorism, downslantingpalpebral fissures, and low-set, posteriorly rotatedears with thickened helices. Approximately 50%of affected individuals have a mutation in thePTPN11 gene.


Figure 16-1. A preauricular tag indicated byarrow. (Reprinted with permission from JonesKL, ed. Smith’s Recognizable Patterns of Hu-man Malformation. 5th ed., p. 730. Copyright1997, with permission from Elsevier.)

Figure 16-2. A preauricular pit indicated byarrow. (Reprinted with permission from JonesKL, ed. Smith’s Recognizable Patterns of Hu-man Malformation. 5th ed., p. 730. Copyright1997, with permission from Elsevier.)

Of particular note, it is important to recog-nize that ear malformations are associated withan increased frequency of structural renal anom-alies compared to the general population.5 Thisis likely due to the fact that ear malformations areoften associated with specific multiple congenitalanomaly syndromes that have a high incidence ofrenal anomalies including CHARGE syndrome, (see

Chap. 17) oculo-auriculo-vertebral (OAV) spectrum,branchio-oto-renal (BOR) syndrome, and TownesBrocks syndrome (TBS).

BOR syndrome is characterized by malfor-mations of the external, middle, and inner ear as-sociated with hearing loss, branchial fistulae andcysts, and renal malformations. The branchialcysts and fistulae are usually found on the lateral

CHAPTER 16 EAR ANOMALIES 113

Figure 16-3. Examples of varying degrees of microtia. (Reprinted with permission from WangRY, Earl DL, Ruder RO, Graham JM, Jr. Syndromic ear anomalies and renal ultrasounds. Pediatrics,Vol. 108, e32. Copyright 2001 by the AAP.)

lower third of the neck at the median border ofthe sternocleidomastoid muscle and occur in ap-proximately 60% of patients. Ear anomalies,ranging from preauricular pits to severe micro-tia, occur in 70–80% of affected individuals. Ap-proximately 12–20% of patients have structuralkidney anomalies. BOR is an autosomal dominantdisorder caused by mutations in the EYA1 gene.

TBS is an autosomal dominant disordercaused by a mutation in the SALL1 transcriptionfactor gene which is expressed in the develop-ing ear, limb buds, and excretory organs.6 Themost common findings in TBS are bilateral ex-ternal ear malformations, hand malformations(typically thumb anomalies), and anal anom-alies (imperforate anus, rectovaginal fistula).

� EVALUATION

Examination of the external ear consists of iden-tifying abnormalities in the size, shape, and po-sitioning of the auricle (Fig. 16-4). Ears are de-fined as low-set when the helix meets thecranium at a level below that of a horizontalplane that is an extension of a line through bothinner canthi (Fig. 16-5). Ears are described asslanted or posteriorly rotated when the angle of

the slope of the auricle exceeds 15 degrees fromthe perpendicular plane (Fig. 16-5). Ear tags orpits are common minor anomalies and may oc-cur as isolated findings or in association withother auricular abnormalities.

Any infant with an abnormality of the exter-nal ear should have a careful physical examina-tion to identify other craniofacial anomalies, fa-cial asymmetry, dysmorphic features, or otherphysical abnormalities that may be associatedwith an underlying genetic disorder or syn-drome. Based upon the physical exam and/orother identified congenital anomalies, additionaldiagnostic studies may be warranted when aspecific syndrome is suspected (e.g., screeningfor abnormalities associated with CHARGE syn-drome or OAV spectrum). All infants with an ex-ternal ear anomaly should have an audiologyevaluation to screen for hearing loss.

Due to the association of ear and renal anom-alies, it has been common practice to obtain arenal ultrasound in all infants with any form ofexternal ear anomaly. This practice has comeinto question recently with reports showing thatthe prevalence of renal abnormalities in infantswith isolated minor ear anomalies (preauricularpits or tags) is no greater than in those withoutthese types of ear anomalies.7,8 This evidencewould support the conclusion that renal ultra-sonography is not indicated in the routine evalu-ation of infants with isolated minor ear anomaliesin the absence of other congenital anomalies ordysmorphic features.5,7,8


Infants with significant structural ear anomaliessuch as severe microtia may be candidates forcosmetic surgery later in life. Small peduncu-lated ear tags may be removed by ligation orsurgery. Infants who have associated significanthearing loss may benefit from assisted-hearingdevices. The management of infants with un-derlying genetic syndromes is dependent uponthe associated medical problems.


� TABLE 16–1 Genetic Disorders andSyndromes with Frequent Ear Anomalies

Branchio-oto-renal (BOR)Cornelia de LangeCostelloCHARGE22q11.2 deletion syndrome and other

chromosome abnormalitiesDiabetic embryopathyKabukiNagerNoonanOculo-auriculo-vertebral (OAV) spectrumSaethre ChotzenSmith-Lemli-OpitzTownes BrocksTreacher Collins


Isolated preauricular ear tags and pits are ofteninherited in an autosomal dominant fashion withan increased risk for other family members. In

cases of ear anomalies in infants with identifiedgenetic disorders, the recurrence risk woulddepend on the mode of inheritance of the spe-cific disorder.

CHAPTER 16 EAR ANOMALIES 115

Figure 16-4. Variability of abnormally shaped and positioned ears in different infants. (Reprintedwith permission from Tellier AL, Cormier-Daire V, Abadie V, et al. CHARGE syndrome: report of 47 casesand review. Am J Med Genet. 1998;76:402–9. Reprinted with permission of Wiley-Liss Inc., a subsidiaryof John Wiley & Sons, Inc.)

REFERENCES

1. Quesser-Luft A, Stolz G, Wiesel A, et al. Associationsbetween renal malformations and abnormallyformed ears: analysis of 32,589 newborns and new-born fetuses of the Mainz Congenital Birth DefectMonitoring System. In: XXI David W Smith Workshopon Malformation and Morphogenesis: 60: San Diego,CA; 2000.

2. Kugelman A, Hadad B, Ben-David J, et al. Preauric-ular tags and pits in the newborn: the role of hear-ing tests. Acta Paediatr. 1997;86:170–2.

3. Jones KL, ed. Smith’s Recognizable Patterns of Hu-man Malformation. 6th ed. Philadelphia, ElsevierSaunders; 2006.

4. Sperber GH. Craniofacial Development. London,BC Decker Inc; 2001:38.

5. Wang RY, Earl DL, Ruder RO, et al. Syndromic earanomalies and renal ultrasounds. Pediatr. 2001;108:E32.

6. Kohlhase J, Wischermann A, Reichenbach H, et al.Mutations in the SALL1 putative transcription factorgene cause Townes-Brocks syndrome. Nat Genet.1998;18:81–3.

7. Kugelman A, Tubi A, Bader D et al. Pre-auriculartags and pits in the newborn: the role of renal ultra-sonography. J Pediatr. 2002;141:388–91.

8. Deshpande SA, Watson H. Renal ultrasonographynot required in babies with isolated minor ear anom-alies. Arch Dis Child Fetal Neonatal Ed. 2001;91:F29–F30.


Figure 16-5. Landmarks used to define low-set and posteriorly rotated ears. (Reprintedwith permission from Jones KL, ed. Smith’sRecognizable Patterns of Human Malformation.5th ed., p. 730. Copyright 1997, with permissionfrom Elsevier.)

Chapter 17

Choanal AtresiaBRAD ANGLE

117

� INTRODUCTION

Congenital choanal anomalies are uncommonbut have the potential of life-threatening airwayobstruction. Choanal atresia is a congenital air-way abnormality caused by significant narrow-ing of the posterior nasal passages (choanae).The condition may be unilateral (40–50%) or bi-lateral (50–60%).1,2 Bilateral choanal atresia pre-sents at birth with respiratory distress, whileunilateral cases may not be detected until afterthe early neonatal period. The condition maybe an isolated finding but is often associatedwith other minor or major malformations.

� EMBRYOLOGY/EPIDEMIOLOGY

The nose is formed by the nasal placodes, whichare of ectodermal origin and appear at approx-imately 3 weeks gestation. The placodes invagi-nate during the fifth week of gestation into pits,which extend posteriorly to form the nasal cav-ity that is separated from the oral cavity by theoronasal membrane. This membrane breaks downbetween fifth and sixth weeks of gestation toform the posterior choanae. Choanal atresia isgenerally believed to be caused by the failure ofthe oronasal membrane to rupture.3 The fourparts of the anatomic deformity include a narrow

nasal cavity, lateral bony obstruction by the lat-eral ptyergoid plate, medial obstruction by thick-ened vomer, and a membranous obstruction.While previous reports have indicated that 90%of choanal atresias are bony and 10% are mem-branous, recent reviews using computed tomog-raphy (CT) have indicated that most atresias aremixed and that all membranous atresias havesome bony component.4

Choanal atresia occurs in approximately 1 in12,000 live births.2 Previous reports have sug-gested that it is twice as common in femalesthan in males, but no significant sex differenceswas noted in an epidemiologic study of threelarge birth defect registries.2


Approximately 50% of infants with choanal atre-sia have other congenital abnormalities.2,3 Bilat-eral choanal atresia is more frequently associatedwith other congenital anomalies than unilateralchoanal atresia. Approximately 75% of patientswith bilateral choanal atresia have other associ-ated congenital abnormalities.3 Other nasal anom-alies, cleft palate and other palatal defects, andcraniosynostosis syndromes (e.g., Crouzon) areoften seen in patients with choanal atresia.3


Choanal atresia is a frequent component in morethan 20 syndromes.5 Some of the more commondisorders are listed in Table 17-1.

In 1981, Pagon et al.6 proposed the acronymCHARGE association (Coloboma, Heart anom-alies, choanal Atresia, growth or developmentalRetardation, Genitourinary anomalies, and Ear ab-normalities and/or hearing loss) to describe a pat-tern of congenital malformations in which choanalatresia is a frequent component (Table 17-2). Anassociation is a nonrandom cluster of anomaliesin which the individual components occur to-gether more frequently than would be expectedby chance. While long considered an associa-tion, recently it has been accepted that since thefindings have been sufficiently delineated and aconsistent recognizable pattern occurs in a sig-nificant portion of patients, CHARGE be desig-nated a syndrome rather than an association.7

The most common and obvious facial fea-ture in CHARGE syndrome is an abnormality inthe shape, size, and/or positioning of the ears

(Fig. 17-1). Additional findings commonly iden-tified in individuals with CHARGE syndrome in-clude facial palsy, central nervous system ab-normalities, and cochleovestibular abnormalities(absence or abnormal semicircular canals andvestibular dysfunction).

The minimal criteria for designation ofCHARGE syndrome has been the subject of muchdebate since Pagon’s original report which sug-gested that a diagnosis of CHARGE requires thepresence of at least four of the defined congeni-tal anomalies.6 Harris et al.2 suggested that theterm CHARGE should be restricted to infants withmultiple malformations and choanal atresia and/orcoloboma, combined with other major malfor-mations (heart, ear, and genital) for a total of atleast three cardinal malformations. Using thesecriteria, approximately 15–20% of patients withchoanal atresia and multiple congenital anomalieswould have a designation of CHARGE syndrome.More recently, alternative diagnostic criteria have


� TABLE 17-1 Common Genetic DisordersAssociated with Choanal Atresia

AchondroplasiaBrachmann-de Lange syndromeCHARGE syndromeChromosome abnormalities Craniosynostosis syndromes (including

Apert, Crouzon, Pfeiffer)Treacher Collins syndrome

� TABLE 17-2 Major Features of CHARGEAssociation and Frequencies of Anomalies

Coloboma 82%Heart malformations 74%Choanal atresia 54%Growth and/or mental 92%

retardationGenitourinary anomalies

Male 71%Female 29%

Ear anomalies/deafness 91% / 62%

Figure 17–1. Abnormal shape and position-ing of ear in infant with CHARGE syndrome.(Reprinted with permission from Tellier AL,Cormier-Daire V, Abadie V, et al. CHARGE syn-drome: report of 47 cases and review. Am J MedGenet. 1998;76:402–9. Reprinted with permis-sion of Wiley-Liss Inc., a subsidiary of John Wiley& Sons, Inc.)

been suggested using a combination of desig-nated “major” and “minor” criteria.8

CHARGE syndrome is a genetically and etio-logically heterogeneous disorder. The CHARGEphenotype may be observed in infants with a va-riety of chromosome abnormalities (including tri-somies 13 and 18, and 22q11 deletion syndrome),OAV spectrum, and VACTERL association (Vertebral-Anal-Cardiac-Tracheo-Esophageal fistula-Renal-Limb anomalies). Until recently, no specific genehas been identified as a cause of CHARGE syn-drome. In 2004, a microdeletion in chromosome8 was identified in a patient and subsequentlymutations in the CHD7 gene located in this chro-mosome region were found in 10 of 17 (59%)well-characterized individuals with CHARGEsyndrome.9


As neonates are obligate nasal breathers, infantswith bilateral choanal atresia present at birth withthe immediate onset of respiratory distress andcyanosis which is relieved by crying. It can be di-agnosed by failure to pass a small 3- to 4-mmthick nasogastric catheter through the nose intothe nasopharynx. Computerized tomographyis the preferred radiographic test to documentthe specific anatomic details of the obstruction.

The frequent occurrence of other congenitalanomalies with choanal atresia dictates a thor-ough physical examination and diagnostic screen-ing to evaluate for other abnormalities, includingfindings associated with CHARGE syndrome(Table 17-3).

Genetic testing is not indicated in infants withisolated choanal atresia but is appropriate incases where other congenital anomalies are iden-tified. Chromosome analysis should be obtainedin all infants who have multiple anomalies and,in infants with features of CHARGE syndrome,FISH testing for 22q11 deletion is also warranted.The option of molecular testing for microdele-tions of chromosome 8 or mutations in the CHD7gene may be considered in infants suspected of

having CHARGE syndrome who do not haveanother identified disorder or chromosomeabnormality.


Infants with bilateral choanal atresia require im-mediate airway support. Definitive managementrequires surgical resection of bony abnormali-ties and/or endoscopic perforation of membra-nous deformities followed by stenting, usuallywithin the first week of life. Infants with unilat-eral choanal atresia usually do not have respi-ratory distress and definitive therapy is per-formed prior to school age.

Infants with isolated choanal atresia are ex-pected to have a good prognosis. In contrast,neonates with CHARGE syndrome have a signif-icant mortality rate, especially in the first 2 yearsof life. Poor prognostic factors include severecardiac anomalies, bilateral choanal atresia, andCNS abnormalities.10 Infants with CHARGE syn-drome are at risk for developmental delay rang-ing from mild delays to profound mental retar-dation, particularly if CNS anomalies are present.


Most cases of isolated choanal atresia are prob-ably multifactorial traits with a low recurrencerisk (2–3%). Rare familial cases occur with a

CHAPTER 17 CHOANAL ATRESIA 119

� TABLE 17-3 Diagnostic Evaluation of Infantwith Choanal Atresia

EchocardiogramRenal ultrasoundHearing evaluationOphthalmology examBrain imaging if abnormal neurological examCT of temporal bones to assess inner ear

abnormalities if high suspicion of CHARGEChromosome analysis in all cases with

multiple anomaliesFISH for 22q11.2 deletion if other features

of CHARGE

corresponding higher recurrence risk. The re-currence risk in cases of choanal atresia withmultiple anomalies depends on the underlyinggenetic cause, if any (e.g., chromosome abnor-malities, specific syndromes). Most cases ofCHARGE syndrome (in the absence of otherspecifically identified syndrome) are sporadicor possible new mutations of the CHD7 genewith a low recurrence risk.

REFERENCES

1. Leclerc JE, Fearon B. Choanal atresia and associ-ated anomalies. Int J Pediatr Otorhinolaryngol.1987;13:265–72.

2. Harris J, Robert E, Källén B. Epidemiology ofchoanal atresia with special reference to theCHARGE association. Pediatr. 1997;99:363–7.

3. Keller JL, Kacker AZ. Choanal atresia, CHARGE as-sociation, and congenital nasal stenosis. Otolaryn-gol Clin North Am. 2000;33:1343–51.

4. Brown OE, Pownell P, Manning SC. Choanal atresia:A new anatomic classification and clinical manage-ment applications. Laryngoscope. 1996;106:97–101.

5. Taybi H, Lachman R. Radiology of Syndromes,Metabolic Disorders and Skeletal Dysplasias.St. Louis, Mosby-Year Book; 1996.

6. Pagon RA, Graham JM, Zonana J, et al. Coloboma,congenital heart disease and choanal atresia withmultiple anomalies: CHARGE association. J Pediatr.1981;99:223–7.

7. Graham JM. A recognizable syndrome withinCHARGE association: Hall-Hittner syndrome.Am J Med Genet. 2001;99:120–3.

8. Verloes A. Updated diagnostic criteria for CHARGEsyndrome: A proposal. Am J Med Genet. 2005;133A:306–8.

9. Vissers LELM, van Ravenswaaij CMA, AdmiraalR, et al. Mutations in a new member of the chro-modomain gene family cause CHARGE syndrome.Nat Genet. 2004;36:955–77.

10. Tellier AL, Cormier-Daire V, Abadie V, et al.CHARGE syndrome: report of 47 cases and review.Am J Med Genet. 1998;76:402–9.


Chapter 18

ColobomaBRAD ANGLE

121

� INTRODUCTION

A coloboma is an ocular malformation consistingof a cleft, notch, gap, hole, or fissure caused byabsent tissue in the eye. All layers of the eye canbe involved, including the cornea, iris, ciliarybody, choroids, retina, and optic nerve. This sec-tion will focus on iris coloboma. Iris colobomacan occur as an isolated malformation, in con-junction with other ocular malformations, or withother congenital anomalies and malformationsyndromes. The most frequently associated ocu-lar anomaly is microphthalmia (small globe).

� EMBRYOLOGY AND INCIDENCE

Congenital ocular colobomata are caused bydefects in embryogenesis. The eye derives fromthree embryological germ layers: neuroecto-derm, which gives rise to optic vesicle; neuralcrest cells, which migrate to the anterior cham-ber of the developing eye; and the ectoderm,from which forms the lens placode. Linear in-vagination of the optic vesicle at approximately30 days gestation results in the formation of adouble-layered optic cup and gives rise to thefetal or choroidal fissure, allowing blood vesselsfrom the vascular mesoderm to enter the devel-oping eye. The fetal fissure narrows and closesduring the fifth or sixth week of gestation.

Ocular colobomata result from failure of aportion of the fetal fissure to close.1 The defectmay appear as a coloboma of one or more oc-ular structures including the iris, lens, ciliarybody, choroid, retina, and the optic nerve. Theincidence of ocular coloboma is approximately1–2.5 per 10,000 births.2


Although most cases of iris coloboma are iso-lated congenital anomalies, they frequently oc-cur in association with other ocular anomaliesor with multiple congenital anomalies in manywell-defined monogenic disorders, chromo-some abnormalities, and recognized malforma-tion syndromes.3 Some of the more commondisorders are listed in Table 18-1 and details ofseveral of those are discussed below.

Iris Coloboma with Primary OcularAbnormalities

Iris coloboma may occur in association with aniridia(complete or partial iris hypoplasia). Aniridia may,in turn, occur as part of the Wilms tumor-aniridia-genital anomalies-retardation (WAGR) syndromecaused by deletion of chromosome 11p13 in-volving genes associated with anirida (PAX6) and


Wilms tumor (WT1). All infants with aniridia re-quire further investigation with molecular test-ing to identify those that are at increased risk forWilms tumor in infancy and early childhood.

Iris colobomata are occasionally observed incases of Rieger syndrome, a multisystem auto-somal dominant disorder in which anterior seg-ment dysgenesis of the eye (Rieger anomaly) isaccompanied by facial, dental, umbilical, andskeletal abnormalities. Infants with Rieger syn-drome may have dysmorphic facial features witha broad nasal root, maxillary hypoplasia, and aprominent lower lip. Failure of involution of theperiumbilical skin is a cardinal feature consist-ing of redundant skin often mistaken for an um-bilical hernia.

Iris Coloboma with MultipleCongenital Anomalies

One of the multiple congenital anomaly disordersmost frequently associated with iris coloboma isCHARGE syndrome (see Chap. 17). Approxi-mately 80% of infants with CHARGE syndromehave an iris coloboma.

Ocular malformations are a major feature ofWalker-Warburg syndrome, an autosomal reces-sive disorder characterized by brain and eyemalformations, and congenital muscular dystro-phy. The typical central nervous system malfor-mation is lissencephaly, although other cerebraland cerebellar malformations may be present.The most common eye abnormalities are retinalmalformations, but other ocular defects may bepresent including anterior chamber malforma-tions such as Peter anomaly, cataract, coloboma,and other defects. Congenital muscular dystro-phy is manifested by hypotonia and elevatedlevels of creatine kinase.

Iris colobomata are frequently observed innumerous chromosome abnormalities, includinga number of common chromosome syndromesthat have recognizable phenotypes (Table 18-1),as well as many nonspecific chromosome aberra-tions. In addition to the well-recognized trisomies,iris colobomata are characteristically associatedwith one particular chromosome abnormality,the so-called “cat eye syndrome.” This chromo-some abnormality involves a marker chromo-some (small extra chromosome) consisting oftwo identical segments of chromosome 22, thusresulting in four copies of chromosome 22 mate-rial (tetrasomy 22p). The syndrome is character-ized by a variable pattern of anomalies includingminor facial features of hypertelorism anddown-slanting palpebral fissures, ear anomalies,imperforate anus or other anal anomalies, andiris colobomata. The name is derived from thecharacteristic appearance of the iris colobomata.Congenital heart defects, particularly total anom-alous pulmonary venous return and tetralogyof Fallot, and various renal malformations mayalso occur. This chromosome abnormality is


� TABLE 18–1 Genetic Disorders Associatedwith Iris Coloboma

Primary Ocular DefectsWilms tumor-aniridia-genital-retardation

(WAGR)Rieger syndromeLenz microphthalmia

Multiple Congenital Anomaly SyndromesCHARGEWalker-WarburgMeckel-GruberRubinstein-TaybiGoltzBranchio-oculo-facialTreacher CollinsOculo-auriculo-vertebral spectrum

Chromosome AbnormalitiesTrisomies

Trisomy 13Trisomy 18Trisomy 22

DuplicationsDuplication 4q+Duplication 9p+Tetrasomy 22p (cat eye syndrome)

DeletionsDeletion 4p− (Wolf-Hirschhorn syndrome)Deletion 13q−Deletion 18q−

typically associated with profound mentalretardation.


An iris coloboma is identified on physical exam asan abnormally shaped iris. The typical colobomais usually inferior and nasal in location, involv-ing both the pigment epithelium and stroma,giving rise to the so-called “keyhole” or “tear drop”pupil (Fig. 18-1).

A diagnostic approach to the evaluation ofan infant with an iris coloboma is illustrated inFig. 18-2. Any infant with an iris coloboma shouldhave a full ophthalmologic exam to evaluate forother ocular anomalies and a complete physicalexam to identify dysmorphic features or additionalcongenital anomalies. In addition, all infants withan iris coloboma should have echocardiographyand renal ultrasound to screen for abnormalities

associated with CHARGE syndrome. Chromosomeanalysis should be obtained in any infant withdysmorphic features or additional congenitalanomalies. Finally, biochemical and/or molecular

CHAPTER 18 COLOBOMA 123

Figure 18-1. Typical iris coloboma with “key-hole” pupil. (Used with permission from UmbertoBenelli, MD, University of Pisa, Italy.)

Iris Coloboma

Complete Opthalmologic and PhysicalExam

Normal Physical Exam with no OtherOcular Anomalies

Familial ColobomaNormal

Positive FamilyHistory

Negative FamilyHistory

Echocardiography andRenal USG for CHARGE

associated anomalies

NormalIsolated Sporadic Coloboma

Abnormal Physical ExamNormal Physical Examwith Other Ocular

Primary Ocular DefectChromosome Analysis

Echocardiography andRenal USG for

CHARGE associatedanomalies

Abnormal CHARGE or Other

Syndrome

NormalNo SpecificDiagnosis

Abnormal

ChromosomeAbnormality

Figure 18-2. Diagnostic approach to the evaluation of iris coloboma.

testing, if available, may be indicated basedupon clinical suspicion of a specific disorder orsyndrome.


The visual prognosis of iris coloboma rangesfrom normal to severe impairment dependingupon the location and associated eye defects.Most isolated small iris colobomata do not causevisual impairment. The presence of microph-thalmia (particularly with cysts) or other oculardefects may result in significant visual deficits.Surgical repair of an iris coloboma is not gener-ally performed unless other intraocular surgeryis indicated (e.g., cataract extraction).


Progress is being made in the understandingof the molecular mechanisms involved in thepathogenesis of ocular coloboma. More than adozen genes that play a role in coloboma for-mation have been identified, although it is likelythat most coloboma genes are still currently notknown.3 Despite the advancements in the under-standing of the genes that are important in eyedevelopment, the underlying etiology of ocularcolobomata is unknown in most cases. A largeproportion of sporadic, unilateral colobomataare likely due to nongenetic factors.3

Genetic counseling for ocular coloboma isdependent upon a specific diagnosis. Heredi-tary forms of coloboma occur and most fre-quently follow an autosomal dominant patternof inheritance. If a familial form of coloboma ora specific systemic disorder or syndrome is iden-tified, recurrence risks would be based uponthe particular pattern of inheritance of that dis-order (e.g., autosomal dominant, recessive, orX-linked). In cases of isolated coloboma in theabsence of a positive family history, the parentsof an affected child should be carefully examinedto identify any occult (often retinal) coloboma orother minor ocular malformations which mightreveal a previously unsuspected hereditary con-dition. If both parents have normal eye exams,the empiric risk for isolated ocular coloboma infuture pregnancies is approximately 3–4%.4

REFERENCES

1. Mann I. Developmental Abnormalities of the Eye.2nd ed. Philadelphia, Lippincott; 1957:81–103.

2. Stoll C, Alembick Y, Dott B, et al. Congenital eyemalformations in 212,479 consecutive births. AnnGenet. 1997;40:122–8.

3. Gregory-Evans CY, Williams MJ, Halford S, et al. Oc-ular coloboma: a reassessment in the age of molec-ular neuroscience. J Med Genet. 2004;41:881–91.

4. Morrison D, FitzPatrick D, Hanson I, et al. Nationalstudy of microphthalmia, anophthalmia, andcoloboma (MAC) in Scotland: investigation of ge-netic aetiology. J Med Genet. 2002;39:16–22.


Chapter 19

CataractBRAD ANGLE

125

� INTRODUCTION

A cataract is an opacification of the crystallinelens of the eye (Fig. 19-1). In infants, a cataractmay interfere with the development of the cen-tral nervous system pathways responsible forvision and cause amblyopia. In older childrenand adults, blurring and distortion of vision arethe major effects of cataracts. Congenital cataractis responsible for 10% of all blindness in chil-dren and is the most common cause of treatablechildhood blindness.1,2 Cataract may occur asan isolated congenital anomaly, in associationwith other ocular abnormalities, or as part of amultisystem disorder or syndrome.


Congenital cataracts occur in 1–4 per 10,000 births.3

Approximately 50% of cases are unilateral and50% bilateral. Approximately one-third of in-fants with congenital cataracts have isolatedhereditary forms, one-third are associated withsystemic or syndromic disorders, and one-thirdhave an idiopathic etiology. Known causes in-clude intrauterine infections, metabolic disor-ders, chromosome abnormalities, and a varietyof systemic or syndromic disorders.

From an anatomic perspective, the eye isdivided into two segments, the anterior and

posterior. The anterior segment consists of thecornea, iris, and lens. The posterior segment con-sists of the vitreous jelly and the retina. The an-terior segment of the eye is derived from surfaceectoderm and the neural crest. The lens developsby the formation of an embryonic nucleus dur-ing morphogenesis, around which lens fibers aredeposited throughout life, initially forming thefetal nuclear region and thereafter the cortex. Ab-normalities of morphogenesis of unknown causeor lens fiber dysfunction caused by mutations ingenes expressed within the lens may result in theformation of congenital cataracts.

Many genes involved in cataractogenesis havebeen identified, including more than a dozen genescausing autosomal dominant cataracts, at least fiveautosomal recessive genes, and one X-linked re-cessive gene.4 Crystallins are stable water-solubleproteins that make up 90% of the lens proteinsand play a critical role in maintaining lens trans-parency. More than 15 crystallin mutations havebeen reported in association with childhoodcataract.4

� CLASSIFICATION OFCONGENITAL CATARACTS

Cataracts are often classified according to eithermorphology or etiology. Congenital cataractscan be classified morphologically into four broad


categories: zonular, polar, total (mature), andmembranous. Zonular cataracts involve one areaof the lens and can be subdivided into nuclear,lamellar, and other types. Lamellar cataract is themost common type of congenital cataract and ischaracterized by an opaque layer surrounding arelatively clear nucleus. Nuclear cataract is usu-ally present at birth and is nonprogressive, whilethe lamellar type usually develops in the first fewmonths and is progressive.5

From a genetic perspective, cataracts canalso be grouped in four categories: isolatedhereditary congenital cataracts, cataracts associ-ated primarily with ocular disorders, cataractsassociated with syndromes, and cataracts associ-ated with metabolic disorders. This classificationmay be helpful when considering a diagnosticapproach to the evaluation of an infant withcongenital cataracts.

Cataracts are often associated with otheranomalies and are a feature of numerous sys-temic disorders and genetic syndromes. Cataractsmay appear in childhood or adulthood in many

of these conditions. The disorders discussed inthis chapter are limited to those that are themost common disorders associated with con-genital cataracts identifiable in the neonatalperiod (Table 19-1). More inclusive lists ofthe many disorders associated with cataracts(congenital and later onset) may be foundelsewhere.6


Figure 19-1. Opacification of lens in infantwith congenital cataract. (Reprinted fromJournal of Medical Genetics. 2000;37:481–8.Reproduced with permission from the BMJ Pub-lishing Group.)

� TABLE 19-1 Causes of Congenital Cataracts

Isolated CataractsSporadic (no family history)Hereditary

Autosomal dominantAutosomal recessiveX-linked recessive

Ocular DisordersAniridiaRieger anomalyPeters anomalyMicrophthalmia

Systemic Disorders and SyndromesLowe syndromeZellweger syndromeChondrodysplasia punctataSmith-Lemli-Opitz syndromeCockayne syndromeIncontinentia pigmentiIcthyosisChromosome abnormalities

Trisomy 13Trisomy 18Trisomy 21 (Down syndrome)Others

Intrauterine infectionsToxoplasmosisRubellaCytomegalovirusHerpesSyphilisVaricella

Metabolic DisordersGalactosemiaGalactokinase deficiency

Isolated Cataracts

Congenital cataract (unilateral or bilateral) fre-quently occurs as an isolated congenital anom-aly, either as a sporadic case or in families withother affected individuals. Most familial casesoccur in an autosomal dominant pattern, althoughX-linked and autosomal recessive inheritancehas been observed in a few families. Bilateralcataracts are present in most familial cases,although unilateral cataracts may occur occa-sionally. Penetrance is usually high and cataractmorphology may vary among family members.

Cataracts Associated with OtherOcular Abnormalities

Congenital cataracts often occur in conjunctionwith other ocular abnormalities, suggesting a de-velopmental defect as being the cause for thecataract. Interference of embryologic develop-ment may result in anterior segment abnormali-ties such as aniridia (absent iris), Rieger anomaly(iris hypoplasia and abnormal angle structures),Peters anomaly (central corneal leukoma andcataract, and microphthalmia (small, abnormallydeveloped eye), all of which have been reportedin association with cataracts.7

Congenital Cataracts Associatedwith Systemic Disorders andSyndromes

Lowe syndrome (oculocerebrorenal syndrome)is an X-linked disorder in which affected maleshave renal Fanconi syndrome (aminoaciduria),mental retardation, and ocular abnormalities, in-cluding congenital cataracts. Other ocular anom-alies include papillary abnormalities and glaucoma.Approximately 95% of affected males have a de-tectable mutation in the OCRL-1 gene whichcauses Lowe syndrome.

Zellweger syndrome (cerebrohepatorenal syn-drome) is a multisystem disorder of peroxisomal

biogenesis resulting in dysmorphic facies, hypo-tonia, liver cysts with hepatic dysfunction, renalcysts, ocular anomalies, and chondrodysplasiapunctata. Infants are usually severely affectedand most die during the first year of life due toprogressive apnea or complications of respira-tory infection. Biochemical testing to identify ab-normal levels and ratios of very long chain fattyacids (VLCFA) is the most informative initialscreen for a defect in perixosomal fatty acid me-tabolism. Mutations in 12 different PEX geneswhich encode for proteins required for peroxi-some assembly have been identified in patientswith Zellweger syndrome. Approximately 50%of individuals with Zellweger syndrome havemutations in the PEX1 gene.8

Chondrodysplasia punctata is another disor-der of peroxisomal biogenesis and is character-ized by punctate calcifications in cartilage withepiphyseal and metaphyseal abnormalities, ver-tebral abnormalities, congenital cataracts and, inmost cases, asymmetric limb shortening (usuallyrhizomelic). Later, severe developmental prob-lems and postnatal growth retardation becomeevident. The condition is often lethal in infancyor childhood, but individuals with milder phe-notypes are observed. There are different formsof this disorder including autosomal dominantand recessive, and X-linked dominant and re-cessive types. Biochemical testing of peroxiso-mal function including VLCFA, phytanic acid,and plasmalogens can confirm a diagnosis andmolecular testing for mutations in PEX7, a geneassociated with one form of chondrodysplasiapunctata, is available on a clinical basis.

Smith-Lemli-Opitz (SLOS) is an autosomalrecessive multiple congenital anomaly syn-drome caused by an abnormality in cholesterolmetabolism resulting from deficiency of the en-zyme 7-dehydrocholesterol reductase. It is char-acterized by dysmorphic features, genital anom-alies, microcephaly, prenatal and postnatalgrowth retardation, polydactyly, syndactyly of thesecond and third toes, and mental retardation.Confirmation of a suspected diagnosis requiresdetection of an elevated serum concentration of

CHAPTER 19 CATARACT 127

7-dehydrocholesterol (7-DHC). Mutations in theDHCR7 gene are identified in more than 80% ofaffected individuals.

Cataracts have been identified in both neona-tal and classic Cockayne syndrome (CS). NeonatalCS (also known as cerebro-oculo-facial syndromeand Pena-Shokeir type II syndrome) is charac-terized by growth failure at birth, little or no post-natal neurological development, and early post-natal contractures of the spine and joints.Congenital cataracts or other structural anom-alies of the eye may be present. Affected indi-viduals typically die by age seven years. CS is anautosomal recessive disorder. CS is diagnosedby clinical findings and by assay of DNA repairin skin fibroblasts. Mutations have been identifiedin the two genes that cause CS, ERCC6 (75% ofindividuals) and CKN1 (25% of individuals).

Cataracts may occur in a number of condi-tions that affect the skin. Incontinentia pigmenti(IP) is a disorder that affects the skin, hair, teeth,and nails. The skin lesions begin as blistering inthe newborn period and evolve into a wart-likerash during infancy and swirling areas of hy-perpigmentation in late infancy through adult-hood. Alopecia, hypodontia, abnormal toothshape, and dystrophic nails are also observed.Approximately 40% of affected individuals haveabnormalities of the retinal vessels and pigmentcells predisposing to retinal detachment in earlychildhood. Other ocular abnormalities, includ-ing congenital cataracts, may also be observed.Cognitive delays and mental retardation are occa-sionally seen. A clinical diagnosis of IP can be con-firmed by skin biopsy and/or molecular testingof the causative IKBKG gene. IP is an X-linkeddominant disorder that is lethal in most, but notall, males.

Congenital cataracts occur occasionally ininfants with autosomal recessive congenitalichthyosis who present with features of brown,scaly skin, and possible ectropium (eversion ofeyelids). Mutations may be identified in one offive genes known to cause this disorder. Cataractsmay be one of multiple congenital anomalies pre-sent in infants with chromosome abnormalities,

including those with recognizable phenotypessuch as trisomies 13, 18, and 21, as well as manyother nonspecific chromosome abnormalities.

While not discussed in this chapter, severalintrauterine infections including TORCH andothers (toxoplasmosis, rubella, cytomegalovirus[CMV], herpes, varicella, syphilis) can cause con-genital cataracts and must be considered in thedifferential diagnosis in an affected infant.

Cataracts Associated withMetabolic Diseases

Galactosemia is the most common metabolicdisorder which may cause congenital cataracts.Classical galactosemia is an autosomal recessivedisorder of galactose metabolism caused by se-vere deficiency or complete absence of the en-zyme galactose-1-phosphate uridyl transferase(GALT). Untreated classical galactosemia pre-sents in the neonatal period with failure to thrive,jaundice, bleeding diathesis, and sepsis (mostnotably Escherichia coli infection). Approxi-mately 10% of infants have congenital cataracts.Dietary management with a galactose-free diet isthe mainstay of treatment of classical galactosemia.Some individuals have a milder variant form ofgalactosemia with partial enzyme deficiency thatdoes not require long-term treatment.

Virtually 100% of affected infants can beidentified in areas which include galactosemiatesting in newborn screening programs. New-born screening tests most commonly includeassays of GALT and/or galactose. Infants withabnormal newborn screening tests should haveconfirmatory testing by quantitative measure-ment of erythrocyte GALT enzyme activity.

The cataracts in galactosemia most likely re-sult from the accumulation of galactitol, a by-product of galactose metabolism. Most cataractsin infants with galactosemia will regress or com-pletely resolve with proper dietary treatment.

Congenital cataracts also occur in galactok-inase deficiency, another disorder of galactosemetabolism. Galactokinase deficiency is not


associated with the systemic manifestations ofgalactosemia. Affected infants can be identifiedby newborn screening and treatment is similarto galactosemia. As with galactosemia, treatmentusually results in regression of the cataracts.


The presence of a congenital cataract is usuallyfirst suspected on physical exam by the lack ofa red reflex and the presence of leukokoria(white pupillary reflex produced by reflection oflight from a light-colored intraocular mass orstructure). Numerous ocular abnormalities mayproduce leukokoria including cataracts, colobo-mas, retinoblastoma, retinopathy of prematurity,and others. Direct ophthalmoscopy and dilatedslit-lamp and fundal examination are necessaryto confirm the diagnosis of a cataract and iden-tify any other ophthalmologic abnormalities.

A detailed prenatal and family history shouldbe obtained when cataracts are identified in anewborn. A detailed prenatal history should in-clude any exposures to environmental agents ordrugs, and any symptoms or diagnosis of ma-ternal infections. A thorough family history isessential to determine if the condition may behereditary. While most congenital cataracts areisolated abnormalities, all infants with cataractsshould have a careful physical examination and,when indicated, undergo evaluation for otheranomalies and associated disorders.

A diagnostic approach to the evaluation ofcongenital cataracts is outlined in Fig. 19-2. In-fants with isolated cataracts should have TORCHscreening and testing for galactosemia and galac-tokinase deficiency (or confirmation of normalnewborn screening tests). Infants with other ab-normalities on physical examination or identi-fied congenital anomalies should have a chro-mosome analysis. Testing for specific syndromes


Cataract Identified on Inital Exam

Complete Physical and Ophthalmologic Exam

Primary Ocular Defect 1. Evaluate Family History For Possible Hereditary Cataracts2. TORCH Titers for Intrauterine Infection3. Test For Galactosemia and Galactokinase Deficiency

1. Chromosome Analysis2. Testing for Specific Genetic Disorders Based Upon Clinical Findings (See Table 19-2)

Normal Physical Examwith Other Ocular

Anomalies

Normal Physical Examwith No Other Ocular Anomalies: Isolated

Cataracts

Abnormal Physical Examwith Other Congenital

Anomalies

Figure 19-2. Diagnostic approach to the evaluation of congenital cataracts.

should be considered based upon clinical sus-picion (Table 19-2).


Management of congenital cataracts involvesobservation if the opacities are minimal and donot interfere with vision. For congenital cataractsthat interfere with vision, surgical lens extrac-tion is the only option. The early removal ofcataracts within the first few weeks of life or assoon as possible after diagnosis has been ad-vocated to prevent irreversible central nervoussystem damage. The visual outcome of surgerydepends on a variety of factors includingwhether the cataract is unilateral or bilateral, thetype of cataract, and the presence or absence ofother ocular abnormalities.


While identification of genes causing inheritedforms of cataract will be crucial to understandinglens development and the pathogenesis ofcataracts, molecular testing for inherited forms ofcataracts does not currently play a significant rolein diagnosis or genetic counseling for affectedindividuals and families. Clinical diagnosis re-mains the key component in providing the mostaccurate genetic counseling possible at this time.

In cases of isolated bilateral cataract wherethe abnormality is confined to the lens and thereis a positive family history, most will demon-strate an autosomal dominant inheritance pat-tern with a 50% risk of recurrence. Unilateralcongenital cataract in the absence of a positivefamily history is generally not associated withsystemic disease and is rarely inherited. Mostcases of unilateral cataract are of idiopathiccause with a low recurrence risk.

Genetic counseling in sporadic cases (thosewithout a positive family history) of bilateralcongenital cataracts history is more uncertain.In cases of bilateral cataract associated with anidentified hereditary or genetic etiology, the re-currence risk is that which is attributed to theknown disorder. In cases of sporadic bilateralcataract of idiopathic etiology, all first degree rel-atives (parents and sibs) should have ophthal-mology examinations to exclude mild congenitalopacities which might identify a previously un-recognized hereditary form. In the absence ofan identified cause and other affected relatives,a precise recurrence risk of congenital cataractsin future children is difficult to quantify but islikely less than 10%.

REFERENCES

1. Nelson LB, Maumenee IH. Diagnosis and manage-ment of cataracts in infancy and childhood. Oph-thalmic Surg. 1982;15:688–97.


� TABLE 19-2 Testing for Genetic Syndromes Associated with Cataracts

Biochemical/ MolecularCausative Histopathologic Testing

Disorder Gene(s) Testing Available

Lowe syndrome OCRL-1 Urine amino acids YesZellweger syndrome PEX1 Serum very long chain fatty acids YesChondrodysplasia punctata PEX7 Serum very long chain fatty acids YesSmith-Lemli-Opitz syndrome DHCR7 Serum 7-dehydrocholesterol YesCockayne syndrome ERCC6 and Fibroblast assay for DNA repair No

CKN1Incontinentia pigmenti IKBKG Skin biopsy YesCongenital ichthyosis TGM1 and Skin biopsy Yes

others

2. Zetterström C, Lundvall A, Kugelberg M. Cataracts inchildren. J Cataract Refract Surg. 2005;31:824–40.

3. Foster A, Gilbert C, Rahi J. Epidemiology of cataractin childhood: a global perspective. J Cataract Re-fract Surg. 1997;23:601–4.

4. Francis PJ, Moore AT. Genetics of childhood cataract.Curr Opin Ophthalmol. 2004;15:10–5.

5. Parks MM, Johnson DA, Reed GW. Long-term visualresults and complications in children with aphakia;a function of cataract type. Ophthalmology. 1993;100:826–40.

6. Holmstrom GE, Rearson WP, Baraister M, et al. Het-erogeneity in dominant anterior segment malforma-tions. Br J Ophthalmol. 1991;75:591–7.

7. Rabinowitz YS, Cotlier E, Bergwerk KL. Anomalies ofthe lens. In: Rimoin DL, Conner JM, Pyeritz, et al.,eds. Principles and Practice of Medical Genetics. 4thed. New York, Churchill Livingstone; 2002:3543.

8. Steinberg S, Chen L, Wei L, et al. The PEX GeneScreen: molecular diagnosis of peroxisome biogen-esis disorders in the Zellweger syndrome spectrum.Mol Genet Metab. 2004;83:252–63.



Part IV

RespiratoryMalformations



Chapter 20

Congenital High AirwayObstruction Syndrome

SANDRA B. CADICHON

135

� INTRODUCTION

Congenital high airway obstruction syndrome(CHAOS) was first described in 1826 and sincethen only a few cases of long-term survivorshave been described in the literature.1 Thisclinical syndrome is caused by complete ornear complete obstruction of the fetal airwayleading to extreme respiratory distress at birthand has a high mortality rate. On prenatal ul-trasound the lungs appear as large echogenicstructures, the diaphragm is inverted or flat-tened and often there is associated fetal ascitesand or nonimmune hydrops. The findings ob-served on prenatal ultrasound are thought tobe a result of upper airway obstruction, whichprevents the normal flow of fetal lung fluidinto the amniotic fluid. The lungs therefore ex-pand and produce a flattening of the diaphragmand appear hyperechogenic on ultrasound; ifthe lung fields expand to the point of produc-ing esophageal compression, polyhydramniosmay occur as a result of impaired swallowingof amniotic fluid.2 Airway abnormalities andlesions presenting as congenital high airwayobstruction syndrome at birth are listed inTable 20-1.


Most cases of CHAOS are sporadic and the trueincidence is unknown. Only 52 cases have beenreported with 22 of these cases reported since1989;3 though the true incidence may be higherthan suggested by these case reports. A geneticcause or predisposition for CHAOS has not beendetermined. However, there has been one reportof a unique family with autosomal dominant in-heritance of CHAOS and variable expression inthe affected father and two affected children.4

The father in this case had a history of beingtreated for “chronic croup” by tracheal cannula-tion. The father underwent an indirect laryn-goscopy, after his child’s presentation withCHAOS, which revealed a partial subglotticwebbing suggesting that the father was alsomildly affected by CHAOS.4

� EMBRYOLOGY

The laryngotracheal groove develops by the fourthweek of gestation on the ventral surface of thecaudal end of the pharynx. The groove progres-sively deepens forming a diverticulum anterior to


the pharynx. The distal portion will become thelungs and the proximal lateral walls of the di-verticulum invaginate to form the tracheoe-sophageal folds which eventually fuse in themidline. This fusion forms a septum separatingthe primitive airway from the pharynx and theesophagus. During the 5th week of gestation,the fourth and sixth pairs of the branchial archesform the cartilaginous structures of the larynx.The glottic epithelium proliferates rapidly dur-ing early gestation forming a temporary occlu-sion of the laryngeal lumen.5 This resulting plugis recanalized by the 10th week of gestation.5

CHAOS results from the failure of complete re-canalization of the larynx and/or trachea.


CHAOS is often diagnosed or suspected prenatallyby the presence of enlarged lung fields associatedwith a flattened or inverted diaphragm, ascites,and/or hydr ops. In the event that prenatal ultra-sound was not performed and the diagnosis isunknown, the infant usually presents withcyanosis, absent or weak phonation, and respi-ratory failure immediately after delivery. At-tempted endotracheal intubation will reveal ab-normalities of the larynx or trachea (atresia,stenosis, or cysts). Without immediate tra-cheotomy, survival is unlikely in severely af-fected cases. Mildly affected cases with partialobstruction may have variable symptoms in theneonatal period. On rare occasions, the pres-ence of a tracheo-esophageal fistula (TEF) may

allow for temporary ventilation and can be life-saving.5


The most frequently associated syndrome ob-served with CHAOS is Fraser syndrome. Frasersyndrome is characterized by malformations of thelarynx, cryptophthalmos, syndactyly, genitourinarytract, craniofacial dysmorphism, orofacial clefting,mental retardation, and musculoskeletal anom-alies. Other syndromes that have been reportedin association with CHAOS include: Short-ribpolydactyly syndrome,6 Cri-du-Chat syndrome,7

and Velo-cardio-facial syndrome.8 Recently CHAOShas been described as part of a newly proposedassociation, TACRD (Tracheal Agenesis, complexcongenital Cardiac abnormalities, Radial ray de-fects, and Duodenal atresia) pattern.9 This associ-ation is distinct from the more common VACTERL(Vertebral-Anal-Cardiac-Tracheo-Esophageal

136 PART IV RESPIRATORY MALFORMATIONS

� TABLE 20-1 Airway Anomalies in InfantsPresenting with CHAOS

Laryngeal atresiaLaryngeal stenosisLaryngeal cystLaryngeal webTracheal stenosisTracheal atresia

� TABLE 20-2 Systemic MalformationsReported in Association with CHAOS

Brain/Central Nervous SystemHydrocephalusMalformation of the aqueduct of SylviusAnophthalmia

SkeletalVertebral anomaliesAbsent radiusSyndactylyClub foot

PulmonaryBronchotracheal fistulaTracheo-esophageal fistulaTracheobronchomalacia

GastrointestinalEsophageal atresiaImperforate anusOmphalocele

GenitourinaryRenal agenesis

fistula-Renal-Limb anomalies) association whichhas TEF and not tracheal agenesis as part of itssequence. Table 20-2 lists the malformations thathave been reported in association with CHAOS.

� EVALUATION

The diagnosis is often made in utero with ultra-sound findings revealing large echogenic lungs,dilated airways, flattened or inverted di-aphragms, ascites, and/or hydrops. Postnatally,the diagnosis is suspected if there is absent orweak phonation and inability or difficulty toperform an endotracheal intubation and is con-firmed by direct laryngoscopic examination ofthe upper airways. Careful examination for dys-morphic features and associated anomalies maygive a clue to the underlying etiology. TEF andanorectal malformations should be excludedand skeletal survey, cranial and abdominal ul-trasound should be considered.


Prenatally, fetoscopic tracheoscopy has beenperformed to delineate and treat the cause ofobstruction.1 A favorable outcome following in-utero ultrasound-guided decompression of thefetal trachea was recently reported in an infantwith CHAOS from laryngeal atresia.10

At delivery, the management of prenatallydiagnosed CHAOS requires the presence of amultidisciplinary team including: neonatologists,pediatric otorhinolaryngologist, and pediatricsurgeons. The EXIT procedure (ex utero intra-partum treatment), which was first developedfor reversing tracheal occlusion in fetuses withsevere congenital diaphragmatic hernia, offersthe advantage of ensuring uteroplacental gas ex-change while on placental support and has re-sulted in favorable outcome in some cases ofprenatally diagnosed CHAOS.1,3,11,12 The centralprinciple of the EXIT procedure is controlleduterine hypotonia to preserve the uteroplacentalcirculation until the fetal airway is secured by

endotracheal intubation or emergent tracheotomyin cases of complete laryngotracheal obstruc-tion.3 After delivery with a secure airway, the in-fant is then managed on mechanical ventilationuntil airway reconstruction can occur.

The prognosis for CHAOS depends on thetiming of the diagnosis. Prenatal diagnosis withdelivery utilizing the EXIT procedure has resultedin favorable outcome in some cases.1,3,11,12 How-ever, infants delivered with unsuspected CHAOSfrequently die shortly after birth. In rare circum-stances, the presence of a TEF may be lifesavingby allowing some air exchange until an emer-gent tracheotomy can be placed.2,5


The recurrence rate of isolated CHAOS withnegative family history is unknown as there havebeen only a limited number of cases reported inthe literature. However, in infants with positivefamily history, autosomal dominant pattern ofinheritance with its associated recurrence riskhas been suggested.4 The recurrence risk in in-fants with identifiable associated syndromeswould be dependent on the inheritance patternspecific to those syndromes.

REFERENCES

1. Lim FY, Crombleholme TM, Hedrick HL, et al.Congenital high airway obstruction syndrome:natural history and management. J Pediatr Surg.Jun 2003;38(6):940–5.

2. Hartnick CJ, Rutter M, Lang F, et al. Congenitalhigh airway obstruction syndrome and airway re-construction: an evolving paradigm. Arch Oto-laryngol Head Neck Surg. May 2002;128(5):567–70.

3. Marwan A, Crombleholme TM. The EXIT proce-dure: principles, pitfalls, and progress. SeminPediatr Surg. May 2006;15(2):107–15.

4. Vanhaesebrouck P, De Coen K, Defoort P, et al. Evi-dence for autosomal dominant inheritance in prena-tally diagnosed CHAOS. Eur J Pediatr. Apr 2006.

5. Cohen MS, Rothschild MA, Moscoso J, et al. Peri-natal management of unanticipated congenitallaryngeal atresia. Arch Otolaryngol Head NeckSurg. Dec 1998;124(12):1368–71.

CHAPTER 20 CONGENITAL HIGH AIRWAY OBSTRUCTION SYNDROME 137

6. Chen CP, Shih JC, Tzen CY, et al. Recurrent short-ribpolydactyly syndrome: prenatal three-dimensionalultrasound findings and associations with con-genital high airway obstruction and pyelectasia.Prenat Diagn. May 2005;25(5):417–8.

7. Kanamori Y, Kitano Y, Hashizume K, et al. A caseof laryngeal atresia (congenital high airway ob-struction syndrome) with chromosome 5p dele-tion syndrome rescued by ex utero intrapartumtreatment. J Pediatr Surg. Jan 2004;39(1):E25–8.

8. Fokstuen S, Bottani A, Medeiros PF, et al. Laryn-geal atresia type III (glottic web) with 22q11.2microdeletion: report of three patients. Am J MedGenet. May 16 1997;70(2):130–3.

9. Wei JL, Rodeberg D, Thompson DM. Trachealagenesis with anomalies found in both VACTERLand TACRD associations. Int J Pediatr Otorhino-laryngol. Sep 2003;67(9):1013–7.

10. Kohl T, Hering R, Bauriedel G, et al. Fetoscopicand ultrasound-guided decompression of the fe-tal trachea in a human fetus with Fraser syndromeand congenital high airway obstruction syndrome(CHAOS) from laryngeal atresia. Ultrasound ObstetGynecol. Jan 2006;27(1):84–8; discussion 88.

11. Crombleholme TM, Sylvester K, Flake AW, et al.Salvage of a fetus with congenital high airwayobstruction syndrome by ex utero intrapartumtreatment (EXIT) procedure. Fetal Diagn Ther.Sep–Oct 2000;15(5):280–2.

12. Bui TH, Grunewald C, Frenckner B, et al. Suc-cessful EXIT (ex utero intrapartum treatment)procedure in a fetus diagnosed prenatally withcongenital high-airway obstruction syndrome dueto laryngeal atresia. Eur J Pediatr Surg. Oct2000;10(5):328–33.


Chapter 21

Pulmonary AgenesisSANDRA B. CADICHON

139

� INTRODUCTION

Pulmonary agenesis was first described in 1874 ina report by E. Klebs on a patient with a “missinglung.”1 This is a rare abnormality that results fromfailure of development of the primitive lungbuds.2,3 Three types are recognized: (1) bilateralcomplete agenesis of the lungs, which is incom-patible with life; (2) unilateral lung agenesis, whichcan occur in isolation, but is often associated withadditional congenital anomalies of the cardiovas-cular, vertebral, facial, urogenital, or gastrointesti-nal systems; and (3) lobar agenesis.4 The range ofmaldevelopment in a patient with unilateral lungagenesis includes: (a) complete absence of bronchi,(b) rudimentary bronchus present but no alveolartissue, or (c) poorly developed main bronchuswith poorly organized parenchyma. Unilaterallung agenesis is more common than bilateral age-nesis and the prognosis for unilateral agenesis isdependent on the complexity of the associatedanomalies. Agenesis of the right or left lung is re-ported to occur with similar frequencies although,patients with left lung agenesis are likely to havea much better prognosis.5


Agenesis of a lung occurs in approximately1 per 100,000 births.6 While the true etiology of

pulmonary agenesis is unknown, animal studiessuggest a possible association with maternalgestational vitamin A deficiency.5 Chromosomalabnormalities such as duplications and trisomiesof chromosome 2 and reciprocal translocationt (2; 21) have also been reported, and suggest apossible genetic etiology in some cases of pul-monary agenesis.5 Familial pulmonary agenesis,though rare, has been described.5,7,8 Consan-guinity was documented in two of these familieswhich supports a possible autosomal recessiveinheritance pattern for unilateral pulmonaryagenesis in some cases.7,9

EMBRYOLOGY/PATHOLOGY

Lung development is divided into five stages: (1)Embryonic (0–7 weeks gestation); (2) Pseudog-landular (7–17 weeks gestation); (3) Canalicular(17–27 weeks gestation); (4) Saccular (28–36 weeksgestation); and (5) Alveolar (36 weeks gestation-2 years of age). During the embryonic stage, thelung develops as an out-pouching of the ventralwall of the primitive foregut endoderm; dichoto-mous branching occurs to form the proximalstructures of the tracheo-bronchial tree and thepulmonary arteries are derived from the sixth aorticarches concurrent with the developing airways.Disruptions during the embryonic stages of devel-opment result in pulmonary agenesis.


Vascular disruption during this stage of lungdevelopment has been suggested as a likely rea-son for isolated pulmonary agenesis.10 Cunning-ham and Mann suggested that an alteration ordisruption in the dorsal aortic arch blood flow inthe fourth week of gestation could selectively in-terfere with the development of lung, limb, andderivatives of the first and second branchial archesexplaining the ipsilateral malformations found inmany patients with pulmonary agenesis.11 In a re-view of cases of pulmonary agenesis reportedbetween 1937 and 1997, they found that 82% ofthe cases of pulmonary agenesis were associ-ated with malformations of the first and secondbranchial arches and or radial ray defects;11 andproposed that the inclusion of pulmonary age-nesis as part of the VACTERL sequence or Gold-enhar syndrome should be considered.11–13


Unilateral pulmonary agenesis has variable pre-sentation and can be asymptomatic in the neona-tal period or present with cyanosis, tachypnea,stridor, respiratory distress, or failure to thrive.Late presentation is also variable and can presentas recurrent respiratory tract infections, wheezingand worsening cough, or acute respiratory dis-tress if the solitary lung becomes obstructed.1,14

Bilateral pulmonary agenesis is incompatible withlife and presents with respiratory failure, severehypercarbia, hypoxemia, and rapid progressionto death.


Left pulmonary agenesis is often an isolated find-ing, whereas right pulmonary agenesis is fre-quently associated with congenital malformationsinvolving cardiac (14%), gastrointestinal (14%),skeletal (12%), vascular (9%), and genitouri-nary (9%) systems.15 Table 21-1 summarizes the

malformations reported to occur in associationwith pulmonary agenesis. Syndromes associatedwith pulmonary agenesis include VACTERL se-quence and Goldenhar syndrome. At least onecase of an association with velocardiofacial(VCF)/DiGeorge syndrome has also been re-ported.6 Common syndromes that have a rareassociation with pulmonary agenesis includePallister-Hall and Apert syndromes.

� EVALUATION

A presumptive diagnosis can be made on prenatalultrasound, which reveals a shifted mediastinumwith an enlarged echogenic lung herniatingtoward the affected side and elevation of thediaphragm on the ipsilateral side. A level II ultra-sound should be done to evaluate for any associ-ated anomalies. These mothers should be referredto high risk obstetrics centers for consideration offetal echocardiogram and amniocentesis for


� TABLE 21-1 Malformations Observed inPulmonary Agenesis

CardiacAnomalous pulmonary venous returnTetralogy of FallotSingle ventricleDextrocardia

GastrointestinalTracheo-esophageal fistulaImperforate anusMeckel’s diverticulum

SkeletalVertebral segmentationRib dysplasiaScoliosisLimb abnormalities

Urinary TractRenal ectopiaRenal agenesisHorseshoe kidneyPolycystic kidney disease

karyotyping. Delivery should be planned at atertiary care center.

Postnatally, all infants should have a thor-ough exam including assessment for dysmor-phic features. Initial evaluation should include achest x-ray, which often reveals an opacificationon the side of the agenesis, and quite frequentlymediastinal shift towards the agenetic side; withhyperinflation of the unaffected side. A chest com-puted tomography (CT) scan will confirm the ab-sence of the lung or lobe. Given the frequentassociation with other malformations, an echocar-diogram and renal ultrasound should be ob-tained. If the infant has signs and symptomsconsistent with gastrointestinal abnormalitiesor abdominal film suggests gastrointestinalpathology, evaluation of the gastrointestinal tractwould be indicated. Cytogenetics studies or mi-croarray evaluation is recommended as there area few published reports of pulmonary agenesisobserved with chromosomal anomalies.6,16–18


Bilateral agenesis of the lungs is incompatiblewith life. By contrast, unilateral absence is com-patible with life, but has a high mortality whichis most likely a result of associated malforma-tions and/or infections of the remaining lungtissue.5 Infants with right-sided lung agenesishave a higher mortality and die significantly ear-lier than infants with left sided agenesis.5 Thisclinical observation has been ascribed to thegreater rotation of the heart and mediastinum,causing impaired bronchial drainage and greatersusceptibility to pulmonary infections; further-more, right sided agenesis is associated with agreater number of cardiac and vascular anom-alies which contribute to its poorer prognosis.1

Survival into adulthood has been reported.5,19,20


The recurrence risk is unknown but is likely tobe very low in isolated cases with negative

family history. However, a few cases of recur-rence in families have been reported. The recur-rence risk for infants with an identified syndromeor chromosomal abnormality (e.g., Goldenharor DiGeorge) will depend on the inheritancepattern of the specific disorder.

REFERENCES

1. Bentsianov BL, Goldstein NA, Giuste R, et al. Uni-lateral pulmonary agenesis presenting as an air-way lesion. Arch Otolaryngol Head Neck Surg.Nov 2000;126(11):1386–9.

2. Toriello HV, Bauserman SC. Bilateral pulmonaryagenesis: association with the hydrolethalus syn-drome and review of the literature from a devel-opmental field perspective. Am J Med Genet. May1985;21(1):93–103.

3. Campanella C, Odell JA. Unilateral pulmonaryagenesis. A report of 4 cases. S Afr Med J. Jun1987;71(12):785–7.

4. Spencer H. Pathology of the Lung. 3rd ed. Oxford:Pergamon Press; 1977.

5. Fokstuen S, Schinzel A. Unilateral lobar pulmonaryagenesis in sibs. J Med Genet. Jul 2000;37(7):557–9.

6. Conway K, Gibson R, Perkins J, et al. Pulmonaryagenesis: expansion of the VCFS phenotype.Am J Med Genet. Nov 2002;113(1):89–92.

7. Brimblecombe FS. Pulmonary agenesis. Br J TubercDis Chest. Jan 1951;45(1):7–14.

8. Podlech J, Richter J, Czygan P, et al. Bilateralagenesis/aplasia of the lungs: report of a secondcase in the offspring of one woman. Pediatr PatholLab Med. Sep–Oct 1995;15(5):781–90.

9. Mardini MK, Nyhan WL. Agenesis of the lung. Re-port of four patients with unusual anomalies. Chest.Apr 1985;87(4):522–7.

10. Van Allen MI. Structural anomalies resultingfrom vascular disruption. Pediatr Clin North Am.Apr 1992;39(2):255–77.

11. Cunningham ML, Mann N. Pulmonary agenesis:a predictor of ipsilateral malformations. Am J MedGenet. Jun 1997;70(4):391–8.

12. Knowles S, Thomas RM, Lindenbaum RH, et al.Pulmonary agenesis as part of the VACTERL se-quence. Arch Dis Child. Jul 1988;63(7 Spec No):723–6.

13. Bowen AD, 3rd, Parry WH. Bronchopulmonaryforegut malformation in the Goldenhar anomalad.AJR Am J Roentgenol. Jan 1980;134(1):186–8.

CHAPTER 21 PULMONARY AGENESIS 141

14. Thomas RJ, Lathif HC, Sen S, et al. Varied presen-tations of unilateral lung hypoplasia and agenesis:a report of four cases. Pediatr Surg Int. Nov 1998;14(1–2):94–5.

15. Eroglu A, Alper F, Turkyilmaz A, et al. Pulmonaryagenesis associated with dextrocardia, sternal defects,and ectopic kidney. Pediatr Pulmonol. Dec 2005;40(6):547–9.

16. Say B, Carpenter NJ, Giacoia G, et al. Agenesisof the lung associated with a chromosome ab-normality (46,XX,2p+). J Med Genet. Dec 1980;17(6):477–8.

17. Say B, Carpenter NJ. Pulmonary agenesis: impor-tance of detailed cytogenetic studies. Am J MedGenet. Apr 1998;76(5):446.

18. Schober PH, Muller WD, Behmel A, et al. [Pul-monary agenesis in partial trisomy 2 p and 21 q].Klin Padiatr. Jul–Aug 1983;195(4):291–3.

19. Shenoy SS, Culver GJ, Pirson HS. Agenesis oflung in an adult. AJR Am J Roentgenol. Oct 1979;133(4):755–7.

20. Musleh GS, Fernandez P, Jha PK, et al. Mitral valverepair in a 55-year-old man with left lung agenesis.Ann Thorac Surg. May 2004;77(5):1810–1.


Chapter 22

Pulmonary HypoplasiaSANDRA B. CADICHON

143

� INTRODUCTION

Pulmonary hypoplasia refers to a decrease innumber and size of the airways and alveoli. Iso-lated primary pulmonary hypoplasia is a rarecondition that is usually not associated withother maternal or fetal disorders. Congenital aci-nar dysplasia is an extremely rare primarymaldevelopment of the lungs that results in pul-monary hypoplasia.1 Pulmonary hypoplasia isoften associated with other congenital condi-tions such as: (1) space occupying lesions in thechest (diaphragmatic hernia, cystic adenoma-toid malformation, teratoma, pleural effusions);(2) restrictive malformations of the chest wall(skeletal dysplasias, scoliosis); (3) reduction inamniotic fluid volume as seen in congenital re-nal anomalies (renal agenesis, bilateral polycys-tic kidney disease, bilateral dysplastic kidneys),and premature rupture of membranes; (4) de-creased fetal breathing as a result of neuromus-cular disorders; (5) decreased vascular supplyas in interrupted pulmonary artery.

In 1981, Wigglesworth and Desai originallysuggested a definition of pulmonary hypoplasiaas a lung weight to body weight ratio (LW/BW)of <0.015 in infants at >28 weeks gestation.2 Ina more recent study, a much larger sample sizeconfirmed similar LW/BW ratio of <0.015 as be-ing consistent with pulmonary hypoplasia anddefined the 10th percentile for LW/BW ratio

at 28–36 weeks gestation as 0.0227, and for37–41 weeks gestation as 0.0124.3 Other criteriaused for a prenatal diagnosis include the mea-surement of chest/trunk-length ratio; a ratio of0.32 or less is reported to have a sensitivity of92%, specificity of 95.5%, a positive predictivevalue of 88.5%, and a negative predictive valueof 97.2% for pulmonary hypoplasia.4


The incidence of pulmonary hypoplasia rangesfrom 9 to 11 per 10,000 live births and 14 per10,000 of all births.5 To date, the precise geneticetiology of pulmonary hypoplasia has not beendetermined. However, Cregg and Casey re-ported on two cases of primary congenital pul-monary hypoplasia in siblings of a consan-guineous marriage, suggesting a possiblegenetic component and perhaps a recessivemode of inheritance.6

� EMBRYOLOGY

Lung development is divided into five stages:(1) Embryonic (0–7 weeks gestation); (2) Pseudog-landular (7–17 weeks gestation); (3) Canalicular(17–27 weeks gestation); (4) Saccular (28–36 weeksgestation); (5) alveolar (36 weeks gestation-2


years of age). Lung growth and development isdependent on numerous factors, all of whichare essential for normal lung development tooccur. These factors include; normal fetal breath-ing movements, an adequate intra-thoracic space,sufficient extra- and intra-pulmonary fluid vol-ume and pulmonary blood flow.7

During the embryonic stage, the lung devel-ops as an out-pouching of the ventral wall ofthe primitive foregut endoderm; dichotomousbranching occurs to form the proximal struc-tures of the tracheo-bronchial tree and the pul-monary arteries are derived from the sixth aorticarches concurrent with the developing airways.During the pseudoglandular phase, the branch-ing of airways and blood vessels continue andend with the formation of the terminal bronchi-oles. Disruptions during the remaining threestages of development (the canalicular, saccu-lar, and alveolar phases) can result in pulmonaryor lung hypoplasia. The respiratory bronchi, thealveolar ducts and primitive alveoli formationoccur during the canlicular stage; the peripheralairways enlarge and the gas-exchanging surfaceareas increase as the airway walls thin duringthe saccular stage and finally, the secondarysepta and definitive alveoli form during the alve-olar stage.

As lung growth and development progresses,factors extrinsic to the lung parenchyma itselfmay also contribute to or cause pulmonary hy-poplasia. The importance of fetal breathingmovements and fetal lung fluid for the develop-ment of normal lungs can be inferred from theanimal literature. Animal models in which a neu-romuscular disorder is induced, or amniotic fluidvolume is altered develop pulmonary hypopla-sia.8–10 Human infants born with Potters sequencedevelop pulmonary hypoplasia as a result ofoligohydramnios and are well described in theliterature. Additionally, space occupying lesionssuch as congenital diaphragmatic hernia (CDH)decrease the amount of space available forlung growth and therefore contribute to pul-monary hypoplasia. Finally, the development ofthe airways and pulmonary vasculature occur

simultaneously, therefore, abnormalities in pul-monary vascular development are often seen inassociation with pulmonary hypoplasia, as ex-emplified by Scimitar syndrome.


Prenatally, oligohydramnios and/or small lungfields may be observed on ultrasound. Shortlyafter birth, infants with primary pulmonary hy-poplasia develop profound respiratory distress,marked hypercarbia, hypoxemia, and metabolicacidosis. Patients with milder disease may pre-sent with increased work of breathing and lesssevere respiratory distress. In cases of severepulmonary hypoplasia, with limited amount oflung tissue, infants may demonstrate evidenceof persistent pulmonary hypertension, both clin-ically and by echocardiogram. Quite frequently,these infants rapidly develop pneumothoraces.


Pulmonary hypoplasia frequently occurs in as-sociation with other congenital malformationsand is often the result of some of these malfor-mations. Renal or urinary tract anomalies arethe most common associated abnormalities;other malformations include diaphragmatic her-nia or eventration, skeletal muscle disorders,exomphalos, and skeletal dysplasia.1 Syndromesassociated with pulmonary hypoplasia includePatau syndrome, Edwards syndrome, and Downsyndrome. Occasionally, pulmonary hypoplasiacan be observed in Meckel-Gruber syndrome(characterized by encephalocele, polydactyly,cystic dysplasia of the kidneys). These infantswill have characteristic dysmorphic features ofthese syndromes and karyotyping may furtherassist in the diagnosis. Table 22-1 lists some ofthe common syndromes associated with pul-monary hypoplasia.


� EVALUATION

The diagnosis of pulmonary hypoplasia shouldbe suspected on prenatal ultrasound in all in-fants with an associated intrathoracic pathologysuch as congenital cystic adenomatoid malfor-mation (CCAM), CDH, or pleural effusions andin fetuses with renal anomalies and oligohy-dramnios. These infants should have a detailedlevel II ultrasound to evaluate for other anom-alies and should be referred to a tertiary carecenter for further care and delivery. Additionalevaluation of the fetus should include anechocardiogram, ultrasound with Doppler flow toevaluate for pulmonary sequestration, assessmentof amniotic fluid index, and an amniocentesis forkaryotyping. The fetus should be monitored reg-ularly for development of hydrops.

After birth, a complete physical examina-tion for any dysmorphic features is imperative.A chest x-ray should be obtained as soon as pos-sible to evaluate for the cause of the distress. Itis not uncommon for these infants to havepneumothoraces, both spontaneous and as a

result of aggressive mechanical ventilation. Chestx-ray demonstrates small poorly aerated lungs;the thorax may have a “bell-shaped” appear-ance with elevation of the hemidiaphragm. Fur-ther postnatal evaluation should include detailedexamination including neurological assess-ment to evaluate for neuromuscular disordersand further workup if initial exam is suggestiveof a neuromuscular disorder. A skeletal survey toevaluate for associated skeletal dysplasias suchas achondrogenesis, thanatrophic dysplasia, andosteogenesis imperfecta should be obtained in in-fants with clinical examination suggestive of skele-tal dysplasia. Other studies to consider are anechocardiogram to evaluate for pulmonary hyper-tension and cardiac defects such as tetralogy ofFallot, Ebstein’s anomaly, and hypoplastic rightheart. Pulmonary artery agenesis in particularcan effect pulmonary vascular perfusion andmay contribute to the development of pulmonaryhypoplasia. A renal ultrasound and chromo-some evaluation with microarray analysis shouldbe considered for all infants with pulmonaryhypoplasia.

CHAPTER 22 PULMONARY HYPOPLASIA 145

� TABLE 22-1 Syndromes Associated with Pulmonary Hypoplasia

Syndrome Other Clinical Findings Inheritance

Edwards syndrome Clenched hand; short sternum; low arch dermal Trisomy for allRidge patterning on fingertips; CHD or part of

chromosome 18Ellis-van Creveld Short distal extremities; polydactyly; AR

syndrome nail hypoplasiaPatau syndrome Defects of eye, nose, and lip; holoprosencephaly; Trisomy for all

polydactyly; narrow hyperconvex fingernails; or part ofskin defects of posterior scalp chromosome 13

Potter syndrome Bilateral renal agenesis, oligohydramnios; Unknownflat appearance of nose and face

Scimitar syndrome Partial anomalous pulmonary venous return Unknownto the inferior vena cava, right lung hypoplasia,dextrocardia, anomalous systemic arterial supplyto the right lung

Short rib-polydactyly Short stature; postaxial polydactyly of hands/feet; ARsyndrome CHD

AR, autosomal recessive; AD, autosomal dominant; CHD, congenital heart disease; XR, X-linked recessive.


Management of infants with pulmonary hy-poplasia is both supportive and directed towardtreatment of the underlying defect or malforma-tion that leads to the hypoplastic lungs. Pulmonaryhypoplasia has a high mortality rate when it oc-curs in isolation and most infants do not survivedespite aggressive medical intervention. How-ever, the prognosis is variable in certain cases inwhich the pulmonary hypoplasia is secondaryto a malformation or defect (e.g., CDH); med-ical and surgical management should be aimedat managing the primary disease process.


There are currently no known genetic causesfor primary pulmonary hypoplasia and the re-currence risk is very low in absence of positivefamily history. The recurrence risk in associa-tion with other syndromes will depend on themode of inheritance of that syndrome.

REFERENCES

1. Porter HJ. Pulmonary hypoplasia. Arch Dis ChildFetal Neonatal Ed. Sep 1999;81(2):F81–3.

2. Wigglesworth JS, Desai R, Guerrini P. Fetal lung hy-poplasia: biochemical and structural variations andtheir possible significance. Arch Dis Child. Aug1981;56(8):606–15.

3. De Paepe ME, Friedman RM, Gundogan F, et al.Postmortem lung weight/body weight standardsfor term and preterm infants. Pediatr Pulmonol.Nov 2005;40(5):445–8.

4. Ishikawa S, Kamata S, Usui N, et al. Ultrasono-graphic prediction of clinical pulmonary hypopla-sia: measurement of the chest/trunk-length ratio infetuses. Pediatr Surg Int. May 2003;19(3):172–5.

5. Johnson AM, Hubbard AM. Congenital anomaliesof the fetal/neonatal chest. Semin Roentgenol. Apr2004;39(2):197–214.

6. Cregg N, Casey W. Primary congenital pulmonaryhypoplasia—genetic component to aetiology. Pae-diatr Anaesth. 1997;7(4):329–33.

7. Kotecha S. Lung growth for beginners. PaediatrRespir Rev. Dec 2000;1(4):308–13.

8. Wigglesworth JS, Desai R. Effect on lung growth ofcervical cord section in the rabbit fetus. Early HumDev. Mar 1979;3(1):51–65.

9. Moessinger AC, Harding R, Adamson TM, et al.Role of lung fluid volume in growth and matura-tion of the fetal sheep lung. J Clin Invest. Oct1990;86(4):1270–7.

10. Kizilcan F, Tanyel FC, Cakar N, et al. The effect oflow amniotic pressure without oligohydramnioson fetal lung development in a rabbit model.Am J Obstet Gynecol. Jul 1995;173(1):36–41.


Chapter 23

Congenital CysticAdenomatoid Malformations

SANDRA B. CADICHON

147

� INTRODUCTION

Congenital cystic adenomatoid malformations(CCAM) are rare developmental abnormalitiesof the lung. Early reports date from 1897, butthe term itself was not introduced until 1949.1

The histological descriptions of CCAMs arebased on studies from Stocker et al.2 Initially,three varieties were recognized, types I, II, and IIIand subsequently types 0 and IV have been added.These five pathological types are based on thesite of origin of the malformation.3 Type 0––pre-viously known as acinar dysplasia, but now de-scribed as tracheal CCAM––affects the proximaltracheo-bronchial tree and is composed ofbronchial-like structures with respiratory epithe-lium surrounded by a wall containing smoothmuscle, glands, and numerous cartilage plates;this lesion is incompatible with life. Type I orbronchial CCAM is the most common type ofCCAM and consists of multiple large cysts or asingle dominant cyst. Type II or bronchiolarCCAM consists of multiple small cysts that re-semble dilated terminal bronchioles. Type III orbronchiolar/alveolar duct CCAM is a solid lesionand microscopically shows irregular curvingchannels and small airspaces. Type IV or alveolar/distal acinar CCAM consists of peripheral cysts

with distal acinar (distal airway structures suchas the alveolar ducts and sacs) origin.1,4–6

A revised classification of congenital cysticadenomatous malformations was proposed in1985, when Adzick et al proposed two cate-gories for CCAM based on anatomy, ultrasoundfindings, and prognosis. Macrocystic CCAM,which consists of single or multiple cysts of atleast 5 mm in diameter but often much larger;and microcystic CCAM lesions which are moresolid and bulky with cysts less than 5 mm in di-ameter.7 CCAMs consist of hamartomatous tis-sue characterized by overgrowth of the terminalbronchioles and may be cystic or solid masses.Cystic CCAMs are more common and occupypart or all of a hemithorax, with up to 15% ofcases having bilateral involvement.8 While themajority of CCAMs present in infancy, there area number of patients presenting later in life, oreven in adulthood.1

� EPIDEMIOLOGY

The precise incidence of CCAM is unknown.Literature reviews report a range from 1:25,000to 1:35,000 pregnancies9 to as frequently as1.2:10,000 births.8 Approximately 2% of cases


result in spontaneous abortions and 10% resultin postnatal deaths.9 CCAM affects all lobes withthe same frequency, and there is no right or leftpredominance.10 Type 0 accounts for 1–3% ofcases; type I accounts for >65% of cases; type IIaccounts for 20–25% of cases; type III accountsfor 8%; and type IV is responsible for 2–4%.Males and females are equally affected.11

� EMBRYOLOGY/ETIOLOGY

Lung development occurs in five distinct stages(see Chap. 22). CCAM is thought to occur dur-ing the second stage of lung development, thepseudoglandular period (7–17 weeks of gesta-tional age). This stage of lung development ischaracterized by repeated dichotomous branch-ing leading to formation of the bronchial airways.CCAM results when cystic and adenomatoid over-growth of terminal bronchioles and airspaces de-velop during the branching period, thus leadingto the lack of communication between the lesionand the tracheo-bronchial tree due to an absent oratretic segmental bronchus. It is believed, that mostof these changes result from an imbalance ofthe normal events in development due to an in-crease in cell proliferation and decrease in cellapoptosis.12

CCAM is thought to result from an early de-velopmental anomaly of unknown etiology.However, it has been reported that abnormalgene expression of the Hoxb5 gene, a regula-tory gene that controls embryonic organ-specificpatterning, may be associated with the devel-opment of the abnormal lung tissue seen inCCAM.13


Prenatally, the fetus may have ultrasound findingsconsistent with hydrops and/or polyhydramnios,in addition to cystic pulmonary lesions. Approxi-mately 32% of cases of CCAM in one series wereassociated with nonimmune hydrops fetalis.14

After delivery, the severity of the symptomsand timing of presentation are dependent on thesize of the lesion. Variable degrees of respiratorydistress including cyanosis, retractions, and grunt-ing are the most common modes of presentationin the neonatal period. Infants with significantlylarge lesions may develop pulmonary hypoplasiaand present with respiratory failure and pulmonaryhypertension immediately after delivery. Late pre-sentation with cough, fever, and/or radiologicchanges of recurrent pneumonia localized to onelobe is seen in 10–20%.2 Asymptomatic cases maybe discovered on a routine chest film later in life.


Approximately 20% (range of 7–50%) of cases oftype II CCAM are associated with anomalies andmalformations; malformations are seen in 5-12.5%of type I lesions.2 Reported anomalies withCCAM include: extralobular sequestration (inup to 50% of cases),15 diaphragmatic hernia,pulmonary hypoplasia, cardiovascular malforma-tion (truncus arteriosus and tetralogy of Fallot),hydrocephalus, skeletal malformation, jejunalatresia, bilateral renal agenesis/dysgenesis, andcraniofacial malformations. The reported incidenceof associated chromosomal aberrations is 1.2%.14

There are rare reports of Down syndrome, Patausyndrome, Edwards syndrome, Klinefelter syn-drome, and Pierre-Robin syndrome in associationwith CCAM.14

� EVALUATION

The initial prenatal evaluation of a patient withsuspected CCAM should include a detailed ultra-sound to confirm the diagnosis and evaluate forother anomalies; a color flow Doppler evaluationto exclude bronchopulmonary sequestrationshould also be performed. The fetus should bemonitored regularly, with serial ultrasound, forthe development of hydrops. However, the CCAMfrequently involutes and resolves by the time ofdelivery. An amniocentesis for karyotype analysis


is recommended to exclude chromosomal ab-normalities seen in some patients with CCAM. Afetal echocardiogram should also be performedgiven the increased incidence of associated car-diac anomalies.

All newborn infants with a history of CCAMin utero, even with spontaneous resolution,should undergo postnatal evaluation and shouldbe seen by a pediatric surgeon.12 In addition toa complete physical exam, a chest computed to-mography (CT) or magnetic resonance imaging(MRI) should be done to evaluate for any resid-ual CCAM that is asymptomatic and unidentifi-able on a plain chest x-ray. The presence ofeven subtle changes suggestive of CCAM shouldbe monitored closely even if asymptomatic, asrhabdomyosarcoma4 and rare cases showingmalignant transformation to bronchioloalveolarcarcinoma have been reported.1 A completeevaluation should include an echocardiogramto rule out congenital heart defects, and a renalultrasound to evaluate for renal anomalies as bi-lateral renal agenesis/dysgenesis has been re-ported in some of these infants.


Fetal surgery or interventions, such as thora-coamniotic shunts or resection of the lesion, forlarger lesions with associated hydrops havebeen performed.16 These procedures, however,are not widely available and are performed intertiary care centers with trained experts in thisarea. The major complications of thoracoamni-otic shunts are failure of function due to ob-struction, migration of the catheter, spontaneousdislodgment by normal fetal movements, andfetal deformation due to pigtail shunt limb com-pression.16 Fetuses with CCAM should be re-ferred for delivery at centers with a neonatal in-tensive care unit supported by neonatologistsand pediatric surgeons. After delivery, completeresection of the CCAM is the procedure ofchoice; this often entails a lobectomy.

Outcome of patients with CCAM varies de-pending on the size and associated anomalies.

Antenatally, these lesions can lead to hydrops,polyhydramnios, or spontaneously regress withgood outcome.9,11,15,17 Generally, the develop-ment or presence of fetal hydrops is associatedwith a poor prognosis and often results in fetalor neonatal demise.7

Type 0 lesions are incompatible with life.1

Type I lesions may present later in life and areusually associated with a favorable outcome;however, rare case reports of malignant trans-formations in type I lesions (<1% of cases) havebeen observed.1,18,19 Type II lesions have a highfrequency of associated anomalies and prognosisdepends on the anomaly and its severity. Infantswith type III lesions often present with hydropsand polyhydramnios and frequently have pul-monary hypoplasia with a poor prognosis. TypeIV lesions present in neonates and infants andgenerally have a good prognosis; although re-cent literature suggests a potential for malignanttransformation, none has been reported.1 Over-all long-term outcome for isolated CCAM fol-lowing complete resection is excellent.


Currently, there are no known genetic defectsresponsible for the development of CCAM andno cases of recurrence of this lesion have beenreported in siblings. However, there are a num-ber of case reports of chromosomal anomalieswith CCAM, therefore, karyotyping may be indi-cated, especially if other anomalies are present.

REFERENCES

1. MacSweeney F, Papagiannopoulos K, GoldstrawP, et al. An assessment of the expanded classificationof congenital cystic adenomatoid malformationsand their relationship to malignant transformation.Am J Surg Pathol. Aug 2003;27(8):1139–46.

2. Stocker JT, Madewell JE, Drake RM. Congenitalcystic adenomatoid malformation of the lung. Clas-sification and morphologic spectrum. Hum Pathol.Mar 1977;8(2):155–71.

3. Stocker JT. Pulmonary Pathology. 2 ed. New York:Springer; 1994.

CHAPTER 23 CONGENITAL CYSTIC ADENOMATOID MALFORMATIONS 149

4. Pai S, Eng HL, Lee SY, et al. Rhabdomyosarcomaarising within congenital cystic adenomatoid mal-formation. Pediatr Blood Cancer. Nov 2005;45(6):841–5.

5. Wilson RD, Hedrick HL, Liechty KW, et al. Cysticadenomatoid malformation of the lung: review ofgenetics, prenatal diagnosis, and in utero treatment.Am J Med Genet A. Jan 2006;140(2):151–5.

6. van Koningsbruggen S, Ahrens F, Brockmann M,et al. Congenital cystic adenomatoid malformationtype 4. Pediatr Pulmonol. Dec 2001;32(6):471–5.

7. Adzick NS, Harrison MR, Glick PL, et al. Fetal cys-tic adenomatoid malformation: prenatal diagno-sis and natural history. J Pediatr Surg. Oct 1985;20(5):483–8.

8. Duncombe GJ, Dickinson JE, Kikiros CS. Prenataldiagnosis and management of congenital cysticadenomatoid malformation of the lung. Am J ObstetGynecol. Oct 2002;187(4):950–4.

9. Laberge JM, Flageole H, Pugash D, et al. Out-come of the prenatally diagnosed congenital cys-tic adenomatoid lung malformation: a Canadianexperience. Fetal Diagn Ther. May–Jun 2001;16(3):178–86.

10. Kravitz RM. Congenital malformations of the lung.Pediatr Clin North Am. Jun 1994;41(3):453–72.

11. Calvert JK, Boyd PA, Chamberlain PC, et al. Outcomeof antenatally suspected congenital cystic adenoma-toid malformation of the lung: 10 years’ experience1991–2001. Arch Dis Child Fetal Neonatal Ed.Jan 2006;91(1):F26–8.

12. Cass DL, Quinn TM, Yang EY, et al. Increased cellproliferation and decreased apoptosis characterize

congenital cystic adenomatoid malformation ofthe lung. J Pediatr Surg. Jul 1998;33(7):1043–6;discussion 1047.

13. Volpe MV, Pham L, Lessin M, et al. Expression ofHoxb-5 during human lung development and incongenital lung malformations. Birth Defects ResA Clin Mol Teratol. Aug 2003;67(8):550–6.

14. Heling KS, Tennstedt C, Chaoui R. Unusual caseof a fetus with congenital cystic adenomatoidmalformation of the lung associated with trisomy 13.Prenat Diagn. Apr 2003;23(4):315–8.

15. Shanmugam G, MacArthur K, Pollock JC. Congenitallung malformations—antenatal and postnatal evalu-ation and management. Eur J Cardiothorac Surg.Jan 2005;27(1):45–52.

16. Wilson RD, Baxter JK, Johnson MP, et al. Tho-racoamniotic shunts: fetal treatment of pleuraleffusions and congenital cystic adenomatoidmalformations. Fetal Diagn Ther. Sep–Oct 2004;19(5):413–20.

17. Ierullo AM, Ganapathy R, Crowley S, et al. Neona-tal outcome of antenatally diagnosed congenitalcystic adenomatoid malformations. UltrasoundObstet Gynecol. Aug 2005;26(2):150–3.

18. de Perrot M, Pache JC, Spiliopoulos A. Carcinomaarising in congenital lung cysts. Thorac Cardio-vasc Surg. Jun 2001;49(3):184–5.

19. Granata C, Gambini C, Balducci T, et al. Bron-chioloalveolar carcinoma arising in congenital cys-tic adenomatoid malformation in a child: a casereport and review on malignancies originatingin congenital cystic adenomatoid malformation.Pediatr Pulmonol. Jan 1998;25(1):62–6.


Chapter 24

Congenital DiaphragmaticHernia

SANDRA B. CADICHON

151

� INTRODUCTION

Congenital diaphragmatic hernia (CDH) remainsa major cause of respiratory failure in the new-born with a high mortality and morbidity rate.The first reported case was an incidental findingon postmortem evaluation in a 24-year-old manin 1679. The first description of this defect in theneonate was in the early 1800s. The first success-ful surgery in an infant with CDH was reported in1902.1 During the first quarter of the twentiethcentury, due to the variable success rates, surgerywas rarely used in the management of CDH; infact, it was not until the 1940s that surgical repairof CDH became an accepted treatment.1

Clinically, four types of CDH have been de-scribed: (1) the anterolateral hernia, a congeni-tal absence of the diaphragm due to failure offormation of the lateral component of the sep-tum transversum in early embryogenesis; (2) theposterolateral hernia (also known as Bochdalekhernia) caused by failure of closure of the pleu-roperitoneal canal; (3) the pars sternalis herniaresulting from a deficiency of the medial retroster-nal portion of the septum transversum; 4) theMorgagni hernia resulting from failure of themuscular consolidation around the foramen ofMorgagni.2 While the defect occurs most com-monly on the left side, right-sided and bilateral

defects have also been described. Congenitaldiaphragmatic hernia can be an isolated findingor associated with a number of genetic or addi-tional congenital malformations.3


Congenital diaphragmatic hernia is estimated tooccur in 1:2000 to 1:3000 births.2,4,5 Bochdalektype hernias account for 96% of cases with 84%being left-sided, 13% right-sided, and 2% bilat-eral.6 Male-female ratio varies from 0.92 to 1.25.7

There have been no reports of racial, ethnic, orother demographic risk factors.

Isolated CDH, in the absence of other mal-formations or congenital anomalies, is thoughtto be familial with an estimated occurrence ofless than 2%.8 Autosomal recessive inheritancehas been described in consanguineous Pakistaniand Arab families9,10 and more than 40 cases ofrecurrence in siblings have been identified.11,12

Autosomal dominant and X-linked inheritancepatterns are also described in families with iso-lated CDH.13 Chromosomal abnormalities arepresent in an estimated 33% of cases withCDH.6,14–16 Table 24-1 summarizes the chromo-somal anomalies that have been associated withCDH.


�TABLE 24-1 Chromosome Anomalies Reported with CDH

Monosomy/Trisomy/Aneuploidy Deletions/Translocations X-Chromosome

45, X (Ulrich-Turner syndrome) Chromosome 1 delXp22.2pterTrisomy 2p 46,XY,del(1)(pter–q32.3::q42.3–qter) (MIDAS syndrome)Parital trisomy 5 del(1)(q32–q42) 46,X,del(X)(p22.1)Trisomy 11p15 (BWS) dup(1)(q24–31.2) Trisomy 13 46,XY/46,XYdup(1)(q24–q31.2)Trisomy 18 46,XY,t(1;15)(q41;q21.2)Trisomy 20p 46,XY,t(1;21)(q32;q22)patTrisomy 21 t(1;21)Trisomy 22 der(1)47,XX,+mar Chromosome 347,XY+mar16 46,XY,del(3)(q21q23)47, XY+18,inv(2)(p11.2;q13) del(3)Mosiac trisomy 46,XY,der(3;8)(q23;q23.1)46, XY/47,XY+14 Chromosome 4Triploidy 69, XXX 4p-Tetrasomy 12p Chromosome 6Tetraploidy 21 del6q23-ter

46,XY,t(6;8)(q24;q23)Chromosome 7

46,XY,–7+der(7)t(2;7)(p25.3;q34)mat46,XY,7–(q32)7q-ctb(7)(q31.3)

Chromosome 846,XY,del(8)(p23.1)del (8)Balanced 8;14(q24;q21)46,XX,t(8;13)(q22.3;q22)46,XX,t(8;15)(q22.3;q15)r4,7q+,del(8),+mar

Chromosome 946,XY,–9+t(5q;9p)46,XY,–9+der(9)t(9;11)(p24;p12)pat46,XY,–9+der(9)t(9;11)(p24;p13)

Chromosome 10Balanced 10;X translocation

Chromosome 1246,XY, del(12)Balanced 12;15 translocation

Chromosome 1313q-

Chromosome 14Abnormal 14 centromere

Chromosome 1546,XY,del(15)(q24-qter)46,XX,–15,+der(15)t(15;17)

(q24.3:q23.3)47,XY,t(15;21)(p12;p12)

BWS, Beckwith-Weideman syndrome.Source: Enns et al. 1998, with permission of Wiley-Liss, Inc.

� EMBRYOLOGY

The diaphragm develops from four embryonicstructures: (1) the septum transversum; (2) pleu-roperitoneal membranes; (3) dorsal mesenteryof the esophagus; and (4) muscular ingrowthfrom the lateral body walls.17 During the fourththrough the fifth weeks of gestation, the septumtransversum, composed of mesodermal tissue,forms an incomplete partition between the tho-racic and abdominal cavities leaving a largeopening on either side of the esophagus. Dur-ing the sixth week of gestation, the pleuroperi-toneal membranes become more prominent asthe lungs enlarge cranially and the liver expandscaudally; these membranes are produced as thedeveloping lungs and pleural cavities expandand invade the body wall ultimately fusing withthe septum transversum and the dorsal mesenteryof the esophagus, thus completing the separa-tion of the thoracic from the abdominal cavities.17

Finally, during the 9th through the 12th weeks ofgestation, muscular ingrowth occurs from the lat-eral body walls. Of note, the right side of thediaphragm closes earlier than the left which maypartially explain the higher incidence of leftsided hernias.

Concurrent with the development of the di-aphragm and separation of the thoracic cavityfrom the abdominal cavity lung development isalso occurring. Lung development begins withformation of the tracheal bud during the fourthweek of gestation. From this tracheal bud, thebronchial buds and subsequent branching andsubdivisions eventually lead to the development ofrespiratory bronchioles by 24 weeks of gestation.17

The sixth week of gestation is an important timeperiod during which lung growth contributes tothe expansion of the pleuroperitoneal mem-branes eventually leading to separation of thethoracic cavity from the abdominal cavity. Giventhe overlap in lung and diaphragm development,some investigators have questioned whether it isthe pulmonary malformation that leads to malde-velopment of the diaphragm or the diaphragmaticmalformation that leads to pulmonary hypoplasia.

While this question remains debatable in hu-mans, animal studies have shown that the di-aphragm develops normally in the absence of lungdevelopment.18

� PATHOGENESIS

The lungs in CDH patients are physically smallerthan normal, with fewer airway branches, with areduced number of alveoli related to each termi-nal airway (pulmonary hypoplasia), and reducedsurfactant production.19 Additionally, CDH pa-tients frequently have pulmonary hypertensionthought to be related to small arterioles and ex-cessive smooth muscle formation.19 Although thepulmonary hypoplasia seen in CDH may be par-tially due to the space occupying herniated vis-cus and thus infringement of lung growth, morerecent data suggests that lung growth and devel-opment are multifactorial and the resulting pul-monary hypoplasia is not completely explainedby herniation of the abdominal viscus.

In addition to the body of literature suggest-ing possible environmental and/or genetic fac-tors, there is growing evidence in the literatureto support the theory that deficiency of retinoicacid, the active form of vitamin A, may also beinvolved in CDH in animal models20,21 and in-terestingly, infants with CDH have decreasedlevels of vitamin A.22 This area of research isongoing and presents a very intriguing question.


The severity of symptoms observed in patientswith CDH depends on the timing, the size ofthe defect, and the resultant amount of herni-ated bowel. Patients with small defects may notpresent until much later in life. However, pa-tients with larger defects and significant bowelherniation often develop pulmonary hypopla-sia; these patients present with scaphoid ab-domen, cyanosis, severe respiratory distress,and pulmonary hypertension shortly after birth.

CHAPTER 24 CONGENITAL DIAPHRAGMATIC HERNIA 153

On prenatal ultrasound, there is often evidenceof polyhydramnios; an absent or intrathoracicstomach bubble, with mediastinal or cardiacshift away from the side of the hernia.


The incidence of additional malformations ob-served in infants with CDH is about 40% with arange of 25.6–58.3%.23 In a review of data fromthe Congenital Diaphragmatic Hernia StudyGroup, it was found that 10.6% of the 2636 CDHpatients had associated significant heart defects.24

The most frequently observed cardiac lesionswere: ventricular septal defect (42.2%), aorticarch obstruction (15%), univentricular anatomy(13.9%), tetralogy of Fallot variants (11.1%), totalanomalous pulmonary venous return (3.9%),double outlet right ventricle (3.2%), pulmonarystenosis (2.5%), transposition of the great arteries(2.5%), and other defects (5.7%).24 Other systemswith malformations associated with CDH in-clude genitourinary system (23%), gastrointestinal

system (14%), central nervous system (10%).25

Table 24-3 summarizes the commonly reportedmalformations seen in infants with CDH.

According to Enns et al at least 10% of pa-tients with CDH and additional birth defects havean underlying syndrome.6 There are two maincategories of syndromes associated with CDHthat are linked to an identified gene: (1) syn-dromes featuring overgrowth, embryonal tumors,and CDH (Simpson-Golabi-Behlmel syndrome,Denys-Drash syndrome, Beckwith-Wiedemannsyndrome, and Perlman syndrome); (2) syndromesin which defective mesoderm or connective tissueformation may cause CDH (craniofrontonasal syn-drome, spondylocostal dysostosis, and Marfansyndrome).3 Table 24-2 summarizes the syndromesthat have been reported to occur in associationwith CDH.

� EVALUATION

Diagnosis is frequently made prenatally withevidence of bowel in the thoracic cavity ob-served on ultrasound. Evaluation at this time


� TABLE 24-2 Syndromes Most Commonly Associated with CDH

Syndrome Other Clinical Findings Inheritance

Fryns syndrome Coarse face, broad nasal bridge, distal digital ARhypoplasia, Dandy-Walker malformation,agenesis of corpus callosum

Beckwith-Wiedemann Macrosomia, omphalocele, macroglossia, ADsyndrome ear creases

Brachmann-de Lange Microbrachycephaly, synophyrs, thin, downturned Sporadicsyndrome upper lip, micromelia

Simpson-Golabi-Behmel Macrosomia, hypertelorism, macrostomia, XRsyndrome postaxial polydactyly, umbilical/inguinal hernias

Donnai syndrome Absent corpus callosum, hypertelorism, myopia, ARcoloboma, sensorineural deafness, omphalocele,malrotation

Denys-Drash syndrome Males pseudohermaphroditism, nephritic syndrome, ADWilms tumor

Perlman syndrome Macrosomia, nephroblastomatosis, Wilms tumor, ARCHD, Hypospadias, polysplenia, visceromegaly

AR, autosomal recessive; AD, autosomal dominant; CHD, congenital heart disease; XR, X-linked recessive.Source: Enns et al. 1998, with permission of Wiley-Liss, Inc.

should include ultrasound visualization of otherorgans with close attention to the heart, geni-tourinary, and central nervous systems. Geneticcounseling should be offered and, with parentalconsent, karyotype with microarray analysisshould be obtained.

Postnatally, an echocardiogram is recom-mended to look for cardiac anomalies and toevaluate for pulmonary hypertension. A renalultrasound may be helpful in detecting renalanomalies and head ultrasound should be com-pleted to exclude any intracranial hemorrhageprior to placing the infant on extracorporealmembrane oxygenation (ECMO). If prenatalkaryotyping was not performed, it is recom-mended that a high-resolution karyotype be per-formed on every infant with CDH presentingwith additional malformations which are notsecondary to the hernia itself.3


Every effort should be made to deliver all infants,known prenatally to have CDH, at a multidisci-plinary center offering tertiary care including

neonatology and pediatric surgical services. In-fants born without a prenatal diagnosis usuallypresent with severe respiratory distress and pul-monary hypertension and should be transferredto facilities equipped to provide care for theseinfants.

Fetal surgery is offered under investigativeprotocols to patients who meet certain criteriaat selected academic medical centers. Gener-ally, patients deemed appropriate for fetal in-tervention are those who would not survivewith postnatal therapy alone.26 Some of theselection criteria include gestational age of22–28 weeks with liver herniation into the tho-racic cavity and absence of other anomalies;liver herniation, a lung-to-head circumferenceratio (LHR) <1.0, and absence of otheranomalies.

The three types of fetal surgeries are: (1) openfetal repair, (2)open tracheal occlusion, and (3)fetoscopic tracheal occlusion. Open fetal repairis directed toward open, in utero, repair withone-stage surgical correction of the anatomicaldefect. Complications after open repair includepreterm labor and fetal death. Of the 21 fetusesthat had open fetal surgery repair, only five (24%)survived.26 Open tracheal occlusion is based onthe findings in animal studies showing that de-creasing the egress of lung fluid by plugging oroccluding the trachea, promotes lung growth. Inhuman fetuses that have undergone in utero tra-cheal occlusion, the ex utero intrapartum treat-ment procedure (EXIT) is then used to deliverand intubate the fetus and safely remove the tra-cheal plug. Survival after tracheal occlusion withherniated liver is 15% and for herniated liver andLHR <1.4 is 33%.26 At present the best fetalsurgery option appears to be fetoscopic trachealocclusion using a clip on the trachea (Fetendoclip), or an intratracheal balloon. Survival ratesreported for fetoscopic tracheal occlusion are48% in patients with herniated liver and LHR<1.0, and 73% in patients with herniated liverand LHR <1.4.26 Morbidities reported for thisapproach are: bilateral recurrent laryngeal nerveinjuries, and tracheal stenosis.26


� TABLE 24-3 Malformations Associatedwith CDH

Cardiac 11%Ventricular septal defects 42%Aortic arch obstruction 15%Univentricular anatomy 14%Tetralogy of Fallot variants 11%TAPVR 4%Double outlet right ventricle 3%Pulmonary stenosis 2%TGA 2%

Genitourinary 23%

Gastrointestinal 14%

Central Nervous System 10%

TAPVR, total anomalous pulmonary venous return; TGA,transposition of the great arteries.

In cases of prenatally diagnosed CDH, theinfant should immediately undergo endotra-cheal intubation upon delivery to facilitate me-chanical ventilation. The bag and mask ventila-tion of these infants should be avoided and anasogastric tube should be inserted to preventgaseous distention of the bowel. Pre- and post-ductal saturations should be monitored for evi-dence of right to left ductal shunting secondaryto pulmonary hypertension. An arterial bloodsample should be obtained as soon as possibleto determine ventilation, oxygenation, and acidbase status. A chest x-ray should be obtained toevaluate for the side and extent of intestinal her-niation. Infants who present with severe respi-ratory distress, severe pulmonary hypertensioncomplicated by persistent hypoxemia and se-vere hypercapnia, may be candidates for ECMOand should be transferred, when stable, to fa-cilities with ECMO capabilities.

Based on observations of decreased surfac-tant in animal models of CDH, several authorshave reported the use of exogenous surfactantin infants with CDH.27,28 According to Doyleand Lally, numerous reports using data from theCDH registry have been presented on surfactantuse in infants with CDH, however, investigatorshave failed to demonstrate any benefit with sur-factant use.29 The use of surfactant has beenstudied in both term and preterm infants with CDHand these studies have suggested evidence of harmwith surfactant use and no evidence of any bene-fit.29,30 Therefore, routine use of exogenous sur-factant cannot be recommended for these infants.

Nitric oxide, when used as initial therapy forinfants with CDH and severe respiratory failuredoes not appear to improve overall survival orreduce the need for ECMO.31 However, it maybe useful in patients with CDH later in their hos-pital course after the surgical repair of the di-aphragmatic defect as many infants with CDHhave pulmonary hypertension that may last formonths or longer.32

After birth, surgical repair of the defect is theprimary goal of treatment but the optimal tim-ing of surgery remains unclear.25 During the

1980s, emergency surgery for CDH was thoughtto be the rule rather than the exception. Whenit was discovered that the pulmonary hyperten-sion and pulmonary hypoplasia were responsi-ble for the high mortality and morbidity rates,delayed surgical approach was introduced. Di-aphragm reconstruction with a prosthetic material,such as Gortex is the preferred surgical proce-dure.25 Postoperative management involves closeattention to ventilator management with the goalof minimizing barotrauma, ensuring adequateoxygenation while minimizing hypercarbia andacidosis. Monitoring of the infants’ fluid status,cardiovascular function, nutrition, and pain man-agement is also imperative.

While CDH remains a high-risk disease, cur-rent management strategies have resulted in sur-vivals of 85–90% in some centers.31 However,the overall mortality rate remains at 50% withsignificant morbidity in survivors.33 At presentthe best prognostic indicators for CDH are thepresence or absence of liver herniation into thechest across the diaphragmatic defect and pre-natal sonographic measurement of lung/headratio.26,34 Prognosis is poor when the liver is in-trathoracic and LHR is less than 1.35 Additionalfindings associated with a poor prognosisinclude: the presence of polyhydramnios, thepresence of CDH at less than 25 weeks estimatedgestational age, and the presence of associatedchromosomal or congenital anomalies.36 Otherfactors associated with a significant decrease insurvival rate are: initial PCO2 >50, PO2 <40, car-diac defects, and renal failure.34

Long-term outcome of patients with CDHdepends on the degree and severity of pul-monary hypoplasia. In long-term survivors, inaddition to reactive airway disease, extrapul-monary complications such as failure to thrive,gastroesophageal reflux, and musculoskeletaldeformities are not uncommon. There is a highincidence of neurological complications in chil-dren with CDH, independent of exposure toECMO. Sensorineural hearing loss, seizures anddevelopmental delay may be seen in up to 20%of patients.36



The inheritance pattern for sporadic CDH ispoorly understood, but, the recurrence risk insiblings is estimated to be up to 2%.8,36 In casesof CDH occurring as part of an autosomal reces-sive syndrome (e.g., Fryns syndrome), the recur-rence risk could be as high as 25%. Familial CDH,which is inherited as an autosomal dominantcondition has a 50% recurrence risk.36 Prenatalscreening by early prenatal sonography shouldbe offered in subsequent pregnancies.

REFERENCES

1. Puri P, Wester T. Historical aspects of congenitaldiaphragmatic hernia. Pediatr Surg Int. Mar1997;12(2/3):95–100.

2. Torfs CP, Curry CJ, Bateson TF, et al. A population-based study of congenital diaphragmatic hernia.Teratology. Dec 1992;46(6):555–65.

3. Slavotinek AM. The genetics of congenital di-aphragmatic hernia. Semin Perinatol. Apr 2005;29(2):77–85.

4. Butler N, Claireaux AE. Congenital diaphragmatichernia as a cause of perinatal mortality. Lancet.Mar 1962;1:659–63.

5. Harrison MR, de Lorimier AA. Congenital di-aphragmatic hernia. Surg Clin North Am. Oct 1981;61(5):1023–35.

6. Enns GM, Cox VA, Goldstein RB, et al. Congenitaldiphragmatic defects and associated syndromes,malformations, and chromosome anomalies: a ret-rospective study of 60 patients and literature re-view. Am J Med Genet. Sep 1998;79(3):215–25.

7. Van Meurs K, Lou Short B. Congenital diaphrag-matic hernia: the neonatologist’s perspective. Pe-diatr Rev. Oct 1999;20(10):e79–87.

8. Tibboel D, Gaag AV. Etiologic and genetic factorsin congenital diaphragmatic hernia. Clin Perina-tol. Dec 1996;23(4):689–99.

9. Farag TI, Bastaki L, Marafie M, et al. Autosomalrecessive congenital diaphragmatic defects in theArabs. Am J Med Genet. Apr 1994;50(3):300–1.

10. Mitchell SJ, Cole T, Redford DH. Congenital di-aphragmatic hernia with probable autosomalrecessive inheritance in an extended consan-guineous Pakistani pedigree. J Med Genet. Jul 1997;34(7):601–3.

11. Hitch DC, Carson JA, Smith EI, et al. Familial con-genital diaphragmatic hernia is an autosomal re-cessive variant. J Pediatr Surg. Sep 1989;24(9):860–4.

12. Kufeji DI, Crabbe DC. Familial bilateral congeni-tal diaphragmatic hernia. Pediatr Surg Int. 1999;15(1):58–60.

13. Austin-Ward ED, Taucher SC. Familial congenitaldiaphragmatic hernia: is an imprinting mecha-nism involved? J Med Genet. Jul 1999;36(7):578–9.

14. Howe DT, Kilby MD, Sirry H, et al. Structural chro-mosome anomalies in congenital diaphragmatichernia. Prenat Diagn. Nov 1996;16(11):1003–9.

15. Lurie IW. Where to look for the genes related todiaphragmatic hernia? Genet Couns. 2003;14(1):75–93.

16. Witters I, Legius E, Moerman P, et al. Associatedmalformations and chromosomal anomalies in42 cases of prenatally diagnosed diaphragmatic her-nia. Am J Med Genet. Nov 2001;103(4):278–82.

17. Moore KL, Persaud TVN. The Developing Human:Clinically oriented Embryology. 7th ed. Philadelphia:Saunders; 2003:192–197.

18. Babiuk RP, Greer JJ. Diaphragm defects occur ina CDH hernia model independently of myogen-esis and lung formation. Am J Physiol Lung CellMol Physiol. Dec 2002;283(6):L1310–4.

19. Chinoy MR. Pulmonary hypoplasia and congeni-tal diaphragmatic hernia: advances in the patho-genetics and regulation of lung development.J Surg Res. Jul 2002;106(1):209–23.

20. Greer JJ, Babiuk RP, Thebaud B. Etiology of con-genital diaphragmatic hernia: the retinoid hy-pothesis. Pediatr Res. May 2003;53(5):726–30.

21. Thebaud B, Tibboel D, Rambaud C, et al. Vitamin Adecreases the incidence and severity of nitrofen-induced congenital diaphragmatic hernia in rats.Am J Physiol. Aug 1999;277(2 Pt 1):L423–9.

22. Major D, Cadenas M, Fournier L, et al. Retinol sta-tus of newborn infants with congenital diaphrag-matic hernia. Pediatr Surg Int. Oct 1998;13(8):547–9.

23. Skari H, Bjornland K, Haugen G, et al. Congenitaldiaphragmatic hernia: a meta-analysis of mortalityfactors. J Pediatr Surg. Aug 2000;35(8):1187–97.

24. Graziano JN. Cardiac anomalies in patients withcongenital diaphragmatic hernia and their prog-nosis: a report from the Congenital Diaphrag-matic Hernia Study Group. J Pediatr Surg. Jun 2005;40(6):1045-9; discussion 1049–50.


25. Skarsgard ED, Harrison MR. Congenital diaphrag-matic hernia: the surgeon’s perspective. Pediatr Rev.Oct 1999;20(10):e71–8.

26. Cass DL. Fetal surgery for congenital diaphrag-matic hernia: the North American experience.Semin Perinatol. Apr 2005;29(2):104–11.

27. Glick PL, Leach CL, Besner GE, et al. Pathophys-iology of congenital diaphragmatic hernia. III:Exogenous surfactant therapy for the high-riskneonate with CDH. J Pediatr Surg. Jul 1992;27(7):866–9.

28. Bae CW, Jang CK, Chung SJ, et al. Exogenouspulmonary surfactant replacement therapy in aneonate with pulmonary hypoplasia accompany-ing congenital diaphragmatic hernia–a case re-port. J Korean Med Sci. Jun 1996;11(3):265–70.

29. Doyle NM, Lally KP. The CDH Study Group andadvances in the clinical care of the patient withcongenital diaphragmatic hernia. Semin Perinatol.Jun 2004;28(3):174–84.

30. Van Meurs K. Is surfactant therapy beneficial inthe treatment of the term newborn infant with con-genital diaphragmatic hernia? J Pediatr. Sep 2004;145(3):312–6.

31. Lally KP. Congenital diaphragmatic hernia. CurrOpin Pediatr. Aug 2002;14(4):486–90.

32. Iocono JA, Cilley RE, Mauger DT, et al. Postnatalpulmonary hypertension after repair of congeni-tal diaphragmatic hernia: predicting risk and out-come. J Pediatr Surg. Feb 1999;34(2):349–53.

33. Grethel EJ, Nobuhara KK. Fetal surgery for con-genital diaphragmatic hernia. J Paediatr ChildHealth. Mar 2006;42(3):79–85.

34. Rozmiarek AJ, Qureshi FG, Cassidy L, et al. Fac-tors influencing survival in newborns with con-genital diaphragmatic hernia: the relative role oftiming of surgery. J Pediatr Surg. Jun 2004;39(6):821–4; discussion 821–4.

35. Deprest J, Jani J, Van Schoubroeck D, et al. Currentconsequences of prenatal diagnosis of congenitaldiaphragmatic hernia. J Pediatr Surg. Feb 2006;41(2):423–30.

36. Bianchi DW, Crombleholme TM, D’Alton ME. Fe-tology: Diagnosis & Management of the Fetal Pa-tient. New York: McGraw-Hill; 2000.


Chapter 25

Congenital HydrothoraxSANDRA B. CADICHON

159

� INTRODUCTION

Fetal hydrothorax or congenital hydrothoraxrefers to a collection of fluid within the fetalthoracic cavity as a result of lymphatic leakageor generalized fluid retention from a variety ofcauses. Congenital hydrothorax can occur bilat-erally or unilaterally and can be divided intotwo broad categories: (1) primary hydrothorax,also known as chylothorax, is frequently a resultof damage to the lymphatic ducts or channels;(2) secondary hydrothorax is a pleural effusion(s)resulting from or associated with chromosomalanomalies, congenital heart defects, cardiac ar-rhythmias, multiple malformations, or hydrops.The natural history of hydrothorax varies fromspontaneous regression with intact survival tofetal or neonatal death and the prognosis de-pends on the underlying pathology leading tothe hydrothorax.


Primary hydrothorax occurs in approximately1:10,000–15,000 pregnancies. This type of hy-drothorax is usually bilateral, with no right or leftside predominance noted for unilateral lesions.1

Secondary hydrothorax has a prevalence of 1case per 1500 live births2 and often occurs sec-ondary to maternal or fetal disorders such as

isoimmunization, infection, aneuploidy, fetal ar-rhythmias, structural anomalies of the fetal tho-rax, and malformations of the placenta and theumbilical cord.

Primary hydrothorax occurs as a result ofdamage to the thoracic duct, or abnormal devel-opment of the lymphatic channels; in many cases,no underlying cause can be found. In contrast,conditions to consider in the differential diagno-sis of causes of secondary hydrothorax include:(1) immune hydrops with fetal anemia and heartfailure usually resulting from Rh isoimmuniza-tion or similar disorders; (2) nonimmune hy-drops resulting from (a) fetal heart failure andanemia (e.g., twin-twin transfusion, chronic fetal-maternal hemorrhage, fetal parvo virus infec-tion) (b) fetal heart failure resulting from fetaltachyarrhythmia, bradyarrythmia, arteriovenousmalformations (at various locations includingthe placenta and causing large systemic-to-venousshunts), cardiac malformations with ventricularhypoplasia and premature closure of the fora-men ovale, fetal viral infections often associatedwith myocarditis; (3) large space-occupying le-sions within the thorax that obstruct venous returnto the heart (e.g., congenital cystic adenomatoidmalformation [CCAM], congenital mediastinalteratoma, congenital diaphragmatic hernia [CDH],enlarged fetal lungs associated with laryngealatresia); and (4) chromosomal abnormalitiessuch as Turner syndrome and Down syndrome.3


A 7% fetal aneuploidy rate, without associatedstructural anomalies, has been reported in anumber of studies.1,4,5 In a large study by Walleret al, 246 cases of congenital pleural effusionswere evaluated and the prevalence of chromo-somal abnormalities was 35.4%; the aneuploidyrate was 63% among the first trimester cases inthis study.6


Prenatally, the fetus will be noted to have pleuraleffusions and often polyhydramnios on ultra-sound. Depending on the severity and durationof the hydrothorax, hydrops fetalis with skinedema, scalp edema, and ascites may be present.

After delivery, clinical presentation can varyfrom an asymptomatic infant in the presence ofsmall effusion to a critically ill infant with largeeffusions presenting with cyanosis and respira-tory distress requiring mechanical ventilation. Ifthere was progression to hydrops in utero, post-natal physical examination will also reveal gen-eralized body edema.


Primary hydrothorax often occurs as an isolatedfinding. Secondary hydrothorax is more likelyto be associated with malformations or multiplecongenital anomalies. Associated malformationsinclude: cardiac defects, renal anomalies, andomphalocele.6 Syndromes frequently associatedwith hydrothorax include Noonan syndrome,Turner syndrome, Down syndrome, and Ed-wards syndrome. The important clinical featuresassociated with these syndromes and other syn-dromes presenting with hydrothorax in the peri-natal period are summarized in Table 25-1.

� EVALUATION

Carroll was the first to describe the sonographicdiagnosis of fetal hydrothorax in 1977.7 Serial

ultrasounds may demonstrate spontaneous re-gression of the effusion in utero, or develop-ment of polyhydramnios, hydrops, and fetaldemise; therefore, it is crucial to monitor af-fected fetuses on a regular basis. Prenatal diag-nostic evaluation should include ultrasoundto evaluate for multiple gestations. Referral toa high-risk obstetrics group is recommended.A level II ultrasound to document presence ofother anatomic abnormalities as well as a fetalechocardiogram to evaluate for congenital heartdefects are both essential. Maternal laboratoryevaluation for blood type, Rh, antibody screen,Kleinhauer-Betke stain, as well as, serology forparvo virus infection should be considered. Ad-ditional evaluation should include cordocentesisto evaluate for fetal anemia and an amniocen-tesis for karyotyping. Figure 25-1 offers a sug-gested algorithm for evaluation of a fetus withcongenital hydrothorax.

After delivery, a careful examination to evalu-ate for dysmorphic features is important. However,this may be difficult to assess in the presence ofsignificant body edema in some cases. MaternalKleinhauer-Betke stain may be helpful if the in-fant presents with significant anemia. MaternalTORCH (toxoplasmosis, rubella, cytomegalovirus[CMV], herpes, varicella, syphilis) titers, serologyfor parvo virus should be considered. A chestand abdominal x-ray should be performed toevaluate for the extent of the effusions and as-cites. An echocardiogram is necessary to evalu-ate for congenital heart defects and to excludeassociated pericardial effusion. Renal ultrasoundto evaluate for renal anomalies and chromoso-mal analysis are also useful in establishing thediagnosis. If sufficient pleural fluid is drained,this fluid should be sent for analysis and mayhelp differentiate chylous from nonchylous effu-sion. Chylothorax is suggested by the predomi-nance of lymphocytes (>70–90%), high triglyceridecount, elevated protein, and albumin concentra-tions. However, analysis of pleural fluid may beunreliable in infants who are not being fed orhave never been fed enterally, in these patientsa diagnosis of chylothorax is suggested by de-tecting a high lymphocyte count in the pleural


fluid. If the fluid proves to be chylous in natureand dysmorphic features and other findings aresuggestive of Noonan syndrome (see Table 25-1),evaluation for a mutation in the PTPN11 (Pro-tein Tyrosine Phosphatase, Nonreceptor type11) gene should be done. This mutation is pre-sent in approximately 50% of cases of Noonansyndrome.


Conservative management of the pregnancy isthe preferred management option in most casesof fetal hydrothorax.5 However, interventionshould be considered if the hydrothorax worsens

or progression to hydrops is identified. Currentlythree techniques are described for managementof worsening hydrothorax in a fetus. Thoraco-centesis was first described as a treatment for pri-mary fetal hydrothorax in 1982. The procedure,however, is limited by the rapid reaccumulationof fluid,2 additionally, there has been a concernthat repeated thoracocentesis can produce hy-poproteinemia which could favor the develop-ment of hydrops.1 Pleuroamniotic shunting forfetal hydrothorax was proposed in 1986 and uti-lizes the same basic principles used for drainingfetal urinary collections and hydrocephalus. Inthis procedure, a surgically placed catheter createsa communication between the fetal pleural spaceand the amniotic cavity allowing for continuous

CHAPTER 25 CONGENITAL HYDROTHORAX 161

� TABLE 25-1 Syndromes Associated with Congenital Hydrothorax


Adams-Oliver syndrome Aplasia cutis congenital;terminal ADtransverse defects of the limbs;microcephaly, encephalocele;cleft lip/palate; cardiac defects

Down syndrome Hypotonia; flat facies; slanted Trisomy 21palpebral fissures; small ears; Xp11.23,21q22.3,1q43simian crease; congenitalheart defect; variable range ofmental retardation

Edwards syndrome Clenched hand; tendency for Trisomy 18overlapping of index fingerover third, fifth finger over fourth;prominent occiput; narrow bifrontaldiameter; low set ears; shortsternum; low arch dermal ridgepatterning on fingertips;

Noonan syndrome Webbing and short appearance ADof neck; pectus excavatum; ptosis; 12p12.1hypertelorism; downward 12q24.1sloping eyes; pulmonary valve 50% with mutations instenosis; PDA; thrombocytopenia; PTPN11 genedelayed puberty, short stature;mental retardation

Turner syndrome Short female; low posterior hair line Monosomy XOwith webbing of neck; broad chestwith wide spacing of nipples;congenital lymphedema

PDA, patent ductus arteriosus; AD, autosomal dominant.

drainage of fluid. While studies demonstrate that20–30% of shunts may migrate or obstruct, in mostcases, the shunt allows for continuous decom-pression of the effusion.2 Other reported compli-cations of pleuroamniotic shunting include: shuntreversal where amniotic fluid drains into the fetalthoracic cavity, and maternal ascites.1 Finally, asingle case of pleurocutaneous drainage was re-ported in 1986 with favorable outcome.8 To date,no other reports of successes or failures havebeen described in the use of pleurocutaneousdrainage.

After delivery, the newborn is at risk for sig-nificant respiratory insufficiency secondary toeffusion and associated pulmonary hypoplasia.It is recommended that infants with prenatallydiagnosed hydrothorax be delivered at a tertiarycare center. Prenatally placed shunts should be

removed or clamped during delivery to avoidpneumothorax. Thoracentesis and possiblyparacentesis may be required in the deliveryroom to facilitate resuscitation if large effusionsare present. Chest and abdominal x-rays shouldbe obtained once the infant is stable. If the in-fant does not develop respiratory distress, onlya period of close observation may be required.Other patients may require prolonged mechan-ical ventilation and tube thoracostomy for anextended period of time to facilitate resolutionof large effusions.

When stable and ready to feed, infants withchylous effusions should be given a diet high inmedium-chain triglycerides; this will allow di-rect absorption of triglycerides into the blood-stream effectively, decreasing its absorption andflow from the thoracic duct in the form of chyle.


Fetus with Pleural Effusions

Diagnostic Evaluation SonogramThoracentesis, Cell Count, CultureKaryotype AnalysisFetal Echocardiogram

PrimaryFHT

SecondaryFHT

AssociatedLife-Threatening

AnomalyCounsel

Response to2nd Thoracentesis

RapidReaccumulation

Resolves:Follow to Term

LargeMediastinal ShiftPolyhydramniosHydrops

Small

SerialUltrasound

SerialUltrasound

ThoracoamnioticShunt

Followto Term

OfferTermination <24 Weeks

TermVaginalDelivery

TermVaginalDelivery

TermVaginalDelivery

Figure 25–1. Algorithm for management of fetal hydrothorax. (Reprinted from Bianchi, DW,Crombleholme TM, D’Alton ME, eds. Fetology: Diagnosis and Management of the Fetal Patient.New York: McGraw-Hill; 2000:317.)

If tube thoracostomy and dietary restrictionsprove ineffective, then pleurodesis or thoracicduct ligation may be indicated and there maybe a need for prolonged total parenteral nutri-tion in these cases.

In the last decade, the use of octreotide inthe treatment of congenital chylothorax hasbeen increasing especially in difficult cases inwhich there has been a failure of traditionalmedical and surgical approaches. Octreotide, asomatostatin analogue, used to treat chylotho-rax was first reported in an adult in 1990.9 In2003, the first report of successful use of oc-treotide in a neonate with chylothorax was re-ported.10 Since then a number of case reports ofoctreotide for treatment of congenital hydrotho-rax have been described in the literature.11–13

While the exact mechanism of action in the treat-ment of chylothorax is unclear, it is believed thatoctreotide causes mild vasoconstriction of splanch-nic vessels and reduces gastric, pancreatic, andintestinal secretions as well as intestinal absorp-tion and hepatic venous flow; this may collec-tively act in concert to reduce chyle flow, thus fa-cilitating resolution of the pleural effusions.14

Potential side effects relate to the suppressive ac-tions on the gastrointestinal motility and secre-tions, with transient loose stools, nausea, flatu-lence, hypoglycemia, and liver dysfunction beingthe most common.11

In a large review of 204 cases of primary hy-drothorax spontaneous regression was docu-mented in 29%; this was more likely to occur ifthe diagnosis was made early in the secondtrimester, in the presence of unilateral effusion,and in absence of polyhydramnios or hydrops.1

Mortality is often due to pulmonary hypoplasiawhich can occur in up to 30% of affected fetuses.15

Since the advent of prenatal therapy (fetal thora-centesis and thoracoamniotic shunting), the mor-tality rate has improved, especially in fetuses withisolated pleural effusions and normal chromo-some complements.6 Nonetheless, the prognosisfor primary hydrothorax is better than the outcomefor secondary hydrothorax. The fetal mortality ratefor primary hydrothorax ranges from 22% to

53% as compared to 95–98% mortality reportedfor secondary hydrothorax.1,4,5,16


To date, there have been no reports of isolatedprimary hydrothorax occurring in siblings. Ge-netic counseling in cases that are found to beassociated with chromosomal anomalies or doc-umented syndromes will depend on the inheri-tance pattern of the individual syndrome.

REFERENCES

1. Aubard Y, Derouineau I, Aubard V, et al. Primaryfetal hydrothorax: a literature review and pro-posed antenatal clinical strategy. Fetal DiagnTher. Nov–Dec 1998;13(6):325–33.

2. Devine PC, Malone FD. Noncardiac thoracicanomalies. Clin Perinatol. Dec 2000;27(4):865–99.

3. Taeusch HW, Ballard RA, Gleason CA. Avery’sDiseases of the Newborn. 8 ed. Philadelphia:Elsevier/Saunders; 2005.

4. Weber AM, Philipson EH. Fetal pleural effusion:a review and meta-analysis for prognostic indica-tors. Obstet Gynecol. Feb 1992;79(2):281–6.

5. Klam S, Bigras JL, Hudon L. Predicting outcomein primary fetal hydrothorax. Fetal Diagn Ther.Sep–Oct 2005;20(5):366–70.

6. Waller K, Chaithongwongwatthana S, YamasmitW, et al. Chromosomal abnormalities among 246fetuses with pleural effusions detected on prena-tal ultrasound examination: factors associatedwith an increased risk of aneuploidy. Genet Med.Jul–Aug 2005;7(6):417–21.

7. Carroll B. Pulmonary hypoplasia and pleural ef-fusions associated with fetal death in utero: ul-trasonic findings. AJR Am J Roentgenol. Oct 1977;129(4):749–50.

8. Roberts AB, Clarkson PM, Pattison NS, et al. Fe-tal hydrothorax in the second trimester of preg-nancy: successful intra-uterine treatment at24 weeks gestation. Fetal Ther. 1986;1(4):203–9.

9. Ulibarri JI, Sanz Y, Fuentes C, et al. Reduction oflymphorrhagia from ruptured thoracic duct bysomatostatin. Lancet. Jul 1990;336(8709):258.

10. Au M, Weber TR, Fleming RE. Successful use ofsomatostatin in a case of neonatal chylothorax.J Pediatr Surg. Jul 2003;38(7):1106–7.

CHAPTER 25 CONGENITAL HYDROTHORAX 163

11. Rasiah SV, Oei J, Lui K. Octreotide in the treat-ment of congenital chylothorax. J Paediatr ChildHealth. Sep–Oct 2004;40(9–10):585–8.

12. Paget-Brown A, Kattwinkel J, Rodgers BM, et al.The use of octreotide to treat congenital chy-lothorax. J Pediatr Surg. Apr 2006;41(4):845–7.

13. Goto M, Kawamata K, Kitano M, et al. Treatmentof chylothorax in a premature infant using so-matostatin. J Perinatol. Oct 2003;23(7):563–4.

14. Siu SL, Lam DS. Spontaneous neonatal chylotho-rax treated with octreotide. J Paediatr ChildHealth. Jan–Feb 2006;42(1–2):65–7.

15. Estoff JA, Parad RB, Frigoletto FD, Jr., et al. The nat-ural history of isolated fetal hydrothorax. UltrasoundObstet Gynecol. May 1992;2(3):162–5.

16. Longaker MT, Laberge JM, Dansereau J, et al. Pri-mary fetal hydrothorax: natural history and man-agement. J Pediatr Surg. Jun 1989;24(6):573–6.


Chapter 26

Congenital PulmonaryLymphangiectasia

SANDRA B. CADICHON

165

� INTRODUCTION

Congenital pulmonary lymphangiectasia (CPL)is a rare disorder of the lymphatic system char-acterized by diffuse dilation of the lymphaticchannels in the peribronchial, subpleural, andinterlobular septa in the lungs. Two forms ofpulmonary lymphangiectasia are clinically rec-ognized: primary or congenital and secondary,which occurs as a result of injury to the lym-phatic vessels. Noonan et al classified CPL intothree groups: (1) generalized lymphangiectasia,(2) pulmonary venous obstruction with sec-ondary lymphangiectasia, and (3) primary pul-monary lymphatic developmental anomaly.1

The generalized form of CPL has less severepulmonary disease and is characterized by in-testinal lymphangiectasia, hemihypertrophy,and angiomatosis; this form has a better prog-nosis.1 In the second group, the primary fea-tures are cardiac anomalies that cause obstruc-tion of pulmonary venous return and pulmonaryvenous hypertension with pulmonary lymphang-iectasia being a result of this obstructive process.The third group is isolated lymphangiectasia ofthe lungs without cardiac or other lymphatic ab-normalities. Occasional cases of CPL involving

only one or two lobes of the lung and the me-diastinum have also been reported.2,3

� EPIDEMIOLOGY

Pulmonary lymphangiectasia is a rare disorderand its incidence is unknown. Autopsy resultssuggests that 0.5–1% of infants who are stillbornor die in the neonatal period have pulmonarylymphangiectasia.4–6 A number of case seriessuggests that there is a male predominance.While this disorder is usually fatal in the neona-tal period, cases of survival beyond infancy havebeen reported7,8 and presentation during adult-hood has also been documented.2,8


The pulmonary lymphatics system is normally welldeveloped by the end of the 14th week of gesta-tion. Initially, large lymph channels are present inthe normal fetal lungs which later undergo spon-taneous regression. It is believed that failure ofthese channels to undergo the normal regressionleads to primary pulmonary lymphangiectasia.9


Congenital pulmonary lymphangiectasia is thoughtto be a heterogeneous disorder, with most casesoccurring sporadically.9 Reports of occurrence insiblings suggest a genetic inheritance in somefamilies and possibly an autosomal recessivemode of transmission in some cases.9–13


In the prenatal period the fetus may developnonimmune hydrops, bilateral pleural effusionsor chylothorax, and often polyhydramnios.Many infants are stillborn. Most neonates bornwith this disorder develop cyanosis, tachypnea,and worsening respiratory distress either imme-diately or within hours after birth and usuallyrequire mechanical ventilation support for sur-vival. Patients surviving the neonatal period andwho present later in life typically present withtachypnea, recurrent cough, wheezing, andchest pain in some. Not uncommonly, chylouseffusions are present. Patients with intestinal in-volvement may develop chylous ascites.


Congenital pulmonary lymphangiectasia can befound in up to 62% of the cases of total anom-alous pulmonary venous return.14 Other con-genital cardiac malformations observed withcongenital pulmonary lymphangiectasia includehypoplastic left heart syndrome, pulmonary veinatresia, congenital mitral stenosis, and cor-triatriatum.15 The majority of malformations oc-curring with congenital pulmonary lymphang-iectasia are cardiac, however, hemihypertrophyand angiomatosis can occur in the generalizedform of congenital pulmonary lymphangiectasia.

Syndromes that may occur in conjunctionwith CPL include: Noonan, Down, Turner, Fryns,and congenital ichthyosis. There has been atleast one case report of congenital pulmonary

lymphangiectasia occurring in a patient withHennekam syndrome.16 Table 26-1 summarizesthe hereditary syndromes associated with con-genital pulmonary lymphangiectasia.

� EVALUATION AND MANAGEMENT

As with all infants presenting with unusual orcongenital pathology, a complete and thoroughphysical examination is essential. Patients pre-senting in the neonatal period demonstrate aground glass appearance on chest x-ray andpleural effusions are evident. In infancy andchildhood, chest x-ray typically shows reticu-lonodular interstitial markings and hyperinfla-tion.4 If significant pleural effusions are present,a chest tube should be placed; the pleural fluidshould be sampled and analyzed. In infants whoare not being fed or have never fed enterally,pleural fluid may be unreliable. Therefore, inthese patients, a diagnosis of chylothorax is sug-gested by detection of a high lymphocyte countin the pleural fluid.

Recently, high resolution computed tomog-raphy (CT) scan has been used as a diagnosticmodality to assist in the diagnosis of congenitalpulmonary lymphangiectasia. A constellation offeatures that include intralobular and peri-bronchial thickening, patchy ground-glass opaci-fication, pleural effusion, and pleural thickeningfound on CT are highly suggestive of congenitalpulmonary lymphangiectasia.4 In many patients,an open-lung biopsy may assist in the diagnosisand differentiation from other forms of lungdisease but may not be feasible in a criticallyill infant. Other studies to consider include:an echocardiogram to evaluate for congenitalheart defects, karyotyping, and genetic testingto evaluate for chromosomal anomalies. If otherfindings are suggestive of Noonan syndrome(see Table 26-1) evaluation for a mutation inthe protein tyrosine phosphatase, nonreceptortype 11 (PTPN11) gene should be done. Fur-thermore, evaluation of the parents should be


CHAPTER 26 CONGENITAL PULMONARY LYMPHANGIECTASIA 167

� TABLE 26-1 Syndromes Associated with Pulmonary Lymphangiectasia (Modified from: Bellini C,Boccardo F, Campisi C, et al. Pulmonary lymphangiectasia. Lymphology. 2005;38:111–21.)


Camptomelia, Cumming Generalized lymphedema; cervical lymphocele; Autosomal recessivetype shortness of limbs; bowed long bones;

multicystic kidneys; fibrotic liver or pancreasGerman syndrome Arthrogryposis; hypotonia-hypokinesia Autosomal recessive

sequence; lymphedemaHennekam Flat face; flat nasal bridge; hypertelorism; Autosomal recessive

lymphangiectasia epicanthal folds; small mouth; teethanomalies; intestinal lymphangiectasia;lymphedema of the limbs, genitaliaand face; severe mental retardation;

Hypotrichosis-lymphedema- Hypotrichosis; lymphedema; telangiectasia Autosomal recessivetelangiectasia syndrome 20q13.33

Idiopathic hydrops fetalis Generalized edema of the fetus; congenital Autosomal recessivepulmonary lymphangiectasia

Intestinal lymphangiectasia Edema of the legs; ulcers in males; Autosomal dominantdysproteinemia; lymphangiectasias;lymphocytopenia; hypogammaglobulinemia;protein-losing enteropathy

Knobloch syndrome Retinal detachment; high myopia; occipital Autosomal recessiveencephalocele; normal intelligence 21q22.3

Lymphedema/cerebral Lymphedema of the feet; cerebrovascular Autosomal dominantarteriovenous anomaly malformations

Lymphedema Congenital lymphedema; hypoparathyroidism; X-linkedhypoparathyroidism nephropathy; mitral valve prolapse;syndrome brachytelephalangy

Noonan syndrome Webbing and short appearance of neck; Autosomal dominantpectus excavatum; ptosis; hypertelorism; 12p12.1downward sloping eyes; pulmonary valve 12q24.1stenosis; PDA; thrombocytopenia; delayed 50% with mutationspuberty, short stature; mental retardation in PTPN11 gene

PEHO syndrome Severe hypotonia; hyperreflexia; convulsions Autosomal recessive(Progressive with hypsarrhythmia; mental retardation;Encephalopathy with encephalopathy; transient orEdema, persistent edemaHypsarrhythmia, andOptic atrophy)

Urioste syndrome Prenatal growth deficiency; hypertrophied Autosomal recessive(persistence of alveolar ridges; redundant nuchal skin;Mullerian derivatives, postaxial polydactyly; cryptorchidism;with lymphangiectasia lymphangiectasia; renal anomaliesand postaxialpolydactyly)

Yellow nail syndrome Yellow nails; lymphedema; edema of genitalia, Autosomal dominanthands, face, and vocal cords; primary 16q24.3hypoplasia of lymphatics

considered for undiagnosed mild cases of Noo-nan syndrome.


Management of these patients is typically sup-portive in nature, with mechanical ventilationfor respiratory failure, pleural drains, and re-placement of fluids as needed. A diet rich inmedium-chain triglycerides and total parenteralnutrition have been found to decrease forma-tion of the chylous effusion.4 Antiplasmin andoctreotide have been used to reduce lymphaticlosses in intestinal lymphangiectasia, but havenot been evaluated in congenital pulmonarylymphangiectasia.4 Surgical procedures such aspleurodesis and pleuroperitoneal shunts havebeen used for intractable pleural effusions.

Mortality from congenital pulmonary lym-phangiectasia was previously thought to be 100%in the neonatal period. However, with improvedneonatal intensive care management, this is nolonger thought to be a universally fatal disease.A number of cases describing survival beyondinfancy have been reported.7,8,17,18

An improvement in respiratory status duringinfancy and childhood has been reported inmost long-term survivors, with many of thesepatients having only minimal symptoms by theage of 6 years.4 Some patients, however, con-tinue to have recurrent respiratory problems forthe first several years of life.4,17,19 Commonsymptoms include recurrent cough and wheezethat is variably responsive to bronchodilators,increased sensitivity to respiratory infection andmultiple hospitalizations; a few patients are re-ported to require home supplemental oxygenfor a period of time.4 While the pleural effu-sions eventually resolve, chest x-rays continueto show hyperinflation with stable or decreas-ing interstitial markings.4 Other medical prob-lems that occur in long-term survivors includegastroesophageal reflux and poor growth in thefirst few years of life; with resumption of nor-mal growth pattern by age 3 years.4,19


Since congenital pulmonary lymphangiectasiahas no known definitive genetic basis, the recur-rence risk is unknown and has not been reportedto our knowledge. However, the recurrence riskin subsequent pregnancies is considered to behigher than in the general population and couldbe as high as 25% due to undiagnosed autoso-mal recessive disorders in the index pregnancy.Future pregnancies should be closely monitoredby serial ultrasound for early detection of pleuraleffusions. Genetic counseling for families of in-fants with a known syndrome or chromosomalanomaly should be based on recurrence risk ofthe syndrome or anomaly itself.

REFERENCES

1. Noonan JA, Walters LR, Reeves JT. Congenitalpulmonary lymphangiectasis. Am J Dis Child.Oct 1970;120(4):314–9.

2. White JE, Veale D, Fishwick D, et al. Generalisedlymphangiectasia: pulmonary presentation in anadult. Thorax. Jul 1996;51(7):767–8.

3. Wagenaar SS, Swierenga J, Wagenvoort CA. Latepresentation of primary pulmonary lymphangiec-tasis. Thorax. Dec 1978;33(6):791–5.

4. Esther CR, Jr., Barker PM. Pulmonary lymphangiec-tasia: diagnosis and clinical course. Pediatr Pulmonol.Oct 2004;38(4):308–13.

5. France NE, Brown RJ. Congenital pulmonary lym-phangiectasis. Report of 11 examples with specialreference to cardiovascular findings. Arch Dis Child.Aug 1971;46(248):528–32.

6. Laurence KM. Congenital pulmonary lymphang-iectasis. J Clin Pathol. Jan 1959;12(1):62–9.

7. Chung CJ, Fordham LA, Barker P, et al. Childrenwith congenital pulmonary lymphangiectasia: af-ter infancy. AJR Am J Roentgenol. Dec 1999;173(6):1583–8.

8. Nobre LF, Muller NL, de Souza AS Jr., et al. Con-genital pulmonary lymphangiectasia: CT andpathologic findings. J Thorac Imaging. Jan 2004;19(1):56–9.

9. Moerman P, Vandenberghe K, Devlieger H, et al.Congenital pulmonary lymphangiectasis with chy-lothorax: a heterogeneous lymphatic vessel abnor-mality. Am J Med Genet. Aug 1993;47(1):54–8.


10. Njolstad PR, Reigstad H, Westby J, et al. Familialnon-immune hydrops fetalis and congenital pul-monary lymphangiectasia. Eur J Pediatr. Jun 1998;157(6):498–501.

11. Jacquemont S, Barbarot S, Boceno M, et al. Fa-milial congenital pulmonary lymphangectasia,non-immune hydrops fetalis, facial and lowerlimb lymphedema: confirmation of Njolstad’s re-port. Am J Med Genet. Aug 2000;93(4):264–8.

12. Stevenson DA, Pysher TJ, Ward RM, et al. Famil-ial congenital non-immune hydrops, chylotho-rax, and pulmonary lymphangiectasia. Am J MedGenet A. Feb 2006;140(4):368–72.

13. Scott-Emuakpor AB, Warren ST, Kapur S, et al.Familial occurrence of congenital pulmonary lym-phangiectasis. Genetic implications. Am J Dis Child.Jun 1981;135(6):532–4.

14. Yamaki S, Tsunemoto M, Shimada M, et al. Quan-titative analysis of pulmonary vascular disease intotal anomalous pulmonary venous connection

in sixty infants. J Thorac Cardiovasc Surg. Sep 1992;104(3):728–35.

15. Bellini C, Boccardo F, Campisi C, et al. Pulmonarylymphangiectasia. Lymphology. Sep 2005;38(3):111–21.

16. Bellini C, Mazzella M, Arioni C, et al. Hennekamsyndrome presenting as nonimmune hydrops fe-talis, congenital chylothorax, and congenital pul-monary lymphangiectasia. Am J Med Genet A.Jul 2003;120(1):92–6.

17. Bouchard S, Di Lorenzo M, Youssef S, et al. Pul-monary lymphangiectasia revisited. J Pediatr Surg.May 2000;35(5):796–800.

18. Scott C, Wallis C, Dinwiddie R, et al. Primary pul-monary lymphangiectasis in a premature infant:resolution following intensive care. Pediatr Pul-monol. May 2003;35(5):405–6.

19. Barker PM, Esther CR, Jr., Fordham LA, et al. Pri-mary pulmonary lymphangiectasia in infancy andchildhood. Eur Respir J. Sep 2004;24(3):413–9.

CHAPTER 26 CONGENITAL PULMONARY LYMPHANGIECTASIA 169


Part V

Cardiac Malformations



Chapter 27

Septal DefectsBARBARA K. BURTON

173

� ATRIAL SEPTAL DEFECT(EXCLUDES PATENT FORAMENOVALE)

� INTRODUCTION

Atrial septal defect (ASD) is a defect in the atrialseptum which leads to a communication betweenthe right and left atrium. The most common formis the secundum type of ASD which represents85% of all ASDs and 8–10% of all congenitalheart defects.

� DIAGNOSIS

Most infants with a secundum ASD do not havesymptoms and the defect is rarely diagnosed inthe neonatal period unless an echocardiogramis performed. The diagnosis is usually madewhen a child is evaluated for a systolic murmurwhich may be difficult to distinguish from themurmur of pulmonic stenosis. The characteristicfinding of an ASD is a fixed split second heartsound, however. When a large left to right shuntis present, a mid-diastolic murmur can be heardacross the tricuspid valve in addition to the sys-tolic murmur across the pulmonic valve. Chestradiography reveals volume overload on theright side of the heart and increased pulmonaryvasculature. Electrocardiogram (ECG) reveals

right axis deviation and right ventricular hyper-trophy with an incomplete right bundle branchblock pattern. The defect can be identified byechocardiography.

� INCIDENCE AND ETIOLOGY

ASD usually occurs as an isolated anomaly withan incidence of close to 1 per 1000 in the generalpopulation. The defect is more common in femalesthan in males with a sex ratio of 1:2. Althoughmost commonly isolated, it can be associated witha number of different malformation syndromes in-cluding chromosome anomalies, single gene dis-orders, and teratogenic syndromes. These arelisted in Table 27-1. One of the best known syn-dromes associated with ASD is the Holt-Oram syn-drome which is associated with ASD in over 50%of cases. Other characteristic features of this auto-somal dominant disorder include defects of theupper limb and shoulder girdle.

Although isolated sporadic cases of ASD arefelt to most often be multifactorial in nature withmultiple genes or genes and environmental fac-tors playing a role in causation, specific envi-ronmental factors have not been identified. Insome families, ASD may be inherited in a singlegene pattern with autosomal dominant trans-mission being well-documented. Two specificgenes have been linked to families in which


174 PART V CARDIAC MALFORMATIONS

� TABLE 27–1 Syndromes Commonly Associated with Cardiac Septal Defects

Type of Cardiac Other AssociatedSyndrome Defect Findings Etiology

ChromosomeAnomalies:Trisomy 13 ASD, VSD, AVC Eye malformations; scalp De novo due to

(Fig. 27-2) defects; oral clefts; nondisjunction inpolydactyly; vast majority; familialcryptorchidism translocation in

small percentageTrisomy 18 VSD, AVC Intrauterine growth De novo due to

(Fig. 27-1) retardation; overlapping nondisjunction infingers; prominent vast majority; familial occiput translocation in

small percentageTrisomy 21 AVC, VSD Characteristic facies; De novo due to

(Down syndrome) hypotonia; excess skin nondisjunction innape of neck; single vast majority; familialpalmar crease translocation in

small percentage4p deletion syndrome ASD Intrauterine growth Deletion may be

(Wolf-Hirschhorn retardation; submicroscopicsyndrome) microcephaly; detectable only by

hypertelorism; cleft FISH; De novo inlip/palate; hypospadias most cases; parents

must be studied torule out balancedrearrangement

22q11 deletion VSD Cleft palate; narrow Submicroscopicsyndrome palpebral fissures; deletion; de novo in(Velocardiofacial hypocalcemia; 90% of cases;syndrome) hypotonia; thymic inherited from

hypoplasia parent in 10%

Single Gene Disorders:ASD with ASD Progressive Autosomal dominant

conduction defects atrioventricular block NKX2.5, 5q343C syndrome VSD, AVC Macrocephaly; Autosomal recessive

(Craniocerebello- downslanting palpebralcardiac dysplasia; fissures; hypertelorism;Ritscher-Schinzel Dandy-Walkersyndrome) malformation

CHARGE syndrome ASD, VSD Retinal colobomas; Autosomal dominantchoanal atresia; growth CHD7, 8q12.1and developmentalretardation; genitalanomalies; earanomalies; deafness

CHAPTER 27 SEPTAL DEFECTS 175

� TABLE 27–1 Syndromes Commonly Associated with Cardiac Septal Defects (Continued)


Ellis-van Creveld ASD Short limbs; short ribs; Autosomal recessivesyndrome polydactyly; dysplastic EVC, 4p16(Chondroectodermal nails and teethdysplasia)

Fryns syndrome VSD Coarse facies; Autosomal recessivediaphragmatic hernia;hypoplastic nails anddistal phalanges; usuallylethal in newborn

Holt-Oram syndrome ASD, VSD, AVC Upper limb defects ranging Autosomal dominantfrom absent, hypoplastic, TBX5, 12q24.1or triphalangeal thumbsto limb reduction defects;narrow, sloping shoulders

Hydrolethalus AVC Hydrocephalus; polydactyly; Autosomal recessivesyndrome duplicated great toes; 11q23–q25

small eyes, small nose,oral clefts; unusuallylethal in newborn

Kabuki syndrome ASD, VSD Characteristic facies with Autosomal dominantlong palpebral fissures;eversion of lower lids;cleft palate; hypotonia

McKusick-Kaufman AVC Hydrometrocolpos; Autosomal recessivesyndrome hypospadias; polydactyly 20p12

Noonan syndrome ASD, AVC Short stature; dysmorphic Autosomal dominantfacies; excess skin folds PTPN11, 12q24nape of neck or webbedneck; hypertrophiccardiomyopathy;cryptorchidism

Oral-facial-digital AVC Pseudocleft of upper lip; Autosomal recessive(OFD) syndrome II lobate tongue;(Mohr syndrome) polydactyly; syndactyly;

tachypnea; laryngealanomalies

Rubinstein-Taybi ASD Microcephaly; beaked Autosomal dominantsyndrome nose; broad thumbs CREBBP, 16p13

and great toes EP300, 22q13Simpson-Golabi- VSD Macroglossia; coarse X-linked

Behmel syndrome facies; accelerated Glypican-3, Xq26growth; polydactyly;arrhythmias

(Continued)




Smith-Lemli-Opitz AVC Microcephaly; anteverted Autosomal recessivesyndrome nares; syndactyly of DHCR7, 11q12-q13

toes; polydactyly;hypospadias; cleft palate;elevated7-dehydrocholesterollevel

Thrombocytopenia- ASD, VSD Bilateral absence of radius Autosomal recessiveabsent radius with presence of fingers(TAR) syndrome and thumbs;

thrombocytopenia;other skeletal anomalies

Toriello-Carey ASD, VSD Agenesis of corpus Autosomal recessivesyndrome callosum; Pierre-Robin

sequence; shortpalpebral fissures;laryngeal anomalies;hypotonia

Townes-Brock VSD Imperforate anus; Autosomal dominantsyndrome triphalangeal and/or SALL1, 16q12.1

supernumerary thumbs;abnormal ears; renalanomalies; hearing loss

Disorders of UnclearEtiology:

Heterotaxy syndromes AVC Asplenia or polysplenia Most cases sporadic.(asplenia/polysplenia with splenic dysfunction; Probablyor Ivemark syndrome abnormal visceral heterogenous.

lateralization; multiple orcomplex cardiac defectscommon

Oculoauriculovertebral VSD Underdevelopment of one Heterogenous with(OAV) syndrome side of face; unilateral or many cases(includes Goldenhar asymmetrical ear sporadic; fewsyndrome and deformities; epibulbar autosomal dominanthemifacial dermoid; oral clefts;microsomia vertebral anomalies

VACTERL syndrome VSD Vertebral anomalies; Unknowntracheoesophagealfistula; anal atresia;renal anomalies; limbdefects

ASD is inherited in an autosomal dominant pat-tern. Mutations in NKX2.5 have been identifiedin families in which ASD is associated with con-duction abnormalities, specifically progres-sive atrioventricular block, as well as in a smallpercentage of sporadic ASD patients.1,2 Mutationsin the GATA4 zinc finger transcription factor genehave been identified in families with autosomaldominant ASDs and normal conduction.3 Somepatients with the latter defects have had addi-tional cardiac lesions, particularly valvar pul-monic stenosis.

� TREATMENT AND PROGNOSIS

Most ASDs remain asymptomatic, even whenuntreated and do not pose a risk for bacterialendocarditis. Spontaneous closure often occursin the first year of life. Defects associated witha significant left to right shunt may produce pul-monary obstructive vascular disease in 5–10%of cases. Large atrial communications increase

the risk of paradoxical emboli. For large defects,surgical closure is usually the accepted methodof treatment, regardless of the presence or ab-sence of symptoms. In some cases, catheter-basedrepair may be possible.


A complete family history should be obtainedprior to providing genetic counseling to the par-ents of an infant with an ASD. If there are anyother family members with structural cardiac de-fects, conduction disorders, or arrhythmias, cau-tion should be exercised before assuming thatthe patient has an isolated, multifactorial defect.Such a history may suggest autosomal dominantinheritance, particularly if a parent is affected. Infamilies with autosomal dominant inheritance ofASD, the recurrence risk in future pregnancies is50%. In the case of isolated sporadic cases withno other family history, the recurrence risk forfuture siblings is approximately 3%.




Teratogenic Syndromes:Fetal alcohol VSD, ASD Microcephaly; small size; Prenatal alcohol

syndrome short palpebral fissures; exposuresimple philtrum; thinupper lip

Maternal diabetic VSD Other cardiac defects such Abnormal maternalembryopathy as tetralogy of Fallot glucose metabolism

and truncus arteriosus;neural tube defects;holoprosencephaly;caudal regressionsyndrome; focal femoralhypoplasia

Maternal PKU VSD Microcephaly; intrauterine Intrauterine exposuresyndrome growth retardation; to high phenylalanine

dysmorphic facies levelsresembling those seenin fetal alcohol syndrome

Valproic acid ASD,VSD Dysmorphic facies; joint Prenatal exposure toembryopathy contractures; spina bifida valproic acid

� VENTRICULAR SEPTAL DEFECT

� INTRODUCTION

Ventricular septal defect (VSD) is a defect in theclosure of the ventricular septum of the heartresulting in an abnormal communication be-tween the right and left ventricle.

� DIAGNOSIS

The clinical findings in patients with a VSD varydepending on the size of the defect. Many smalldefects are asymptomatic and are diagnosedon the basis of the characteristic holosystolicmurmur heard at the left sternal border. In thecase of larger defects associated with a large left


Figure 27-1. Infant with trisomy 18, a condi-tion associated with cardiac defects in over90% of cases. Cardiac septal defects are themost common lesions observed. Other typicalfindings seen in this infant include micrognathia,dysmorphic ears, overlapping fingers, a shortsternum, and exaggerated cutis marmorata.A radial defect and club hand are noted onthe left.

Figure 27-2. Infant with trisomy 13, a condi-tion associated with cardiac defects in over90% of cases, with ventricular septal defectbeing the most common. Other characteristicfeatures include scalp defects, eye anom-alies such as anophthalmia (as in this case),microphthalmia or colobomas, a large bul-bous nose as seen here, cleft lip or palateand polydactyly.

to right shunt and pulmonary hypertension, thesecond heart sound will be loud and narrowlysplit. Once right to left shunting develops acrossthe defect (the Eisenmenger complex), the pa-tient becomes cyanotic.

In patients with small VSDs, chest radi-ographs and ECG are normal. As the extent ofleft to right shunting increases, there is an in-crease in pulmonary vascularity. In addition,the ECG reveals left atrial enlargement and leftventricular hypertrophy or, in some cases,biventricular hypertrophy. As pulmonary hy-pertension develops, only right ventricular hy-pertrophy and right atrial enlargement may beobserved. The presence of a VSD and any as-sociated cardiac lesions can be confirmed byechocardiography.


VSD is one of the most common types of con-genital heart disease but its exact incidence isdifficult to determine. Widely varying figuresexist in the literature clearly reflecting the methodof ascertainment and the fact that many VSDswill close spontaneously and therefore may goundetected. A prospective Doppler echocardio-graphic study of 1-week-old newborns reportedan incidence of 53 per 1000 births4 with mostaffected infants being asymptomatic. In con-trast, a study based on children with a clinicalor autopsy diagnosis yielded an incidence of1.17 per 1000; almost 50 times lower.5 Presumablymost of the defects detected in the prospectivestudy were in the process of closing. Males and fe-males are affected with VSD with equal frequency.It occurs most commonly in an otherwise normalhealthy child. However, it can be observed in as-sociation with a large number of different mal-formation syndromes. The most common onesare listed in Table 27-1. Several specific geneshave been found to have a role in the occur-rence of VSD in some individuals. In addition tobeing linked to ASD, mutations in the TBX5 genemay produce VSDs, most notably those associ-ated with a “Swiss cheese septum.”6 This is the

gene linked to the Holt-Oram or Heart-Handsyndrome, which is also associated with con-genital anomalies of the upper extremities andshoulder girdle. Mutations in GATA4 can alsoproduce VSD in association with ASD.7 A num-ber of different teratogens have been found toplay a role in the occurrence of VSD, amongthem phenylalanine (in maternal phenylke-tonuria [PKU]), derangements in glucose me-tabolism (in maternal diabetes), alcohol, andvalproic acid.


Small VSDs have an excellent long term prog-nosis and require no therapy, but are associatedwith a risk of subacute bacterial endocarditis.Antibiotic prophylaxis at times of predictable riskis required. Medical therapy with digoxin or di-uretics or both is typically used in children whohave signs of congestive heart failure. Pulmonaryartery banding was commonly practiced in thepast with definitive surgery deferred for severalyears but direct surgical closure in infancy isnow standard practice. A significant percentageof defects will close spontaneously during in-fancy with the likelihood of closure varying de-pending on the size and nature of the defect.


A complete family history should be obtainedfrom the parents of every infant with a VSDprior to providing genetic counseling. If thereare any other family members with structuralcardiac defects, conduction disturbances, or ar-rhythmias, consideration should be given to thepossibility that one is dealing with a family inwhich the defect is inherited in a Mendelian,autosomal dominant pattern as opposed to thetypical multifactorial pattern. This is particularlytrue if either parent or a sibling has any find-ings. Further evaluation of the family memberswould be warranted. In the case of autosomaldominant inheritance, the recurrence risk in


future pregnancies would be 1 in 2 or 50%. Inthe case of an isolated sporadically occurringVSD in an otherwise healthy normal child withno history of other affected family members, therecurrence risk in future siblings is approxi-mately 3%.

� ATRIOVENTRICULAR SEPTALDEFECT (INCLUDESATRIOVENTRICULAR CANALDEFECT; ENDOCARDIALCUSHION DEFECT)

� INTRODUCTION

Atrioventricular (AV) septal defects are defectsresulting from incomplete formation of the AVseptum, usually accompanied by abnormalitiesof the AV valves. They are also referred to asAV canal defects or endocardial cushion de-fects. The term includes ostium primum typeatrial septal defects, which are also associatedwith a cleft anterior mitral valve leaflet. Thistype of defect may be referred to as a partialAV septal defect in contrast to the complete AVseptal defect, which has both large atrial andventricular components and common AV valveleaflets.

� DIAGNOSIS

The clinical findings associated with an ostiumprimum ASD are similar to those associated withother ASDs with a significant left to right shuntwith the addition of a murmur of mitral insuffi-ciency. A wide range of findings are observedin infants with a complete AV septal defect de-pending in the degree of pulmonary resistanceand pulmonary blood flow. Many affected in-fants develop signs of congestive heart failurewith a hyperactive precordium, loud systolicmurmur, and a gallop rhythm with the singleand/or narrowly split second heart sound asso-ciated with pulmonary hypertension. In rarecases, there may be no systolic murmur.

Cardiomegaly and increased pulmonary vas-cular markings are typically seen on chest radi-ographs. ECG reveals a superior axis with acounterclockwise loop and variable ventricularhypertrophy. The presence of the defect can bedocumented by echocardiography. Cardiaccatheterization to define the magnitude of theleft to right shunt and to evaluate the extent ofpulmonary hypertension is considered in manycases and is particularly important for childrenwith Down syndrome in whom the develop-ment of pulmonary hypertension appears to beaccelerated.


In contrast to most other congenital cardiac de-fects, AV septal defects rarely occur as an isolatedanomaly but are most often associated with abroader malformation syndrome. The best knownassociation is with Down syndrome but thesedefects can be observed in association with otherchromosome anomalies and many other nonchro-mosomal multiple birth defect syndromes as well.The second most common association afterDown syndrome is with heterotaxy or Ivemarksyndrome. In one large series of congenital heartdefects, the Baltimore-Washington Infant Study,only 22% of AV septal defects were not associatedwith noncardiac anomalies.8 The most commonsyndromes associated with AV septal defects arelisted in Table 27-1.

The incidence of AV septal defect is esti-mated to be approximately 1 in 3000 births.9

When it occurs as an isolated defect, it is inher-ited as an autosomal dominant disorder with vari-able penetrance. Mutations in the gene CRELD1have been identified as causative in some patientswith isolated AV septal defects as well as in somefamilies with AV septal defects associated withheterotaxy.9


All forms of AV septal defect require surgical re-pair with the timing dependent on the severity


of the defect. The prognosis is generally depen-dent on associated malformations and the pres-ence or absence of pulmonary vascular disease.


Genetic counseling for patients with AV septaldefects is dependent on the underlying diagnosis.Since most patients have associated malforma-tions, it is essential that a thorough assessmentof the patient be performed to identify any as-sociated anomalies and that every effort bemade to establish a unifying diagnosis. In thecase of the patient with multiple malformationswithout a clear diagnosis, consultation with aclinical geneticist should be obtained. If a pa-tient has an isolated AV septal defect with nofamily history of other family members withcongenital heart defects or ECG abnormalities,the recurrence risk for future siblings is approx-imately 2%. If two or more family members areaffected, the risk rises to 50%.

REFERENCES

1. McElhinney DB, Geiger E, Blinder J, et al. NKX2.5mutations in patients with congenital heart dis-ease. J Am Coll Cardiol. 2003;42:1650–5.

2. Sarkozy A, Conti E, Neri C, et al. Spectrum of atrialseptal defects associated with mutations of NKX2.5and GATA4 transcription factors. J Med Genet.2005;42:e16.

3. Okubo A, Miyoshi O, Baba K, et al. A novel GATA4mutation completely segregated with atrial septaldefect in a large Japanese family. J Med Genet.2004;41:e97.

4. Roguin N, Du ZD, Barak, M, et al. High preva-lence of muscular ventricular septal defect inneonates. J Am Coll Cardiol. 1995;26:1545–8.

5. Martin GR, Perry LW, Ferencz C. Increased preva-lence of ventricular septal defect: epidemic or im-proved diagnosis. Pediatrics. 1989;83:200–3.

6. Brassington AM, Sung SS, Toydemir RM, et al.Expressivity of Holt-Oram Syndrome is not pre-dicted by TBX5 genotype. Am J Hum Genet. 2003;73:74–85.

7. Garg V, Kathiriya IS, Barness R, et al. GATA4 mu-tations cause human congenital heart defects andreveal an interaction with TBX5. Nature. 2003;424:443–7.

8. Loffredo CA, Hirata J, Wilson PD, et al. Atrioven-tricular septal defects: possible etiologic differencesbetween complete and partial defects. Teratology.2001;63:87–93.

9. Robinson SW, Morris CD, Goldmuntz E, et al. Mis-sense mutations in CRELD1 are associated withcardiac atrioventricular septal defects. Am J HumGenet. 2003;72:1047–52.



Chapter 28

Conotruncal Heart DefectsAMY WU

183

The conotruncal region of the developing heart

refers to the area of the development and even-

tual location of the aortic and pulmonary valves,

as well as the conal or outlet septum portion of

the ventricular septum that lies in the plane be-

tween the two valves. Conotruncal defects result

from either an error in septation, rotation, or a

misalignment of their union. There are several

defects classified as conotruncal defects, and

even more variations of each defect. In this

chapter, three major conotruncal defects will be

discussed in their simplest form; truncus arte-

riosus (TA), transposition of the great arteries

(TGA), and tetralogy of Fallot (TOF).

� TRUNCUS ARTERIOSUS

� INTRODUCTION

Truncus arteriosus is an early embryological fail-ure of truncal septation, which occurs aroundthe fifth week of gestation. At that time there isa single outflow tract overriding the incompleteventricular conus. Truncal swellings originate atthe base of the outflow tract on both the rightand left side. They grow into the lumen andfuse to form the truncal septum, dividing theoutflow tract into two separate vessels; the aortaand the main pulmonary artery. Conal swellings,which will complete the ventricular septum be-tween the pulmonary and aortic valves, are in-tended to meet the proximal truncal swellings.Their union leads to the formation of the aortic andpulmonary valves. Distally, the truncal septum will

fuse with the aortopulmonary septum, the prim-itive pulmonary arteries on the leftward aspect,and the aortic arch to the right.1

Failure of truncal septation leads therefore,not only to a single outflow tract, but multipleconsequential defects. There is a single and ab-normal truncal valve with various numbers ofleaflets which is frequently regurgitant. The si-nuses of valsalva are improperly formed leadingto anomalies in coronary artery origins and theirproximal course. Improper fusion with the conalswellings leads to a large ventricular septal de-fect (VSD). The common truncus remains over-riding the VSD in 68–83% of patients.1 Distally,the primitive aortic arches and aortopulmonaryseptum fuse with the common truncus. The pul-monary arteries either fuse as a common baseand then branch, or enter the ascending truncusas two separate branch pulmonary arteries.


� EPIDEMIOLOGY

One of the least common forms of congenitalheart disease, truncus arteriosus accounts for<1% of all heart defects. The incidence is re-ported to be as low as .0006 per 1000 live births,with near equal distribution between the sexes.2

Environmental factors also play a role, with se-vere maternal diabetes and maternal use ofthalidomide and retinoic acid associated withTA.1


The clinical presentation of a newborn with TAwill depend on the severity of the truncal valveinsufficiency and the pulmonary vascular resis-tance. In rare instances the truncal valve will beseverely regurgitant and the neonate will pre-sent in congestive heart failure (CHF). Morecommonly the infant will be mildly cyanoticand tachypneic in the immediate newbornperiod.

Physical exam will be remarkable for themild cyanosis. A prominent right ventricular im-pulse is palpable. Cardiac auscultation will re-veal a single S1 and single S2 which is likely tobe preceded by an ejection click. Truncal valveswith multiple leaflets and redundant tissue mayproject a split S2 representing delayed closureof one or more leaflet. Truncal valve regurgita-tion is heard as a high-pitched diastolic murmurlocalized to the apex. A diastolic rumble mayalso be auscultated in this area representing in-creased flow across the mitral valve. Boundingpulses should be easily appreciated accompa-nied by a widened pulse pressure secondaryto diastolic runoff into the pulmonary arteries.Importantly, a continuous murmur should notbe present. This would suggest a lesion with apatent ductus arteriosus (PDA) and not TA.3

The differential diagnosis for TA is extensive,including single ventricle lesions and otherconotruncal defects.


The most common associated heart defect, seenin up to 36% of patients, is a right aortic arch.Interrupted aortic arch with the descendingaorta arising from the PDA occurs in only11–19% of patients and strongly suggests DiGe-orge syndrome.1 Anomalies of the coronaryartery origins are common and of surgical im-portance only. Less than 30% of patients willhave extra cardiac anomalies not associatedwith a syndrome—including skeletal defects,hydroureter, and malrotation of the bowel.1

Approximately 30% of patients with TA are syn-dromic. The most commonly associated geneticdisorders are the 22q11 deletion syndromes, in-cluding DiGeorge and velocardiofacial syn-dromes. The more complex the associated heartdefects, the more likely it is to be associatedwith this genetic anomaly.1,2 In patients with22q11 deletion syndrome, truncus arteriosus isreported to occur with an incidence as high as34.5%;1 conversely, as many as 50% of patientswith TA have the 22q11 deletion.2,4 Other syn-dromes observed in patients with TA are listedin Table 28-1.

� EVALUATION

A standard evaluation for suspected cyanoticheart defect should be performed, includingevaluation for differential oxygen saturations,chest x-ray, and electrocardiogram (ECG). ECGwill show biventricular hypertrophy and occa-sionally left atrial enlargement. Cardiomegalyshould be seen on chest x-ray, along with in-creased pulmonary vascular markings reflectingthe increased pulmonary blood flow. Once TAis suspected a cardiology consult with echocar-diogram should be requested for confirmationof the diagnosis. Chromosome analysis and flu-orescent in situ hybridization (FISH) for the22q11 deletion should be obtained. If associated


CHAPTER 28 CONOTRUNCAL HEART DEFECTS 185

� TABLE 28-1 Syndromes Associated with Conotruncal Defects

ConotruncalSyndrome Defect Associated Findings

Chromosomal AnomaliesPartial Trisomy 8 TOF, TA Thick and full lips; cupped ears; deep creases palms

and soles; deep set eyes; wide spaced nipplesTrisomy 13 TOF Defects of posterior-occipital scalp; microphthalmia

and other eye defects; polydactyly; cleft lip or palate;forebrain defects including holoprosencephaly

Trisomy 18 TOF Fisted hand with overlapping fingers; paucity of muscleand adipose tissue, intrauterine growth retardation;single umbilical artery; microstomia; large, prominentocciput

Trisomy 21 TOF Upslanting palpebral fissures, flattened mid facies;Brushfield spots; protruding tongue; redundantnuchal skin folds; palmar simian crease; hypotonia

Chromosome 22q11 TOF, TA Cleft palate of variable severity; long face; narrowDeletion syndrome palpebral fissures; hypotonic and hyperextensible(Velocardiofacial extremities; hypocalcemia; absence or hypoplasiasyndrome, DiGeorge of thymussequence)

Cat-eye syndrome TOF Coloboma; hypertelorism; down slanting palpebralfissures; anal atresia

Single Gene DisordersAlagille syndrome TOF Prominent, broad forehead with deep set eyes;

ear anomalies; peripheral pulmonary artery stenosis;vertebral defects; bile duct hypoplasia or absence;cholestasis

CHARGE association TOF, TA Coloboma; choanal atresia; postnatal growthretardation; genital hypoplasia; ear anomalies

Kabuki syndrome TOF Long palpebral fissures with lateral lower eyelid eversionand ptosis; scoliosis; hyperextensible joints

Teratogenic EffectsFetal alcohol syndrome TOF Microcephaly; smooth philtrum and small upper lip;

growth retardation; facial hirsutism in the newbornMaternal diabetes TOF, TA Caudal regression syndrome; renal anomalies;

embryopathy neural tube defectsMaternal PKU TOF Microcephaly; growth retardation; prominent glabella;

syndrome epicanthal folds; thin upper lip with relatively smoothphiltrum

Retinoic acid TOF, TA, TGA Microtia or absence of auricle; facial asymmetry;embryopathy micrognathia; hypertelorism; hydrocephalus; thyroid

and/or parathyroid anomaliesFetal trimethadione TOF, TGA Upslanted eyebrows with synophrys; brachycephaly;

syndrome micrognathia; ambiguous genitalia

(Continued)

anomalies are present, a genetic consultationshould be requested. Calcium levels should bemonitored closely given the frequency of asso-ciation with DiGeorge syndrome.


A hypoxic infant should receive oxygen, titratedto keep saturations above 85%. Diuretics andinotropic support should be considered for in-fants presenting with signs of CHF. Left un-treated, the natural history of these patients isdeath from CHF within the first year of life. Pa-tients that develop pulmonary hypertensionwithin the first 6 months of life succumb in theirteens to twenties from complications of irre-versible pulmonary hypertension.3

Currently patients undergo primary repairoften within the first month, or at the latest,within the first 3 months of life, barring extenu-ating circumstances. The ventricular septal defectis closed such that the truncal valve is isolated tothe left ventricle. An extracardiac, valved conduitis used to create the right ventricular outflowtract to the pulmonary arteries. Complications in-clude accelerated calcification of the conduitnecessitating replacement or stenting in the firstmonths to years post placement. By 5 years ofage the majority of patients have outgrown theirconduits and require surgical replacement.1

Eventually the dysplastic truncal valve will be-come severely regurgitant leading to left ven-tricular dilatation and dysfunction. Additional

valvuloplasty may be attempted to avoid artifi-cial valve placement.


The relative infrequency of this defect makes itdifficult to predict a recurrence risk for families.It has been reported to be as high as 13.6%when the proband has a complex form of TA,and as low as 1.6% with simple TA.1 There is anincreased risk of other conoventricular regiondefects in family members, including VSD andatrioventricular canal defects.1 22q11 deletionsyndromes have a prevalence of 1 in 4000 livebirths.4 The majority of patients represent aspontaneous mutation; however, it may be in-herited as an autosomal dominant trait. If thepatient is found to have the 22q11 deletion, par-ents should be screened for the presence of thedeletion. Fetal echocardiography should be per-formed with each subsequent pregnancy.

� TRANSPOSITION OF THE GREATARTERIES

� INTRODUCTION

Although there are several variations in anatomyand terminology that address this lesion, in thissection we will refer only to the clinical scenarioof simple transposition of the great arteries


� TABLE 28-1 Syndromes Associated with Conotruncal Defects (Continued)

ConotruncalSyndrome Defect Associated Findings

OtherVACTERL syndrome TOF Vertebral anomalies; anal atresia; esophageal atresia

and tracheoesophageal fistula; radial defect; renalanomalies; single umbilical artery

Goldenhar syndrome TOF Epibulbar dermoid, unilateral; vertebral anomalies,primarily hemivertebrae; macrostomia; microtia

TOF, tetratology of Fallot; TA, truncus arteriosus; TGA, transposition of the great arteries.

(TGA); normal atrioventricular relationship, withventriculo-arterial discordance where the pul-monary artery arises from the left ventricle, andthe aorta from the right ventricle.

This defect is a result of failure of the greatarteries to rotate following septation of the trun-cus. Normally, the muscle bundle below the de-veloping outflow tracts involutes on the aorticside allowing the aortic valve to be committed tothe left ventricle in fibrous continuity with themitral valve. The persistent muscle bundle, or in-fundibulum, guides the pulmonary valve as it ro-tates from posterior to anterior of the aortic valve.In TGA, it is the subaortic infundibulum that per-sists. The pulmonary valve does not rotate andthe aortic valve remains anterior, pushed superi-orly and typically rightward of the pulmonaryvalve.5–7 The subpulmonary infundibulum invo-lutes, thus allowing the pulmonary valve to be infibrous continuity with the mitral valve.5

Functionally, the cardiovascular system is twoparallel circuits; deoxygenated venous blood fromthe body returning to the right heart pumped tothe aorta, and oxygenated blood from the lungsreturning to the left heart pumped to the pul-monary arteries. Although there is some obliga-tory and miniscule exchange at the systemic andpulmonary capillary level that keeps the respec-tive volumes equal, without a true mixing lesionthis type of circuitry is incompatible with life.5,7

Fortunately, nearly every infant with TGA has apatent foramen ovale (PFO) which permits ade-quate exchange of left sided oxygenated and rightsided deoxygenated blood to sustain life until ei-ther an urgent or emergent palliative procedureor definitive repair can be performed.

� EPIDEMIOLOGY

Transposition of the great arteries represents5–7% of all congenital heart disease. The inci-dence is reported to be between 0.2 and 0.3 per1000 live births with a strong predominance ofmales (60–70%).2,5 Similar to other conotruncallesions, maternal use of retinoic acid and

trimethadione are associated with an increasedincidence of this defect.3


Despite the technological advances in fetal di-agnosis, TGA can be missed on routine ultra-sound evaluations that do not directly visualizethe ventriculo-arterial relationships. TGA has lit-tle visible consequence to the fetus; the ventri-cles develop normally, the direction of flowacross the PFO is unchanged, and the remainderof fetal development is only subtly affected bythe redirection of placental blood high in glu-cose and dissolved O2 to the descending aorta,and fetal venous blood to the ascending aorta andpulmonary arteries. The result is a well developedand often large for date fetus.

The postnatal clinical presentation is depen-dent on the mixing lesion. An infant with no sig-nificant exchange between the two circulationswill become extremely cyanotic within momentsof delivery, develop acidosis, and soon succumbto these overwhelming insults despite resuscita-tion attempts. More typically, the infant presentssoon after delivery with cyanosis and tachypnea.TGA should be suspected when these are thestriking features of an otherwise nondysmorphic,large for gestational age, male infant.

On cardiac examination, there will be a singleS1 and a single, loud S2 reflecting the proxim-ity of timing and physical locale of the aorticand pulmonary valves. A PFO is the most commonmixing lesion, and has no associated murmur. Aholosystolic murmur at the left sternal borderwould suggest the presence of a VSD. In rarecases there is a large VSD and the infant will havehepatomegaly and respiratory distress associatedwith congestive heart failure.


Approximately 50% of patients have a life-sustaining PFO and PDA and no other associated


congenital heart defect.5 The most common as-sociated heart defect is a VSD (40–45%), singleor multiple, in various locations in the septum.5

A malaligned VSD can cause outflow obstruc-tion to the pulmonary artery. Coronary originanomalies are common, however are not clini-cally significant. Unlike the other conotruncaldefects discussed in this chapter, TGA is notcommonly associated with an inherited malfor-mation syndrome, however this lesion is seenwith teratogenic syndromes which are listed inTable 28-1. Extracardiac anomalies are infre-quent, found in less than 10% of patients.5

� EVALUATION

Suspicion of cyanotic heart disease should beinvestigated with a hyperoxia test, chest x-ray,and ECG. On chest x-ray, the mediastinum isnarrow due to the great arteries projecting inline in the AP or PA view creating the classic“egg on a string” cardiac silhouette. Arterialblood gas will demonstrate low PaO2, rarelyabove 35 mmHg on room air, and a normal ormildly elevated PaCO2. With 100% oxygen ad-ministration, the increase in PaO2 directly re-flects the effective size of the shunting lesion.3

This increase, however, is not significant enoughto pass the hyperoxia test in which the PaO2 willtypically rise above 100 mmHg after receiving100% oxygen if cyanosis is caused by pul-monary disease but the PaO2 will remain lessthan 100 mmHg with less than a 30 mmHg riseif the cyanosis is due to right to left shunting froman intracardiac defect. A cardiology consult forevaluation and possible emergent interventionshould be requested immediately. Echocardiogra-phy alone can confirm the diagnosis. Occasionallycardiac catheterization with angiography may benecessary to delineate the coronary arteryanatomy prior to surgical intervention. Becausethis is typically an isolated defect, a geneticsevaluation should be reserved for those patientswho appear dysmorphic or have complex TGA.

� THERAPY AND PROGNOSIS

If there is no adequate mixing lesion, a balloonatrial septostomy or Rashkind procedure can beperformed emergently at the bedside undertransthoracic echo guidance. A balloon tippedcatheter is advanced from the inferior venacavainto the right atrium and through the septuminto the left atrium. The balloon is then inflatedand quickly jerked across the septum into theright atrium. The objective is to tear the septumcreating an unrestricted atrial septal defect.

The surgical repair of choice is the arterialswitch operation. The ascending aorta and mainpulmonary artery are transected above their re-spective valves and transposed such that themorphologic left ventricular outflow is to theaorta, and right ventricular flow to the pul-monary artery. The coronary artery origins areremoved from the sinuses of the native aortaand relocated to the supravalvar neoaortic area.Complications are mainly related to coronarycompromise and outflow tract obstruction.Overall, the long-term prognosis is excellent.


The risk of recurrence of TGA is relatively lowat 1.5%. Fetal echocardiography should be per-formed with each subsequent pregnancy.

� TETRALOGY OF FALLOT

� INTRODUCTION

Tetralogy of Fallot (TOF) has four cardinal fea-tures; VSD, pulmonary stenosis, overriding aorta,and right ventricular hypertrophy. It is the degreeof obstruction of flow to the pulmonary arteriesthat determines the clinical and surgical course.

Where TGA represents no rotation of thegreat arteries, TOF is an incomplete rotation ofthe arteries occurring during the sixth week ofgestation. The truncal division is complete and


the outlet ventricular septum and aortic and pul-monary valves have formed. With incompleterotation, the arteries have a normal or near normalrelationship, but the aorta does not shift to commitcompletely to the left ventricle. The outlet portionof the ventricular septum is displaced anteriorlyand cephalad, creating the VSD and obstructingflow to the main pulmonary artery. The earlierand more severe the obstruction in fetal life, thesmaller the pulmonary valve annulus and the morecommon distal areas of obstruction to pulmonaryflow become. The right ventricle pumps againstobstruction, and has volume overload due to shunt-ing at the VSD, both of which lead to ventricularhypertrophy.

The clinical presentation is determined bythe relative resistance to blood flow to the pul-monary arteries, compared to the resistance outto the aorta. Cyanosis becomes more severewhen increasing resistance to the pulmonary ar-teries limits the amount of blood that can go tothe lungs to be oxygenated. When systemic pres-sures drop there is relative increased resistanceto flow to the pulmonary arteries; increasing aor-tic outflow decreases pulmonary outflow.

� EPIDEMIOLOGY

Tetralogy of Fallot is the most common cyanoticheart defect. Prevalence of TOF has been re-ported between 0.26 and 0.48 per 1000 livebirths.8 It represents between 3.5% and 9% of allcongenital heart defects. There is no predilec-tion toward either sex.2,8 Infants of diabeticmothers who had poor blood glucose controlhave higher risk of TOF, as do infants of moth-ers with phenylketonuria (PKU), and retinoicacid or trimethadione exposure.8


Although TOF is increasingly a fetal diagnosis,the degree of pulmonary stenosis may not befully delineated. The infant always should be

reassessed after delivery. On physical examina-tion cyanosis and tachypnea are common. Theright ventricular impulse may be prominent.Auscultation reveals a normal S1 and single S2. Apulmonary outflow systolic ejection murmur is aus-cultated along the left sternal boarder. Typicallythere is no VSD murmur due to equal or nearequal right and left ventricular pressures. If pre-sent, a PDA may be audible.

With critical pulmonary stenosis or pul-monary atresia, the pulmonary blood flow isdependent on the PDA and/or multiple aor-topulmonary collaterals (MAPCAS). A continuousmurmur in the infraclavicular areas and backshould be audible. Congestive heart failure maydevelop in this setting.


Patients with TOF frequently have other associ-ated cardiac defects. Approximately 80% willhave an ASD. A right sided aortic arch is seen innearly 25%.8 Left pulmonary artery atresia andanomalous origins of the coronary arteries arealso frequently encountered. Complex tetralogyof Fallot includes TOF with absent pulmonaryvalve, and TOF with complete AV canal.

Trisomy and the 22q11 deletion syndrome arefrequent comorbidities with 11.9% of patients withTOF having, in order of frequency, trisomy 21, 18,or 13.8 Population studies have concluded thatover 9% of patients are syndromic or have extracardiac anomalies.2,8 From 8% to 23% of patientswith TOF, especially complex TOF, have the 22q11deletion syndrome (Fig. 28-1). Alagille patientstypically have peripheral pulmonary stenosis;however 10–15% of these patients will haveTetralogy of Fallot.8 Other common syndromesassociated with TOF are listed in Table 28-1.

� EVALUATION

Once cyanotic heart disease is suspected, thepatient should be evaluated by chest x-ray, ECG,


and hyperoxia test. Chest x-ray findings reflectventricular hypertrophy with a “boot shaped”heart and a paucity of pulmonary vascular mark-ings. ECG will reveal a right axis deviation andright ventricular hypertrophy and these cardinalfeatures of TOF on echocardiogram are highlysuggestive of the diagnosis. A cardiology con-sult with echocardiogram will confirm the diag-nosis. Additional imaging may be warranted forcoronary artery anatomy, or for evaluation ofaortopulmonary collaterals.

Genetics consult, chromosome analysis, andFISH for 22q11 deletion should be requested.Calcium levels should be monitored closely dueto the high incidence of DiGeorge syndrome.The remainder of the evaluation should reflectany other suspected genetic disorder.


For patients with severe pulmonary stenosis, orpulmonary atresia, who are ductal dependent, im-mediate therapies include PGE1 and O2. Patientswith unrepaired TOF are at risk for “tet spells” orhypercyanotic spells. These hypoxic episodes re-sult from an acute decrease in pulmonary bloodflow due to obstruction to outflow from the spasmof the subpulmonary infundibulum. The scenariois frequently a crying or choking infant. Theseacute hypoxic spells can be lethal if not immedi-ately and appropriately addressed. “Knees tochest” position increases the systemic pressuresand inhaled O2 decreases pulmonary vascularresistance encouraging flow to the pulmonaryarteries. If these initial measures fail, further re-suscitation efforts include: sedation with morphineor ketamine (also increases the systemic vascularresistance), volume to increase the ventricular pre-load and increase systemic resistance, and bicar-bonate to decrease pulmonary vascular resistance.Rapid sequence intubation and deep sedationshould be initiated for life-threatening events.

Historically, patients underwent shunt place-ment between the subclavian artery and pulmonaryartery (a surgical PDA) with complete repair inchildhood. Now, complete repair in infancy pre-dominates. The VSD is closed and subpulmonaryobstruction resected with surgical approach fromthe right atrium across the tricuspid valve. If thepulmonary valve area is exceedingly small, atransannular patch is used to relieve the stenosis;however significant pulmonary regurgitation typ-ically results from this type of repair.8 Postopera-tive prognosis is dependent on type of repair.Complications with arrhythmia and right ventric-ular dysfunction secondary to severe pulmonaryregurgitation are significant. The pulmonary valvemay need to be replaced.


Both genetic and environmental influences shouldbe carefully investigated. Recurrence risk of TOF


Figure 28-1. A patient with the 22q11 dele-tion syndrome who exhibits common dys-morphic facial features including narrowpalpebral fissures and protruding ears.(Reprinted with permission from Digilio MC,Marino B, Capolino R, et al. Clinical manifesta-tions of Deletion 22q11.2 syndrome [DiGeorge/Velo Cardio-Facio syndrome]. Images PaediatrCardiol. 2005;23:23–34.)

in siblings is 2.5–8%, with increasing risk witheach additional affected sibling.8 Families withmore than one occurrence have demonstratedmultiple patterns of inheritance.8 There is alsoan increased incidence of other conotruncal andseptal defects within the same family.8 If the pa-tient is found to have the 22q11 deletion, par-ents should be screened for presence of thedeletion before genetic counseling is provided.Fetal echocardiography should be performedwith each subsequent pregnancy. In the case ofother malformation syndromes associated withTOF, the appropriate genetic counseling willdepend on the underlying diagnosis.

REFERENCES

1. Mair DD, Edwards WD, Julsrud PR, et al. Truncus ar-teriosus. In: Allen H, Gutgesell HP, Clark EB, et al,eds. Moss and Adams’ Heart Disease in Infants,Children, and Adolescents: Including the Fetus andYound Adult. Vol I and II, 6th ed. Philadelphia: Lip-pincott Williams & Wilkins; 2001:910.

2. Perry LW, Neill CA, Ferencz C, et al. Infants withcongenital heart disease: the cases. In: Ferencz C,Rubin JD, Loffredo CA, et al, eds. Perspectives in pe-

diatric cardiology: epidemiology of congenital heartdisease, the Baltimore-Washington infant Study1981-1989. Armonk, NY: Futura Publishing Com-pany, Inc.; 1993:33.

3. Park MK. Pediatric Cardiology for Practitioners.4th ed. St. Louis: Mosby, Inc.; 2002.

4. Khositseth A, Tocharoentanaphol C, Khowsathit P,et al. Chromosome 22q11 Deletions in patients withConotruncal Heart Defects. Pediatr Cardiol. 2005;26:570.

5. Wernovsky Gil. Transposition of the great arteries.In: Allen H, Gutgesell HP, Clark EB, et al, eds. Mossand Adams’ Heart Disease in Infants, Children,and Adolescents: Including the Fetus and YoungAdult. Vol I and II, 6th ed. Philadelphia: LippincottWilliams & Wilkins; 2001:1027.

6. Anderson RH, Freedom RM. Normal and abnormalstructure of the ventriculo-arterial junctions. CardiolYoung. 2005;15(1):3.

7. Anderson RH, Weinberg PM. The Clinical Anatomyof Transposition. Cardiol Young. 2005;15(1):76.

8. Siwik ES, Patel CR, Zahka KG, et al. Tetralogy ofFallot. In: Allen H, Gutgesell HP, Clark EB, et al, eds.Moss and Adams’ Heart Disease in Infants, Chil-dren, and Adolescents: Including the Fetus andYoung Adult. Vol I and II, 6th ed. Philadelphia:Lippincott Williams & Wilkins; 2001:880.



Chapter 29

Right Ventricular OutflowTract Obstructive Defects

BARBARA K. BURTON

193

� INTRODUCTION

Right ventricular outflow tract obstructive de-fects are congenital cardiac malformations whichimpede right ventricular outflow. These includetricuspid atresia, Ebstein anomaly, pulmonic steno-sis, and pulmonary atresia with an intact ventricu-lar septum.

� DESCRIPTION AND CLINICALPRESENTATION

In tricuspid atresia, there is complete absence ofthe tricuspid valve. Therefore a shunt at the atriallevel is always present and there is some degreeof desaturation although cyanosis may or maynot be clinically evident. In addition to the atrialdefect, other associated anomalies are commonand include ventricular septal defect and pulmonicstenosis. About 25% of patients have transpositionof the great arteries. Because of the variable na-ture of the associated defects, the clinical findingsare also highly variable. Electrocardiogram (ECG)reveals right atrial enlargement, and left axis devi-ation with decreased ventricular forces. The diag-nosis can be established by echocardiography.Cardiac catheterization may be required for

defining pulmonary artery and venous anatomyand for balloon atrial septostomy if there is inad-equate shunting at the atrial level.

Ebstein anomaly is a congenital anomaly ofthe tricuspid valve in which there is downwarddisplacement of the septal and posterior leaflets tothe right ventricular wall resulting in atrializationof the upper portion of the right ventricle. The an-terior leaflet is usually not displaced but is de-scribed as “sail-like.” Some type of shunt at theatrial level is typically present. The anomaly variesgreatly in severity as do the clinical symptoms. In-fants may present with severe cyanosis and respi-ratory distress or may remain asymptomatic formany years. A classic finding on physical exami-nation is the quadruple gallop. Chest radiographsmay or may not reveal cardiomegaly; ECG may re-veal right bundle branch block. Wolff-Parkinson-White syndrome is seen in about 25% of patients.The diagnosis can be made by echocardiography.

Pulmonic stenosis refers to obstruction at thelevel of the pulmonic valve, in the subvalvar orsupravalvar regions or in the pulmonary arteries.In the case of valvar pulmonic stenosis, a dis-tinction should be made between typical valvarpulmonic stenosis and a dysplastic stenotic pul-monary valve since the latter is commonly asso-ciated with Noonan syndrome. When all types


and levels of pulmonic stenosis are considered, itis extremely common, occurring in about 25% ofall patients with congenital heart disease. Typicalpulmonary valve stenosis is usually accompaniedby a characteristic systolic murmur at the upperleft sternal border, associated with a click. If thevalve is dysplastic, the click is absent. Childrenwith pulmonic stenosis are usually asymptomaticat presentation. In contrast to valvar pulmonicstenosis, peripheral pulmonic stenosis presentswith a continuous murmur which radiates widelyto the axilla and back. Chest radiographs in pul-monic valvar stenosis often reveal poststenoticdilatation of the main pulmonary artery whilethey are typically normal in supravalvar pulmonicstenosis. Depending on the severity of the valvarstenosis, ECG reveals a right axis deviation and avariable degree of right ventricular hypertrophy.In patients with Noonan syndrome, the axis is of-ten superiorly oriented. In mild peripheral pul-monic stenosis, the ECG is usually normal.Echocardiography with Doppler will establish thediagnosis of pulmonic stenosis, define the levelof the lesion and estimate the pressure gradientacross the obstruction for all defects except thosein the peripheral pulmonary arteries. For thoselesions, magnetic resonance imaging (MRI) is thepreferred method of imaging. Cardiac catheteri-zation with balloon valvuloplasty is the preferredtreatment for patients with simple pulmonaryvalve stenosis. Those with a dysplastic valve re-quire surgical correction.

In pulmonary atresia with an intact ventricu-lar septum, blood flow is maintained by a patentductus arteriosus. The resulting condition is en-tirely different clinically from pulmonary atresiawith a ventricular septal defect (discussed in theChap. 28 on Conotruncal Heart Defects). Thereis a spectrum of severity with some patients hav-ing variable hypoplasia of the tricuspid valveand of the right ventricle, which in some casescan be severe. Myocardial abnormalities are com-mon with characteristic ventriculocoronary con-nections referred to as sinusoids. Progressivecyanosis is a consistent clinical finding. A systolicmurmur of tricuspid regurgitation or a continuous

murmur from the patent ductus arteriosus may bepresent. On chest radiographs, there is a defect inthe area typically occupied by the main pul-monary artery and there is decreased pulmonaryvascularity. ECG shows decreased or absent rightventricular forces, left ventricular dominance, andright atrial enlargement. Echocardiography withDoppler can define the defect. Angiocardiogra-phy is used to identify the ventriculocoronaryartery connections.

� ASSOCIATED SYNDROMES

Tricuspid atresia is usually an isolated malfor-mation and is rarely familial. It is not a commonfeature of any malformation syndrome. Someyears ago, there were reports of Ebstein anom-aly in infants exposed to lithium in utero and itwas long felt that there was a direct teratogenicrelationship between lithium exposure and thisspecific congenital heart defect. Since then, ad-ditional data have accumulated and suggest thatthere is only a modest increased risk of con-genital cardiovascular defects associated withintrauterine exposure to lithium and that therisk is not specific for Ebstein anomaly.1 Ebsteinanomaly can be familial, inherited in an autoso-mal dominant pattern, in which case, the ex-pression of the defect can be highly variableamong affected family members. It can also beassociated with a newly described but relativelycommon submicroscopic deletion of chromo-some 1 (the 1p36 deletion syndrome).2 This ab-normality is detected by microarray analysis.

Pulmonic stenosis occurs in a large numberof malformation syndromes. The most commonof these are listed in Table 29-1. By far the mostcommon condition on the list, and the mostvariable in its clinical manifestations, is Noonansyndrome (Fig. 29-1). In the neonate, the find-ings in this autosomal dominant disorder canrange from overt to extremely subtle. The find-ing of a dysplastic stenotic pulmonary valve inany infant should immediately lead to the searchfor other clinical features suggestive of this


diagnosis. The finding of even a single addi-tional feature, whether dysmorphic or posteri-orly rotated ears, a webbed neck, pectus exca-vatum, or any other finding, should lead toserious consideration of the diagnosis. DNA test-ing will be helpful in confirming the diagnosis inabout 50% of cases. Close to 50% of patients havea detectable mutation in PTPN113 while a smallnumber of patients have been shown to havemutations in KRAS.4 Other Noonan-like disor-ders also associated with pulmonic stenosis in-clude the cardio-facio-cutaneous (CFC) syn-drome and Costello syndrome. Molecular testingis also available for these disorders.

Peripheral pulmonic stenosis is seen in sev-eral common malformation syndromes as well.An important one is Alagille syndrome, which isalso associated with valvar pulmonic stenosis.Patients with this autosomal dominant disordertypically have characteristic facies and cholesta-sis as well. Peripheral pulmonic stenosis alsooccurs in Williams syndrome although the morecommon lesion in that disorder is supravalvularaortic stenosis.

Pulmonary atresia is rarely familial and typi-cally is an isolated anomaly. Like tricuspid atresia,it is not a common feature of any malformationsyndromes.

CHAPTER 29 RIGHT VENTRICULAR OUTFLOW TRACT OBSTRUCTIVE DEFECTS 195

� TABLE 29-1 Syndromes Commonly Associated with Pulmonic Stenosis


Alagille syndrome Deep set eyes; prominent chin; small or malformed Autosomal dominantears; cholestasis; butterfly vertebrae; posterior JAG1, 20p12embryotoxon in the eye

CFC syndrome Hypertelorism; downslanting palpebral fissures; Autosomal dominantepicanthal folds; posteriorly rotated ears; BRAF, 7q34sparse hair; skin abnormalities; mental KRAS, 12p12.1retardation MEK1, 15q21

MEK2, 7q32Costello syndrome Macrocephaly; coarse facies; lax skin; deep Autosomal dominant

palmar creases; hypertrophic cardiomyopathy; HRAS, 11p15.5perioral, nasal and anal papillomas; mentalretardation

LEOPARD syndrome Multiple lentigenes; hypertrophic cardiomyopathy; Autosomal dominanthypertelorism; pectus excavatum; normal PTPN11, 12q24intelligence in most

Noonan syndrome Hypertelorism; ptosis; posteriorly rotated ears; Autosomal dominantshort or webbed neck; pectus excavatum; PTPN11, 12q24hypertrophic cardiomyopathy; bleeding diathesis; (50% of cases)lymphatic abnormalities including hydrops fetalis; KRAS, 12p12.2mild mental retardation in 25% (small % of cases)

Rubella embryopathy Microcephaly; intrauterine growth retardation; In utero exposure tocataracts; mental retardation rubella virus

Simpson-Golabi-Behmel Large birth weight; macrocephaly; coarse facies; X-linkedsyndrome polydactyly; syndactyly; mental retardation GPC3, Xq26

Williams syndrome Periorbital puffiness; full lips; short palpebral Submicroscopicfissures; hoarse voice; mild microcephaly; deletionhypercalcemia; renal or cerebral artery chromosomestenosis; mental retardation 7q11.2 detectable

by FISH

� PROGNOSIS

Most patients with tricuspid atresia requiresurgery and a significant majority survive. Theprognosis for patients with Ebstein anomalyvaries widely depending on the severity of thedefect. In infants with a severely abnormal valveor associated defects, surgery or even cardiactransplantation is often necessary and surgicalprocedures are associated with high mortality.Sudden death may occur in older children oradults with the defect, presumably due to ar-rhythmias. The prognosis for children with pul-monic stenosis is generally good. Mild pulmonicstenosis rarely progresses in severity over timeand therefore typically does not require inter-vention. More severe forms do progress and re-quire early treatment with valvuloplasty orsurgery. The results are generally good. Treat-ment of pulmonary atresia is more difficult.Prostaglandin infusion in the neonatal period isnecessary to keep the ductus open and provideadequate pulmonary blood flow. Multiple sur-gical procedures are often necessary, the nature

and timing of which are dependent on rightventricular size, associated defects, and otherfactors.


Patients with right ventricular outflow tract ob-structive defects should be carefully examined forthe presence of any associated anomalies sug-gesting the diagnosis of a malformation syndrome.If the diagnosis of a multiple malformation syn-drome is established, the appropriate geneticcounseling should be provided for that disorder.If the patient has multiple malformations and aspecific diagnosis cannot be readily established,consultation should be obtained from a clinicalgeneticist prior to offering any genetic counseling.

The estimated recurrence risk for siblings ofpatients with isolated right ventricular outflowtract defects, assuming a negative family history isgiven in Table 29-2. If there is any uncertaintywith regard to whether the family history is in-deed negative (e.g., if a parent reports a history ofarrhythmia), then echocardiography should berecommended for the individual in question be-fore genetic counseling is provided. Fetal echocar-diography should be offered in future pregnancies.

REFERENCES

1. Cohen LS, Friedman JM, Jefferson JW. A reevalua-tion of risk of in utero exposure to lithium. JAMA.1994;271:146–50.

2. Battaglia A. Deletion 1p36 syndrome: a newlyemerging clinical entity. Brain Dev. 2005;5:358–61.


Figure 29-1. Infant with Noonan syndrome.Note the typical downward slanting palpebralfissures, hypertelorism, and low-set posteri-orly rotated ears. (Photograph reprinted withpermission from Digilio MC, Marino B. Clinicalmanifestations of Noonan syndrome. ImagesPaed Cardiol. 2001;7:19–30.)

� TABLE 29-2 Risk of Recurrence in DifferentTypes of Right Ventricle Obstructive Lesions

Type of Defect Risk of Recurrence

Tricuspid atresia 1%Ebstein anomaly 2%Pulmonic stenosis 2%Pulmonary atresia 1%

3. Jongmans M, Sistermans EA, Rikken A, et al. Geno-typic and phenotypic characterization of Noonansyndrome: new data and review of the literature.Am J Med Genet. 2005;A134:165–70.

4. Schubbert S, Zenker M, Rowe SL, et al. GermlineKRAS mutations cause Noonan syndrome. Nat Genet.2006;38:331–6.

CHAPTER 29 RIGHT VENTRICULAR OUTFLOW TRACT OBSTRUCTIVE DEFECTS 197


Chapter 30

Left Ventricular Outflow TractObstructive Defects

BARBARA K. BURTON

199

� INTRODUCTION

Left ventricular outflow tract obstructive (LVOTO)defects are congenital defects of the heart andaorta that reduce outflow into the systemic circu-lation. They include mitral stenosis or atresia,subaortic stenosis, bicuspid aortic valve, aorticvalve stenosis, supravalvular aortic stenosis, coarc-tation of the aorta, interrupted aortic arch, and hy-poplastic left heart syndrome.

� DESCRIPTION AND CLINICALPRESENTATION

Infants with mitral stenosis typically present withtachypnea, diaphoresis, respiratory distress, andfailure to thrive—a common array of symptomsseen in most forms of LVOTO defects. Chest ra-diographs reveal pulmonary venous congestionand cardiomegaly with enlargement of the rightventricle. The left atrium may be enlarged. Elec-trocardiogram (ECG) findings are variable butusually include right ventricular hypertrophy.The diagnosis can be established by echocar-diography while cardiac catheterization may benecessary for assessment of pressure gradients.

The aortic valve is normally composed ofthree leaflets. Fusion of two of these leafletsgives rise to a bicuspid aortic valve in which theleaflets have straight rather than semicircularfree margins. Although this results in some lim-itation in the size of the valve orifice and somedecrease in mobility, it is usually a benign anom-aly in childhood. In adult life, it is associatedwith an increased risk of calcific aortic stenosisand of aortic aneurysms.1

A large majority of patients with aortic steno-sis have aortic valvar stenosis. Approximately 10%have supravalvular stenosis and a slightly greaternumber have subaortic stenosis. The clinical find-ings are variable depending on the severity of thelesion. Patients with mild defects may be asympto-matic while infants with severe defects may presentin shock. Physical examination reveals a systolic mur-mur of variable intensity and may reveal reducedpulses, a systolic click and gallop. A minority of pa-tients will exhibit an early diastolic murmur ofaortic insufficiency. Chest radiographs reveal di-latation of the ascending aorta with eventual leftventricular enlargement. ECG can be normal orcan show left ventricular hypertrophy with strain,depending on the severity of the obstruction. Thediagnosis can be established and the pressure


gradient between the left ventricle and the aortacan be assessed by two-dimensional and Dopplerechocardiography.

Coarctation of the aorta refers to narrowingof the thoracic descending aorta caused bythickening of the aortic media. It may be an iso-lated defect but often occurs in association withother LVOTO defects, commonly in associationwith aortic stenosis. Coarctations are frequentlyclassified as being preductal, juxtaductal, orpostductal although most are juxtaductal.

Most patients with an isolated coarctation ofthe aorta are asymptomatic. When symptoms arenoted in infancy, it is most often because of as-sociated cardiovascular anomalies or becausethere is diffuse tubular hypoplasia of the aorta, adefect that is histologically different than coarcta-tion. In tubular hypoplasia of the aorta, there is along narrow segment of proximal or distal aorticarch and isthmus but the media of the aorta isnormal. When an infant with a severe coarctationor tubular hypoplasia presents in infancy, a previ-ously asymptomatic infant may suffer sudden car-diovascular collapse at the time of closure of theductus when there is a sudden precipitous drop inblood being delivered to the systemic circulation.The classical physical findings in less severely af-fected patients are elevated blood pressure in theupper extremities, decreased blood pressure inthe lower extremities, and decreased or absentpulses in the lower extremities. The chest radi-ograph and ECG are usually normal. Over time,the typical rib notching may develop because ofthe gradual dilatation of intercostal collateral arter-ies. The diagnosis can be established by two-dimensional and Doppler echocardiography usingsuprasternal notch views.

Interrupted aortic arch is a discontinuity inthe aorta with the blood supplied to the de-scending aorta either by the ductus arteriosus orby a proximal aortic branch vessel. It is subdi-vided into three types: (1) type A, in which theinterruption is distal to the origin of the left sub-clavian artery; (2) type B, in which the interrup-tion is proximal to the origin of the subclavianartery and between the left common carotid

and left subclavian arteries; and (3) type C, inwhich the interruption is proximal to the left com-mon carotid artery between the innominate andthe left common carotid arteries. Type B is themost common, accounting for approximately65% of all cases. In virtually every case, inter-rupted aortic arch is associated with intracardiacanomalies, the nature of which affects clinicalpresentation. Most affected infants present withrespiratory distress, cyanosis, and variably de-creased peripheral pulses. Differential cyanosisis a useful clinical sign, if present, but rarely oc-curs because 85% of affected infants have an as-sociated ventricular septal defect. Most cases ofinterrupted aortic arch can be diagnosed accu-rately by echocardiography.

Hypoplastic left heart syndrome is a com-plex congenital heart malformation associatedwith atresia or severe hypoplasia of the aorticand mitral valves, severe hypoplasia of the leftventricle and hypoplasia of the ascending aorta.Other cardiac defects may also be present in-cluding atrioventricular septal defect, atrial septaldefect, anomalous pulmonary venous connec-tions, and persistent left vena cava. Infants withthis severe disorder are typically asymptomaticat birth because the open ductus arteriosus sup-plies blood to the systemic circulation. As soonas the ductus begins to constrict, however, thereis a dramatic reduction in systemic blood flowand the signs and symptoms of shock developrapidly. Most affected infants develop a signifi-cant metabolic acidosis with elevated lactic acidlevels. The chest radiograph reveals cardiomegalywith increased pulmonary vascularity. ECG re-veals right atrial enlargement with peaked Pwaves and right ventricular hypertrophy. Thediagnosis can be confirmed by two-dimensionaland Doppler echocardiography.

� ASSOCIATED SYNDROMES

The multiple malformation syndromes mostcommonly associated with LVOTO defects arelisted in Table 30-1. Among the most common


CHAPTER 30 LEFT VENTRICULAR OUTFLOW TRACT OBSTRUCTIVE DEFECTS 201

� TABLE 30-1 Syndromes Commonly Associated with Left Ventricle Outlet Obstructive Defects

Syndrome Cardiac Lesions Other Clinical Findings Etiology

Adams-Oliver Coarct, BAV Congenital scalp and skull Autosomal dominantsyndrome defects; terminal transverse

limb defectsDiGeorge IAA Cleft palate; minor dysmorphic Submicroscopic deletion

syndrome facial features; hypocalcemia; chromosome 22q11.2absent thymus

Jacobsen HLHS, Coarct Intrauterine growth retardation; Deletionsyndrome hypertelorism; ptosis; malformed chromosome 11q23

ears; joint contractures;hypospadias; thrombocytopenia;mental retardation

Kabuki Coarct Long palpebral fissures; everted Autosomal dominantsyndrome lower lids; hyperextensible joints;

mild mental retardationPallister-Hall BAV, MV Hypothalamic hamartoblastoma; Autosomal dominant

syndrome anomalies hypopituitarism; imperforate GLI3, 7p13anus; polydactyly

PHACES Coarct Posterior fossa malformations; Undeterminedsyndrome hemangiomas; cleft sternum;

supraumbilical abdominal raphe;eye malformations

Maternal PKU Coarct, AS, Microcephaly; intrauterine growth Prenatal exposure tosyndrome HLHS retardation; mental retardation elevated blood

phenylalanine levelsSmith-Lemli- AS, Coarct, Microcephaly; anteverted nares; Autosomal recessive

Opitz HLHS ptosis; syndactyly; hypospadias; DHCR7, 11q12syndrome mental retardation

Trisomy 13 BAV, HLHS Eye malformations; cleft lip palate; Nondisjunction in mostpolydactyly; scalp defects; cases; translocation90% mortality by age 12 months which may be inherited

from a balancedtranslocation carrierparent in a smallpercentage of cases

Trisomy 18 BAV, Coarct, Intrauterine growth retardation; Nondisjunction in mostHLHS overlapping fingers; short cases; translocation

sternum; small pelvis; which may be inherited90% mortality by age from a balanced12 months translocation carrier

parent in a smallpercentage of cases

Turner BAV, Coarct, Lymphedema; short or webbed 45,X chromosomesyndrome AS, MS, neck; posteriorly rotated ears; complement in most

HLHS short stature; ovarian dysgenesis cases

Coarct, coarctation of aorta; BAV, bicuspid aortic valve; HLHS, hypoplastic left heart syndrome; MV, mitral valve; AS,aortic stenosis; IAA, interrupted aortic arch; MS, mitral stenosis.

conditions are Turner syndrome, which is mostoften the result of a 45,X karyotype , and maybe associated with coarctation of the aorta, aor-tic stenosis, or rarely even hypoplastic left heartsyndrome (Fig. 30-1). In addition, up to 50% ofpatients with Turner syndrome have a bicuspidaortic valve. Another common condition with acharacteristic lesion is Williams syndrome, asso-ciated with supravalvular aortic stenosis. Thesubmicroscopic chromosome deletion that ac-companies this common disorder encompassesthe elastin gene resulting in an elastin-deficientvasculopathy that can result in multiple vascu-lar stenoses among other phenotypic findings.The DiGeorge syndrome is an important disor-der associated with interrupted aortic arch. In-deed two-thirds of all patients with interruptedaortic arch and 80–90% of patients with type Binterrupted aortic arch have this condition, whichis associated with a submicroscopic deletion ofchromosome 22q11.2 detectable by fluorescencein-situ hybridization (FISH) or by microarrayanalysis.


The prognosis for left ventricular outflow tract de-fects is related to the nature and severity of the ob-struction. Congenital mitral stenosis is not typically

relieved by balloon dilatation so when interven-tion is required, surgery is usually necessary. Aor-tic valve abnormalities tend to increase in severityover time. Sudden death is a well-known com-plication of moderate to severe aortic stenosis,and bacterial endocarditis occurs in dysplasticaortic valves with an annual incidence of about1%. Newborns with critical aortic stenosis can betreated with prostaglandin E1 infusion to openthe ductus. Subsequently the preferred procedurefor most patients is a limited valvotomy becauseof the high mortality associated with surgicalcorrection of infantile aortic stenosis. Balloonaortic valvotomy is preferred in most of the olderpatients over open commissurotomy using car-diopulmonary bypass because of the high inci-dence of aortic insufficiency postoperatively.Valve replacement can be done but is difficult.Surgical correction of supravalvar aortic stenosisis by lateral aortotomy with resection of thestenotic areas and insertion of a Dacron graft andis effective. Surgery for subvalvar stenosis is pos-sible in most patients but the prognosis dependson the severity and extent of the lesion.

Hypoplastic left heart syndrome was once auniformly lethal birth defect. Surgical optionsnow include either a three-stage reconstruction,beginning with the Norwood procedure to en-large the hypoplastic aorta, or cardiac transplanta-tion. Mortality remains high despite these options,


A B

Figure 30-1. A and B. Typical findings in a newborn female infant with Turner syndrome. Notethe redundant skin folds at the nape of the neck in 30-1A, and the edema of the dorsum of thefoot in 30-1B.

however, and some families continue to choosepalliative care without surgical intervention. Anincreasing number of fetuses with severe aorticstenosis at risk for the development of hypoplas-tic left heart syndrome are being identified inutero as high-resolution ultrasonography and fe-tal echocardiography are becoming more widelyavailable. Echocardiographic features associatedwith progression of midgestation aortic stenosisto hypoplastic left heart syndrome have beenidentified and described.2 Fetal surgery with bal-loon aortic valvotomy has been shown to im-prove the outcome in some fetuses otherwisedestined to develop hypoplastic left heart syn-drome.3 Although these techniques are still highlyexperimental, they demonstrate that preventionof this devastating birth defect may be possiblein at least some cases.

Treatment of interrupted aortic arch is by sur-gical repair. Infusion of prostaglandin E1 is oftenused to maintain flow through the ductus priorto surgical intervention. Mortality is significant.


Prior to providing genetic counseling to the par-ents of a patient with a LVOTO defect, every ef-fort should be made to be certain that the defectis, indeed, isolated and not part of a broader mal-formation syndrome. If a syndromic diagnosis isestablished, the appropriate genetic counselingshould be provided for that diagnosis. If the pa-tient has multiple malformations without a unify-ing diagnosis, consultation with a clinical geneticistshould be obtained prior to providing any ge-netic counseling.

Isolated LVOTO defects have long been con-sidered to be multifactorial birth defects and

early family studies suggested recurrence risksafter one affected family member in the rangeof 2–4%. More recent studies with detailedechocardiographic assessment of first-degreefamily members reveal that the incidence of re-lated anomalies in family members is muchhigher than anticipated. Bicuspid aortic valveoccurs in 5.1% of asymptomatic first-degree rela-tives of probands with aortic stenosis, coarctationof the aorta, and hypoplastic left heart syndromewhile more serious LVOTO defects occur in anadditional 3.7%.4 These findings suggest that allparents and siblings of patients with LVOTO de-fects should be screened by echocardiography.Fetal echocardiography should be recom-mended for all subsequent pregnancies.

REFERENCES

1. Sabet HY, Edwards WD, Tazelaar HD, et al. Con-genitally bicuspid aortic valves: a surgical pathol-ogy study of 542 cases (1991 through 1996) and aliterature review of 2,715 additional cases. MayoClin Proc. 1999;74:14–26.

2. Makikallio K, McElhinney DB, Levine JC, et al.Fetal aortic valve stenosis and the evolution ofhypoplastic left heart syndrome: patient selec-tion for fetal intervention. Circulation. 2006;113:1401–5.

3. Tworetzky W, Wilkins-Haug L, Jennings RW, et al.Balloon dilation of severe aortic stenosis in the fe-tus: potential for prevention of hypoplastic leftheart syndrome: candidate selection, technique,and results of successful intervention. Circulation.2004;110:2125–31.

4. McBride KL, Pignatelli R, Lewin M, et al. Inheri-tance of congenital left ventricular outflow tractobstruction malformations: segregation, multiplexrelative risk, and heritability. Am J Med Genet.2005;A134:180–6.

CHAPTER 30 LEFT VENTRICULAR OUTFLOW TRACT OBSTRUCTIVE DEFECTS 203


Chapter 31

DextrocardiaBARBARA K. BURTON

205

� INTRODUCTION

Dextrocardia is a congenital anomaly in whichthe heart is positioned abnormally within theright side of the chest with the apex pointing tothe right rather than to the left. It is often asso-ciated either with situs inversus totalis, in whichthe normal left-right anatomy of the thoracic andabdominal organs is reversed in mirror image, orwith heterotaxy, in which there is some de-rangement of left-right anatomy. When dextro-cardia occurs in the context of situs inversus, theincidence of congenital heart defects is muchlower than it is in the case of either heterotaxysyndromes or situs solitus, in which there is noalteration in normal anatomy and the normalleft-right alignment of other organs is maintained.


Situs inversus totalis is estimated to occur insomewhere between 1 in 8000 and 1 in 25,000births.1 Although it can occur sporadically in anotherwise completely healthy normal child, itoccurs most commonly in association with agroup of autosomal recessive disorders referredto collectively as primary ciliary dyskinesia dis-orders. All are associated with abnormal ciliaryfunction or absent cilia and are characterized byclinical findings which may include recurrent

sinusitis, bronchitis and rhinitis, infertility, hy-drocephalus, anosmia, and retinitis pigmentosa.Mutations in the axonemal heavy chain dyneintype 11 gene have been identified in some pa-tients with primary ciliary dyskinesia.2

Dextrocardia in association with a hetero-taxy syndrome occurs in about 1 in every 10,000births and represents approximately 3% of allcases of congenital heart disease. It is morelikely to come to attention than the dextro-cardia associated with situs inversus because ofthe high risk of associated cardiac malforma-tions. Most cases of heterotaxy are sporadic butX-linked recessive inheritance has been clearlydocumented in a subset of families. Mutationsin the zinc finger transcription factor ZIC3 genehave been identified as the underlying defect inX-linked heterotaxy and appear to be responsi-ble for about 1% of all sporadically occurringcases of heterotaxy as well.3 Other genes thathave been shown to play a role in some casesof human heterotaxy include CRYPTIC/CFC1,4

LEFTY,5 and ACVR2B.6

Dextrocardia has been described in associa-tion with a large number of different chromo-some anomalies but it is not a common feature ofany one specific chromosomal syndrome. Non-genetic factors that have been shown to increasethe risk of dextrocardia, with or without hetero-taxy, include maternal diabetes, first trimester co-caine use, and monozygotic twinning.7



The congenital heart malformations present in as-sociation with dextrocardia are often multiple andcomplex. This is particularly true in the form ofheterotaxy known as asplenia. The most com-mon cardiac lesions found in patients with eitherdextrocardia in association with situs inversus ordextrocardia in association with the asplenia syn-drome are listed in Table 31-1. The cardiac le-sions in the polysplenia syndrome tend to be lesscomplex than those noted above in the aspleniasyndrome. In addition, there are several cardio-vascular findings that are common in polyspleniabut rarely seen in asplenia. These include partialanomalous pulmonary venous return, intrahep-atic interruption of the inferior vena cava withconnection to the azygous or hemiazygous veinand left ventricular outflow tract obstruction. Mul-tiple congenital anomalies in other organ systemsare common in both asplenia and polysplenia.

� EVALUATION

The following studies are recommended for theinfant identified as having dextrocardia:

1. Electrocardiogram (ECG) and echocar-diogram. Depending on the results of these

studies and on clinical assessment, cardiacmagnetic resonance imaging (MRI) or angiog-raphy may be required to further define distalpulmonary arteries or venous connections.

2. Abdominal ultrasound to determine spleensize and position, liver situs, and position ofpancreas.

3. Overpenetrated chest radiograph to deter-mine pulmonary situs.

4. Complete blood count (CBC) with smear tolook for Howell-Jolly bodies as a test forfunctional asplenia, which may be seen inboth asplenia and polysplenia syndromes.

5. Chromosome analysis. If normal, con-sider microarray analysis, particularly if otheranomalies are present.

� PROGNOSIS AND TREATMENT

The prognosis for dextrocardia varies dramaticallydepending on the associated cardiac malforma-tions and the underlying systemic diagnosis. Inthe patient with an otherwise normal heart, theprognosis can be excellent. More commonly, inthe patient with a heterotaxy syndrome andcomplex congenital heart disease, the progno-sis is poor. Medical treatment is indicated forcongestive heart failure and arrhythmias. Correc-tive surgery is possible in some cases. Antibioticprophylaxis should be considered for infants


� TABLE 31-1 Congenital Heart Defects in Association with Dextrocardiawith Situs Inversus and Asplenia Syndrome

Situs Inversus Asplenia Syndrome

Right aortic arch 80% Common atrium or ASD 90%VSD 60% AV septal defect 80%TGA 50% DORV 80%PS 50% PS 80%DORV 30% TGA 80%

TAPVR 70%Single ventricle 50%Bilateral SVC 50%

VSD, ventricular septal defect; TGA, transposition of the great arteries; PS, pulmonicstenosis; DORV, double outlet right ventricle; ASD, atrial septal defect; AV, atrioventricular;TAPVR, total anomalous pulmonary venous return; SVC, superior vena cava.

with functional asplenia to reduce the risk ofdeath from sepsis.


Genetic counseling for patients with dextrocar-dia will be dependent on the underlying diag-nosis. Most of the primary ciliary dyskinesia syn-dromes associated with situs inversus totalis areinherited in an autosomal recessive pattern. Par-ents of a child affected with one of these disor-ders face a recurrence risk of 1 in 4 in any fu-ture pregnancy.

REFERENCES

1. Zhu L, Belmont JW, Ware SM. Genetics of humanheterotaxias. Europ J Hum Genet. 2006;14:17–25.

2. Bartolini L, Blouin JL, Pan Y, et al. Mutations in theDNAH11 (axonemal heavy chain dynein type 11)

gene cause one form of situs inversus totalis andmost likely primary ciliary dyskinesia. Proc NatlAcad Sci USA. 2002;99:10282–6.

3. Ware SM, Peng J, Zhu L, et al. Identification andfunctional analysis of ZIC3 mutations in heterotaxyand related congenital heart defects. Am J Hum Genet.2004;74:93–105.

4. Bamford RN, Roessler E, Burdine RD, et al. Loss-of-function mutations in the EGF-CFC gene CFC1 areassociated with human left-right laterality defects.Nat Genet. 2000;26:365–9.

5. Kosaki K, Bassi MT, Kosaki R, et al. Characterizationand mutation analysis of human LEFTY A andLEFTY B, homologues of murine genes implicatedin left-right axis development. Am J Hum Genet.1999;64:712–21.

6. Kosaki R, Gebbia M, Kosaki K, et al. Left-rightaxis malformations associated with mutations inACVR2B, the gene for human activin receptor typeIIB. Am J Med Genet. 1999;82:70–6.

7. Kuehl KS, Loffredo C. Risk factors for heart diseaseassociated with abnormal sidedness. Teratology.2002;66:242–8.

CHAPTER 31 DEXTROCARDIA 207


Chapter 32

CardiomyopathyBARBARA K. BURTON

209

� INTRODUCTION

Cardiomyopathy is a disorder that results fun-damentally from a defect in the cardiac myocytein the absence of a gross anatomic anomaly ofthe heart. Dilated cardiomyopathy is character-ized by diminished cardiac contractility with ven-tricular enlargement, abnormal diastolic functionand congestive heart failure. In contrast, hyper-trophic cardiomyopathy is characterized by inap-propriate thickening of the ventricular walls withnormal, hyperdynamic, or decreased systolicperformance and normal or decreased ventric-ular chamber size.


The etiology of cardiomyopathy is extraordinar-ily diverse, particularly in the neonate. Many dif-ferent insults, including infection, asphyxia, or ex-posure to toxic metabolites may result in myocyteinjury with subsequent myocardial dysfunction.1

The estimated incidence of cardiomyopathy fromall causes, in the absence of structural heart dis-ease, is approximately 1 in 10, 000 births. Amongthe infectious causes known to be associatedwith neonatal dilated cardiomyopathy are bacte-rial sepsis and viral myocarditis associated withagents such as echovirus and Coxsackie virus, type

B. Many inherited metabolic disorders are asso-ciated with dilated cardiomyopathy. Some maypresent acutely with other systemic findings thatgive clues to the diagnosis while in other cases,cardiomyopathy may be the sole presenting man-ifestation. Disorders associated with congenital lac-tic acidosis, such as mitochondrial respiratory chaindefects or defects in pyruvate metabolism, areoften associated with cardiomyopathy, whichmay be either dilated or hypertrophic. When ele-vated plasma lactic acid levels are noted in aninfant with severe cardiomyopathy and signs ofcongestive heart failure, there may be difficulty indetermining whether the lactic acidosis is a pri-mary finding or secondary to decreased peripheralperfusion. Sequential determinations followinginitiation of treatment may be helpful in sortingthis out. In addition, measurement of lactic acid incerebrospinal fluid or in brain by magnetic reso-nance spectroscopy is often abnormal in infantswith defects in the respiratory chain or in pyruvatemetabolism, and can be helpful diagnostically.

Patients with Barth syndrome characteristicallyexhibit a finding of ventricular noncompactionon echocardiogram in addition to dilated car-diomyopathy, neutropenia, and 3-methyglutaconicaciduria. They have a mutation in the X-linkedgene that codes for the protein tafazzin. Mutationsin the tafazzin gene may also give rise to variantphenotypes including X-linked cardiomyopathy


without noncompaction or cardiomyopathy andnoncompaction without the other phenotypicfeatures of Barth syndrome.

A common cause of hypertrophic cardiomy-opathy in neonates which is usually transientbut occasionally severe is maternal diabetes mel-litus. It results from the myocardial trophic re-sponse to fetal hyperinsulinemia provoked bymaternal hyperglycemia. Transient hypertrophiccardiomyopathy may also occur with in uteroexposure to sympathomimetic agents. An im-portant cause of hypertrophic cardiomyopathyfor which early diagnosis is critical is Pompe dis-ease, the lysosomal form of glycogen storage dis-ease associated with a deficiency of α-glucosidaseactivity (Fig. 32-1). Enzyme replacement therapyis now available for this disorder but is effectiveonly when started before muscle fiber destruc-tion is too far advanced so findings suggestive ofthis disorder should lead to immediate assay ofα-glucosidase activity.2 Another common causeof hypertrophic cardiomyopathy is Noonan syn-drome which is often also associated with a dys-plastic pulmonic valve. The dysmorphic featuresthat accompany this highly variable conditioncan range from very obvious with hypertelorism,low set, dysmorphic ears, a Turner-like webbedneck, pectus excavatum, and cryptorchidism tovery subtle with only one or two minor abnor-mal findings being present. Other genetic disor-ders associated with cardiomyopathy are listedin Table 32-1.

Isolated familial dilated cardiomyopathy andfamilial hypertrophic cardiomyopathy both maypresent in infancy although it is more commonfor these disorders to be detected in later child-hood or adult life. Over 25 different genes havebeen identified as causative of familial dilatedcardiomyopathy.3 The most common modeof inheritance is autosomal dominant althoughX-linked, autosomal recessive and mitochondr-ial patterns of inheritance are also observed.Familial hypertrophic cardiomyopathy is an au-tosomal dominant disorder that represents one ofthe most common single gene defects in the pop-ulation, affecting about 1 in every 500 individuals

worldwide.4 It is a disorder of the sarcomere, re-sulting from a mutation in 1 of 11 different sar-comeric proteins (Fig. 32-2). The most commongene affected is the β-myosin heavy chain gene.Familial hypertrophic cardiomyopathy is themost common cause of sudden death in ath-letes in the United States.


Figure 32-1. Infant with Pompe disease.Note the hypotonic posture and macroglos-sia. This infant also presented with hyper-trophic cardiomyopathy with massive QRScomplexes on ECG and a short PR interval.

CHAPTER 32 CARDIOMYOPATHY 211

� TABLE 32-1 Genetic Disorders Associated with Cardiomyopathy

Disorder Other Findings Pattern of Inheritance

Barth syndrome Cyclic neutropenia; elevated plasma X-linked; mutation in thelactate; 3-methylglutaconic aciduria; G4.5 gene for tafazzinventricular non-compaction

Beckwith-Wiedemann Macrosomia; macroglossia; umbilical Defect in genomic imprintingsyndrome defects; hypoglycemia; with overexpression of

hepatosplenomegaly genes on chromosome11p15

Cardio-facio-cutaneous Dysmorphic facies, pulmonic stenosis, Autosomal dominant;(CFC) syndrome sparse hair, skin lesions; mental most cases new mutations

retardationCongenital disorders Mental retardation; hypotonia; Autosomal recessive

of glycosylation hepatomegaly; abnormal fat(CDG syndromes) distribution

Costello syndrome Macrocephaly; coarse facies; loose skin Autosomal dominanton hands and feet; perioral, nasal, andperianal papillomata; mental retardation

Leopard syndrome Hypertelorism; multiple lentigenes; pectus Autosomal dominant;excavatum; pulmonic stenosis mutation in PTPN11

Long chain fatty acid Hypotonia; hypoglycemia triggered by Autosomal recessiveoxidation disorders fasting or intercurrent illness; elevated(VLCAD deficiency, CK; abnormal acylcarnitine profileLCHAD deficiency)

Mitochondrial Widely variable clinical and laboratory Autosomal recessive orrespiratory findings. May include hypotonia, mitochondrial (maternal)chain defects seizures, lactic acidosis, abnormal

urine organic acidsMucopolysaccharidoses Coarse facies; hepatosplenomegaly; Most are autosomal

stiff joints; recurrent respiratory recessiveinfections; dysostosis multiplex; valve Mucopolysaccharidosisthickening; cardiac findings may be type II (Hunter syndrome)first manifestation is X-linked

Noonan syndrome Hypertelorism; low set, posteriorly rotated Autosomal dominant;ears; webbed neck; pectus excavatum; mutation in PTPN11,cryptorchidism; dysplastic stenotic KRAS, or unidentifiedpulmonary valve; lymphatic abnormalities; genemental retardation in 25%

Pompe disease Hypotonia; macroglossia; short PR interval Autosomal recessive;and huge QRS complexes on ECG deficiency of

alpha-glucosidasePrimary carnitine Fasting hypoglycemia; hypotonia; weakness Autosomal recessive

deficiency (carnitineuptake defect)

� DIAGNOSIS

The primary signs and symptoms of dilated car-diomyopathy are those of combined right and leftcongestive heart failure including decreased feed-ing and activity, hepatomegaly, tachypnea, retrac-tions, a gallop rhythm, systolic regurgitant murmurand variable signs of decreased cardiac output in-cluding tachycardia, hypotension, diminishedpulses, decreased perfusion and oliguria. Chest ra-diographs reveal cardiomegaly and pulmonaryedema. Electrocardiography (ECG) reveals tachy-cardia, often diffusely decreased voltage ampli-tudes, occasionally diffusely increased voltage am-plitudes, and often diffuse repolarization changes.The diagnosis is established by echocardiography.Other diagnoses with a similar presentation, suchas certain cardiac structural defects or anomalousorigin of the left coronary artery from the pul-monary artery should be differentiated by echocar-diography with angiography, if needed.

Patients with hypertrophic cardiomyopathypresent with clinical findings very similar tothose observed in patients with dilated car-diomyopathy with evidence of right and leftcongestive heart failure. A prominent murmurfrom ventricular outflow stenosis and/or mitralregurgitation is often present. Chest radiographsoften reveal cardiomegaly and pulmonary edema.The ECG reveals diffusely increased QRS volt-age amplitude and repolarization changes. InPompe disease, the QRS complexes are partic-ularly huge and an additional finding of note inmany patients is a short PR interval. The diag-nosis of hypertrophic cardiomyopathy is againestablished by echocardiography.

� EVALUATION

1. Complete prenatal and perinatal history.Factors of particular importance in the case


Troponin T (~15%)

a-Tropornyosin(<5%)

Troponin C Troponin IMyosin-Binding

Protein C(~15%)

Actin

MyosinHead

MyosinRod

b-MyosinHeavy Chain

(~35&)

MyosinLight Chain

(<1%)

Figure 32-2. A diagram of the sarcomere identifying the site of gene muta-tions in familial hypertrophic cardiomyopathy. (Reprinted with permission fromSpirito P, Seidman CE, McKenna WJ, et al. The management of hypertrophic car-diomyopathy. New Eng J Med. 1997;336:775–85.)

of dilated cardiomyopathy include any fac-tors suggesting risk of infection or asphyxia.In the case of hypertrophic cardiomyopa-thy, exposure to sympathomimetic agentsand maternal diabetes are factors of note.

2. Complete family history including attention toany family members with history of cardiomy-opathy, heart failure, arrhythmia, early death,or neuromuscular disease. Parental consan-guinity, if present, would be of significance.

3. Complete physical examination to docu-ment cardiovascular findings as well as anyassociated findings such as hypotonia thatmight suggest a diagnosis such as Pompedisease or a mitochondrial disorder or dys-morphic features that might suggest a spe-cific syndrome such as Noonan syndrome.

4. Chest radiograph, ECG, echocardiogram.5. Cardiology consultation.6. Blood electrolytes with total CO2 or bicar-

bonate, glucose, blood urea nitrogen (BUN),creatinine, and complete blood count.

7. If infection is suspected, bacterial cultures(blood, urine, cerebrospinal fluid [CSF]), vi-ral cultures (nasopharyngeal and CSF), andserology.

8. If metabolic disease is suspected, blood am-monia, blood gases, plasma lactic acid, pyru-vic acid, total and free carnitine, acylcarnitineprofile, creatine kinase, liver function tests,quantitative plasma amino acids, urine organicacids.

9. In selected cases, urine mucopolysaccharideanalysis and carbohydrate deficient transfer-rin (or other form of testing for congenital dis-orders of glycosylation).

10. Consultation with metabolic disease specialist.

� TREATMENT

Treatment of dilated cardiomyopathy in theacute phase includes correction of electrolyte,calcium- and acid-base abnormalities, provisionof intravenous glucose, careful fluid management

to maintain cardiac output while minimizingedema, and supporting myocardial function withinotropic agents. Other supportive intensive caremeasures may be employed as needed. Chronicsupportive therapy is aimed at maximizing thestrength and longevity of cardiovascular perfor-mance, controlling symptoms of congestive heartfailure and controlling arrhythmias. Spironolac-tone, angiotensin-converting enzyme inhibitors,and β blockers are often used. Digitalis and diuret-ics may help with symptoms related to systemicand pulmonary edema. Cardiac transplantation isconsidered if the course appears likely to be fataldespite treatment of the primary disease, if known,and if there is no irreversible dysfunction of otherorgans.

In patients with hypertrophic cardiomyopathy,inotropic agents and diuretic agents are potentiallyharmful and are generally not used. β-Adrenergicreceptor blockers can improve symptoms but donot affect the progression of hypertrophy or sur-vival. Ventricular septal myomectomy is the treat-ment of choice for patients who do not respondto medical management. Cardiac transplantationis required in some severely affected patients.Holter monitoring for ventricular arrhythmiasshould routinely be performed in all patients withhypertrophic cardiomyopathy and treatment withantiarrhythmic agents initiated in those with ven-tricular tachycardia.

REFERENCES

1. Ferencz C, Neill CA. Cardiomyopathy in infancy: ob-servations in an epidemiologic study. Pediatr Cardiol.1992;13:65–71.

2. ACMG Work Group on Management of Pompe Dis-ease: Kishnani PS, Steiner RD, Bali D, et al. Pompedisease diagnosis and management guideline. GenetMed. 2006;8:267–88.

3. Schönberger J, Seidman C. Many roads lead to abroken heart: the genetics of dilated cardiomyopa-thy. Am J Hum Genet. 2001;69:249–260.

4. Ahmad F, Seidman JG, Seidman CE. The genetic ba-sis for cardiac remodeling. Annu Rev GenomicsHum Genet. 2005;6:185–216.

CHAPTER 32 CARDIOMYOPATHY 213


Part 6

GastrointestinalMalformations



Chapter 33

Esophageal Atresia andTracheoesophageal Fistula

PRAVEEN KUMAR

217

� INTRODUCTION

Esophageal atresia (EA) is defined as the absenceof an esophageal segment and is often associatedwith tracheoesophageal fistula (TEF), which is anabnormal communication between the lumen ofthe trachea and the esophagus. The Gross classi-fication is commonly used anatomic classifica-tion system for this malformation and describesthe following five major variations (Fig. 33-1).1

1. Type A—lesions include isolated esophagealatresia without TEF and are seen in nearly8% of all infants with this malformation.

2. Type B—defects include EA with TEF betweenproximal pouch of esophagus and trachea.This defect accounts for less than 1% of lesions.

3. Type C—defects are most common and seenin 85–90% of all infants with TEFs and in-clude EA with TEF between distal pouch ofesophagus and trachea.

4. Type D—defects are characterized by EA andtwo TEF between trachea and both proximaland distal esophageal pouches. These de-fects account for nearly 1% of all cases.

5. Type E—defects are characterized by pres-ence of TEF without an EA and are also calledH-type fistula. These defects are seen in 2–5%of all cases.


EA with or without TEF occurs in between1:3000 and 1:4000 births with no reported sec-ular trends or seasonal variation. A higher inci-dence of these malformations has been reportedin non-Hispanic whites and in pregnancies withmultiple births. A higher male to female ratio(1.3:1), higher incidence of prematurity andsmall for gestational age have also been re-ported.2–4 It usually occurs sporadically with noidentifiable genetic predisposition. The reportsof familial occurrences and presence of coexis-tent anomalies suggest the possibility of herita-ble genetic factors, teratogens, and more wide-spread defects of embryogenesis in some cases.The etiology when not part of a multiple malfor-mation syndrome is thought to be multifactorial.

� EMBRYOLOGY

The esophagus and trachea develop from theforegut between third and fifth week of gesta-tion. It is widely believed that two lateral longi-tudinal tracheoesophageal folds develop andfuse to form tracheoesophageal septum, whichseparates ventral trachea from dorsal esopha-gus. Disruption of normal partitioning by the


tracheoesophageal septum results in EA with orwithout TEF. Recent studies have questioned thepresence of lateral tracheoesophageal folds andhave proposed that different types of EA and TEFcan be better explained by imbalance in thegrowth of cranial and caudal folds in the area oftracheoesophageal separation.5,6 Localized alter-ations in epithelial proliferation and apoptosishave also been proposed to play a role. Isolatedesophageal atresia may result from failure of re-canalization of the esophagus during the eighthweek of development. These disruptions of nor-mal embryogenesis are associated with abnormaldevelopment of enteric neural plexuses and ab-normal histopathology of surrounding esophagealand tracheobronchial tissue and are responsiblefor various structural and functional defects in thetrachea and esophagus following repair.


The diagnosis of EA/TEF requires a high degreeof suspicion. The earliest clinical signs are ex-cessive oral secretions and drooling of saliva.Attempts at feeding result in choking, coughing,

regurgitation, and cyanosis. The abdomen willbe scaphoid in the absence of TEF but abdom-inal distension is a common feature in infantswith a fistula between distal esophagus and therespiratory tract. Respiratory symptoms such astachypnea, distress, cyanosis secondary to aspira-tion of saliva and/or gastric contents with resul-tant chemical pneumonitis will soon supervene ifdiagnosis is delayed.


The incidence of associated malformations inthese infants is high and ranges from 50% to 70%.As a group, infants with type A TEF have thehighest incidence of associated malformationsand infants with type E TEF are least likely tohave other malformations. Table 33-1 summa-rizes commonly associated malformations inthese infants. The presence of associated malfor-mations particularly cardiac, skeletal, and chro-mosomal abnormalities have significant negativeimpact on survival and outcome. Infants with

218 PART VI GASTROINTESTINAL MALFORMATIONS

Figure 33-1. Classification of esophageal atresia and tracheoesophageal fistulae. (Reprintedfrom Brunner HG, van Bokhoven H. Genetic players in esophageal atresia and tracheoesophagealfistula. Curr Opin Genet Dev. Jun 2005;15(3):341–7,with permission from Elsevier.)

Normal

TracheaEsophagus

Stomach

EA + Distal TEF 87%

Isolated EA8%

IsolatedTEF 4%

EA + ProximalTEF 1%

EA + DoubleTEF 1%

associated skeletal malformations are more likelyto have a complex cardiac malformation.

The presence of other malformations indi-cates the need for careful evaluation for associ-ated syndromes and associations because oftheir potential impact on ultimate outcome, re-currence risk, and counseling. Nearly 5–10% of allinfants with EA/TEF have associated chromosomeabnormalities including trisomy 21 and trisomy 18.As many as 50–60% of patients with VACTERL(Vertebral-Anal-Cardiac-Tracheo-Esophagealfistula-Renal-Limb anomalies) association haveeither tracheoesophageal fistula or esophagealatresia, nearly 10% of infants with EA/TEF meetcriteria for VACTERL association and nearly 80%of these infants will also have an associatedcardiac defect. Table 33-2 summarizes com-monly associated syndromes reported in theseinfants.

� EVALUATION

Most cases of EA and TEF are not suspectedprenatally. The presence of both polyhydram-nios and an absent stomach bubble have a pos-itive predictive value of 56% but either of thesetwo findings alone is a poor predictor of thiscondition.7,8 These ultrasound findings are rarelypresent before late second trimester and theirabsence does not exclude the diagnosis. If sus-pected, thorough sonographic survey includingfetal echocardiography should be performed forcoexistent anomalies. Genetic amniocentesisshould be considered particularly in the pres-ence of associated malformations.

After birth, inability to pass a nasogastric ororogastric tube is strongly suggestive of EA/TEF.The tube typically stops at 10–12 cm distance.An x-ray of chest and abdomen with tube coil-ing in the proximal esophageal pouch is diag-nostic of EA. The presence of air in the stomachconfirms the presence of a distal fistula. Contraststudies are seldom necessary to confirm the di-agnosis. All infants with EA/TEF should be eval-uated for other associated congenital defects.

CHAPTER 33 ESOPHAGEAL ATRESIA AND TRACHEOESOPHAGEAL FISTULA 219

� TABLE 33-1 Malformations Associated withEA and TEF

System Incidence

Cardiovascular System 15–40%• VSD (most common)• ASD• Tetrology of Fallot• PDA• Coarctation of aortaGastrointestinal System 25–30%• Anorectal atresia• Intestinal atresia• Pyloric stenosis• Annular pancreasGenitourinary System 20–25%• Renal agenesis

or dysplasia• Horseshoe kidney• Ureteral and urethral

malformations• HypospadiasMusculoskeletal System 10–15%• Vertebral anomalies• Radial dysplasia• Rib malformations• Polydactyly/syndactyly• ScoliosisCentral Nervous System ~10%• Hydrocephalus• Microcephaly• Holoprosencephaly• Neural tube defectsRespiratory System <5%• Pulmonary and lobar

agenesis• Tracheobronchomalacia• Ectopic/absent right-upper

lobe bronchus• Diaphragmatic hernia• Congenital cystic

adenomatoidmalformation

Others <5%• Cleft lip/palate• Abdominal wall defect• Single umbilical artery

VSD, ventricular septal defect; ASD, atrial septal defect;GI, gastrointestinal; PDA, patent ductus arteriosus.


�TABLE 33-2 Syndromes Associated with Esophageal Atresia and Tracheoesophageal Fistula

Syndrome Other Common Clinical Features Etiology

Apert syndrome Craniosynostosis, agenesis of corpus callosum, Autosomal dominantmidfacial hypoplasia, syndactyly, pulmonaryagenesis, cardiac defects, genitourinaryanomalies

CHARGE association Colobomas, heart defects, atresia of choanae, Unknownretarded growth and development, genitalanomalies, ear anomalies

Fanconi pancytopenia Short stature, microcephaly, eye anomalies, Autosomal recessivesyndrome radial ray defects in upper limbs,

pancytopenia, brownish pigmentation of skincardiac, GI and CNS anomalies

Feingold syndrome Microcephaly, limb malformations, esophageal Autosomal dominant(Oculo-duodeno- and duodenal atresias, hypoplastic thumbs,esophageal-digital syndactyly, cardiac and renal malformations(ODED) syndrome)

Metaphyseal dysplasia IUGR, short limb, sparse hair, irregular sclerotic Autosomal recessive(Cartilage-hair metaphysic on x-rays, immunodeficiencyhypoplasiasyndrome)

Opitz syndrome Hypertelorism, hypospadias, cleft lip with X-linked andor without cleft palate, micrognathia, autosomal dominantcryptorchidism, bifid scrotum, agenesisof corpus callosum, cardiac defects

Trisomy 18 IUGR, low-set malformed ears, clenched hand, Trisomy(Edwards syndrome) heart defects, rocker bottom feet, microcephaly,

genital anomaliesTrisomy 21 Hypotonia, brachycephaly, Brushfield spots in iris, Trisomy

(Down syndrome) short metacarpal and phalanges, simiancreases, cardiac defects, loose skin folds,hyperlaxity of joints, flat facial profile withupslanting palpebral fissures and innerepicanthal folds

VACTERL Vertebral, anal, cardiac, tracheal, esophageal, Unknown, moreassociation renal and limb anomalies, single umbilical frequently reported

artery, spinal dysraphia, genital abnormalities in infants of diabeticmothers

Velocardiofacial Aortic arch anomalies, cleft palate, micrognathia, Single gene disordersyndrome ear anomalies, narrow palpebral fissures, 22q11 deletion

thymic hypoplasia, hypoparathyroidismvelopharyngeal insufficiency, diaphragmatichernia

Waardenburg Lateral displacement of medial canthi, deafness, Autosomal dominantsyndrome partial albinism, VSD, neural tube defects,

supernumerary vertebrae and ribs, upper limbdefects

VSD, ventricular septal defect; IUGR; intrauterine growth retardation.

A detailed family history and physical examina-tion should be completed. Cardiac echo, renalultrasound, skeletal survey, and chromosomalanalysis should be done in all infants.

The frequency of a VACTERL phenotype inpatients with Fanconi anemia is estimated to beat about 5–10%. Limb, gastrointestinal, and tra-cheoesophageal abnormalities are found at ahigher frequency and vertebral, cardiac, andrenal abnormalities are found at a lower fre-quency in patients with VACTERL associationwith Fanconi anemia compared to patients withsporadic VACTERL alone.9 Fanconi anemia, acomplex recessive disorder, is associated withbone marrow failure, and predisposition to ma-lignancies in addition to diverse congenitalanomalies. Since the early diagnosis of Fanconianemia is important for genetic counseling andearly therapeutic interventions in affected fami-lies, it is proposed that chromosomal breakagestudies for the diagnosis of Fanconi anemiashould be performed in all patients with VAC-TERL association if clinical examination revealsskin pigmentation abnormalities, growth retar-dation, microcephaly, or dysmorphism.9 Thechromosomal breakage studies for the diagnosisof Fanconi anemia should also be performed inall patients with VACTERL association with hy-drocephaly (VACTERL-H).9


Preoperative management includes measuresto prevent aspiration, treatment of pneumonitisand prematurity, if present, and close attention tofluid and nutrition management. Healthy infantswithout pulmonary complications and other majoranomalies can undergo primary repair, division offistula and anastomosis of esophagus, with survivalrates approaching 100%. The remaining infantsare treated with parenteral nutrition, gastrostomy,and upper pouch suction until they are appro-priate surgical candidates. The survival rate inthis group is lower and can range from 25% to60% depending on their risk factors.10

Long-term complications include esophagealstricture (20–40%), dysmotility and dysphagia(50–70%), gastroesophageal reflux (40–70%),tracheomalacia (10–20%), recurrent tracheoe-sophageal fistula (3–14%) and rarely Barrett’sesophagus and adenocarcinoma of esophagus.


Parents with one affected child have a <1% chanceof having EA/TEF in subsequent pregnancies, therisk of other VACTERL malformations in subse-quent pregnancies is approximately 0.5–2%. Riskof EA/TEF is about 2–4% if a parent has a historyof EA/TEF.11

REFERENCES

1. Brunner HG, van Bokhoven H. Genetic playersin esophageal atresia and tracheoesophageal fis-tula. Curr Opin Genet Dev. Jun 2005;15(3):341–7.

2. Depaepe A, Dolk H, Lechat MF. The epidemiol-ogy of tracheo-oesophageal fistula and oe-sophageal atresia in Europe. EUROCAT WorkingGroup. Arch Dis Child. Jun 1993;68(6):743–8.

3. Forrester MB, Merz RD. Epidemiology of oe-sophageal atresia and tracheo-oesophageal fistulain Hawaii, 1986–2000. Public Health. Jun 2005;119(6):483–8.

4. Torfs CP, Curry CJ, Bateson TF. Population-basedstudy of tracheoesophageal fistula and esophagealatresia. Teratology. Oct 1995;52(4):220–32.

5. Felix JF, Keijzer R, van Dooren MF, et al. Genet-ics and developmental biology of oesophagealatresia and tracheo-oesophageal fistula: lessonsfrom mice relevant for paediatric surgeons. PediatrSurg Int. Oct 2004;20(10):731–6.

6. Kluth D, Fiegel H. The embryology of the foregut.Semin Pediatr Surg. Feb 2003;12(1):3–9.

7. Sparey C, Jawaheer G, Barrett AM, et al. Esophagealatresia in the Northern Region Congenital Anom-aly Survey, 1985–1997: prenatal diagnosis andoutcome. Am J Obstet Gynecol. Feb 2000;182(2):427–31.

8. Stringer MD, McKenna KM, Goldstein RB, et al. Pre-natal diagnosis of esophageal atresia. J Pediatr Surg.Sep 1995;30(9):1258–63.

CHAPTER 33 ESOPHAGEAL ATRESIA AND TRACHEOESOPHAGEAL FISTULA 221

9. Faivre L, Portnoi MF, Pals G, et al. Should chro-mosome breakage studies be performed in patientswith VACTERL association? Am J Med Genet A.Aug 2005;137(1):55–8.

10. Spitz L. Esophageal atresia: past, present, and fu-ture. J Pediatr Surg. Jan 1996;31(1):19–25.

11. McMullen KP, Karnes PS, Moir CR, et al. Familialrecurrence of tracheoesophageal fistula andassociated malformations. Am J Med Genet.Jun 1996;63(4):525–8.


Chapter 34

Duodenal AtresiaPRAVEEN KUMAR

223

� INTRODUCTION

Duodenal atresia, complete occlusion of theduodenal lumen, is a frequent cause of con-genital intestinal obstruction. Duodenal atresiacan be classified into the following three typesas described by Gray and Skandalakis: (1) type Idefects are most common and represent a mu-cosal web with normal muscular wall; (2) type IIdefects represent a short fibrous cord connect-ing the two atretic ends of the duodenum; and(3) type III defects are least common and rep-resent complete separation of atretic ends withno connecting tissue.


Duodenal atresia is reported to occur in 1 per5000–10,000 live births. Nearly 50% of all in-testinal atresias occur in the duodenum.2 Poly-hydramnios and prematurity are present innearly half of all cases. Initial studies had re-ported a male preponderance which has notbeen confirmed by more recent studies.1,3 Largeepidemiological studies have not reported anysignificant changes in its incidence over the lastseveral decades, but observed higher incidencewith multiple births.2,4,5

� EMBRYOLOGY

The development of the duodenum begins in theearly fourth week from the caudal part of theforegut, proximal part of the midgut, and the sur-rounding splanchnic mesenchyme. The foregutand midgut junction is just distal to the origin ofcommon bile duct and is a frequent site for atre-sia. During the fifth and sixth weeks of gestation,there is exuberant growth of the intestinal ep-ithelial lining which completely blocks the smalllumen of the developing gut. Subsequent de-generation of these cells and recanalization of thelumen is complete by the end of the eighth totenth week of gestation and an interruption of thisprocess can lead to loss of lumen in that area. Ex-cessive epithelial formation versus failure of re-canalization as a cause of atresia remains an issueof debate. Another mechanism proposed is vascu-lar infarction followed by atrophy of the affectedsegment in a small number of cases. Observationsof duodenal stenosis in sonic hedgehog mutantmice have suggested that mutations in signalingpathways may play a role in the development ofduodenal atresia.6 Recently, fibroblast growthfactor 10 is reported to serve as a regulator innormal duodenal growth and development andits deletion has been implicated in the patho-genesis of duodenal atresia.7



Most cases of duodenal atresia are being diag-nosed on prenatal ultrasound and are suggestedby the presence of a dilated stomach and duo-denal bulb with or without polyhydramnios. Aninfant without a prenatal diagnosis usually pre-sents shortly after birth with bilious emesis afterfeeding and epigastric fullness. Nearly half of allinfants with duodenal atresia will pass meco-nium initially which should not be taken as asign to exclude intestinal obstruction. A classic“double bubble” sign due to air within the stom-ach and the proximal duodenum, with no gas indistal bowel on a plain noncontrast abdominalradiograph is pathognomonic of this diagnosis.


Associated malformations are present in nearly50% of cases with duodenal atresia, ranging from38% to 78%.8,9 Nearly 10% of all patients havethree or more other anomalies.9 The incidence ofassociated anomalies is higher in infants withduodenal atresia compared to the infants with je-junoileal and colonic atresias. In nonsyndromiccases of duodenal atresia, other anomalies of thegastrointestinal tract and cardiovascular systemare most common. Table 34-1 summarizes vari-ous malformations commonly seen in infants withduodenal atresia. In addition to these, structuralmalformations of genitourinary system and mus-culoskeletal system have been reported in about5–15% of the cases and central nervous systemabnormalities in less than 3% of all infants withduodenal atresia.

Table 34-2 summarizes the syndromes fre-quently associated with duodenal atresia. Themost common associated syndrome is trisomy21 as nearly 30% of all infants with duodenalatresia have trisomy 21 and approximately 10%of all fetuses with trisomy 21 have duodenal atre-sia. The association with other syndromes is notas strong.

� EVALUATION

A detailed physical examination should be doneto look for any signs of associated major or minormalformations and to exclude other GI malfor-mations such as tracheoesophageal fistula andanal anomalies. In view of a nearly 30% incidenceof Down syndrome in infants with duodenalatresia, it is reasonable to obtain a karyotype inall infants with duodenal atresia, if not doneprenatally.10 Some authors also recommend ra-diographic evaluation for vertebral anomalies, anechocardiogram and a renal ultrasound in all in-fants with duodenal atresia.1,11,12 A voiding cys-tourethrogram should be performed in infantswith urinary tract anomalies on ultrasound or anassociated anorectal anomaly.1,11,12 In a prospec-tive study, 9% of infants with gastrointestinal mal-formations were diagnosed to have congenitalheart defects based on clinical examination alone,but 23% of these infants had congenital heart de-fects using echocardiography.12 A high index ofsuspicion should be kept and a rectal biopsy toexclude Hirschsprung disease has been recom-mended in infants with duodenal atresia and


� TABLE 34-1 Congenital MalformationsAssociated with Duodenal Atresia

Gastrointestinal System• Malrotation• Annular pancreas• Esophageal atresia • Tracheoesophageal fistula• Biliary tract anomalies• Imperforate anus

Cardiovascular System• Ventricular septal defect• Atrial septal defect• Tetralogy of Fallot

Other• Situs inversus • Vascular ring• Subglottic stenosis

Down syndrome.11 A routine cranial ultrasoundis not necessary in an infant with an isolated duo-denal atresia.


Duodenoduodenostomy remains the treatmentof choice. For patients with a duodenal web,excision and duodenoplasty is performed.Ladd’s procedure with appendectomy is done ifassociated malrotation is noted. Early and latermortality is significantly increased for infantswith associated malformations or karyotypicanomalies. Overall, survival rates for infants withduodenal atresia have gradually improved overlast two decades and 95% of all infants are dis-charged home after a repair. However, late com-plications such as gastroesophageal reflux disease,duodenal motility disorders, peptic ulcer, adhesivebowel obstruction, and stricture can occur innearly 12% of patients. Sixty-eight percent ofpatients with duodenal atresia require additional

operations and the associated late mortality ratehas been reported to be about 6%.13


Most cases of duodenal atresia are sporadic andare likely to be of multifactorial inheritance. How-ever, the familial occurrence of duodenal atresiasuggests an autosomal recessive inheritance pat-tern in a small number of cases with a recurrencerisk of up to 25%.14 The recurrence risk for in-fants with an identifiable syndrome will dependon the inheritance pattern of the specific disorder.

REFERENCES

1. Dalla Vecchia LK, Grosfeld JL, West KW, et al. In-testinal atresia and stenosis: a 25-year experiencewith 277 cases. Arch Surg. 1998;133(5):490–6; dis-cussion 6–7.

2. Francannet C, Robert E. Epidemiological study ofintestinal atresias: central-eastern France Registry1976–1992. J Gynecol Obstet Biol Reprod. (Paris)1996;25(5):485–94.

CHAPTER 34 DUODENAL ATRESIA 225

� TABLE 34-2 Syndromes Associated with Duodenal Atresia


Diabetic embryopathy Heart defect, neural tube defects, caudal Maternal diabetesregression syndrome

Fanconi pancytopenia Short stature, microcephaly, eye anomalies, Autosomal recessivesyndrome radial ray defects in upper limbs,

pancytopenia, brownish pigmentationof skin, cardiac, GI and CNS anomalies

Feingold/ODED Microcephaly, limb malformations, esophageal Autosomal dominantsyndrome and duodenal atresias, hypoplastic thumbs,

syndactyly, cardiac and renal malformationsHydantoin embryopathy Growth deficiency, mental retardation, Sporadic, teratogen

cleft lip/palate exposureOpitz-Frias syndrome Congenital heart defect, dysmorphic features, Autosomal dominant

genital abnormalitiesTownes-Brocks Branchial arch defects, renal anomalies, Autosomal dominant

syndrome deafness, thumb and other limb anomaliesTACRD association Tracheal agenesis, cardiac, renal and Unknown

duodenal malformationsTrisomy 21 Mental retardation, congenital heart defects, Trisomy

characteristic facial features, hypotonia

3. Murshed R, Nicholls G, Spitz L. Intrinsic duodenalobstruction: trends in management and outcomeover 45 years (1951–1995) with relevance to pre-natal counselling. Br J Obstet Gynaecol. 1999;106(11):1197–9.

4. Martinez-Frias ML, Castilla EE, Bermejo E, et al. Iso-lated small intestinal atresias in Latin America andSpain: epidemiological analysis. Am J Med Genet.2000;93(5):355–9.

5. Forrester MB, Merz RD. Population-based studyof small intestinal atresia and stenosis, Hawaii,1986–2000. Public Health. 2004;118(6):434–8.

6. Ramalho-Santos M, Melton DA, McMahon AP.Hedgehog signals regulate multiple aspects ofgastrointestinal development. Development. 2000;127(12):2763–72.

7. Kanard RC, Fairbanks TJ, De Langhe SP, et al. Fi-broblast growth factor-10 serves a regulatory rolein duodenal development. J Pediatr Surg. 2005;40(2):313–6.

8. Akhtar J, Guiney EJ. Congenital duodenal obstruc-tion. Br J Surg. 1992;79(2):133–5.

9. Bailey PV, Tracy TF, Jr., Connors RH, et al. Con-genital duodenal obstruction: a 32-year review.J Pediatr Surg. 1993;28(1):92–5.

10. Fogel M, Copel JA, Cullen MT, et al. Congenitalheart disease and fetal thoracoabdominal anomalies:associations in utero and the importance of cytoge-netic analysis. Am J Perinatol. 1991;8(6):411–6.

11. Kimble RM, Harding J, Kolbe A. Additional con-genital anomalies in babies with gut atresia orstenosis: when to investigate, and which investiga-tion. Pediatr Surg Int. 1997;12(8):565–70.

12. Tulloh RM, Tansey SP, Parashar K, et al. Echocardio-graphic screening in neonates undergoing surgeryfor selected gastrointestinal malformations. Arch DisChild Fetal Neonatal Ed. 1994;70(3):F206–8.

13. Escobar MA, Ladd AP, Grosfeld JL, et al. Duode-nal atresia and stenosis: long-term follow-up over30 years. J Pediatr Surg. 2004;39(6):867–71; dis-cussion 71.

14. Best LG, Wiseman NE, Chudley AE. Familial duo-denal atresia: a report of two families and review.Am J Med Genet. 1989;34(3):442–4.


Chapter 35

Anorectal MalformationsPRAVEEN KUMAR

227

� INTRODUCTION

Anorectal malformations are among the commoncongenital malformations of the gastrointestinaltract and include a spectrum of defects rangingfrom imperforate anal membrane to persistence ofan undifferentiated cloaca. Most of these defectsrequire surgical repair in the early neonatal periodand are frequently associated with long-term se-quelae such as fecal and urinary incontinence andsexual dysfunction. The term imperforate anushas been used interchangeably to describe thesemalformations in the past.

Several different classifications of anorectalanomalies have been proposed over the years.The earliest classification divided these defectsinto high and low depending on the relation-ship of the defect to the puborectalis muscle.Subsequently, the Wingspread classification hasbeen widely used and includes three broad cat-egories based upon the level of the terminationof the anorectum in relation to the levator-ani muscle: (1) High anomalies have a terminalrectal pouch above the pubococcygeal line andusually end in a fistula with prostatic urethra orbladder in males, or high in the vagina in females;(2) low anomalies have a terminal rectal pouchbelow the lowest quarter of the ossified ischium(the “I” point) and terminate in an external fis-tula on the perineum or as anal stenosis; and(3) intermediate forms have a terminal rectal

pouch between pubococcygeal line and theI point and terminate in a fistula to the bulbarurethra in males, the distal vagina in females oras an anal atresia without a fistula. These classi-fications have been criticized by some for beingarbitrary without therapeutic or prognostic sig-nificance and propose the classification sum-marized in Table 35-1.1,2


Anorectal malformations have been reported tooccur in nearly 3–5 per 10,000 live births.3–6 Nosecular trends in their incidence rates have beenreported. The risk of these malformations is notdependent on maternal race/ethnicity, gravid-ity, or prenatal care. Conflicting results havebeen reported regarding risk of these anomaliesby maternal age. Most studies have reported amale preponderance among affected infants butmale to female ratios vary from study to study.There is a higher incidence of prematurity, lowbirth weight, and multiple births among infantswith anorectal malformations. An anorectal mal-formation is an isolated birth defect in nearlyone-third (25–45%) of all infants with this defect.Overall, nearly 60% of all anorectal malforma-tions are low type but almost 80% of girls and50% of boys with anorectal malformations havea low defect. Rectocutaneous and rectourethraldefects are most common among boys and


rectovestibular fistula is by far the most com-mon defect in females.2,7

Genetic predisposition plays a role in someinfants as there is an increased incidence of con-sanguinity and an increased risk of recurrencein siblings. In addition, anorectal malformationsin association with a well recognized syndromemay also have an identifiable genetic etiology.However, no clear etiology can be identified inlarge majority of infants with isolated anorectalmalformations. Recently, a higher incidence ofanorectal malformations after in utero exposureto lorazepam and a lower incidence of anorec-tal malformations after maternal folic acid sup-plementation have been reported but requirefurther confirmation.8,9

� EMBRYOLOGY

Developmentally, the cloaca, the expanded ter-minal part of hindgut, is the most complex regionof the hindgut. Between the sixth and seventhweeks of gestation, the cloaca is divided by the

urorectal septum into the urogenital sinus ven-trally and the anorectal portion dorsally. Theanorectal portion of the cloaca develops into therectum and the superior two-thirds of the analcanal; the inferior one-third of the anal canal de-velops from the ectoderm of proctodeum. Thenormal development of the urorectal septumalso divides the cloacal membrane into the uro-genital diaphragm anteriorly and the anal mem-brane posteriorly. Approximately at the end ofthe eighth week of gestation, the anal membraneruptures creating the anal opening. Most anorec-tal anomalies result from abnormal developmentof the urorectal septum and cloacal membrane.


Most infants are diagnosed at or soon after birthwhen no anal opening is noted on physical ex-amination or because of failure to pass meconium.Abdominal distension and emesis are late find-ings in these infants, but can dominate the clini-cal presentation in infants with delayed or misseddiagnosis.


Associated malformations are present in 50–70%of infants with anorectal malformations10,11 andemphasize the need for a thorough evaluationbecause these coexisting anomalies account forsignificant morbidity and mortality in these in-fants. The genitourinary and musculoskeletalanomalies are most frequent. Table 35-2 summa-rizes commonly reported associated malforma-tions in these infants. The more common urinaryanomalies in these infants are hydronephrosisand vesicoureteral reflux. Varying degree of sacralabnormalities are most common skeletal malfor-mations and presence of a sacral abnormality sig-nificantly increases the chances of an associatedgenitourinary malformation. Boys with anorectalmalformations are much more likely to have gen-itourinary anomalies.12


� TABLE 35-1 Classification of AnorectalMalformations (Reprinted from Pena A, HongA. Advances in the management of anorectalmalformations. Am J Surg. Nov 2000;180(5):370–6, with permission from ExcerptaMedica, Inc.)

Male Defects• Perineal fistula• Rectourethral bulbar fistula• Rectourethral prostatic fistula• Rectovesical (bladder-neck) fistula• Imperforate anus without fistula• Rectal atresia and stenosis

Female Defects• Perineal fistula• Vestibular fistula• Imperforate anus with no fistula• Rectal atresia and stenosis• Cloaca

Associated malformations are nearly twice ascommon in infants with high and intermediatetype defects when compared to infants with alow anorectal malformation.7,13 An infant with ananorectal malformation and an additional anomaly

is 13 times more likely to have a high lesion thana patient with an isolated anorectal malforma-tion. Recent reports of magnetic resonance imag-ing (MRI) evaluation of the spine in these infantsindicate that nearly one-third of all infants withanorectal malformations have occult myelodys-plasia and tethered cord and there is no correla-tion between these findings and the level ofanorectal malformation, the gender of the infantor the coexistence of a sacral anomaly.14,15

Anorectal malformations are frequently seenin association with other syndromes, chromoso-mal anomalies, and sequences. As summarizedin Table 35-3, nearly one-fourth of all infantswith anorectal malformations have an identifi-able pattern of several congenital malformationsand nearly half of these or 10–20% of all infantswith anorectal malformations have the VACTERL(Vertebral-Anal-Cardiac-Tracheo-Esophagealfistula-Renal-Limb anomalies) association. Someauthors have reported the incidence of VACTERLassociation to be as high as 45% among infantswith anorectal malformations.11 Infants withanorectal malformations as part of VACTERL as-sociation are more likely to have a high defectand anal atresia with no fistula.

CHAPTER 35 ANORECTAL MALFORMATIONS 229

� TABLE 35-3 Anorectal Malformations andIncidence of Other Anomalies (Based ondata from EUROCAT working group,Cuschieri A. Descriptive epidemiology ofisolated anal anomalies: a survey of4.6 million births in Europe. Am J Med Genet.Oct 15, 2001;103(3):207–15.)

Isolated 36%With other anomalies 64%

Chromosomal 7%abnormalities

Syndromes 2%Sequences 6%Associations 10%Multiple congenital 39%

anomalies with noidentifiable pattern

Total 100%

� TABLE 35-2 Commonly ObservedCongenital Anomalies in Infants withAnorectal Malformations

System Incidence

Genitourinary 40–60%• Renal agenesis• Ectopic kidney• Hydronephrosis• Vesicoureter reflux• Cryptorchidism• Hypospadiasis• Ambiguous genitalia• Neurogenic bladder

Musculoskeletal 30–50%• Vertebral anomalies• Congenital hip dysplasia• Polydactyly

Cardiovascular 15–30%• Ventricular septal defect• Tetralogy of Fallot• Atrial septal defect

Gastrointestinal 10–25%• Esophageal atresia/

tracheoesophagealfistula

• Duodenal atresia• Omphalocele• Hirschsprung disease

Central Nervous System 10–15%• Meningomyelocele• Tethered cord

Respiratory 5–10%• Pulmonary hypoplasia• Diaphragmatic hernia

Others• Cleft palate• Choanal atresia

The most commonly reported chromosomalabnormality in infants with anorectal malforma-tions is trisomy 21. The incidence of anorectalmalformations in infants with Down syndromeis reported to range from 0.36% to 2.7%. Con-versely, 2–5% of all infants with anorectal mal-formations have Down syndrome.7,16 Althoughanal atresia without fistula occurs in 5% of all in-fants with anorectal malformations, this defectis seen in 95% of all Down syndrome patientswith anorectal malformations. Cardiovasculardefects are nearly five times more commonamong infants with anorectal malformations andDown syndrome compared to infants withanorectal malformations without Down syn-drome. Nearly half of all infants with anal atre-sia without fistula have Down syndrome and theother half are likely to be associated with othersyndromes. Common syndromes frequently as-sociated with anorectal malformations are sum-marized in Table 35-4.

� EVALUATION

Postnatal, preoperative evaluation of these in-fants has two important goals: (1) assessment forthe presence of associated congenital malforma-tions and assignment of a syndrome, if present;(2) assessment for the type of anorectal malfor-mation to decide the timing of a surgical proce-dure most appropriate for the defect.

A careful examination of perineum is ex-tremely important and may provide clues to thetype of defect. The presence of meconium on theperineum indicates the presence of a perinealfistula from a low or intermediate defect andrules out a high defect. However, it is importantto remember that it may take up to 24 hours forthe intraluminal pressure of the bowel to in-crease enough to force the meconium throughthe fistula. Presence of meconium in urine indi-cates the presence of a fistula between rectumand urinary tract, and suggests an intermediate orhigh defect. A smooth “rocker bottom” perineumwith shallow or absent gluteal cleft and faint or

absent anal pit is usually associated with a highdefect and implies a poor prognosis. Female in-fants with a cloacal defect have a single perinealopening. Sacral defects are common and may bediagnosed on examination. A detailed systemicexamination for other associated anomalies andcareful examination of external genitalia are alsovery important. A nasogastric or orogastric tubeshould be passed to exclude tracheoesophagealfistula/esophageal atresia.

In addition, all infants with anorectal mal-formations should have the following studies toexclude associated malformations:

1. Echocardiogram2. Abdominal ultrasound3. Radiographs for vertebral anomalies4. Radiographs for other skeletal anomalies, if

suspected on clinical examination5. Ultrasound or MRI of spine6. Voiding cystourethrogram

Karyotype evaluation should be consideredin infants with anorectal malformations with as-sociated congenital anomalies and urodynamicsstudies should be done for infants with associ-ated genitourinary abnormalities.


Surgical correction of anorectal malformationsis the mainstay of treatment. The choice of sur-gical procedure depends on the type of anorec-tal malformation. Anoplasty is the procedure ofchoice for infants with anal membrane and per-ineal fistulae. In male infants with other low de-fects and no associated anomalies and in femaleinfants with vestibular fistula, primary repair byposterior sagittal anorectoplasty (PSARP) withor without colostomy is preferred. For all otherdefects, colostomy is indicated and main repairis deferred till 4–8 weeks or later. Careful atten-tion to detection and treatment of associatedgenitourinary abnormalities is extremely impor-tant for good outcome.


CHAPTER 35 ANORECTAL MALFORMATIONS 231

�TABLE 35-4 Syndromes Associated with Anorectal Malformations


Caudal regression Incomplete development of sacrum, flattening of Unknown, more commonsyndrome buttocks, disruption of distal spinal cord, poor in infants of diabetic

growth and skeletal deformities of lower mothersextremities

CDAGS Craniosynostosis and clavicular hypoplasia; Autosomal recessivedelayed closure of the fontanel, cranial defects,deafness; anal anomalies including anteriorplacement of the anus and imperforate anus;genitourinary malformations; skin eruption

Johanson-Blizzard IUGR, microcephaly, deafness, midline scalp Autosomal recessivesyndrome defect, hypoplastic alae nasi, nasolacrimal duct

cutaneous fistulae, hypothyroidism, hypogonadism,cardiac defect, situs inversus

Opitz syndrome Hypertelorism, hypospadias, cleft lip with or without X-linked and autosomalcleft palate, micrognathia, cryptorchidism, bifid dominantscrotum, agenesis of corpus callosum, cardiacdefects

OEIS complex Omphalocele, exstrophy of bladder, imperforate anus, Unknownspinal defects

Pallister-Hall IUGR, hypothalamic hamartoblastoma, ear anomalies, Autosomal dominantsyndrome laryngeal cleft, lung agenesis, syndactyly,

polydactyly, anal anomalies, heart defectsTrisomy 13 Holoprosencephaly, microphthalmia, cyclopia, Trisomy

microcephaly, cleft lip and palate, heart defects,IUGR, genital abnormalities

Trisomy 18 IUGR, low-set malformed ears, clenched hand, Trisomyheart defects, rocker bottom feet, microcephaly,genital anomalies

Trisomy 21 Hypotonia, brachycephaly, Brushfield spots in iris, Trisomyshort metacarpal and phalanges, simian creases,cardiac defects, loose skin folds, hyperlaxityof joints, flat facial profile with upslanting palpebralfissures and inner epicanthal folds

Townes-Brocks Ear anomalies, thumb anomalies, and other limb Autosomal dominantsyndrome malformations, microcephaly, cardiac defects,

duodenal atresia, syndactylyUrorectal septum Ambiguous genitalia, imperforate anus, rectal fistulas, Unknown

malformation müllerian duct defectssequence

VACTERL Vertebral, anal, cardiac, tracheal, esophageal, Unknown, more commonassociation renal and limb anomalies, single umbilical artery, in infants of diabetic

spinal dysraphia, genital abnormalities mothersVelocardiofacial Aortic arch anomalies, cleft palate, micrognathia, Single gene disorder,

syndrome ear anomalies, narrow palpebral fissures, de novo mutationthymic hypoplasia, hypoparathyroidism,velopharyngeal insufficiency, diaphragmatic hernia

IUGR, intrauterine growth retardation.

The long-term outcome of these infants de-pends on the type of defect, presence, or absenceof associated malformations and syndromes. Incases uncomplicated by associated anomalies,survival approaches 100%. Overall 75% of all pa-tients have voluntary bowel movements but onlyhalf of these are totally continent. Constipationis the most common sequelae. Urinary inconti-nence is rare in male patients but relatively com-mon in female patients after the repair of cloaca.Patients with high defects have a higher likeli-hood of long-term sequelae. The presence of asacral anomaly is a strong predicator of boweland urinary incontinence.


If the diagnosis of a specific chromosomal ab-normality or malformation syndrome is estab-lished, recurrence risk should be assessed basedon the underlying diagnosis. The recurrencerisk for first-degree relatives of a proband withan isolated anorectal malformation is estimatedto be in the range of 2–4%. First-degree relativesof probands also have more than twice theprevalence of other congenital malformationsthan controls.17

REFERENCES

1. Levitt MA, Pena A. Outcomes from the correctionof anorectal malformations. Curr Opin Pediatr.Jun 2005;17(3):394–401.

2. Pena A, Hong A. Advances in the management ofanorectal malformations. Am J Surg. Nov 2000;180(5):370–6.

3. Cuschieri A. Descriptive epidemiology of isolatedanal anomalies: a survey of 4.6 million births inEurope. Am J Med Genet. Oct 15, 2001;103(3):207–15.

4. Forrester MB, Merz RD. Descriptive epidemiologyof anal atresia in Hawaii, 1986-1999. Teratology.2002;66(1):S12–16.

5. Harris J, Kallen B, Robert E. Descriptive epidemi-ology of alimentary tract atresia. Teratology. Jul 1995;52(1):15–29.

6. Spouge D, Baird PA. Imperforate anus in 700,000consecutive liveborn infants. Am J Med GenetSuppl. 1986;2:151–61.

7. Endo M, Hayashi A, Ishihara M, et al. Analysis of1,992 patients with anorectal malformations overthe past two decades in Japan. Steering Committeeof Japanese Study Group of Anorectal Anomalies.J Pediatr Surg. Mar 1999;34(3):435–41.

8. Bonnot O, Vollset SE, Godet PF, D’Amato T, RobertE. Maternal exposure to lorazepam and anal atresiain newborns: results from a hypothesis-generatingstudy of benzodiazepines and malformations.J Clin Psychopharmacol. Aug 2001;21(4):456–8.

9. Myers MF, Li S, Correa-Villasenor A, et al. Folic acidsupplementation and risk for imperforate anus inChina. Am J Epidemiol. Dec 1, 2001;154(11):1051–6.

10. Cho S, Moore SP, Fangman T. One hundred threeconsecutive patients with anorectal malformationsand their associated anomalies. Arch Pediatr Ado-lesc Med. May 2001;155(5):587–91.

11. Hassink EA, Rieu PN, Hamel BC, et al. Additionalcongenital defects in anorectal malformations.Eur J Pediatr. Jun 1996;155(6):477–82.

12. Metts JC, 3rd, Kotkin L, Kasper S, et al. Genital mal-formations and coexistent urinary tract or spinalanomalies in patients with imperforate anus. J Urol.Sep 1997;158(3 Pt 2):1298–1300.

13. Mittal A, Airon RK, Magu S, et al. Associated anom-alies with anorectal malformation (ARM). IndianJ Pediatr. Jun 2004;71(6):509–14.

14. Golonka NR, Haga LJ, Keating RP, et al. RoutineMRI evaluation of low imperforate anus reveals un-expected high incidence of tethered spinal cord.J Pediatr Surg. Jul 2002;37(7):966–9; discussion966–9.

15. Mosiello G, Capitanucci ML, Gatti C, et al. How toinvestigate neurovesical dysfunction in childrenwith anorectal malformations. J Urol. Oct 2003;170(4 Pt 2):1610–3.

16. Torres R, Levitt MA, Tovilla JM, et al. Anorectal mal-formations and Down’s syndrome. J Pediatr Surg.Feb 1998;33(2):194–7.

17. Stoll C, Alembik Y, Roth MP, et al. Risk factors in con-genital anal atresias. Ann Genet. 1997;40(4):197–204.


Chapter 36

Hirschsprung Disease PRAVEEN KUMAR

233

� INTRODUCTION

Hirschsprung disease (Congenital intestinal agan-glionosis, HSCR) is a genetically determined, sur-gically correctable, neonatal intestinal obstructionsyndrome which was first described by HaraldHirschsprung in 1888. It is caused by abnormalinnervation of the bowel, extending proximallyfrom the internal anal sphincter to involve a vari-able length of gut. Hirschsprung disease has tra-ditionally been divided into two types: a morecommon short segment disease (S-HSCR, alsocalled type I HSCR) in which the aganglionic seg-ment is restricted to the portion of the colon be-low the splenic flexure; and a less common longsegment disease (L-HSCR, or type II HSCR) whichaffects a portion of intestine including and ex-tending beyond the splenic flexure.


Hirschsprung disease is the most common causeof lower intestinal obstruction in neonates andhas an overall incidence of 1 in 5000 live births.However, the incidence varies among differentethnic groups. The California Birth Defects Moni-toring Program reported an incidence of 1.0/10,000live births in Hispanics, 1.5/10,000 live births inwhites, 2.1/10,000 live births in African Ameri-cans, and 2.8/10,000 live births in Asians.1 The

male:female ratio is 4:1 for short segment diseaseand approaches 1:1 as the length of involvedsegment increases to total colonic aganglionosis(TCA). S-HSCR is far more frequent than L-HSCR(80% versus 20%). Overall, a family history ofHSCR is present in 7–10% of cases but as manyas 21% of patients with TCA have a positive fam-ily history.

Hirschsprung disease was initially thoughtto be a sex-modified multifactorial disorder.Early genetic studies of the familial cases of non-syndromic Hirschsprung disease suggested amultigenic model to explain the usually non-mendelian inheritance pattern. However, greatprogress has been made in understanding themolecular genetics of Hirschsprung disease inrecent years.1–3 So far, mutations in nine partiallyinterdependent genes have been shown to be as-sociated with Hirschsprung disease (Table 36-1).These genes are associated with three differentsignaling pathways: (1) the RET receptor tyrosinekinase pathway; (2) the endothelin type B re-ceptor pathway; and (3) the SOX 10 mediatedtranscription pathway. Some of the same RET mu-tations that cause Hirschsprung disease also causemultiple endocrine neoplasia, type 2A (MEN2A).Segregation analyses suggest an oligogenic modeof inheritance with little or no effect of environ-mental factors. Most identified gene mutationsassociated with Hirschsprung disease are bestthought of as susceptibility genes which means


� TABLE 36-1 Gene Mutations Associated with Hirschsprung Disease

Gene Mutations Associated with Hirschsprung Disease (HSCR) Phenotype

Gene Genetic Locus Inheritance Penetrance Frequency in HSCR Homozygote Heterozygote

RET 10q11.2 AD Female 50% Familial–50% L-HSCR Hirschsprung diseaseMale 70% Sposedic–15–35%

S-HSCR–17–38%L-HSCR–70–80%

GDNF 5p12–13.1 AD Unknown <1% Unknown Hirschsprung diseaseNTN 19p13 AD Unknown <1% Uknown Hirschsprung diseaseEDNRB 13q22 AD/AR 30–85% 3–7% L-HSCR HSCR with or

Shah-Waardenburg without Shah-syndrome Waardenburg

syndromeEDN 3 20q13.2–13.3 AD/AR Unknown <5% L-HSCR Shah-Waardenburg

Shah-Waardenburg syndromesyndrome

ECE 1 1p36.1 AD Unknown <1% Uknown HSCR, cardiacdefects, craniofacialdefects, autonomicdysfuntion

SOX 10 22q13.1 AD >80% <1% Unknown Shah-Waardenburgsyndrome with otherneurologic deficits

SIP 1 2q22 Sporadic Unknown <1% Unknown HSCR, CNSanomalies,dysmorphicfeatures

PHOX 2B 4p12 AD Unknown <1% Unknown HSCR and Congenitalcentral hypoventilationsyndrome

23

4

that the mutation increases the risk of having thedisease, but is not predictive of the abnormality.3

� EMBRYOLOGY

Hirschsprung disease is characterized by the ab-sence of ganglion cells in the myenteric andsubmucosal plexuses in the bowel wall, ex-tending proximally and continuously for a vari-able distance from the internal anal sphincter.This embryonic disorder of the enteric nervoussystem (ENS) arises from a disruption of cranio-caudal migration, differentiation and maturationof neuroblasts from the neural crest (NC), agroup of cells that detach from the neuroep-ithelium of the folding neural tube and migratein the embryo to various organs. Normally thesecells reach the small intestine by the 7th weekof gestation and the rectum by the 12th week.The cells of the neural crest are pluripotent anddifferentiate into numerous cell types. These in-clude cells of the adrenal medulla, neurons, andglia of the autonomic nervous system includingthe ENS, melanocytes, and neuroendocrinecells. Therefore, the disorders of the neural crestcan have wide ranging manifestations. The termneurocristopathy is used to describe a group ofdiverse disorders resulting from defective growth,differentiation, and migration of the NC cells.Hirschsprung disease is, therefore, considered aneurocristopathy.


The cardinal symptom of Hirschsprung diseasein a newborn infant is failure or delay in pass-ing meconium. Ninety-nine percent of healthyterm infants pass meconium within 48 hours ofbirth and failure to pass meconium by that timein an otherwise normal term infant is highly sug-gestive of Hirchsprung disease. However, theonset and severity of symptoms are variable.While some infants will present with complete

intestinal obstruction at birth, others will pre-sent later with chronic constipation and failureto thrive. Infants with delayed diagnosis can pre-sent with complications such as enterocolitis, uri-nary tract infection, and urosepsis.


Hirschsprung disease occurs as an isolated trait in70% of cases (nonsyndromic HSCR). The remaining30% of infants with Hirschsprung disease haveassociated congenital abnormalities (syndromicHSCR). A chromosomal abnormality is associatedwith this disorder in about 12% of cases and con-genital abnormalities with no apparent chromo-some abnormalities are present in about 18% ofinfants with Hirschsprung disease.2,3 Trisomy 21is the most commonly associated chromosomeabnormality and is found in about 10% of patientswith HSCR and accounts for >90% of all chromo-somal abnormalities in these infants (Fig. 36-1).The number of males affected (5.5–10.5 male:1 female) and the percentage of S-HSCR (85%) iseven greater in Hirschsprung disease infants withtrisomy 21 compared to overall Hirschsprungdisease infants. Even after excluding infants withtrisomy 21, cardiac, central nervous system (CNS),genitourinary, and other gastrointestinal anom-alies are commonly reported in patients withHirschsprung disease (Table 36-2).1,3,4 Otheranomalies occurring at a frequency above thatexpected by chance include polydactyly, distallimb hypoplasia, cleft palate, and other craniofa-cial anomalies. Sensorineural hearing loss and per-sistent autonomic dysfunction have been reportedin a significant number of infants with apparentlyisolated Hirschsprung disease.5,6

Hirschsprung disease patients with other asso-ciated congenital anomalies belong to one of thefollowing three categories: (1) Neurocristopathysyndromes; (2) non-neurocristopathy syndromes;and (3) those with other isolated anomalies. Thisdistinction is important, as prognosis and geneticcounseling will vary significantly based on the

CHAPTER 36 HIRSCHSPRUNG DISEASE 235

underlying diagnosis, and thus emphasizing theimportance of a detailed evaluation by a dys-morphologist. Table 36-3 summarizes the im-portant syndromes frequently associated withHirschsprung disease.

� EVALUATION

The diagnosis of Hirschsprung disease is con-firmed by barium enema, rectal manometry, andrectal biopsy. An equally important goal in addi-tion to establishing an early and accurate diag-nosis of Hirschsprung disease is the identificationof associated anomalies and syndromes in orderto complete an accurate risk assessment andfamily counseling. The guidelines for the evalu-ation of associated anomalies and underlying eti-ology in these infants are less clear. However, inview of significantly high incidence of associated

malformations it is considered appropriate thatall infants with Hirschsprung disease should havethe following workup: (1) detailed family historyand physical examination; (2) cardiac echo; (3) ab-dominal ultrasound; (4) brain computed tomog-raphy (CT) or magnetic resonance imaging (MRI);and (5) karyotype analysis particularly in pres-ence of any additional malformation.7 The pres-ence of any of the following features wouldalso suggest a higher likelihood of syndromicHirschsprung disease and would indicate a de-tailed review and evaluation: (1) a family historyof Hirschsprung disease, pigmentary abnormali-ties, congenital sensorineural deafness, and/orendocrine tumors related to MEN2A; (2) L-HSCR ortotal colonic aganglionosis; (3) abnormal hearingscreen; (4) the presence of any other associatedcongenital malformations.

It is estimated that as many as 5% of allHirschsprung disease patients with genetic


Detailed Physical Exam

No Associated AnomaliesPresent

Associated Anomalies

Nonsyndromic HSCR(70%)

Syndromic HSCR (30%)

Karyotype

Normal (18%)

Abnormal (12%)NeurocristopathySyndrome

Non-NeurocristopathySyndrome

Isolated HSCR withAssociated Anomalies

Waardenburg SyndromeHaddad SyndromeMEN2A

Aarskog SyndromeBardet-Biedl SyndromeFryns SyndromePallister Hall SyndromeSmith-Lemli-Opitz Syndrome

Down SyndromeDel 10q11Del 13q22

Figure 36-1. Evaluation algorithm for an infant with Hirschsprung disease.

mutation involve the cysteine residues on exon10 which is known to predispose to the develop-ment of MEN2A or FMTC.8 In view of these find-ings, a recent consensus statement from an inter-national group of endocrinologists recommendedRET exon10 mutation analysis in all children withHirschsprung disease,9 but this recommendationis not well accepted and is not the standard ofcare yet. However, a strong consideration shouldbe given to genetic workup if there is a family his-tory of thyroid, parathyroid, or adrenal cancer.


The mainstay of treatment is surgical which canbe done as an either single stage procedure or

in two stages depending on the length of theaganglionic segment and the clinical conditionof the patient. The overall prognosis of an infantwith isolated Hirschsprung disease is very good.Most infants achieve fecal continence. Long-termproblems include incontinence, stricture, recurrententerocolitis, rectal prolapse, perineal abscesses,and require close follow-up. The prognosis of aninfant with the syndromic form of Hirschsprungdisease depends on the underlying syndrome.Infants found to be positive for a genetic muta-tion of the RET gene should be followed closelyfor development of MEN2A.


The overall recurrence risk in siblings of an in-fant with Hirschsprung disease is about 3–4%which is about 200 times higher than the risk inthe general population. However, the recur-rence risk in a given family depends on the gen-der of the proband and the sibling, the lengthof aganglionic segment, the presence of associ-ated syndromes, and the underlying genetic mu-tation. The recurrence risks for the sibling of apatient with Hirschsprung disease are summa-rized in Table 36-4. The risk to sibs is high whenthe proband is female (Carter effect). Siblings offemale probands have a 360 times increasedrisk and siblings of male patients have a 130-foldrisk of developing Hirschsprung disease. Prenataldiagnosis is possible if the genetic mutationwithin the family is known. However, becausethe penetrance of single gene mutations is vari-able, the clinical usefulness of genetic testing islimited3 and its role in counseling Hirschsprungdisease patients is not yet well-defined butcould be used in some situations to give moreaccurate estimation of recurrence risks. Forexample, the finding of a RET mutation in amale proband with L-HSCR and the exclusionof this mutation in the parents may allow low-ering of the recurrence risk from 13% to 17% toless than 1%.10


� TABLE 36–2 Associated Anomalies inInfants with Nonsyndromic HirschsprungDisease

Cardiovascular System 2.3–4.8%• Atrial septal defect• Ventricular septal defect• Patent ductus arteriosus• Tetralogy of Fallot

Genitourinary System 5.6–7.3%• Renal agenesis• Renal dysplasia• Hypospadias• Uretheral fistulas

Gastrointestinal System 3.3–3.9%• Pyloric stenosis• Meckel diverticulum• Small bowel atresia• Inguinal hernia• Malrotation• Imperforate anus

Central Nervous System 3.6–3.9%• Microcephaly• Dandy-Walker malformation• Mental retardation• Sensorineural hearing loss


�TABLE 36-3 Syndromes Associated with Hirschsprung Disease


Aarskog syndrome Hypertelorism, anteverted nares, maxillary X-linked recessivehypoplasia, brachydactyly, simian crease,cleinodactyly, broad thumbs and toes,“shawl” scrotum, cryptorchidism, vertebralanomalies

Bardet-Biedl syndrome Postaxial polydactyly, syndactyly, Autosomal recessivehypogonadism, retinal dystrophy, cysticrenal disease

Fryns syndrome Diaphragmatic defects, distal digital Autosomal recessivehypoplasia, pulmonary hypoplasia,Dandy-Walker malformation, agenesis ofcorpus callosum, VSD, cystic renaldisease

Haddad syndrome Congenital central hypoventilation Autosomal dominant(Ondine’s curse), esophageal dysmotility,neuroblastoma, profuse sweating

Metaphyseal dysplasia IUGR, short limb, sparse hair, irregular Autosomal recessive(Cartilage-hair sclerotic metaphysic on xrays,hypoplasia syndrome) immunodeficiency

Multiple endocrine Familial medullary thyroid carcinoma Autosomal dominantneoplasia type 2 (FMTC), pheochromocytoma,

parathyroid hyperplasiaMowat-Wilson syndrome Dysmorphic features, microcephaly, Sporadic

malformations of the brain, seizures,congenital heart defects, and urogenitalanomalies

Nager syndrome Malar hypoplasia, radial limb anomalies, Autosomal dominant,micrognathia, ear anomalies, cleft lip, Autosomal recessivehypoplasia of larynx or epiglottis in some families

Smith-Lemli-Opitz Growth retardation, mental deficiency, Autosomal recessivesyndrome microcephaly, syndactyly, genital

abnormalities, anteverted nostrilTrisomy 21 Hypotonia, brachycephaly, Brushfield Trisomy

(Down syndrome) spots in iris, short metacarpal andphalanges, simian creases, cardiacdefects, loose skin folds, hyperlaxity ofjoints, flat facial profile with upslantingpalpebral fissures and inner epicanthalfolds

VSD, ventricular septal defect; IUGR, intrauterine growth retardation.

REFERENCES

1. Stewart DR, von Allmen D. The genetics ofHirschsprung disease. Gastroenterol Clin North Am.Sep 2003;32(3):819–37, vi.

2. Amiel J, Lyonnet S. Hirschsprung disease, associ-ated syndromes, and genetics: a review. J Med Genet.Nov 2001;38(11):729–39.

3. Gariepy CE. Genetic basis of Hirschsprung disease:implications in clinical practice. Mol Genet Metab.Sep–Oct 2003;80(1–2):66–73.

4. Ryan ET, Ecker JL, Christakis NA, et al. Hirschsprung’sdisease: associated abnormalities and demography.J Pediatr Surg. Jan 1992;27(1):76–81.

5. Cheng W, Au DK, Knowles CH, et al. Hirschsprung’sdisease: a more generalised neuropathy? J Pediatr Surg.Feb 2001;36(2):296–300.

6. Staiano A, Santoro L, De Marco R, et al. Autonomicdysfunction in children with Hirschsprung’s disease.Dig Dis Sci. May 1999;44(5):960–5.

7. Chakravarti A. Lyonnet S. Hirschsprung disease. In:Scriver BA, Sly W, Valle D, eds. The Metabolic andMolecular Basis of Inherited Diseases. New York:McGraw Hill; 2001:931–42.

8. Martucciello G, Ceccherini I, Lerone M, et al. Patho-genesis of Hirschsprung’s disease. J Pediatr Surg.Jul 2000;35(7):1017–25.

9. Brandi ML, Gagel RF, Angeli A, et al. Guidelines fordiagnosis and therapy of MEN type 1 and type 2.J Clin Endocrinol Metab. Dec 2001;86(12):5658–71.

10. Brooks AS, Oostra BA, Hofstra RM. Studying thegenetics of Hirschsprung’s disease: unraveling anoligogenic disorder. Clin Genet. Jan 2005;67(1):6–14.


� TABLE 36-4 Recurrence Risk (%) of Hirschsprung Disease by Gender andExtent of Aganglionosis

Proband

Consultand L-HSCR S-HSCR

Male Female Male Female

Sib of affected male 11 8 4 1Sib of affected female 23 18 6 2Offspring of affected male 18 13 ~0 ~0Offspring of affected female 28 22 ~0 ~0

Modified from table in The Metabolic and Molecular Bases of Inherited Diseases.7


Chapter 37

OmphalocelePRAVEEN KUMAR

241

� INTRODUCTION

Omphalocele is characterized by a congenitaldefect of the anterior abdominal wall resultingfrom failure of infolding of the body wall. As aresult, abdominal viscera herniate into a sac atthe base of the umbilical cord and are coveredby amnio-peritoneal membrane. The umbilicalcord is attached at the apex of the sac. Abdomi-nal muscles, fascia, and skin are absent. In a smalldefect, <4 cm in diameter, the sac usually con-tains only intestine but in a large defect, >4 cmin diameter, liver, and other organs can also her-niate into the sac. Normal midgut rotation doesnot take place, so all infants with omphalocelealso have associated malrotation of intestine butboth intestines and liver remain morphologicallyand functionally normal.1


The incidence of omphalocele has been reportedto range from 1 in 4000 to 10,000 live births butincreases to 1 in 3000–4000 if abortions and still-births are included.2,3 Based on a follow-up study,nearly 50% of fetuses with isolated omphaloceleat 12 weeks gestation had complete resolution ofthe defect by 24 weeks and were normal at birth.In contrast, only 5% of infants with omphaloceleassociated with other structural malformations

had a resolution of abdominal wall defect duringsecond trimester.4 The incidence of omphalocelehas remained stable over the last decade aroundthe world. A higher incidence has been reportedamong mothers over 35 years of age, but race andethnicity have not been found to affect the risk.2,5

The incidences of prematurity and low birthweight are higher among infants with omphalo-cele than in general population. The incidence ofomphalocele is reported to be similar for bothgenders in most large epidemiologic studies.2

Nearly one-third of all infants with omphalo-cele have an associated syndrome with or withouta definitive genetic basis. Familial recurrenceshave been reported and both autosomal domi-nant and recessive modes of inheritance havebeen suggested. No clear etiological factors havebeen identified in remaining infants. No terato-gens have been implicated in its etiology so far.2,5

� EMBRYOLOGY

During normal development, the anterior ab-dominal wall is formed by fusion of two lateral,one caudal, and one cephalic abdominal folds.The failure of these folds to fuse results in an om-phalocele and is associated with failure of themidgut to return to the abdominal cavity. How-ever, it is unclear if the failure of the midgut to re-turn to the abdominal cavity prevents the fusion


of abdominal folds or if the lack of fusion of ab-dominal folds leads to herniation of intestine andabdominal viscera. A predominant disorder ofcephalic fold leads to associated defects of thesternum, diaphragm, pericardium, and heart asseen in pentalogy of Cantrell. Similarly, a pre-dominantly abnormal development of caudal foldwould lead to associated cloacal and bladderexstrophy.


Most cases of omphalocele are being diagnosedon prenatal ultrasound and appear as a roundmass in the midline with the umbilical vessels in-serting into the mass. In an infant without a pre-natal diagnosis, omphalocele is easily diagnosedat birth by a congenital defect of the anterior

abdominal wall with absent abdominal muscles,fascia, and skin. As a result, abdominal visceraherniate into a sac at the base of the umbilicalcord and are covered by a membrane. The um-bilical vessels are on the surface of the sac andumbilical cord is attached at the apex of the sac(Fig. 37-1).


Associated congenital malformations are fre-quently seen in infants with omphalocele andtheir incidence varies widely from 40% to 90%in different reports. A higher incidence has beenreported in studies which included abortionsand stillbirths. A defect is considered isolated ifno other congenital malformations are noted


Figure 37-1. An infant with omphalocele with umbilical cord attached at the apex of the sac.(Used with permission from Drs. Marleta Reynolds and Anthony Chin, Department of Pediatric Surgery,Children’s Memorial Hospital, Chicago, IL)

except those directly related to the defect such asmalrotation of the gut, pulmonary hypoplasia. As-sociated chromosomal abnormalities are rare ininfants with isolated omphalocele but nearlyhalf of all omphalocele infants with other struc-tural anomalies have an associated chromoso-mal abnormality.5,6 The commonly associatedstructural anomalies in omphalocele infants witha normal karyotype are listed in Table 37-1. Thelikelihood of associated malformations is higherin infants with a larger omphalocele.

According to the Online Mendelian Inheri-tance in Man (OMIM) database, >50 syndromeshave been described in association with om-phalocele. Chromosomal abnormalities have beenreported in 20–60% of all liveborn infants withomphalocele. The most frequently associated syn-dromes are Beckwith-Wiedemann syndrome andtrisomy 13 and 18. The other commonly associ-ated syndromes are listed in Table 37-2. Associ-ated chromosomal abnormalities are more likelyin infants with small omphalocele with intra-corporeal liver.1

� EVALUATION

Prenatal diagnosis of omphalocele is easy andfairly common. Maternal serum alpha-fetoprotein(MSAFP) level is elevated in majority of fetuseswith omphalocele and nearly all infants can be di-agnosed on prenatal ultrasound. However, it isimportant to remember that the late first trimesterultrasound can result in an erroneous diagnosis ofabdominal wall defects because of normal physi-ologic herniation of bowel into the base of theumbilical cord. Amniocentesis for karyotype, pre-natal echocardiography, and detailed ultrasonog-raphy evaluation for associated malformationsshould be offered as soon as possible after a pre-natal diagnosis of omphalocele is made. All in-fants should undergo echocardiography after birthto exclude any congenital cardiac abnormalitiesand karyotype should be obtained if not doneprenatally. The need for a cranial or a renal ultra-sound is less clear in the absence of any associ-ated malformations on clinical exam and cardiacecho. Infants with Beckwith-Wiedemann syn-drome should be monitored for ongoing episodesof hypoglycemia and should have kayotype andmethylation testing of chromosome 11p15.


In several studies and meta-analyses, the mode ofdelivery has not been shown to affect either sur-vival or morbidity in these infants.7 All infants withomphalocele should be carefully examined afterbirth for the presence of associated anomalies andclues to associated syndromes such as Beckwith-Wiedemann syndrome. Serum blood sugar shouldbe monitored closely to exclude hypoglycemiawhich is commonly seen in infants with Beckwith-Wiedemann syndrome. These infants should alsobe monitored closely after birth for signs of pul-monary insufficiency and persistent pulmonaryhypertension of newborn. Primary repair and clo-sure of abdominal wall defect is the procedure ofchoice but placement of silo and sequential reduc-tions are offered to infants with larger defects inwhom primary repair can compromise pulmonary

CHAPTER 37 OMPHALOCELE 243

� TABLE 37-1 Common CongenitalMalformations in Infants with Omphaloceleand a Normal Karyotype

Central nervous system• Spinal defects• Anencephaly• Craniosynostosis

Cardiovascular system• Ventricular septal defect• Atrial septal defect• Tetralogy of Fallot• Coarctation of aorta• Persistent pulmonary hypertension of

newborn

Genitourinary system• Renal agenesis• Hypospadias

Others• Skeletal dysplasia• Arthrogryposis• Diaphragmatic hernia• Cystic hygroma


� TABLE 37-2 Syndromes Associated with Omphalocele


Beckwith-Wiedemann Macroglossia, linear fissure in ear lobule, Sporadic, BWS genesyndrome (BWS) visceromegaly, neonatal hypoglycemia, at 11p15.5

hemihypertrophy, cryptorchidismCarpenter syndrome Brachycephaly, hypoplastic maxilla/mandible, Autosomal recessive

corneal opacity, syndactyly, camptodactyly,cardiac defects, cryptorchidism, postaxialpolydactyly

CHARGE association Colobomas, heart defects, atresia of choanae, Autosomal dominantretarded growth and development, genitalanomalies, ear anomalies

Cloacal exstrophy Persistence of cloaca, omphalocele, hydromyelia, Unknownsequence cryptorchidism, pelvic kidneys, multicystic

kidneysFibrochondrogenesis Short stature, megalocornea, hypoplastic nose, Autosomal recessive

cleft palate, vertebral hypoplasia, rhizomelicshortening of limbs, hypoplastic nails

Fryns syndrome Diaphragmatic defects, distal digital hypoplasia, Autosomal recessivepulmonary hypoplasia, Dandy-Walkermalformation, agenesis of corpus callosum,VSD

Meckel-Gruber Occipital encephalocele, polydactyly, cleft lip Autosomal recessivesyndrome and/or palate, microphthalmia, ambiguous

genitalia, IUGR, microcephaly, cryptorchidism,cardiac defects

OEIS complex Omphalocele, exstrophy of bladder, imperforate Unknownanus, spinal defects

Pentalogy of cantrell Defects in the closing of the supraumbilical Unknownabdominal wall, in the anterior portionof the diaphragm, and in the diaphragmaticpericardium; ectopia cordis, and intracardiacdefects

Trisomy 13 Holoprosencephaly, microphthalmia, cyclopia, Trisomymicrocephaly, cleft lip and palate, heart defects,IUGR, genital abnormalities


Trisomy 21 Hypotonia, brachycephaly, brushfield spots in iris, Trisomyshort metacarpal and phalanges, simian creases,cardiac defects, loose skin folds, hyperlaxityof joints, flat facial profile with upslantingpalpebral fissures and inner epicanthal folds

Triploidy syndrome Large placenta with hydatidiform changes, IUGR, 69xxy or 46xx/69xxysyndactyly, club feet, cardiac defects,hydrocephalus, holoprosencephaly,genitourinary anomalies

IUGR, intrauterine growth retardation; VSD, ventricular septal defect.

status, intestinal viability, and compromise venousreturn from lower half of the body.

The outcome of an infant with omphalocelewill depend on the size of the defect, presence,and severity of associated congenital malforma-tions; and presence of chromosomal abnormali-ties, if any. A higher incidence of intrauterinedeath has been reported in these pregnancies.Nearly 100% survival has been reported in in-fants with isolated omphalocele.3 The overallmortality for all infants with omphalocele is inthe range of 20–50%.8,9 A high incidence of short-term complications such as gastroesophageal re-flux have been reported in survivors but thelong-term outcome based on limited data ap-pears reassuring. A survey of adult age patientswith neonatal repair of omphalocele concludedthat average body mass index (BMI), bodyheight, and morbidity from acquired disorders issimilar to morbidity in general population, andthe majority of these patients had a quality of lifenot different from the general population.10


The recurrence risk in siblings of an infant with om-phalocele with negative family history is low (<1%).The sib risk for infant with syndromic form will de-pend on the underlying cause and may be as highas 50% in Beckwith-Wiedemann syndrome whichmay occur as an autosomal dominant condition.

REFERENCES

1. Langer JC. Abdominal wall defects. World J Surg.2003;27(1):117–24.

2. Forrester MB, Merz RD. Epidemiology of abdominalwall defects, Hawaii, 1986–1997. Teratology. 1999;60(3):117–23.

3. Heider AL, Strauss RA, Kuller JA. Omphalocele:clinical outcomes in cases with normal karyotypes.Am J Obstet Gynecol. 2004;190(1):135–41.

4. Blazer S, Zimmer EZ, Gover A, et al. Fetal om-phalocele detected early in pregnancy: associ-ated anomalies and outcomes. Radiology. 2004;232(1):191–5.

5. Rankin J, Dillon E, Wright C. Congenital anteriorabdominal wall defects in the north of England,1986–1996: occurrence and outcome. Prenat Diagn.1999;19(7):662–8.

6. Calzolari E, Bianchi F, Dolk H, et al. Omphaloceleand gastroschisis in Europe: a survey of 3 millionbirths 1980–1990. EUROCAT Working Group.Am J Med Genet. 1995;58(2):187–94.

7. Segel SY, Marder SJ, Parry S, et al. Fetal abdominalwall defects and mode of delivery: a systematicreview. Obstet Gynecol 2001;98(5 Pt 1):867–73.

8. Hwang PJ, Kousseff BG. Omphalocele and gas-troschisis: an 18-year review study. Genet Med.2004;6(4):232–6.

9. St-Vil D, Shaw KS, Lallier M, et al. Chromo-somal anomalies in newborns with omphalocele.J Pediatr Surg. 1996;31(6):831–4.

10. Koivusalo A, Lindahl H, Rintala RJ. Morbidity andquality of life in adult patients with a congenitalabdominal wall defect: a questionnaire survey.J Pediatr Surg. 2002;37(11):1594–601.

CHAPTER 37 OMPHALOCELE 245


Chapter 38

GastroschisisPRAVEEN KUMAR

247

� INTRODUCTION

Gastroschisis is a congenital paraumbilical defectof the anterior abdominal wall resulting in herni-ation of abdominal viscera outside the abdominalcavity. The abdominal wall defect is usually asmall, smooth-edged opening which is almost al-ways to the right of the umbilicus. In contrast toomphalocele, herniated viscera are not coveredby a sac and are exposed to amniotic fluid in utero.


The incidence of gastroschisis is frequently re-ported to be in the range of 0.5–1 case per 10,000births. However, several reports from differentparts of the world indicate that the incidence ofgastroschisis is increasing worldwide over last fewdecades1,2 and could be as high as 1 in 4000 to 1in 2000 births now.3 This reported increase mayreflect either an actual increase in the gastroschisisbirth rate or more accurate classification of ab-dominal wall defects. These studies also indicatethat women less than age 20 are disproportion-ately more likely to have a gastroschisis-affectedpregnancy.3,4 Race, ethnicity, and infant genderhave not been associated with increased risk.

Gastroschisis has no known genetic asso-ciation and is likely to be a sporadic congenital

malformation in most cases. However, epidemio-logic studies have reported a greater risk for low-income, undernourished young women.5 Similarly,smoking and alcohol use in early pregnancy andmaternal use of certain vasoactive over-the-countermedications such as, pseudoephedrine and phenyl-propanolamine have also been associated with anincreased risk of gastroschisis.2,6 An associationwith preconception and early gestation exposureto aspirin, acetaminophen, oral contraceptives, andsubstance abuse such as cocaine has also been re-ported.7 A few cases of familial inheritance havebeen reported recently.

� EMBRYOLOGY

The embryologic origins of this malformation re-main uncertain. During normal embryogenesis,initially the umbilical veins supply the anteriorabdominal wall until replaced by the om-phalomesenteric arteries. Around the seventhweek of gestation, the right umbilical vein andthe left omphalomesenteric artery involute andthe left umbilical vein and the right omphalome-senteric artery continue to supply the anterior ab-dominal wall. It has been proposed that eitherpremature atrophy of the right umbilical vein ora vascular accident or disruption of the right om-phalomesenteric artery leads to localized damage


to the developing abdominal wall, and resultsin a right paraumbilical defect seen in a largemajority of patients with gastroschisis.8 Othershave proposed that the primary defect is a failureof the umbilical coelom to develop normally whichforces the abdominal contents out of the too smallperitoneal cavity at the weakest part of the ante-rior abdominal wall after resorption of the rightumbilical vein.9


At birth, gastroschisis is characterized by an ab-dominal wall defect with free evisceration of ab-dominal contents with no covering sac (Fig. 38-1).The defect is to the right of the umbilicus in nearly95% of cases. The herniated bowel frequently has

signs of edema and vascular compromise, andmay be covered with a thick fibrous peel. Nearlyhalf of all infants are small for dates and many areborn premature. Table 38-1 summarizes the im-portant differentiating features between omphalo-cele and gastroschisis.

There is no histologic evidence of entericnervous system abnormalities in infants with gas-troschisis. The etiology of bowel damage andsubsequent dysfunction in the immediate post-natal period is likely to be related to chemicalperitonitis caused by exposure of fetal bowel tofetal urine in the amniotic fluid and/or bowel is-chemia/impaired venous return secondary toconstriction of blood flow at the abdominal walldefect site. This in utero bowel injury can resultin postnatal problems with absorptive functionand prolonged hypomotility in some patients.10


Figure 38-1. An infant with gastroschisis with intestine in a silo; note free evisceration of abdom-inal contents with no covering sac and umbilical cord lying left to the abdominal wall defect.(Used with permission from Drs. Marleta Reynolds and Anthony Chin, Department of Pediatric Surgery,Children’s Memorial Hospital, Chicago, IL)


Intestinal atresia and other gastrointestinal anom-alies such as Meckel’s diverticulum and intestinalduplication may be present in as many as 25% ofpatients with gastroschisis. Nearly all infants willalso have some degree of malrotation of gut. An-other associated malformation reported in somestudies is cryptorchidism which is present innearly 30% of infants with gastroschisis.6,11 Mal-formations of other systems are less commonand usually minor in infants with gastroschisis.Hirschsprung disease, heart defects, arthrogrypo-sis, and oromandibular-limb hypogenesis havebeen reported in patients with gastroschisis.Unlike omphalocele, gastroschisis is usually anisolated malformation and is not known to be apart of any reported syndrome.

� EVALUATION

Prenatal diagnosis of gastroschisis has becomeroutine with the use of ultrasound and maternalserum alpha-fetoprotein (MSAFP) screening. Themedian value for MSAFP is reported to be 7–9multiples of the median (MOM). MSAFP levels

are higher in pregnancies with gastroschisis whencompared to pregnancies with omphalocele.Some investigators recommend careful ultrasoundmonitoring of fetuses with gastroschisis to evalu-ate the severity of bowel damage based on boweldilatation and mural thickening and to consider anearly delivery of fetuses with increasing severity ofbowel damage. Preliminary reports have sug-gested some potential benefit from amnioinfusionto reduce bowel injury secondary to chemical peri-tonitis.5 Since chromosomal abnormalities are rarelyassociated with gastroschisis, routine karyotyping,either pre- or postnatal, is not recommended. Acareful detailed examination for any associated mal-formations is important at birth but extensive work-up except cardiac echo in an infant with apparent“isolated” gastroschisis appears unnecessary.


Mode of delivery and timing of delivery havenot been shown to affect outcome conclusively.Delivery room management includes careful at-tention to fluid resuscitation, avoidance of hy-pothermia, and avoidance of injury, ischemia,and contamination of herniated viscera. Completereduction of herniated abdominal contents under

CHAPTER 38 GASTROSCHISIS 249

� TABLE 38–1 Differences between Omphalocele and Gastroschisis

Omphalocele Gastroschisis

Incidence 1 : 4,000 to 1:10,000 1 : 10,000 to 1 : 20,000Change in incidence Stable IncreasingMaternal age Older (>35 yrs) Younger (<20 yrs)Incidence of aneuploidy 9–25% 0–2%Defect size Variable Usually smallHerniation of liver Common Vary rareLocation Umbilicus Paraumbilical

(usually right of umbilicus)Umbilical cord Attached to the sac Normal insertionSac Present AbsentBowel appearance Normal Usually edematous, leatheryBowel atresia Rare CommonAssociated anomalies Common (in 75%) Rare (except for intestinal

atresia and cryptorchidism)Associated syndromes Common RareMortality High Low

minimal pressure with closure of the abdominalwall defect is the goal of repair and depends pri-marily on the size of the abdominal cavity. As-sociated bowel atresia and stenosis will requireidentification and repair but may be precludedby severe matting of the bowel and peel for-mation. Staged closure is performed if an infantcannot tolerate primary repair.

With current advances in neonatal care,long-tem survival for gastroschisis has improveddramatically over the years to a nearly 90–95%survival rate. The size of the abdominal wall de-fect and contents of herniated viscera do not af-fect the outcome but bowel wall thickening of>3 mm and dilatation of bowel in >17 mm at birthhave been associated with a poor outcome. In-testinal atresia and necrosis have also been asso-ciated with increased morbidity and mortality.12

Infants with gastroschisis often have a prolongedileus and require parenteral nutrition support forlonger periods compared to infants with om-phalocele. The overall long-term outcome is goodsince they have few associated anomalies. Long-term complications include short gut syndromeand postoperative intraabdominal adhesions.


Recurrence risk in nonfamilial cases is extremelylow (<1%). An autosomal dominant patternhas been suggested in rare cases with familialinheritance.

REFERENCES

1. Kazaura MR, Lie RT, Irgens LM, et al. Increasingrisk of gastroschisis in Norway: an age-period-cohort analysis. Am J Epidemiol. Feb 2004;159(4):358–63.

2. Weir E. Congenital abdominal wall defects. Cmaj.Oct 2003;169(8):809–10.

3. Rankin J, Dillon E, Wright C. Congenital anteriorabdominal wall defects in the north of England,1986–1996: occurrence and outcome. Prenat Diagn.Jul 1999;19(7):662–8.

4. Forrester MB, Merz RD. Epidemiology of abdominalwall defects, Hawaii, 1986–1997. Teratology. Sep 1999;60(3):117–23.

5. Hunter A, Soothill P. Gastroschisis—an overview.Prenat Diagn. Oct 2002;22(10):869–73.

6. Weber TR, Au-Fliegner M, Downard CD, et al. Ab-dominal wall defects. Curr Opin Pediatr. Aug 2002;14(4):491–7.

7. Werler MM, Sheehan JE, Mitchell AA. Maternalmedication use and risks of gastroschisis and smallintestinal atresia. Am J Epidemiol. Jan 2002;155(1):26–31.

8. deVries PA. The pathogenesis of gastroschisisand omphalocele. J Pediatr Surg. Jun 1980; 15(3):245–51.

9. Shaw A. The myth of gastroschisis. J Pediatr Surg.Apr 1975;10(2):235–44.

10. Langer JC. Abdominal wall defects. World J Surg.Jan 2003;27(1):117–24.

11. Lawson A, de La Hunt MN. Gastroschisis and unde-scended testis. J Pediatr Surg. Feb 2001;36(2):366–7.

12. Baerg J, Kaban G, Tonita J, et al. Gastroschisis: asixteen-year review. J Pediatr Surg. May 2003;38(5):771–4.


Part VII

Renal Malformations



Chapter 39

Renal AgenesisPRAVEEN KUMAR

253

� INTRODUCTION

Renal agenesis is defined as the complete absenceof renal tissue. Renal agenesis may be unilateral orbilateral, isolated or associated with other geni-tourinary or external anomalies. Since bilateralrenal agenesis is incompatible with survival, thesecases are usually diagnosed at birth but unilateralrenal agenesis could remain undiagnosed till laterin life. However, with the widespread use of pre-natal ultrasound these anomalies are being identi-fied before birth in increasing number of cases. Itis important to differentiate cases of renal agene-sis from renal dysplasia in which the kidney ispresent but malformed and consists of undiffer-entiated cells surrounding poorly developedureteric bud derivatives. Several follow-up studieshave shown that many cases of renal dysplasiaregress over time and may become undetectableon subsequent studies.1 These findings indicatethat some cases of renal agenesis should fall intothe category of renal dysplasia.

� EPIDEMIOLOGY

Renal agenesis is one of the common congenitalurinary malformations and unilateral renal age-nesis is more common than bilateral renal age-nesis. The incidence of bilateral renal agenesis isfrequently reported to range from 1 in 4000 to

1 in 10,000 births and the incidence of unilateralrenal agenesis is reported to be in the range of1 in 1000 to 1 in 5000 births.2 The routine ultra-sound screening of healthy children suggeststhat the incidence of unilateral renal agenesis isabout 1 in 1200.2 Renal agenesis has been re-ported in about 30% of all perinatal autopsieswith congenital malformations of the urinarytract and nearly 25% of all antenatally detectedstructural developmental anomalies of kidney,after excluding urinary tract dilatation abnor-malities, were renal agenesis.3 Parikh et al re-ported a combined birth prevalence of renalagenesis as 1 per 2900 live births.4 Howeverthey could not differentiate between unilateraland bilateral agenesis and it was unlikely thatall cases of unilateral renal agenesis were iden-tified in their population. Based on data fromthree large population based congenital malfor-mation registries of infants, Harris et al reportedprevalence rate of 0.54–1.15 per 10,000 birthsfor bilateral renal agenesis and 0.56–0.79 per10,000 births for unilateral renal agenesis.5 Thelower incidence of unilateral renal agenesis inthis report is likely to be secondary to the factthat many cases of unilateral renal agenesis arenot diagnosed at birth.

Most studies have shown a male preponder-ance among patients with both unilateral renalagenesis and bilateral renal agenesis and thismale excess is more pronounced for isolated than


associated cases and in cases with bilateral renalagenesis.4,5 No trends of any change in incidenceover the years have been reported.4,6 Maternalhistory of insulin-dependent diabetes mellitus,black race, and twin gestation have been iden-tified as potential risk factors in infants withrenal agenesis.4,5,7

� EMBRYOLOGY

The human kidney develops from the metanephricdiverticulum or ureteric bud and the metanephricmesoderm or metanephrogenic blastema. Themetanephric diverticulum arises from the distalpart of mesonephric duct and branches multipletimes to form the ureter, renal pelvis, calyces,and collecting tubules. The metanephric meso-derm is part of urogenital ridge on each side ofthe primitive aorta and leads to the formation ofnephrons comprising of a glomerulus, proximalconvoluted tubule, loop of Henle, and distal con-voluted tubules.8 Normal kidney development re-quires close interactions between the metanephricdiverticulum and metanephric mesoderm. Renaldevelopment begins at the start of the fifth weekpost conception and embryonic kidneys are pre-sent in their adult lumbar location by the end ofthe ninth week. However, nephron formationcontinues in fetal kidneys until 34–36 weeks;nephrons continue to elongate and differentiateafter that but no new nephrons are formed.8 Bothanimal studies and human observations haveshown that the etiology of renal agenesis is mul-tifactorial and may include one or the combina-tion of any of the following mechanisms: failureof formation of metanephric diverticulum; failureof metanephric diverticulum to reach metanephricmesoderm; and absent or abnormal inductive in-fluence of the metanephric diverticulum andmetanephric mesoderm on one another.


With increasing use of prenatal ultrasound,more cases of bilateral renal agenesis are being

identified prenatally as these pregnancies arecomplicated by presence of oligohydramniosand intrauterine growth retardation (IUGR). In areport from Europe, 78% of all cases of bilateralrenal agenesis had a prenatal diagnosis, the me-dian gestational age of diagnosis was 21 weeksand pregnancy was terminated in 61% of caseswith a prenatal diagnosis.9 Newborns with bi-lateral renal agenesis usually have characteristicfacial appearance, limb deformities, and associ-ated severe pulmonary hypoplasia. These findingsare considered secondary to severe oligohydram-nios as urine production is largely responsiblefor amniotic fluid volume. The typical Potter faciesof these infants consists of a prominent skincrease beneath each eye with a blunted noseand depression between lower lip and chin; theears appear low set and are often pressed againstthe side of the head but ear canals are in thenormal location. The limb deformities includebowing of legs, club feet, and excessive flexionat the hip and knee joints. These infants usuallyhave significant IUGR and have loose, dry skin.The cause of death in these infants is usuallyrespiratory failure secondary to severe pul-monary hypoplasia that accompanies bilateralrenal agenesis. Air leak syndrome is also notedfrequently in these infants.

In contrast, unilateral renal agenesis is usuallyentirely asymptomatic by itself at birth and can goundetected till later in life unless diagnosed onroutine prenatal ultrasound or postnatal ultra-sound is done to exclude renal malformation inan infant with other associated malformations.


Associated anomalies are frequently seen in in-fants with renal agenesis. Considering the embry-ologic proximity of müllerian and wolffian ducts,it is not surprising that additional genitourinarymalformations are commonly seen in these in-fants. However, malformations of other organsystems have also been reported in a significant

254 PART VII RENAL MALFORMATIONS

proportion of infants with both bilateral andunilateral renal agenesis. Overall associatedanomalies are seen in about 60% of cases withrenal agenesis.4,10,11 Genitourinary anomaliesare seen in 40–50% of cases11,12 and anomaliesof other organs systems are seen in about 40%of cases. Genitourinary anomalies are signifi-cantly more common in females with unilateralrenal agenesis compared to males. The mostcommon urological anomalies in infants withbilateral renal agenesis are atretic ureters andbladder anomalies. The most common associ-ated urologic anomalies in infants with unilat-eral renal agenesis are vesicoureteral reflux andureteral obstruction.12 Absent or maldevelop-ment of ipsilateral uterus and vagina are themost common genital anomalies in women withrenal agenesis. In both sexes, the gonad devel-opment is usually normal. The involvement ofcardiovascular system and gastrointestinal (GI)tract are seen most commonly but any other or-gan can be involved. Cardiovascular anomaliesespecially septal defects are reported in about20% of cases.4 The incidence of congenital car-diovascular malformation is reported to betwelve times greater in both the bilateral renalagenesis and unilateral renal agenesis cases.6 GIanomalies and neural tube defects are morecommon in infants with bilateral renal agenesis.Table 39-1 summarizes the commonly reportedgenitourinary and extrarenal anomalies in infantswith renal agenesis. Based on the high degree ofassociation between müllerian or wolffian ductderivatives and renal agenesis, it is recommendedthat all women with müllerian duct anomaly andall men with congenital bilateral absence of thevas deferens should be evaluated to exclude uni-lateral renal agenesis.13,14 Approximately one-third of women with unilateral renal agenesishave an abnormality of internal genitalia and43% of women with genital anomalies have uni-lateral renal agenesis.2

Renal agenesis has been identified as a partof many different syndromes and thus a carefulreview of all infants with renal agenesis is nec-essary to identify other associated malformations

and appropriate recurrence risk. However, thereis limited data regarding what proportion of re-nal agenesis cases are part of a recognizablesyndrome. In a review of bilateral renal agenesis,80% of all cases were determined to be non-syndromic. In a report on 59 deaths associatedwith renal agenesis, Cunniff et al reported thatrenal agenesis was part of VACTERL (vertebral,

CHAPTER 39 RENAL AGENESIS 255

� TABLE 39-1 Associated Anomalies inInfants with Renal Agenesis

Genitourinary malformations ~40–50%Vesicoureteric refluxUreteral obstructionRenal ectopiaDuplication of ureterNeurogenic bladderAbsent vas deference

or seminal vesicleAbsent or rudimentary

uterus or vaginaUndescended testis

Extragenitourinary malformations ~40%Cardiovascular ~15%

Ventricular septal defectAtrial septal defectPatent ductus arteriosusPulmonary stenosisDouble outlet right ventricle

Gastrointestinal ~10%Anal atresiaRectovesical/rectovaginal

fistulasOesophageal atresiaSmall intestine atresiaMalrotation

Central nervous system ~5%Neural tube defectsHydrocephalus

Others ~10%Cleft lip and palateSacrococcygeal anomaliesMicrognathiaEar anomaliesChoanal atresiaVertebral anomaliesLimb reduction defects

anal, cardiac, tracheal, esophageal, renal, andlimb) association in 19%, unrecognized multiplemalformation syndrome in 17%, and chromoso-mal disorder were identified in 6% of the cases.10

Chromosomal abnormalities were also reportedin 7% of cases with bilateral renal agenesis froma large population based study from Europe.9

Table 39-2 provides a brief list of syndromesfrequently associated with renal agenesis.


A detailed history of index pregnancy, familyhistory and complete physical examination toevaluate for any associated congenital anom-alies of other organ systems are necessary andhelpful in the evaluation of an infant with renalagenesis. A history of oligohydramnios and anuriawith presence of IUGR, Potter facies, and severerespiratory failure strongly indicate the possibilityof bilateral renal agenesis and an emergent re-nal ultrasound should be obtained in these in-fants. In contrast, as noted earlier, an infant withunilateral renal agenesis with normal contralat-eral kidney is likely to have normal amnioticfluid volume, normal urine output and renalfunction studies, and be completely asympto-matic. Renal ultrasound is the quickest and thebest test to evaluate kidneys in a newborn in-fant. However, it is important to remember thatthe absence of kidney/kidneys in its normal po-sition does not always mean renal agenesis asthey could be ectopic or dysplastic and small. Arenal scan or magnetic resonance imaging (MRI)should be considered if ultrasound is inconclu-sive. A fetal MRI to evaluate renal anomalies isparticularly promising because oligohydram-nios can impair visualization of the fetal kid-neys on ultrasound examination. Color Dopplersonography has also been shown to be helpfulin these situations. A skeletal survey andechocardiogram should be done in all infantswith renal agenesis because of high likelihoodof VACTERL association and congenital heart mal-formations in these infants. A plain film of abdomenafter placing a nasogastric tube and careful

perineal examination for imperforate anus are help-ful in excluding common GI anomalies. A cranialultrasound and karytope should be considered inthe presence of extrarenal anomalies but the like-lihood of an abnormal result is low in infantswith unilateral renal agenesis with no extrarenalanomalies. It has been recommended that renalultrasound should be performed on parents andsiblings of an infant with renal agenesis. Rood-hoft et al reported a 9% incidence of asympto-matic renal malformations including unilateralrenal agenesis in 4.5% of parents and siblings.15

The evaluation of contralateral kidney and lowergenitourinary tract on both sides should be donein all infants with unilateral renal agenesis. Rou-tine urine analysis, serum chemistries with bloodurea nitrogen, and serum creatinine are neces-sary to assess the degree of renal impairmentand follow-up of renal function. All infantsshould receive prophylactic antibiotics pending acomplete evaluation. Renal scan and voiding cys-tourethrogram (VCUG), with or without cystoscopyare helpful in evaluation of contralateral kidneyand lower urinary tract. Pelvic ultrasound or com-puted tomography (CT) and colposcopy may behelpful in female patients for early identification ofassociated anomalies of uterus and vagina. Therecommended evaluation for all infants with renalagenesis is summarized in Table 39-3.

� PROGNOSIS

Bilateral renal agenesis is incompatible with life.Majority of infants die secondary to respiratoryfailure unresponsive to maximal medical man-agement. Use of extracorporeal membrane oxy-genation (ECMO) is usually contraindicated inthese infants and withdrawal of support is con-sidered acceptable after parental consent. Thereare no reports of long-term survival among in-fants with bilateral renal agenesis.

Infants with unilateral renal agenesis with nor-mal contralateral kidney have a good prognosiswith high likelihood of normal life span in themajority of cases. The contralateral kidney inthese infants undergoes a prenatal and postnatal



� TABLE 39-2 Syndromes Associated with Renal Agenesis


Branchio-oto-renal Hearing loss, preauricular pits, branchial Autosomal dominant(BOR) syndrome fistulas or cysts, anomalous pinna,

cleft palate, facial paralysisCaudal regression Incomplete development of sacrum, Unknown, more

syndrome flattening of buttocks, disruption of distal common in infantsspinal cord, poor growth and skeletal of diabetic mothersdeformities of lower extremities

CHARGE association Colobomas, heart defects, atresia of choanae, Autosomal dominantretarded growth and development, genitalanomalies, ear anomalies

Cloacal exstrophy Persistence of cloaca, omphalocele, Unknownsequence hydromyelia, cryptorchidism, pelvic kidneys,

multicystic kidneysEctrodactyly-ectodermal Fair and thin skin, light colored sparse hair, Autosomal dominant

dysplasia-clefting hypoplastic nipples, teeth anomalies, cleft lipsyndrome with or without cleft palate limb anomalies,(EEC syndrome) cryptorchidism, holoprosencephaly

Ellis-Van Creveld Short distal extremities, polydactyly, nail Autosomal recessivesyndrome hypoplasia, neonatal teeth, atrial septal(chondroectodermal defectdysplasia)

Goldenhar syndrome Maxillary and mandibular hypoplasia, microtia Unknown(facio-auriculo-vertebral and other ear anomalies, hemivertebrae,spectrum) cleft lip and palate, occasional cardiac and

CNS defectsIvemark syndrome Agenesis of spleen, situs inversus, Usually sporadic,

cardiac defects autosomal dominantand recessivetransmission alsoreported

LEOPARD syndrome Lentigenes, ECG abnormalities, ocular Autosomal dominant(multiple lentigines hypertelorism, pulmonic stenosis,syndromes) abnormalities of genitalia, retardation of

growth, deafnessLimb-body wall complex Thoraco-and/or abdominoschisis, limb Unknown

defects, encephalocele, facial cleftsMURCS association Müllerian duct aplasia, renal aplasia,

cervicothoracic somite dysplasia, upper Unknownlimb defects, deafness, craniofacialanomalies

Smith-Lemli-Opitz Growth retardation, mental deficiency, Autosomal recessivesyndrome microcephaly, syndactyly, genital

abnormalities, anteverted nostrilsVACTERL association Vertebral, anal, cardiac, tracheal, Unknown, more

esophageal, renal, and limb anomalies, frequently seen insingle umbilical artery, spinal dysraphia, infants of diabeticgenital abnormalities mothers

CNS, central nervous system; ECG, electrocardiographic.

compensatory hypertrophy which can make itlarger than normal kidney size and thus moresusceptible to trauma. This compensatory hyper-trophy is so common that failure to undergo

compensatory hypertrophy could be an indica-tion of renal dysplasia and may predict progres-sive renal insufficiency. There are several reportsof focal glomerulosclerosis in patients with unilat-eral renal agenesis which is thought to be relatedto hyperfiltration of the remnant nephrons. Arguesoet al reported an increased risk of proteinuria,hypertension, and renal insufficiency in patientswith unilateral renal agenesis and a normal con-tralateral kidney but their survival rate was similarto that of age, and sex-matched controls.16


Although both unilateral and bilateral renal age-nesis are usually sporadic, recurrences in morethan 70 families have been reported.17 The reportsof skipped generation in some of these familiessuggest an autosomal dominant pattern of inher-itance with incomplete penetrance (50–90%) and


� TABLE 39-3 Recommended Evaluation forInfants with Renal Agenesis

• Detailed history and examination• Rule out tracheoesophageal fistula and

anorectal malformation• Skeletal survey• Echocardiogram• Cranial ultrasound and karyotype in

presence of other congenital malformationon examination and evaluation

• Pelvic ultrasound in female infants• Renal scan/voiding cystourethrogram• Cystoscopy/colposcopy ±• Serum chemistries to evaluate and monitor

renal function• Renal ultrasound on parents and siblings

Renal Agenesis

Family History and/orParent/Sibling Renal Ultrasound

Extrarenal Anomalies

Positivefor URA

Negativefor URA

Positive Negative

Isolated FamilialRenal Agenesis

Isolated SporadicRenal Agenesis Familial

Syndromic RenalAgenesis

-Syndromic Renal Agenesis-Renal Agenesis with Multiple Congenital Anomalies

Likely AutosomalDominant

Likely Sporadic Multifactorial AR,AD, X-linked

-Multifactorial-Sporadic, Mutation-Chromosomal Anomaly

Figure 39-1. Algorithm to help establish etiology and recurrence risk in patients with renalagenesis. (URA, unilateral renal agenesis; AD, autosomal dominant; AR, autosomal recessive)

variable expressivity in majority of these families.17

But autosomal recessive and X-linked inheri-tance have also been described. The recurrencerisk will also depend on the etiology in the in-dex patient and the presence or absence of anassociated syndrome. The recurrence risk for aninfant with renal agenesis and a negative familyhistory is reported to be in the range of3–5%.15,18 The recurrence rate is reported to beabout 8% if renal agenesis is part of a complexof multiple abnormalities. The recurrence risk infamilies with autosomal dominant pattern of in-heritance would be much higher and closer to50%. Level II prenatal ultrasound should be of-fered for all subsequent pregnancies. Figure 39-1provides an algorithm to help establish etiologyand the likely recurrence risk in patients withrenal agenesis.

REFERENCES

1. Hiraoka M, Tsukahara H, Ohshima Y, et al. Renalaplasia is the predominant cause of congenital soli-tary kidneys. Kidney Int. May 2002;61(5):1840–4.

2. Bauer SB. Anomalies of the upper urinary tract. In:Campbell MF, Walsh PC, Retik AB, eds. Campbell’sUrology. 8th ed. Philadelphia, PA: W.B. Saunders;2002:1885.

3. Damen-Elias HA, Stoutenbeek PH, Visser GH, et al.Concomitant anomalies in 100 children with uni-lateral multicystic kidney. Ultrasound ObstetGynecol. Apr 2005;25(4):384–8.

4. Parikh CR, McCall D, Engelman C, et al. Congenitalrenal agenesis: case-control analysis of birth char-acteristics. Am J Kidney Dis. Apr 2002;39(4):689–94.

5. Harris J, Robert E, Kallen B. Epidemiologic charac-teristics of kidney malformations. Eur J Epidemiol.2000;16(11):985–92.

6. Wilson RD, Baird PA. Renal agenesis in British Co-lumbia. Am J Med Genet. May 1985;21(1):153–69.

7. Stroup NE, Edmonds L, O’Brien TR. Renal agenesisand dysgenesis: are they increasing? Teratology.Oct 1990;42(4):383–95.

8. Cuckow PM, Nyirady P, Winyard PJ. Normal andabnormal development of the urogenital tract.Prenat Diagn. Nov 2001;21(11):908–16.

9. Garne E, Loane M, Dolk H, et al. Prenatal diag-nosis of severe structural congenital malfor-mations in Europe. Ultrasound Obstet Gynecol.Jan 2005;25(1):6–11.

10. Cunniff C, Kirby RS, Senner JW, et al. Deaths asso-ciated with renal agenesis: a population-basedstudy of birth prevalence, case ascertainment,and etiologic heterogeneity. Teratology. Sep 1994;50(3):200–4.

11. Dursun H, Bayazit AK, Buyukcelik M, et al. Asso-ciated anomalies in children with congenital soli-tary functioning kidney. Pediatr Surg Int. Jun 2005;21(6):456–9.

12. Cascio S, Paran S, Puri P. Associated urologicalanomalies in children with unilateral renal agenesis.J Urol. Sep 1999;162(3 Pt 2):1081–3.

13. Li S, Qayyum A, Coakley FV, et al. Associationof renal agenesis and mullerian duct anom-alies. J Comput Assist Tomogr. Nov-Dec 2000;24(6):829–34.

14. McCallum T, Milunsky J, Munarriz R, et al. Unilat-eral renal agenesis associated with congenital bi-lateral absence of the vas deferens: phenotypicfindings and genetic considerations. Hum Reprod.Feb 2001;16(2):282–8.

15. Roodhooft AM, Birnholz JC, Holmes LB. Familialnature of congenital absence and severe dysgenesisof both kidneys. N Engl J Med. May 1984;310(21):1341–45.

16. Argueso LR, Ritchey ML, Boyle ET Jr, et al. Prog-nosis of patients with unilateral renal agenesis.Pediatr Nephrol. Sep 1992;6(5):412–6.

17. Pallotta R, Bucci I, Celentano C, et al. The “skippedgeneration” phenomenon in a family with renalagenesis. Ultrasound Obstet Gynecol. Oct 2004;24(5):586–7.

18. Moore D, Tudehope D, Lewis B, et al. Familialrenal abnormalities associated with the oligohy-dramnios tetrad secondary to renal agenesis anddysgenesis. Aust Paediatr J. Apr 1987;23(2):137–41.



Chapter 40

Horseshoe KidneyPRAVEEN KUMAR

261

� INTRODUCTION

Horseshoe kidney is a common congenital anomalyof the kidney which is characterized by an isthmusconnecting right and left kidney. The isthmus canbe a band of fibrous tissue or a rim of functionalrenal parenchyma and crosses the mid-plane ofthe body. While most horseshoe kidneys are fusedat the inferior pole, fusion of the superior poleand of both poles (sigmoid kidney) have beendescribed in 5–10% of patients with horseshoekidney.1 A classification of horseshoe kidneyproposed the following types: A (a)—fused atthe superior pole, A (b)—fused at the inferiorpole, B (a)—fused by fibrous tissue, B (b)—fuseddirectly and, B (c)—fused by mediators.1 How-ever, this classification is not frequently used ordescribed by other authors.

� EPIDEMIOLOGY

The reported prevalence of horseshoe kidneysvaries from 1 in 300 to 1 in 1800 but most reportscite a prevalence of 1 in 400–500.1–3 These esti-mates are based primarily on data from patientsrequiring renal evaluations and epidemiologicpostmortem studies. Based on data from threelarge population based congenital malformationregistries from Europe and the United States,Harris et al reported a much lower prevalence

range of 0.25–0.61 per 10,000 births.4 It is likelythat asymptomatic cases of horseshoe kidneyswere not identified and contributed to the lowerincidence in this report. Tsuchiya et al screened5700 healthy 1-month-old infants in Japan andidentified only one case of horseshoe kidney intheir population.5 It is likely that the low inci-dence was because only healthy infants with noknown malformations were included in this study.Horseshoe kidney may be seen in as many as20% of patients with trisomy 18 and 7% of caseswith Turner syndrome. However, these two stud-ies raise the possibility that the true prevalenceof horseshoe kidney may be lower than the pre-viously cited rate of 1 in 400. Overall a slight malepredominance has been reported.

� EMBRYOLOGY

The horseshoe kidney results from fusion of thetwo kidneys probably around the sixth week ofgestation. Initially the human kidneys lie closeto each other in the pelvis and ventral to thesacrum. With the subsequent growth of the em-bryo, the kidneys migrate cranially and rotatemedially almost ninety degrees to lie in theiradult position by about the ninth week. Abnormalcontact between the developing kidneys leads tofusion. It has been proposed that a slight alter-ation in the position of the umbilical or common


iliac artery could change the orientation of themigrating kidneys leading to contact and fusion.3

A role of teratogenic factors responsible forabnormal migration of nephrogenic cells to forman isthmus has also been suggested.6 The nor-mal ascent or cranial migration is prevented by theinferior mesenteric artery obstructing the move-ment of isthmus, thus resulting in a lower thannormal position of horseshoe kidneys in the ab-domen. As a result, normal rotation of the kidneyis also prevented which places the renal pelvisanteriorly.1 The ureters emerge anteriorly andusually pass in front of the isthmus. Ureters enterthe bladder normally and are rarely ectopic. Theisthmus frequently lies anterior to the aorta andinferior vena cava but could pass between or be-hind both great vessels in some cases.


Horseshoe kidneys are unlikely to present withany symptoms during the newborn period withthe exception of the possibility of a palpablemidline mass. Almost all horseshoe kidneys inthe newborn are diagnosed either on a routineprenatal ultrasound or postnatal ultrasound donefor evaluation of other associated malformations.Almost one-third of all patients with horseshoekidney remain asymptomatic throughout theirlife. Symptoms in the remaining two-thirds arerelated to hydronephrosis, infection or calculusformation.3 Ureteropelvic junction (UPJ) ob-struction causing significant hydronephrosis oc-curs in as many as one-third of adult patientswith horseshoe kidneys.3 UPJ obstruction candevelop secondary to congenital stricture, highureteral insertion, an abnormal ureteral courseover the isthmus, crossing vessels supplying theisthmus, or abnormal motility of UPJ segment.1


Horseshoe kidney is frequently associated withboth genitourinary and extragenitourinarycongenital anomalies. The incidence of associated

anomalies is greater in patients who die in theperinatal period than in those who reach adult-hood. Vesicoureteral reflux and hydronephrosissecondary to ureteropelvic junction obstructionare the most common associated urinary tractanomalies in these infants.3,7 Ureteral duplica-tion has been reported in 10% of cases. Hy-pospadias and undescended testes in males, anda bicornuate uterus and/or septate vagina in fe-males have been reported in <10% of cases.3

Nongenitourinary tract anomalies are re-ported in 79% of infants, 28% of children, and 4%of adults with horseshoe kidneys.7 Harris et al re-ported one or more major extra genitourinarymalformations in 75% of all cases with horseshoekidneys in infants.4 The organ systems most com-monly affected include the musculoskeletal, car-diac, and central nervous systems (CNS). Thecommonly reported malformations include ver-tebral anomalies, neural tube defects, anorectalatresia, and cardiac septal defects.

Horseshoe kidneys have been reported withincreased frequency in association with severalsyndromes. A list of common syndromes asso-ciated with horseshoe kidney is provided inTable 40–1. Horseshoe kidney may be seen in asmany as 20% of patients with trisomy 18 and 7%of cases with Turner syndrome.3,8


A renal ultrasound is usually sufficient to makethe diagnosis of horseshoe kidney but other imag-ing techniques such as computed tomography(CT), magnetic resonance imaging (MRI), and re-nal scan may be necessary in some cases. Strausset al reviewed sonographic features of horseshoekidney and identified the following featureswhich should suggest the diagnosis of this anom-aly; poorly defined inferior border of the kidney,tapering and elongation of the lower pole, bentor curved configuration of the kidney in the longaxis, and low-lying position of kidneys. 9 All in-fants diagnosed to have horseshoe kidneyshould get a voiding cystourethrogram (VCUG)to evaluate for vesicoureteral reflux (VUR) and


should receive antibiotic prophylaxis pending acomplete evaluation. Routine urine analysis,serum chemistries with blood urea nitrogen, andserum creatinine are necessary to assess and fol-low renal function. No other intervention is nec-essary in asymptomatic patients in absence ofany complications.

All infants should undergo a complete physicalexamination to evaluate for any other associated

malformations particularly cutaneous markers ofoccult spinal dysraphism and anorectal atre-sia/rectal fistulas. X-ray of the spine and cardiacecho should be considered. Routine karyotypeis not necessary unless indicated by the pres-ence of other systemic malformations. Althoughhorseshoe kidney has been reported in familymembers, there is no recommendation forscreening family members at present.

CHAPTER 40 HORSESHOE KIDNEY 263

� TABLE 40–1 Syndromes Associated with Horseshoe Kidney


Fanconi pancytopenia Short stature, microcephaly, eye anomalies, radial Autosomal recessivesyndrome ray defects in upper limbs, pancytopenia,

brownish pigmentation of skin, cardiac, GI andCNS anomalies

Goltz syndrome Poikiloderma with focal dermal hypoplasia, sparse X-Linked dominantand brittle hair, dystrophic nails, syndactyly and sporadicand other anomalies of hand/feet, eye colobomas,heart defects

Kabuki syndrome Long palpebral fissures with eversion of the lateral Unknownportion of lower eyelid, ptosis, cleft palate,brachydactyly, rib anomalies, cardiac defects,prominent fingertip pads

Pallister-Hall IUGR, hypothalamic harmartoblastoma, ear Autosomal dominantsyndrome anomalies, laryngeal cleft, lung agenesis,

syndactyly, polydactyly, anal anomalies,heart defects

Roberts-SC Hypomelia limb reduction defects of both upper Autosomal recessivephocomelia and lower limbs midfacial defects such as

cleft lip and palate, microcephaly, severe IUGR,cryptorchidism, eye anomalies

Trisomy 13 Holoprosencephaly, microphthalmia, cyclopia, Trisomy(Patau syndrome) microcephaly, cleft lip and palate, heart defects,

IUGR, genital abnormalitiesTrisomy 18 IUGR, low-set malformed ears, clenched hand, Trisomy

(Edwards heart defects, rocker bottom feet, microcephaly,syndrome) genital anomalies

Turner syndrome IUGR, lymphedema, broad chest with widely spaced Monosomy Xnipples, small maxilla and mandible, low hairline,webbed neck, redundant skin, heart defects,hearing impairment

VACTERL Vertebral, anal, cardiac, tracheal, esophageal, Unknown, moreassociation renal and limb anomalies, single umbilical artery, frequently seen

spinal dysraphia, genital abnormalities in infants ofdiabetic mothers

GI, gastrointestinal; CNS, central nervous system; IUGR, intrauterine growth retardation.

� PROGNOSIS

The presence of a horseshoe kidney by itself hasnot been shown to adversely affect survival andis only rarely a cause for mortality.3 In neonateswith horseshoe kidney, mortality, and long-termoutcome are largely determined by the presenceand prognosis of associated congenital anom-alies and syndromes.

Many different malignancies have been re-ported in horseshoe kidneys. The commonesttumor reported is renal cell carcinoma althoughits incidence is reported to be no higher thanthat in the general population.1,10 A twofold in-creased risk of Wilms tumor is reported in patientswith a horseshoe kidney.2,11 But the NationalWilms Tumor Study Group (NWTSG) estimatesthe risk of Wilms tumor development at <0.001%based on an incidence of 1 in 400 for horseshoekidney in the general population and does notrecommend a specific screening protocol for in-fants with horseshoe kidneys at this time.11

Huang et al reviewed all reported cases of Wilmstumor with horseshoe kidneys in the Englishlanguage literature and found no significant dif-ference in the morbidity or mortality associatedwith Wilms tumor in patients with horseshoekidney when compared with patients with nor-mal appearing kidneys. The relative risk of tran-sitional cell carcinoma has been estimated to be3–4 times higher and risk of carcinoid tumor isreported to be 62 times higher than in the gen-eral population.6 However, these tumors are veryrare both in the general population and in pa-tients with horseshoe kidney. The exact embry-ological pathogenetic mechanisms for an in-creased incidence of these tumors are notcompletely understood so far.


Most cases of horseshoe kidney are sporadic witha very low chance of recurrence in subsequentpregnancies. The recurrence risk in infants withan associated chromosomal abnormality or syn-dromic disorder will depend on the inheritance

pattern of that disorder. Although familial recur-rences have been reported, there is not enoughevidence to characterize the hereditary pattern ofthis anomaly.1 Level II prenatal ultrasound shouldbe offered for all subsequent pregnancies.

REFERENCES

1. Yohannes P, Smith AD. The endourological man-agement of complications associated with horse-shoe kidney. J Urol. Jul 2002;168(1):5–8.

2. Huang EY, Mascarenhas L, Mahour GH. Wilms’tumor and horseshoe kidneys: a case report andreview of the literature. J Pediatr Surg. Feb 2004;39(2):207–12.

3. Bauer SB. Anomalies of the upper urinary tract. In:Campbell MF, Walsh PC, Retik AB, eds. Campbell’sUrology.8th ed. Philadelphia, PA: W.B. Saunders;2002:1885.


5. Tsuchiya M, Hayashida M, Yanagihara T, et al. Ul-trasound screening for renal and urinary tractanomalies in healthy infants. Pediatr Int. Oct 2003;45(5):617–23.

6. Krishnan B, Truong LD, Saleh G, et al. Horseshoekidney is associated with an increased relative riskof primary renal carcinoid tumor. J Urol. Jun 1997;157(6):2059–66.

7. Van Allen MI. Horseshoe kidney. In: Stevenson RE,Hall JG, Goodman RM, eds. Human Malforma-tions and Related Anomalies. Vol 2. New York:Oxford University Press; 1993:546–50.

8. Lippe B, Geffner ME, Dietrich RB, et al. Renal mal-formations in patients with Turner syndrome:imaging in 141 patients. Pediatrics. Dec 1988;82(6):852–6.

9. Strauss S, Dushnitsky T, Peer A, et al. Sonographicfeatures of horseshoe kidney: review of 34 patients.J Ultrasound Med. Jan 2000;19(1):27–31.

10. Stimac G, Dimanovski J, Ruzic B, et al. Tumors inkidney fusion anomalies—report of five cases andreview of the literature. Scand J Urol Nephrol. 2004;38(6):485–9.

11. Neville H, Ritchey ML, Shamberger RC, et al. Theoccurrence of Wilms tumor in horseshoe kidneys: areport from the National Wilms Tumor Study Group(NWTSG). J Pediatr Surg. Aug 2002;37(8):1134–7.


Chapter 41

Renal Cystic Diseases PRAVEEN KUMAR

265

� INTRODUCTION

The term renal cystic disease encompasses acommon and heterogeneous group of condi-tions that can present in fetal life, childhood, orlater in adult life. Renal cysts in the perinatal pe-riod represent abnormal dilatation of a part ofthe renal tubule as a result of hereditary or non-hereditary developmental disorders, and de-pending on the underlying process, either oneor both kidneys can be affected. Renal cysts canpresent as the sole manifestation of disease, canaccompany other renal/extrarenal anomalies, orcan be part of a systemic disorder or syndrome.With the widespread use, better resolution, andincreasing expertise in the use of antenatal andpostnatal ultrasound, these lesions are increas-ingly being detected prenatally and in earlyneonatal period.

Over the years, many different classificationshave been proposed for renal cystic diseases.One of the earliest classifications was proposedby Osathanondh and Potter in 1964 and classi-fied renal cystic disease of the newborn in thefollowing four groups: type I included autoso-mal recessive polycystic kidney disease (ARPKD);type II cystic kidneys included dysplastic andmulticystic kidneys and could be unilateral or bi-lateral; type III represented autosomal dominantpolycystic kidney disease (ADPKD); and type IV

included cystic kidneys due to an obstruction ofthe outflow tract.1 In 1987, The Committee onClassification, Nomenclature, and Terminologyof the American Academy of Pediatrics Sectionon Urology proposed an expanded classifica-tion to include all causes of renal cystic diseases(Table 41-1).2

� EPIDEMIOLOGY

ADPKD is one of the most common hereditarydisorders in humans and accounts for 5% of theend stage renal disease patients in the UnitedStates.3 It affects 1 in 400 to 1 in 1000 live birthsbut only a small percentage of all affected pa-tients present during the perinatal period. Themost common cause of renal cystic disease in anewborn is multicystic dysplastic kidney (MCDK)and the incidence of this disorder is reported torange from 1 in 1000 to 1 in 4500 live births.The estimated prevalence of ARPKD, a rare typeof renal cystic disease with common perinatalpresentation, is 1 in 20,000 live births with aheterozygote frequency of 1 in 70.3,4 Other re-nal cystic diseases of the newborn are encoun-tered only rarely. The overall birth prevalenceof renal cysts in the newborn has been reportedto range from 0.05 to 0.5 per 1000 live births inpopulation based congenital anomaly birth


registries from North America and Europe.1,5

An anomaly of the urinary tract is reported inapproximately 0.1–0.4% of all prenatal ultra-sounds and nearly 30% of these anomalies in-clude cystic renal disease.6,7 More than two-thirds of fetuses with cystic renal disease arediagnosed to have MCDK.

� EMBRYOLOGY

The human kidney develops from metanephroswhich consists of metanephric diverticulum orureteric bud and metanephric mesoderm ormetanephrogenic blastema. Ureteric bud is anoutgrowth from the mesonephric duct andbranches multiple times to form the excretorysystem consisting of renal pelvis, calyces, and col-

lecting tubule. Metanephric mesoderm requiresinductive interaction with branching ureteric bud todevelop into nephrons comprising of glomerulus,proximal convoluted tubule, loop of Henle, anddistal convoluted tubule. Renal development be-gins at the end of fourth week of gestation, thefirst glomeruli form by 8–9 weeks and fetal urineis produced at about the tenth week; however, newnephrons continue to be added until 34–36 weeksof gestation and nephrons continue to elongateand differentiate after that.8

Cystic renal disease in MCDK and severalheritable and nonheritable syndromes representsrenal dysplasia which is characterized by archi-tectural disorganization of the kidney secondaryto atresia or severe hypoplasia of the ipsilateralexcretory system. Renal cystic disease in thesepatients is frequently associated with other renalanomalies on both ipsilateral and contralateralsides. Although the exact pathogenesis in thesepatients is unknown, it is believed that aberrantinductive interaction between epithelial cells ofthe ureteric bud and surrounding mesenchymecells leads to dysregulation of normal renal de-velopment. In contrast, initial renal developmentis normal in other renal cystic diseases such asADPKD and ARPKD and there are no associateddevelopmental structural anomalies of the kid-neys in these patients.


A summary of important clinical features incommon cystic renal diseases of the newborn ispresented in Table 41-2. Presenting symptomscan range from incidental findings on pre- or post-natal ultrasound to massive renomegaly and fromminimal renal dysfunction in mild cases to severerespiratory distress with complete renal failure orstillbirth in severe cases. The degree of respiratoryinsufficiency is usually related to the severity ofrenal disease and is secondary to a combinationof pulmonary hypoplasia and mechanical inter-ference due to a massively distended abdomen.


� TABLE 41-1 Classification of Renal CysticDiseases

GeneticA. Autosomal recessive (infantile) polycystic

kidneysB. Autosomal dominant (adult) polycystic

kidneysC. Juvenile nephronophthisis—medullary

cystic disease complex1. Juvenile nephronophthisis (autosomal

recessive)2. Medullary cystic disease (autosomal

dominant)D. Congenital nephrosis (autosomal reces-

sive)E. Cysts associated with multiple malforma-

tion syndromes

NongeneticA. Multicystic kidney (multicystic dysplasia)B. Multilocular cyst (multilocular cystic

nephroma)C. Simple cystsD. Medullary sponge kidneys (<5% inherited)E. Acquired renal cystic disease in chronic

hemodialysis patientsF. Caliceal diverticulum (pyelogenic cysts)

� TABLE 41-2 Summary of Clinical Presentation in Common Renal Cystic Diseases in Newborn

AssociatedAge at Renal Function Renal Associated

Diagnosis Incidence Family History Presentation at Birth Anomalies Extrarenal Anomalies

ADPKD 1–2/1000 Usually present, Adulthood, Variable None None in newborns;live births absent in perinatal cases cysts in liver, spleen,

10–25% are rare, pancreas and lung in of cases <10% present in 50% of adults,

first decade Berry aneurysm in10–30% of adults;hernia, diverticuli, andcardiovascularabnormalities insome

ARPKD 1 in 20,000 Usually absent, Frequently in Variable None Hepatic fibrosis leadinglive births maybe positive perinatal period; to portal hypertension;

always by late presence of otherchildhood organ involvement

suggest fibrocysticsyndromes otherthan ARPKD

MCDK ~1 in 1000 to Absent Perinatal if bilateral, Affected kidney Present in Present in 10–25%1 in 4500, unilateral disease is nonfunctional 20–40% of unilateral casesbilateral in may be a chance and 50–70% of20–30% finding later in life, bilateral MCDK cases;

most cases are congenital heartdiagnosed by early defects are associatedchildhood/late in about 7–28%infancy of cases

(Continued)

26

7

� TABLE 41-2 Summary of Clinical Presentation in Common Renal Cystic Diseases in Newborn (Continued)

AssociatedAge at Renal Function Renal Associated

Diagnosis Incidence Family History Presentation at Birth Anomalies Extrarenal Anomalies

GCKD Rare Usually present Usually infancy, Variable None Nonecan present inperinatal period

JNPHP Very rare Variable Variable Variable None 10–20% haveTapetoretinaldegeneration; CNS andskeletal anomaliesare reported; usuallyassociated withhepatic fibrosis

Simple Rare Absent Fetal Usually normal None Nonerenalcysts

ADPKD, autosomal dominant polycystic kidney disease; GCKD, glomerulocystic kidney disease; ARPKD, autosomal recessive polycystic kidney disease;JNPHP, juvenile nephronophthisis; PKD, polycystic kidney disease; PKHD, polycystic kidney and hepatic disease; MCDK, multicystic dysplastic kidney;ESRD, end stage renal disease.

26

8


Associated Clinical Course/ Mode of Prenatal diagnosisDiagnosis Syndromes Outcome Inheritance Genetic USG Comments

ADPKD Usually none Progressive deterioration AD Possible Yes Only 1–2% of all nephrons areto ESRD; perinatal affected; need chronicpresentation dialysis and transplant; 56%associated with more of affected patients havesevere disease cysts detected by USG in

first decade, 80% in seconddecade, and virtually all bybeginning of third decade;severity of parental diseasedoes not predict child’sdisease

ARPKD None Progressive deterioration AR Possible Yes Need chronic dialysis andto ESRD; high candidate for liver and renalmortality with perinatal transplant; 80% of tubulespresentation involved in perinatal cases

versus 10% in patientspresenting in childhood

MCDK Associated with Fatal if bilateral, variable Sporadic No Yes Serial USG have shown thatover 80 OUTCOME if unilateral rarely AD MCDK can involute andsyndromes/ and depends on even disappear completelyassociations; contralateral kidney in a significant proportion ofpresent in 10–15% function and cases; more common inof cases, of MCDK; associated renal/extra- males but bilateral diseaseabnormal renal anomalies is more common in females;chromosome in females more likely to haveabout 3%; more extrarenal anomalies andcommon in abnormal chromosomalinfants with studybilateral disease

(Continued)

26

9


Associated Clinical Course/ Mode of Prenatal diagnosisDiagnosis Syndromes Outcome Inheritance Genetic USG Comments

GCKD None in classical Variable from death in AD, sporadic No Yes Sometimes an expression ofGCKD early infancy to early onset ADPKD;

survival in adult life glomerular cysts can bewith little handicap observed in other diseases

and syndromes and shouldnot always be consideredpart of GCKD

JNPHP Uncommon e.g. Progressive deterioration AR Possible RareJeune, Ellis-van to ESRDCreveld, Joubert,Senoir-Lokensyndrome

Simple None Spontaneous resolution Sporadic No Yes Most fetal renal cysts resolverenal to slow progression without any sequelaecysts

27

0


The presence of associated anomalies in an in-fant with cystic renal disease is highly sugges-tive of either MCDK or other syndromic formsof cystic renal disease. Associated anomalies ofthe genitourinary system are significantly morecommon than anomalies of other organ systems.Genitourinary anomalies on either the ipsilat-eral or contralateral side are reported in 20–75%of all infants with unilateral multicystic kidneyand extrarenal anomalies are noted in 5–35% ofthese infants.7 The highest rate of associatedgenitourinary anomalies was noted when cys-toscopy and colposcopy were also done in addi-tion to ultrasound and voiding cystourethrogram(VCUG).7 Table 41-3 summarizes reported renaland extrarenal anomalies in infants with cysticrenal disease.

Renal cysts have been described as part ofseveral common and uncommon syndromes. Thehistopathological, clinical, and radiological find-ings in these cases can be consistent with MCDK,glomerulocystic kidney disease (GCKD), or juve-nile nephronophthisis (JNPHP). Infants with syn-dromic cystic renal disease almost always haveassociated extrarenal anomalies and are likely tohave bilateral disease. Table 41-4 provides a brieflist of common syndromes in which cystic renaldisease has been described and the mode of in-heritance associated with each one.

� EVALUATION

A detailed family history and complete physicalexamination for associated congenital anomaliesof other organ systems are the necessary firststeps in the evaluation of an infant with cysticrenal disease. MCDK, the most common cause ofcystic renal disease in the newborn, is a sporadicdisorder in most cases and is not associated witha positive family history in majority of cases.ADPKD, ARPKD, and GCKD are inheritabledisorders and a careful family history can be very

helpful in providing clues to the diagnosis. It isimportant to remember that a negative familyhistory can not exclude these diagnoses becauseof possibility of spontaneous mutations in the

CHAPTER 41 RENAL CYSTIC DISEASES 271

� TABLE 41-3 Associated Anomalies inPatients with Cystic Renal Disease

Renal anomaliesVesicoureteral refluxUreteral agenesis or hypoplasiaUreteropelvic junction obstructionBladder wall abnormalitiesEctopic ureter/duplex ureter UreteroceleEctopic kidney

ExtrarenalCentral nervous system

HydrocephalusChoroid plexus cystSpina bifida

Cardiovascular systemVentricular septal defectAtrial septal defectEndocardial cushion defectTransposition of great vesselsPulmonary stenosis

Gastrointestinal systemTracheoesophageal fistulaImperforate anusDuodenal atresiaAbdominal wall defect

SkeletalPolydactylyClubbed footHemivertebra

GenitaliaCystic dysplasia of testisVaginal atresiaImperforate hymenPersistent seminal cystsGartner’s cystAmbiguous genitalia

PulmonaryPulmonary hypoplasia

CraniofacialMicrognathiaPotter facies


� TABLE 41-4 Syndromes Associated with Cystic Renal Diseases


Bardet-Biedl syndrome Postaxial polydactyly, syndactyly, Autosomal recessivehypogonadism, retinal dystrophy

Branchio-oto-renal Hearing loss, preauricular pits, branchial Autosomal dominantsyndrome fistulas or cysts, anomalous pinna,

cleft palate, facial paralysisCloacal exstrophy Persistence of cloaca, omphalocele, Unknown

sequence hydromyelia, cryptorchidism, pelvickidneys

Fryns syndrome Diaphragmatic defects, distal digital Autosomal recessivehypoplasia, pulmonary hypoplasia,Dandy-Walker malformation, agenesisof corpus callosum, ventricular septaldefect

Jeune syndrome Bell shaped thorax, pulmonary hypoplasia, Autosomal recessive(asphyxiating thoracic hypoplasia, polydactyly, rhizomelic limbdystrophy) shortening, situs inversus

Meckel-Gruber syndrome Occipital encephalocele, polydactyly, Autosomal recessivecleft lip and/or palate, microphthalmia,ambiguous genitalia, IUGR, microcephaly,cryptorchidism, cardiac defects

Oral-facial-digital syndrome, Lobulated tongue, oral frenulae and clefts, X-linked dominanttype I hypoplastic alae nasi, digital anomalies,

agenesis of corpus callosumShort rib-polydactyly Phocomelia, metaphyseal dysplasia, Autosomal recessive

syndrome, type I postaxial polydactyly, syndactyly,(Saldino-Noonan type) cardiac defects, imperforate anus

Short rib-polydactyly Short ribs and limbs, cleft lip and palate Autosomal recessivesyndrome, type II pulmonary hypoplasia, hypoplasia of(Majewski type) epiglottis and larynx, pre-/postaxial

polydactylySmith-Lemli-Opitz Growth retardation, mental deficiency, Autosomal recessive

syndrome microcephaly, syndactyly, genitalabnormalities, anteverted nostrils

Trisomy 13 Holoprosencephaly, microphthalmia, Trisomycyclopia, microcephaly, cleft lipand palate, heart defects, IUGR,genital abnormalities

Trisomy 18 IUGR, low-set malformed ears, clenched Trisomyhand, heart defects, rocker bottom feet,microcephaly, genital anomalies

Tuberous sclerosis Hypopigmented macule, adenoma Autosomal dominantsebaceum, retinal and brain tumors,rhabdomyoma of heart

index case, absence of a clinical diagnosis in anaffected relative, and the possibility of incorrectpaternity.

Renal ultrasound in index patient is the singlemost helpful study in identifying the etiology. Inan infant with multiple cysts in one kidney, a mul-ticystic dysplastic kidney is the most likely diag-nosis but it needs to be differentiated from cysticchanges secondary to obstructive uropathy. Thepresence of multiple noncommunicating cysts ofvarying size in the absence of an identifiable re-nal sinus and normal renal parenchyma is thecharacteristic sonographic finding in patients withMCDK. The characteristic sonographic finding inARPKD is bilateral medullary cysts with diffusemarked enlargement of both kidneys; the findingof congenital hepatic fibrosis may be difficult todemonstrate in the neonatal period but is highlysuggestive of ARPKD, if present. The finding ofbilateral cortical cysts is suggestive of ADPKD.Renal ultrasound of the parents, siblings or grand-parents can also be helpful if a diagnosis ofADPKD is suspected. Nearly 100% of all ADPKDpatients >30 years will have renal cysts on ultra-sound; cysts on ultrasound are reported in 80%of patients after 20 years of age, and 56% of casesafter 10 years of age.9–11 Figure 41-1 summarizesthe diagnostic approach to a fetus/neonate withbilateral large echogenic kidneys with or withoutidentifiable cysts.

A skeletal survey, cardiac, and cranial ultra-sound should be done if clinical examination is

suggestive of extrarenal anomalies or if a diag-nosis of unilateral or bilateral MCDK is suspectedbased on renal ultrasound results. A karyotypeshould be obtained in the presence of extrarenalanomalies as the likelihood of an abnormal


� TABLE 41-4 Syndromes Associated with Cystic Renal Diseases (Continued)


VACTERL association Vertebral, anal, cardiac, tracheal, Unknown, moreesophageal, renal, and limb anomalies, frequently seen insingle umbilical artery, spinal dysraphia, infants of diabeticgenital abnormalities mothers

Zellweger syndrome Hypotonia, seizures, deafness, Autosomal recessive(cerebro-hepato-renal pachymicrogyria, heterotopias,syndrome) anteverted nares, cataracts, hepatomegaly,

cardiac defects, camptodactyly,cryptorchidism


Bilateral, Large Echogenic Kidneys

ADPKDARPKDMCDKGCKDJNPHP

Family/Parental Renal Ultrasound/History

Cyst Present Cyst Absent*

ADPKD MCDKGCKD ARPKD

JNPHP

Extrarenal Malformations on Examination or Ultrasounds

YesGCKD

NoADPKDGCKD

YesMCDK

NoARPKDJNPHP

Figure 41-1. Diagnostic approach in an infantwith bilateral echogenic kidneys.∗ Negative renal USG on an adult can exclude

ADPKD if that person is over 30 years of age

result is low in infants with unilateral MCDKwith no extrarenal anomalies.

The evaluation of the contralateral kidneyand lower genitourinary tract on both sidesshould be done in infants with unilateral MCDK.Infants with associated renal anomalies shouldreceive prophylactic antibiotics pending a com-plete evaluation. Recent studies have shownthat a routine VCUG in all infants with unilateralMCDK is not necessary if two successive renalultrasound scans can rule out clinically signifi-cant anomalies of the contralateral kidney andupper urinary tract.12,13 Routine urine analysis,serum chemistries with blood urea nitrogen, andserum creatinine are necessary to assess the de-gree of renal impairment and to follow renalfunction. In the event of fetal or neonatal death,autopsy should be obtained to confirm thepathological diagnosis and obtain samples forspecific DNA tests. Molecular genetic studiesare possible but not routinely available forADPKD and ARPKD.


The appropriate management of these infantsrequires careful attention to associated respira-tory and renal insufficiency. The managementof respiratory symptoms may range from supple-mental oxygen by nasal cannula to significant ven-tilatory support in infants with severe pulmonaryhypoplasia. The use of nitric oxide may be nec-essary in some cases with severe pulmonary hy-pertension. Use of extracorporeal membraneoxygenation (ECMO) is usually contraindicatedif severe pulmonary hypertension is associatedwith severe pulmonary hypoplasia and there isextensive bilateral kidney disease with minimalor no renal function. The management of renalinsufficiency may range from careful monitor-ing of renal function to the need for peritonealdialysis based on degree of impairment of renalfunction.

Neonatal outcome is related to the underlyingdiagnosis, extent of renal insufficiency, associ-ated pulmonary hypoplasia, and other extrarenal

congenital anomalies. Severe early onset oligohy-dramnios during pregnancy indicates severe renaldisease and a high likelihood of severe pulmonaryhypoplasia and is usually associated with earlyneonatal death or stillbirth in most cases.

Infants with isolated unilateral MCDK have agood prognosis for survival while bilateral dis-ease is always fatal. However, infants with uni-lateral MCDK should be monitored closely forhypertension and renal function of the con-tralateral kidney. Recent studies have shown thatthe risk of hypertension and malignancy are lowand routine nephrectomy of the diseased kidneyis not necessary. Both pre- and postnatal follow-up ultrasound examinations in children withunilateral MCDK have shown that a significantpercentage (25–50%) of cases have spontaneousinvolution to the point of complete disappearancein some.14,15 A renal length of <62 mm on initialultrasound was predictive of complete involutionduring follow-up.16

Newborns with ADPKD can have more rapidprogression of the disease compared to thosewith adult onset disease. However, more recentdata and longer follow-up suggest that the prog-nosis for prenatally diagnosed ADPKD infants isexcellent unless there is oligohydramnios.11 In arecent report on the outcome of 166 patientswith ARPKD, 73% had perinatal presentation andneed for mechanical ventilation at birth wasstrongly predictive of mortality and the early de-velopment of chronic renal insufficiency amongsurvivors. However, overall survival rate for thiscohort was 79% at 1 year and 75% at 5 years.17


The recurrence risk of cystic renal disease insubsequent pregnancies will depend on the eti-ology in the index patient and the presence or ab-sence of an associated syndrome. Level II prena-tal ultrasound should be offered for all subsequentpregnancies. The majority of cases of unilateralMCDK are isolated and have a sporadic mode ofinheritance; however, autosomal dominant trans-mission has been reported in some families and


the risk of recurrence in these cases is 50%. Theoverall risk in the absence of a family historyand associated syndrome is reported to be 2–3%in infants with isolated MCDK.11 If cystic renaldisease is part of a well-defined syndrome, therecurrence risk will depend on the mode of inher-itance of that syndrome.

The recurrence risk in a family with an in-fant with ARPKD is 25%. If a parent is affectedwith ADPKD, the risk of ADPKD in a subse-quent pregnancy is 50%, but the recurrence riskof early-onset ADPKD is reported to be 22.5%after one infant with early-onset ADPKD.9 Thereis no evidence that early onset cases are homo-zygous. The risk factors for early-onset diseaseare reported to be affected mother, affectedsibling, and a new mutation.11 Families at riskfor either ARPKD or ADPKD should have DNAanalysis prior to contemplating a future pregnancyto identify the genetic mutation so a prenatal DNAdiagnosis can be offered in late first trimester bychorionic villus sampling. DNA testing can alsobe performed on amniotic fluid cells obtainedby amniocentesis.

REFERENCES


2. Glassberg KI, Stephens FD, Lebowitz RL, et al.Renal dysgenesis and cystic disease of the kidney:a report of the Committee on Terminology, Nomen-clature, and Classification, Section on Urology,American Academy of Pediatrics. J Urol. Oct 1987;138(4 Pt 2):1085–92.

3. Rizk D, Chapman AB. Cystic and inherited kidneydiseases. Am J Kidney Dis. Dec 2003;42(6):1305–17.

4. Harris PC, Rossetti S. Molecular genetics of autoso-mal recessive polycystic kidney disease. Mol GenetMetab. Feb 2004;81(2):75–85.

5. Evans JA, Stranc LC. Cystic renal disease and car-diovascular anomalies. Am J Med Genet. Jul 1989;33(3):398–401.

6. Tsuchiya M, Hayashida M, Yanagihara T, et al.Ultrasound screening for renal and urinary tractanomalies in healthy infants. Pediatr Int. Oct 2003;45(5):617–23.

7. Damen-Elias HA, Stoutenbeek PH, Visser GH, et al.Concomitant anomalies in 100 children withunilateral multicystic kidney. Ultrasound ObstetGynecol. Apr 2005;25(4):384–8.

8. Cuckow PM, Nyirady P, Winyard PJ. Normal andabnormal development of the urogenital tract.Prenat Diagn. Nov 2001;21(11):908–16.

9. Zerres K, Mucher G, Becker J, et al. Prenatal diag-nosis of autosomal recessive polycystic kidney dis-ease (ARPKD): molecular genetics, clinical experi-ence, and fetal morphology. Am J Med Genet.Mar 1998;76(2):137–44.

10. Bear JC, Parfrey PS, Morgan JM, et al. Autosomaldominant polycystic kidney disease: new informa-tion for genetic counselling. Am J Med Genet.Jun 1992;43(3):548–53.

11. Winyard P, Chitty L. Dysplastic and polycystic kid-neys: diagnosis, associations, and management.Prenat Diagn. Nov 2001;21(11):924–35.

12. Ismaili K, Avni FE, Alexander M, et al. Routinevoiding cystourethrography is of no value inneonates with unilateral multicystic dysplastickidney. J Pediatr. Jun 2005;146(6):759–63.

13. Kuwertz-Broeking E, Brinkmann OA, Von LengerkeHJ, et al. Unilateral multicystic dysplastic kidney: ex-perience in children. BJU Int. Feb 2004;93(3):388–92.

14. Sukthankar S, Watson AR. Unilateral multicysticdysplastic kidney disease: defining the naturalhistory. Anglia Paediatric Nephrourology Group.Acta Paediatr. Jul 2000;89(7):811–3.

15. Aubertin G, Cripps S, Coleman G, et al. Prenatal di-agnosis of apparently isolated unilateral multicystickidney: implications for counselling and manage-ment. Prenat Diagn. May 2002;22(5):388–94.

16. Rabelo EA, Oliveira EA, Silva GS, et al. Predictivefactors of ultrasonographic involution of prenatallydetected multicystic dysplastic kidney. BJU Int.Apr 2005;95(6):868–71.

17. Guay-Woodford LM, Desmond RA. Autosomalrecessive polycystic kidney disease: the clinicalexperience in North America. Pediatrics. May 2003;111(5 Pt 1):1072–80.



Chapter 42

Posterior Urethral ValvesPRAVEEN KUMAR

277

� INTRODUCTION

Posterior urethral valves are the most commoncause of lower urinary tract obstruction and bi-lateral obstructive uropathy in male infants.These infants have a high incidence of morbid-ity and mortality and it is suggested that early se-vere obstruction during fetal development canexpose the developing kidneys and urinary tractsto very high pressures which may lead to per-manent maldevelopment of the kidneys andbladder. A significant proportion of posteriorurethral valve survivors develop end-stage renaldisease and represent approximately 1% of thoseawaiting renal transplantation.1 In a landmarkpaper in 1919, Young et al described three typesof posterior urethral valves based on their cysto-scopic appearance.2 Type I valves originate distalto the verumontanum on the floor of the poste-rior urethra with the valve cusps diverging dis-tally in an anterolateral orientation and fusinganteriorly in the midline. Type I valves accountfor almost 95% of all infants with posterior ure-thral valves.3 Type II valves were described asfolds of tissue that run between the bladder neckand the verumontanum but most current authorsconsider these findings as artifact and only of his-torical significance.4 Type III valves are centrallyperforated diaphragms that are located eithercephalad or caudal to the verumontanum and areresponsible for lower urinary tract obstruction

in about 5% of the infants with posterior ure-thral valves.4 Recently, Dewan et al have proposedthat these different types of valves represent var-ied manifestations of a congenital posterior ure-thral membrane and coined the term COPUM(congenital obstructive posterior urethral mem-brane) to define abnormalities seen in thesepatients.3,5

� EPIDEMIOLOGY

The incidence of posterior urethral valves in boysis reported to range from 1 in 5000 to 1 in 8000live births.1,4 Anecdotal cases have been reportedin females. A significantly higher incidence of>1 in 250 newborn males was reported in Oman;consanguinity was noted in the majority of casesand an autosomal recessive mode of inheritancewas suspected.6

� EMBRYOLOGY

Urethral development begins during the sixthweek of gestation and is complete by about thefourteenth week in a male fetus. The male urethrais divided into 4 sections. Most proximal are theprostatic and membranous urethra which arederived from the urogenital sinus, a structurewhich is also responsible for the development of


the female urethra. The bulbar and penile ure-thra are derived from the urethral plate of thegenital tubercle which is androgen dependentfor its normal development and present only inmales.7 Several different theories have been pro-posed to explain embryological development ofposterior urethral valves secondary to distur-bances of complex embryological processes, in-volving the urogenital sinus and membrane, theWolffian duct, and the Mullerian duct derived pro-static utricles.6 It is believed that type I posteriorurethral valves result when the mesonephric ductenters the cloaca in a more anterior portion thannormal and type III valves result from incom-plete dissolution of the urogenital portion of thecloacal membrane.3 Although early develop-ment of the upper and lower urinary tract isusually considered to proceed independently,there is some evidence to suggest that the de-velopment of posterior urethral valves may beinfluenced by polygenetic factors similar toother renal and extrarenal anomalies becauseposterior urethral valves have been describedas part of several defined syndromes.6 So far, noclear evidence for a specific gene mutation hasbeen observed for nonsyndromal posterior ure-thral valves but some population based studiespoint to a role of recessive genetic influence inits etiology.6


Although most patients with posterior urethralvalves are diagnosed in prenatal or neonatalperiod, the age of presentation and clinicalsymptoms can be variable in the remaining pa-tients and depend on the severity of obstructionand the degree of renal dysplasia. A prenatal di-agnosis of posterior urethral valves should besuspected in a male fetus with bilateral hy-dronephrosis with a continuously distendedbladder. The amount of amniotic fluid variesfrom normal in mild cases to significantly di-minished in severely obstructed infants. Long-standing severe oligohydramnios can result in

pulmonary hypoplasia and Potter facies as in in-fants with renal agenesis. Perinephric urinomasand urinary ascites can also be present in themost severely affected infants. A prenatal diag-nosis of posterior urethral valves can be madeearly in the second trimester onward and a fairproportion of these patients are diagnosed by24 weeks of gestation.

The symptoms and signs in an infant withpostnatal presentation are usually related eitherto obstruction or infection. An obstructive pre-sentation is more common in the neonate,whereas older children tend to present with in-fections.8 Infants with pulmonary hypoplasiasecondary to oligohydramnios may present witha variable degree of respiratory distress whichmay be fatal in the most severe cases. Nearlyone-third of all patients not diagnosed by pre-natal ultrasound present in the first month oflife, one-third in the first year, and one-thirdthereafter.8 It has been frequently reported thata poor urinary stream is not a sensitive indica-tor of the presence of posterior urethral valves.


Nearly all infants with posterior urethral valveswill have a variable degree of urinary tractchanges such as a thickened trabecular dysfunc-tional bladder, hydronephrosis, and some degreeof renal dysplasia. The extent of these changesdepends on the severity and duration of obstruc-tion. Vesicoureteral reflux is present in 25–50% ofcases with posterior urethral valves and is fre-quently bilateral. The majority of infants with pos-terior urethral valves are otherwise normal withno associated malformations. However, associ-ated anomalies of the genitourinary system suchas hypospadias, double urethra, ureteropelvicjunction stenosis, solitary/dysgenetic kidneys,renal ectopia, and extrarenal anomalies such asimperforate anus and congenital heart defects havebeen reported in some infants with posterior ure-thral valves. The incidence of undescended testes


is almost 12 times higher in these patients com-pared to the general population. Posterior ure-thral valves is an isolated abnormality in a largeproportion of cases but has also been reportedas part of a well-defined syndrome or multiplecongenital anomaly disorder which are listed inTable 42-1.

� EVALUATION

With widespread use of prenatal ultrasound,most infants with posterior urethral valves arediagnosed prenatally but only half of all cases

can be diagnosed before 24 weeks of gestation.3

Initial evaluation of an infant either with a pre-natal diagnosis of posterior urethral valves orsuspected of having posterior urethral valvesshould include renal ultrasound, voiding cys-tourethrogram (VCUG), urinalysis, urine cul-ture, serum electrolyte, blood urea nitrogen,and creatinine. Renal ultrasound should includeimages of ureters and bladder; and could pro-vide important information about renal dysplasia,hydronephrosis, bladder wall thickening, andposterior urethral dilatation. Fluoroscopic VCUGis the gold standard for the diagnosis of posteriorurethral valves. Cystourethroscopy and isotope

CHAPTER 42 POSTERIOR URETHRAL VALVES 279

� TABLE 42-1 Syndromes Associated with Posterior Urethral Valves


Caudal regression Incomplete development of sacrum, Unknown, more commonsyndrome flattening of buttocks, disruption in infants of diabetic

of distal spinal cord, poor growth mothersand skeletal deformities of lowerextremities

Cloacal exstrophy Persistence of cloaca, omphalocele, Unknownsequence hydromyelia, cryptorchidism,

pelvic kidneys, multicystic kidneysKaufman-McKusick Postaxial polydactyly, cardiac Autosomal recessive

syndrome anomalies, hypospadias,hydrometrocolpos, vaginal septum

Limb-body wall Thoraco-and/or abdominoschisis, Unknowncomplex limb defects, encephalocele,

facial cleftsRussell-Silver IUGR, skeletal asymmetry, Unknown

syndrome small/triangular facies, micrognathia,café au lait spots, syndactyly,heart defects

Townes-Brocks Ear anomalies, thumb anomalies, Autosomal dominantsyndrome anal malformations, microcephaly,

cardiac defects, duodenal atresiasyndactyly

Urorectal septum Ambiguous genitalia, imperforate anus, Unknownmalformation sequence rectal fistulas, müllerian duct defects

VACTERL association Vertebral, anal, cardiac, tracheal, Unknown, more commonesophageal, renal, and limb anomalies, in infants of diabeticsingle umbilical artery, spinal dysraphia, mothersgenital abnormalities


renography can provide additional importantinformation. The workup of all infants diag-nosed to have posterior urethral valves shouldalso include a detailed family history and phys-ical examination to evaluate for the presence ofother associated anomalies. Further workupsuch as cardiac echo, chromosome analysisshould be performed in infants with other asso-ciated anomalies.


The role and benefit of various prenatal inter-ventions such as in utero vesicoamniotic shuntor primary fetal valve ablation either by opensurgery or percutaneous fetal cystoscopy re-main controversial.9,10 Although most of theseprocedures achieve the immediate goal of uri-nary diversion and decompression, they gener-ally fail to improve the long-term outcome oftreated infants and may not justify the additionalrisk of morbidity and mortality in the motherand fetus. It is believed that the associatedrenal dysplasia in these infants is either primaryor related to early intrarenal reflux which cannot be influenced by current prenatal urinarydiversion procedures.11 Ongoing studies willhelp in clarifying these issues and may identify anappropriate subgroup of patients and/or timingof prenatal intervention to achieve maximal ben-efits from these procedures.

After birth, the initial goals of management in-clude bladder decompression by placing a uri-nary catheter, correction of fluid and electrolyteabnormalities, initiation of appropriate antibiotics,and management of respiratory insufficiency,if any. After initial stabilization, the options forsurgical repair include: primary valve ablation andobservation, temporary vesicostomy and delayedvalve ablation, and primary valve ablation withupper tract reconstruction.1 Primary valve ablationby transurethral resection is the preferred ap-proach and can be performed in even small pre-mature infants. A temporary vesicostomy shouldbe reserved for very unstable and small infants.

Early diagnosis and improvements in neona-tal care have reduced mortality in these infantsfrom 50% to 1–3% over last several decades butthe progressive deterioration in renal functioncontinues to be a major concern because nearly30–40% of these patients develop chronic renalfailure.8,9,12,13 Prenatal ultrasound findings thatpredict poor postnatal outcome are: (1) early de-tection of upper-tract dilatation; (2) moderate tosevere upper-tract dilatation, defined as a renalpelvic anteroposterior diameter of 10 mm orgreater; (3) increased echogenicity of the renalparenchyma; and (4) cystic changes in the renalparenchyma.12 The antenatal detection of poste-rior urethral valves before 24 weeks gestation hasbeen reported to result in a poorer prognosis witha 50% chance of death or chronic renal failure by4 years of age.14 The degree of renal dysplasiaand bladder dysfunction are major determinantsof future outcome. The reported risk factors forlate development of renal failure in a child withposterior urethral valves are: (1) glomerular fil-tration rate (GFR) <80 mL/min/1.73 m2 at 1 yearof age; (2) a serum creatinine value of >8–10 mg/Lat 1 year of age; (3) poor corticomedullary differ-entiation on renal ultrasound; (4) appearance ofproteinuria during infancy; (5) bilateral vesi-coureteric reflux; and (6) diurnal incontinence atthe age of 5 years.12,13 Incidence of urinary incon-tinence ranges from 13% to 38%, which is relatedto decreased urine concentrating capacity,polyuria and bladder dysfunction.1,9,12 Renaltransplantation has proven successful in thesepatients with an overall 2 year graft survival rate(70–86%) comparable to the control group.9 Mostpatients with treated valves are fertile but may haveimpaired sexual and reproductive function sec-ondary to cryptorchidism, vasal reflux, retrogradeejaculation, and decreased sexual libido and func-tion due to renal failure.1


Although recurrence risks for nonsyndromic pos-terior urethral valves have not been well studied,


this appears to be a sporadic anomaly with noincreased risk of recurrence in most families.The presence of a positive family history in thepresence of parental consanguinity may suggestan autosomal recessive mode of transmissionand a corresponding increase in recurrence risk.The recurrence risk in an infant with an associ-ated syndrome or chromosomal abnormality willdepend on the underlying diagnosis. Level IIprenatal ultrasound should be offered for all sub-sequent pregnancies.

REFERENCES

1. Yohannes P, Hanna M. Current trends in the man-agement of posterior urethral valves in the pedi-atric population. Urology. Dec 2002;60(6):947–53.

2. Young HH, Frontz W.A., Baldwin J.C. Congenitalobstruction of the posterior urethra. Journal ofUrology. 1919;3:289–365.

3. Strand WR. Initial management of complex pedi-atric disorders: prunebelly syndrome, posteriorurethral valves. Urol Clin North Am. Aug 2004;31(3):399–415, vii.

4. Agarwal S. Urethral valves. BJU Int. Sep 1999;84(5):570–8.

5. Dewan PA, Zappala SM, Ransley PG, et al. Endo-scopic reappraisal of the morphology of congenital

obstruction of the posterior urethra. Br J Urol.Oct 1992;70(4):439–44.

6. Weber S, Mir S, Schlingmann KP, et al. Gene locusambiguity in posterior urethral valves/prune-bellysyndrome. Pediatr Nephrol. Aug 2005;20(8):1036–42.

7. Krishnan A, de Souza A, Konijeti R, et al. Theanatomy and embryology of posterior urethralvalves. J Urol. Apr 2006;175(4):1214–20.

8. Dinneen MD, Duffy PG. Posterior urethral valves.Br J Urol. Aug 1996;78(2):275–81.

9. Lopez Pereira P, Martinez Urrutia MJ, Jaureguizar E.Initial and long-term management of posterior ure-thral valves. World J Urol. Dec 2004;22(6):418–24.

10. Perks AE, MacNeily AE, Blair GK. Posterior urethralvalves. J Pediatr Surg. Jul 2002;37(7):1105–7.

11. Haecker FM, Wehrmann M, Hacker HW, et al. Renaldysplasia in children with posterior urethral valves: aprimary or secondary malformation? Pediatr Surg Int.Mar 2002;18(2-3):119–22.

12. Karmarkar SJ. Long-term results of surgery for pos-terior urethral valves: a review. Pediatr Surg Int.2001;17(1):8–10.

13. Lopez Pereira P, Espinosa L, Martinez Urrutina MJ,et al. Posterior urethral valves: prognostic factors.BJU Int. May 2003;91(7):687–90.

14. Becker A, Baum M. Obstructive uropathy.Early Hum Dev. Jan 2006;82(1):15–22.

CHAPTER 42 POSTERIOR URETHRAL VALVES 281


Part VIII

Skeletal Malformations



Chapter 43

PolydactylyPRAVEEN KUMAR

285

� INTRODUCTION

Polydactyly (in Greek “Poly” means many and“dactylos” means digit) is defined as having morethan the normal number of digits in the handsand/or feet, and is one of the most commoncongenital anomalies in a newborn. It can occuras an isolated malformation, in association withother malformations of the hands or feet, or aspart of a multiple congenital anomaly syndrome.A large majority of infants with polydactyly willhave six digits but others may have more.

� EPIDEMIOLOGY

Polydactyly is the one of the most common con-genital anomalies of hands and feet and has beenreported in all races. An overall prevalence of1–2 per 1000 live births has been reported inlarge population based studies but a much higherincidence has been reported in studies focusingon a predominantly black population.1,2 The in-cidence is nearly ten times higher in blacks thanin other ethnic groups. This difference in inci-dence is almost entirely due to a higher rate ofpostaxial polydactyly among blacks which isusually an isolated anomaly with no other asso-ciated congenital malformations. Table 43-1 pro-vides a summary of epidemiological features ofdifferent types of polydactylies. Most studies

have reported a male preponderance and the re-ported incidence in different ethnic populationshas been stable over the last several decades. Anassociation with twin pregnancy and low edu-cation level of mothers was reported from SouthAmerica and a slightly higher prevalence in urbanpopulations was recently reported from China.2,3

A recent large population based study reportedan increased risk of congenital digital anomaliesincluding polydactyly after maternal cigarettesmoking during pregnancy.4 Preaxial polydactylyof hands and feet was noted after thalidomideexposure during pregnancy and preaxial poly-dactyly of feet is reported to be associated withpoorly controlled insulin-dependent diabetesmellitus during pregnancy.5

� EMBRYOLOGY

Based on embryologic classification of congen-ital limb anomalies, polydactylies are a duplica-tion defect. The limb buds first appear duringthe fourth week of gestation and the develop-ment of lower limbs lags behind the upper limbdevelopment by a few days. The developmentof digits from hand and foot plate into well dif-ferentiated fingers and toes takes place between41 and 52 days of gestation in upper limbs and46–56 days of gestation in lower limbs. The numberof cell progenitors, the rate of proliferation and


the process of apoptosis influence the develop-ment of limb buds and an alteration in any ofthese steps can result in abnormal developmentand number of digits. Loss or modifications ofseveral ligands, receptors, and transcriptionfactors have been identified to cause differentlimb abnormalities.6,7


An extra digit in the hand or foot can range froma small nubbin to a complete duplication of oneor several digits. Based on the location of the ex-tra digit, polydactyly can be classified as postax-ial if the fifth digit is duplicated; preaxial if thethumb or big toe is duplicated; and mesoaxial orcentral polydactyly, if there is duplication of thesecond, third, or fourth digit. Polydactyly is con-sidered isolated if there are no other associatedcongenital malformations. Mixed polydactylyrefers to the condition in which both pre- andpostaxial polydactyly are present in the same in-dividual. The term crossed polydactyly is usedwhen postaxial polydactyly in one limb is com-bined with preaxial polydactyly in another.Preaxial polydactyly is usually type I in thesecases and is usually associated with other limb

anomalies such as, syndactyly. Crossed poly-dactyly is very rare and can also occur either asan isolated finding or as a part of syndrome. Theterm synpolydactyly or polysyndactyly is used todescribe the presence of both syndactyly andpolydactyly in the same patient.

Postaxial polydactyly indicates the presenceof an extra digit on the ulnar/fibular side of thelimb and is significantly more common thanpreaxial or mesoaxial polydactyly. In a reviewof nearly 7000 polydactyly cases, almost 75% ofthe cases had postaxial polydactyly.8 Postaxialpolydactyly is more common in hands (76% ofisolated postaxial polydactyly cases) followedby feet (16%) and is noted in both hands andfeet in about 8% of cases.8 It is frequently bilat-eral and affects the left side about twice as of-ten as the right side. Postaxial polydactyly maybe isolated or part of a syndrome. The incidenceof associated congenital defects is highest in in-fants with postaxial polydactyly of both upperand lower extremities and lowest in infants withisolated ulnar polydactyly. The high incidenceof isolated postaxial polydactyly in black infantsis primarily due to a higher incidence of ulnarpolydactyly which is often bilateral while the in-cidence of fibular polydactyly among blacks ap-pears to be comparable to other races.

286 PART VIII SKELETAL MALFORMATIONS

� TABLE 43-1 Epidemiology of Different Types of Polydactylies

Type Incidence Mode of Inheritance Comment

Postaxial 0.48–22.5/1000 Autosomal dominant 10 times moreworldwide with incomplete common in blacks

U.S. white 0.7–1.2/1000 penetrance M:F ratio 1.5:1U.S. black 7–13.5/1000

PreaxialType I 0.15–2.2/1000 Autosomal dominant No racial

predispositionM>F

Type II 1 in 25,000 Autosomal dominant Reported withSporadic prenatal hydantoin

exposureType III Extremely rare Autosomal dominantType IV 1 in 10,000 Autosomal dominant

Temtamy and McKusick defined two types ofpostaxial polydactyly; type A is a fully developedsixth digit which articulates with either the fifthor sixth metacarpal/metatarsal, and type B is apoorly developed, rudimentary, frequentlypedunculated digit with no bony connection tothe fifth metacarpal/metatarsal.9 Postaxial type Bpolydactyly is bilateral in most cases, has a strongfamily history and is rarely associated with othercongenital malformations.7,10,11 Infants born in afamily with history of type A postaxial polydactylycan present with either type A or type B poly-dactyly but infants born in families with historyof type B polydactyly only will not have type Apolydactyly.

Another classification of ulnar polydactylydescribes the following five types: type I cuta-neous nubbin; type II pedunculated digit; type IIIarticulating digit with fifth metacarpal; type IVfully developed digit with sixth metacarpal; andtype V polysyndactyly.7 Based on this classifi-cation, type II is the commonest and types I and IItogether account for nearly 80% of the cases andare more common among blacks. Type IV is theleast common and type III, IV, and V occurredmore frequently among Caucasians.

Preaxial polydactyly is characterized by du-plication of thumb or hallux. The overall inci-dence of preaxial polydactyly and isolatedpreaxial polydactyly were reported to be 0.24and 0.21 per 1000 births respectively in SouthAmerica.12 The thumb involvement is almostseven times more common compared to thehallux. The preaxial polydactyly of both hand andfeet is usually unilateral with a preponderanceof males and right sidedness.9,12 Temtamy andMcKusick subdivided preaxial polydactylies intothe following four types.9 Type I was defined aspartial or complete duplication of a biphalangealthumb; type II is defined as presence of a usu-ally opposable but triphalangeal thumb with orwithout additional duplication of thumb or hallux;type III, is characterized by duplication of theindex finger with or without an additional bipha-langeal or triphalangeal thumb which may or maynot be opposable; and type IV shows variably

mild degrees of thumb duplication and variablesyndactyly of fingers/toes. Type I has furtherbeen divided in six subtypes, depending on thelevel of a duplication considering bony anatomy.In a study of infants with preaxial polydactylyfrom South America, 15% were reported to befamilial.12 There were one or more affected rel-atives in 14% of thumb/hallux duplication cases(type I), in 33% of polysyndactyly (type IV)cases, in 60% of triphalangeal thumb case (type II),and in 100% of both thumb and hallux duplica-tion cases. The pedigrees in all subtypes werecompatible with autosomal dominant inheritancewith variable penetrance.

Mesoaxial or central polydactyly refers toduplication of the index, middle, and ring fin-gers. Often the extra digit is concealed in a webbetween adjoining normal digits.


In two large epidemiological analyses from SouthAmerica and China, polydactyly was reported tobe an isolated finding in 85% and 88% of the casesrespectively.2,13 The associated malformationswere noted in 55% of infants with rare polydactyly,which included all infants with polydactyly afterexcluding postaxial hexadactyly and preaxialtype I hexadactyly. The associated malforma-tions are least common in infants with postaxialpolydactyly (12%).13 The likelihood of an asso-ciated anomaly is higher in a Caucasian infantwith polydactyly and is lowest in a black infantwith type B postaxial polydactyly. An associatedlimb defect with no other organ involvementwas reported in 5% of the cases and syndactylyaccounted for nearly half of these associated limbanomalies. Nearly 10–15% of all infants with poly-dactyly have anomalies of other organ systemsand two-thirds of these are identified as part of anidentifiable syndrome with a recognized patho-genetic entity and the remaining infants had mul-tiple congenital anomalies without a recognizedcommon cause.13 Many different anomalies of all

CHAPTER 43 POLYDACTYLY 287

major organ systems have been reported in asso-ciation with polydactyly (Table 43-2). Based onan in-depth analysis of nearly 6000 cases of poly-dactyly, Castilla et al concluded that polydactyliesare rarely associated with other congenital anom-alies except in recognizable syndromes but theonly significant positive association was noted be-tween preaxial type I polydactyly and esophagealatresia.13

A total of 119 disorders (97 syndromic and22 nonsyndromic) are reported to have polydactyly

as a feature.14 Table 43-3 summarizes the commonsyndromes seen in association with pre- and postaxial polydactyly. Of 338 syndromic polydactylycases, 255 (75%) were part of the following threesyndromes: trisomy 13 (167 cases), Meckel-Grubersyndrome (57 cases), and Down syndrome (31cases).13 Triphalangeal thumbs are frequentlypart of Holt-Oram syndrome and Fanconi pan-cytopenia syndrome.

� EVALUATION

Detailed family history and physical examina-tion for other associated malformations shouldbe performed in all infants with polydactyly.Infants with type B postaxial polydactyly with apositive family history and/or black ethnicity,and no evidence of other anomalies on physi-cal examination do not require any further workup. An x-ray of hands/feet should be done in allother infants with polydactyly to accurately de-fine the malformation. The decision to performimaging studies of other organ systems and akaryotype should be based on the findings ofphysical examination and the type of poly-dactyly. Computed tomography (CT)/magneticresonance imaging (MRI), arteriography of theaffected hand/foot may be necessary in somecases prior to surgical repair. Complete bloodcounts and additional workup should be con-sidered for infants suspected to have Fanconipancytopenia syndrome, a complex recessivedisorder associated with bone marrow failure,and predisposition to malignancies in additionto diverse congenital anomalies. Since the earlydiagnosis of Fanconi pancytopenia syndrome isimportant for genetic counseling and early ther-apeutic interventions in affected families, it isproposed that chromosomal breakage studiesfor the diagnosis of Fanconi pancytopeniasyndrome should be performed in all patientssuspected or diagnosed as having this disorder.A genetic consult may be helpful in infants withassociated malformations and in infants withrare polydactylies.


� TABLE 43-2 Congenital MalformationsAssociated with Polydactyly

Associated Limb AnomaliesSyndactylyHypoplasia or aplasia of long bonesNail dystrophyAmelia

Central Nervous SystemHydrocephalusMicrocephalySpina bifida

Cardiovascular Ventricular septal defectAtrial septal defectConotruncal defects

Gastrointestinal Esophageal atresiaDuodenal atresiaMalrotation Imperforate anusAbdominal wall defects

Genitourinary Renal agenesisPolycystic kidneyHydronephrosis

Others Diaphragmatic herniaCleft lip and palateAnophthalmiaMicrotia


� TABLE 43-3 Syndromes Associated with Polydactylies


Bardet-Biedl syndrome Postaxial polydactyly, syndactyly, hypogonadism, Autosomalretinal dystrophy recessive

Carpenter syndrome Brachycephaly, hypoplastic maxilla/mandible, corneal Autosomalopacity, syndactyly, camptodactyly, cardiac defects, recessivecryptorchidism, postaxial polydactyly

Ellis-Van Creveld Short distal extremities, polydactyly, nail hypoplasia, Autosomalsyndrome neonatal teeth, atrial septal defect recessive(Chondroectodermaldysplasia)

Fanconi pancytopenia Short stature, microcephaly, eye anomalies, Autosomalsyndrome radial ray defects in upper limbs, recessive

pancytopenia, brownish pigmentation of skin,cardiac, GI and CNS anomalies

Greig cephalopolysyndactyly Pre and postaxial polydactyly, frontal bossing, Autosomalsyndrome broad thumb, mild ventriculomegaly, dominant

craniosynostosisHolt-Oram syndrome Thumb anomalies and other skeletal anomalies of Autosomal

(Cardiac-Limb syndrome) upper limbs, ostium secundum atrial septal defect dominantand other cardiac defects, narrow shoulders,hypertelorism, vertebral anomalies, absentpectoralis major

Meckel-Gruber syndrome Occipital encephalocele, polydactyly, cleft lip Autosomaland/or palate, microphthalmia, ambiguous genitalia, recessiveIUGR, microcephaly, cryptorchidism, cardiac defects

Oral-facial-digital syndrome, Lobulated tongue, oral frenulae and clefts, hypoplastic X-linkedtype I alae nasi, digital anomalies, agenesis of dominant

corpus callosumPallister-Hall syndrome IUGR, hypothalamic harmartoblastoma, Autosomal

ear anomalies, laryngeal cleft, lung agenesis, dominantsyndactyly, polydactyly, anal anomalies,heart defects

Short rib-polydactyly Phocomelia, metaphyseal dysplasia, postaxial Autosomalsyndrome, type I polydactyly, syndactyly, cardiac defects, recessive(Saldino-Noonan type) imperforate anus

Short rib-polydactyly Short ribs and limbs, cleft lip and palate, pulmonary AutosomalSyndrome, type II hypoplasia, hypoplasia of epiglottis and larynx, recessive(Majewski type) pre-/postaxial polydactyly

Smith-Lemli-Opitz Growth retardation, mental deficiency, microcephaly, Autosomalsyndrome syndactyly, genital abnormalities, anteverted nostrils recessive

Trisomy 13 Holoprosencephaly, microphthalmia, cyclopia, Trisomymicrocephaly, cleft lip and palate, heart defects,IUGR, genital abnormalities


(Continued)


The goals of treatment are improved function,appearance, and social acceptance. All preaxial,mesoaxial, and type A postaxial polydactyly re-quire surgical correction and should be referredto a surgeon with experience in hand recon-struction surgery. The treatment of type B postaxialpolydactyly is relatively simple but less well-defined. Ligation of these digits in the nurseryhas been a frequently used treatment and wasreported to be simple, safe, and effective byWatson et al.10 However, nearly 40% of theirpatients had a residual bump but all parentswere satisfied with the cosmetic result.10 Inanother series, Rayan and Frey reported a 23.5%complication rate after ligation of ulnar poly-dactyly and the two main complications weretender or unacceptable nubbins and infections.11

A survey of pediatricians and hand surgeonsfrom United Kingdom reported that 79% of pe-diatricians and 67% of hand surgeons would rec-ommend referral of cases with postaxial type Bpolydactyly for specialist assessment and the re-mainder advocated ligation by the pediatricianin the nursery.15 Based on current evidence, lig-ation in nursery before discharge is reasonableonly in infants with a very narrow pedunculatedtype B postaxial polydactyly. The ligation shouldbe applied close to the normal skin and thefamily should be alerted for the possibility ofcomplications such as infection, bleeding, andresidual nubbins requiring subsequent surgical

intervention. All other infants should be referredto a hand surgeon.


The recurrence risk in siblings of an infant withisolated polydactyly with no family history islikely to be very low (<1%) but would rangefrom 10% to 50% in the presence of a positivefamily history. This variability in recurrence riskis related to variable penetrance and expressionin different family members. The recurrence riskin infants with an associated syndrome woulddepend on the mode of inheritance of thatsyndrome.

REFERENCES

1. Boeing M, Paiva Lde C, Garcias Gde L, et al. Epi-demiology of polydactylies: a case-control study inthe population of Pelotas-RS. J Pediatr (Rio J).Mar-Apr 2001;77(2):148–52.

2. Zhou GX, Dai L, Zhu J, et al. Epidemiologicalanalysis of polydactylies in Chinese perinatals.Sichuan Da Xue Xue Bao Yi Xue Ban. Sep 2004;35(5):708–10.

3. Castilla EE, da Graca Dutra M, Lugarinho da Fon-seca R, et al. Hand and foot postaxial polydactyly:two different traits. Am J Med Genet. Nov1997;73(1):48–54.

4. Man LX, Chang B. Maternal cigarette smokingduring pregnancy increases the risk of having a childwith a congenital digital anomaly. Plast ReconstrSurg. Jan 2006;117(1):301–8.


� TABLE 43-3 Syndromes Associated with Polydactylies (Continued)


Trisomy 21 Hypotonia, brachycephaly, brushfield spots in iris, Trisomyshort metacarpal and phalanges, simian creases,cardiac defects, loose skin folds, hyperlaxity of joints,flat facial profile with upslanting palpebral fissuresand inner epicanthal folds

Townes-Brocks syndrome Ear anomalies, thumb anomalies, anal malformations, Autosomalmicrocephaly, cardiac defects, duodenal atresia, dominantsyndactyly

GI, gastrointestinal; CNS, central nervous system; IUGR, intrauterine growth retardation.

5. Holmes LB. Teratogen-induced limb defects.Am J Med Genet. Oct 2002;112(3):297–303.

6. Daluiski A, Yi SE, Lyons KM. The molecular con-trol of upper extremity development: implicationsfor congenital hand anomalies. J Hand Surg [Am].Jan 2001;26(1):8–22.

7. Rayan GM, Haaksma CJ, Tomasek JJ, et al. Base-ment membrane chondroitin sulfate proteo-glycan and vascularization of the developingmammalian limb bud. J Hand Surg [Am]. Jan2000; 25(1):150–8.

8. Castilla EE, Lugarinho da Fonseca R, da GracaDutra M, et al. Epidemiological analysis of rarepolydactylies. Am J Med Genet. Nov 1996;65(4):295–303.

9. Temtamy SA, McKusick VA, Bergsma D, et al. TheGenetics of Hand Malformations. New York: Alan R.Liss Inc. 1978.

10. Watson BT, Hennrikus WL. Postaxial type-B poly-dactyly. Prevalence and treatment. J Bone JointSurg Am. Jan 1997;79(1):65–8.

11. Rayan GM, Frey B. Ulnar polydactyly. PlastReconstr Surg. May 2001;107(6):1449–54.

12. Orioli IM, Castilla EE. Thumb/hallux duplicationand preaxial polydactyly type I. Am J Med Genet.Jan 1999;82(3):219–24.

13. Castilla EE, Lugarinho R, da Graca Dutra M, et al. As-sociated anomalies in individuals with polydactyly.Am J Med Genet. Dec 1998;80(5):459–65.

14. Biesecker LG. Polydactyly: how many disordersand how many genes? Am J Med Genet. Oct2002;112(3):279–83.

15. Dodd JK, Jones PM, Chinn DJ, et al. Neonatal ac-cessory digits: a survey of practice amongst paedia-tricians and hand surgeons in the United Kingdom.Acta Paediatr. Feb 2004;93(2):200–4.



Chapter 44

SyndactylyPRAVEEN KUMAR

293

� INTRODUCTION

Syndactyly (in Greek “Syn” means together, and“dactylos” means digit) is characterized by two ormore fused fingers and toes. It is one of the mostcommon congenital anomalies of hands and feetand can occur as an isolated malformation, in as-sociation with other malformations of the handsor feet, or as part of a multiple congenital anom-aly syndrome.

� EPIDEMIOLOGY

The overall prevalence of syndactyly is reportedto be 3–5 per 10,000 births and the rate of iso-lated syndactyly is 1.3–2.2 per 10,000 births.1-3

Familial syndactyly is reported to constitute about10–40% of the total number of syndactyly cases.4

Unlike polydactyly, the incidence of syndactylyis not higher among blacks but a slightly in-creased prevalence among non-Hispanic whiteshas been reported.2 The male preponderanceand higher prevalence rates in urban areas aresimilar to those reported with polydactyly.2,3

Right and left sides as well as both upper andlower limbs are affected equally. Syndactyly isfrequently bilateral, but involvement of bothupper and lower limbs in the same patient is lesscommon. A recent large population-based studyreported an increased risk of congenital digital

anomalies, including syndactyly after maternalcigarette smoking during pregnancy.5

� EMBRYOLOGY

In contrast to polydactyly, which is a duplicationdefect, syndactyly is a fusion of adjacent digitsdue to an intrauterine failure to separate. The de-velopment of an early limb bud into a complete,well-differentiated limb is under the control ofthree signaling centers: the apical ectodermalridge, the zone of polarizing activity, and theWingless-type (Wnt) signaling center.6 These sig-naling centers function in a coordinated effort toensure normal limb development. Failure of theapical ectodermal ridge has been shown to pro-hibit longitudinal interdigital necrosis betweenthe digits which can result in syndactyly.6 Muta-tions of fibroblast growth factor (FGF) receptorsand alterations of transcription factor Msx-2 havealso been implicated.7


Syndactyly of hands and feet can range from asmall web between two digits to complete fu-sion of the bones and nails of all digits inhands/feet. Syndactyly is frequently bilateral.The most common site in the foot is between


the second and third toes, and the most com-mon site in the hand is between the middle andring fingers. Syndactyly is considered “incom-plete or partial,” if fusion of the two or moredigits involves only partial length of the fuseddigits and is considered “complete” if digits areunited as far as the tip of the distal phalanx.“Simple” syndactyly involves only skin and softtissue while syndactyly is considered “complex”if there is bony union of the involved digits. Thedistinction between simple and complex syn-dactyly can sometimes be made only on radi-ographs. Like polydactyly, syndactyly may bean isolated finding, or a component of a morecomplex congenital hand malformation or canbe part of a generalized syndrome. The term“complicated syndactyly” has been used to de-fine complex cases that involve a mixture orcollection of synostoses. The skin and subcuta-neous tissues are usually normal but an affectedjoint’s mobility may be reduced. Ligaments, ten-dons, nerves, and vessels are usually normal incases with simple syndactyly but may be grosslyabnormal in more complex cases. Temtamy andMcKusick’s classification of syndactyly was ex-panded by Goldstein et al in 1994.8 They pro-posed the following eight types of syndactylies.

1. Syndactyly type I. This is also called Zy-godactyly and is characterized by cutaneoussyndactyly of third and fourth fingers in thehand or second and third toe in the foot. Itis frequently bilateral and could be eithercomplete or partial. It is the most frequenttype of isolated syndactyly.

2. Syndactyly type II. This is also called syn-polydactyly or polysyndactyly. It is character-ized by syndactyly of third and fourth fingerwith partial or complete duplication of third,fourth, or fifth finger in hand; and fusion offourth and fifth toe with partial or completeduplication of fifth toe in the foot. Other sig-nificant hand anomalies can also be associated.

3. Syndactyly type III. This is rare and is char-acterized by bilateral or unilateral, variablecutaneous or osseous fusion of fingers 3–5.

The middle phalanx of the fifth digit is fre-quently hypoplastic or absent. No abnor-malities of the feet are reported. Similar handabnormalities have been described in pa-tients with the Oculo-dento-digital (ODD)syndrome.

4. Syndactyly type IV. This is characterizedby complete complex fusion of all digits. • IVa (Haas type). This includes patients

with complete syndactyly of all digits ofhands, including the thumb of one orboth hands with or without associatedpolydactyly. Feet are not involved.

• IVb. Patients are similar to IVa but alsohave complete fusion of all digits of oneor both feet with or without associatedpolydactyly.

Infants with Apert syndrome have type IV syn-dactyly in association with craniosynostosis.

5. Syndactyly type V. This is characterizedby fusion of fourth and fifth metacarpal ormetatarsal on one or both sides with a vari-able degree of syndactyly of fingers or toes.Associated polydactyly may or may not bepresent. Urogenital abnormalities have beenreported in affected infants.

6. Syndactyly type VI. Syndactyly type VI orcomplete syndactyly or mitten syndactyly isdescribed as unilateral syndactyly of digits 2–5which could be mistaken for congenital ringconstrictions.

7. Syndactyly type VII. (Cenani-Lenz syn-drome). This is characterized by irregularsynostosis of all bones of hands and feet withor without fusion of radius-ulna and tibia-fibula.

8. Syndactyly type VIII. This is characterizedby fusion of fourth and fifth metacarpal withno other abnormalities.

The mode of inheritance for all types of iso-lated syndactylies is likely to be autosomal dom-inant with incomplete penetrance and variableexpression with the exception of type VIII inwhich autosomal recessive transmission withvariable expression is suggested.



Associated anomalies are reported in nearly halfof all cases with syndactyly.3 A significant pro-portion of these associated anomalies are othermalformations of hands, feet, and limbs and themajority of cases with other organ involvementare part of a syndrome. Musculoskeletal andcraniofacial anomalies are most common fol-lowed by genitourinary anomalies. Recently, theassociation of syndactyly with long QT syndromehas been reported in both boys and girls. None ofthese cases had a positive family history of syn-dactyly and four of five cases in one report diedsuddenly at an early age which prompted theauthors to recommend that all infants with syn-dactyly have a screening electrocardiogram(ECG) to rule out long QT syndrome.4,9,10

Syndactyly has been described as part ofover 60 syndromes. A brief list of common syn-dromes frequently associated with syndactyly isprovided in Table 44-1.

� EVALUATION

As in infants with polydactyly, a detailed familyhistory and physical examination for other asso-ciated malformations should be performed in allinfants with syndactyly. An x-ray of hands/feetshould also be obtained in all infants to accu-rately define the extent and type of malformation.The decision to perform imaging studies of otherorgan systems and a karyotype should be basedon the findings on physical examination and thetype of syndactyly. No further workup may benecessary in infants with simple, isolated syn-dactyly. A genetic consult may be helpful in in-fants with associated malformations and sus-pected syndromic syndactyly. Only a handful ofcases of syndactyly associated with long QT syn-drome have been reported and there are no cur-rent guidelines indicating whether an ECG shouldbe done in all infants with syndactyly. However,it is important to be aware of this association and

to have a low threshold for obtaining an ECGwith or without cardiac echo in these infants.4,9,10

Computed tomography (CT)/magnetic resonanceimagimg (MRI), and arteriography of the affectedhand/foot may be necessary prior to surgicalrepair.

� MANAGEMENT

The goals of management are improved func-tion, appearance, and social acceptance. Iso-lated simple syndactyly of feet does not causeany functional problems and usually does notrequire repair. Timing for surgical interventionin infants with syndactyly of the hands is gener-ally between 6 and 18 months of age and shouldbe performed by a surgeon with experience inhand reconstruction surgery for optimal results.The prognosis is poorer when surgery is delayedbeyond age 2 years because the cerebral cortexpatterns of hand use will need to be retrained.11

Complexity of the syndactyly and the presenceof other congenital abnormalities of the handalso predict poorer outcomes.11 Many patientswith complex and complicated syndactyly willrequire several procedures to achieve a func-tional hand. The most common complicationsare scar formation and web creep and the mostserious complication is necrosis of the digit sec-ondary to vascular compromise. Appropriatemanagement of associated anomalies in caseswith syndromic syndactyly is equally important.


The recurrence risk in siblings of an infant withisolated syndactyly with no family history is likelyto be very low (<1%) but would range from 10%to 50% in the presence of a positive family his-tory. This variability in recurrence risk is related tovariable penetrance and expressivity in differentfamily members. The recurrence risk in infantswith an associated syndrome would depend onthe mode of inheritance of that syndrome.

CHAPTER 44 SYNDACTYLY 295

� TABLE 44-1 Syndromes Associated with Syndactyly


Apert syndrome Craniosynostosis, agenesis of corpus callosum, Autosomal dominantmidfacial hypoplasia, pulmonary agenesis,cardiac defects, genitourinary anomalies,esophageal atresia, and tracheoesophagealfistula

Carpenter syndrome Brachycephaly, hypoplastic maxilla/mandible, Autosomal recessivecorneal opacity, syndactyly, camptodactyly,cardiac defects, cryptorchidism, postaxialpolydactyly

Ectrodactyly-ectodermal Fair and thin skin, light colored sparse hair, Autosomal dominantdysplasia-clefting hypoplastic nipples, teeth anomalies, cleft lipsyndrome with or without cleft palate, limb anomalies,(EEC syndrome) cryptorchidism, holoprosencephaly

Fraser syndrome Cryptopthalmos, hypoplastic notched nares, Autosomal recessivegenital anomalies, laryngeal stenosisor atresia, renal hypoplasia or agenesis,microcephaly, cleft lip

Goltz syndrome Poikiloderma with focal dermal hypoplasia, X-linked dominantsparse and brittle hair, dystrophic nails, or sporadicsyndactyly and other anomalies ofhand/feet, eye colobomas, heart defects,horseshoe kidney

Greig Pre- and postaxial polydactyly, frontal Autosomal dominantCephalopolysyndactyly bossing, broad thumb, mild ventriculomegaly,syndrome craniosynostosis

Holt-Oram syndrome Thumb anomalies and other skeletal anomalies Autosomal dominant(Cardiac-Limb of upper limbs, ostium secundum atrial septalsyndrome) defect and other cardiac defects, narrow

shoulders, hypertelorism, vertebral anomalies,absent pectoralis major

Oculodentodigital Micropthalmos, hypoplastic nares, camptodactyly Autosomal dominantsyndrome of fifth fingers, microcephaly, cataract,

glaucoma, cleft lip and palateOral-facial-digital Multiple frenuli, median cleft lip, cleft palate, X-linked dominant

syndrome asymmetric shortening of digits, agenesisof corpus callosum, heterotopia of gray matter

Pfeiffer syndrome Craniosynostosis, brachycephaly, hypertelorism, Autosomal dominantbroad thumb and toes, choanal atresia,hydrocephalus

Poland sequence Hypoplasia of pectoralis major muscle, nipple Unknownand areola, hemivertebrae, renal anomalies,dextrocardia, limb reduction defects ofupper limb

Smith-lemli-opitz Growth retardation, mental deficiency, Autosomal recessivesyndrome microcephaly, genital abnormalities,

anteverted nostrils, renal agenesisTriploidy syndrome Large placenta with hydatidiform changes, Chromosomal

intrauterine growth retardation, omphalocele, anomalyclub feet, cardiac defects, hydrocephalus, (69XXY orholoprosencephaly, genitourinary anomalies 46XX/69XXY)

296

REFERENCES

1. Temtamy SA, McKusick VA, Bergsma D, et al. TheGenetics of Hand Malformations. New York: AlanR. Liss Inc; 1978.

2. Castilla EE, Paz JE, Orioli-Parreiras IM. Syndactyly:frequency of specific types. Am J Med Genet.1980;5(4):357–64.

3. Dai L, Zhou GX, Zhu J, Mao M, et al. Epidemio-logical analysis of syndactyly in Chinese perina-tals. Zhonghua Fu Chan Ke Za Zhi. Jul 2004;39(7):436–8.

4. Marks ML, Whisler SL, Clericuzio C, et al. A newform of long QT syndrome associated with syn-dactyly. J Am Coll Cardiol. Jan 1995;25(1):59–64.

5. Man LX, Chang B. Maternal cigarette smokingduring pregnancy increases the risk of having achild with a congenital digital anomaly. Plast Re-constr Surg. Jan 2006;117(1):301–8.

6. Kozin SH. Upper-extremity congenital anomalies.J Bone Joint Surg Am. Aug 2003;85-A(8):1564–76.

7. Daluiski A, Yi SE, Lyons KM. The molecular con-trol of upper extremity development: implicationsfor congenital hand anomalies. J Hand Surg [Am].Jan 2001;26(1):8–22.

8. Goldstein DJ, Kambouris M, Ward RE. Familialcrossed polysyndactyly. Am J Med Genet. Apr1994;50(3):215–23.

9. Marks ML, Trippel DL, Keating MT. Long QT syn-drome associated with syndactyly identified in fe-males. Am J Cardiol. Oct 1995;76(10):744–5.

10. Gasparini M, Lunati M, Galimberti P, et al. Imagesin cardiovascular medicine. Endocardial implanta-tion of a cardioverter-defibrillator in a 13-month-oldchild affected by long-QT syndrome and syndactyly.Circulation. Dec 2004;110(23):e525–527.

11. Dao KD, Shin AY, Billings A, et al. Surgical treatmentof congenital syndactyly of the hand. J Am AcadOrthop Surg. Jan–Feb 2004;12(1):39–48.

CHAPTER 44 SYNDACTYLY 297


Chapter 45

Limb Reduction DefectsPRAVEEN KUMAR

299

� INTRODUCTION

Limb reduction defects (LRD), also known ascongenital limb deficiency (CLD), are a diversegroup of birth defects which are characterizedby congenital absence of either part or all of oneor more limbs. These rare but very visible con-genital malformations are potentially devastatingfor both patients and parents since they can havesignificant adverse impact on everyday functionand quality of life. These defects can present aseither isolated malformations or as part of a com-plex of multiple congenital anomalies due tosyndromes, sequences, and associations.

Many different classification systems havebeen proposed to describe limb reduction de-fects which pose considerable difficulty in com-paring data from different studies. Frantz andO’Rahilly proposed a classification system in1961 which is still widely used and is particularlyhelpful in describing longitudinal deficiencies.1

They first divided all limb deficiencies into eitherterminal or intercalary deficiencies. Terminal de-ficiencies are those in which all skeletal elementsare absent beyond a given point; intercalary de-ficiencies are characterized by absence of theproximal or middle segment of a limb with all orpart of the distal segment being present. Bothterminal and intercalary deficiencies can be fur-ther subdivided into either transverse or paraxialdefects. In a transverse defect, the entire width

of a limb is affected while in a paraxial defect ei-ther the preaxial or postaxial part of the limb isinvolved. In 1991, the International StandardsOrganization (ISO) and the International Societyfor Prosthetics and Orthotics (ISPO) proposed anew classification to improve consistency. In thisclassification, all limb deficiencies were dividedinto either transverse or longitudinal and missingbones were described as either complete or par-tial. Many studies have used the following EU-ROCAT (a European network of population-basedregistries for the epidemiologic surveillance ofcongenital anomalies) classification which assignseach limb reduction defect to one of the follow-ing six categories:2

1. Terminal transverse: absence of all distalstructures of the affected limb; the proximalstructures can be normal or deficient. Thefollowing types are included:a. Ectrodactyly: total or partial absence of

all phalanges, metacarpals/metatarsals,or full hands/feet.

b. Amelia: total absence of entire extremity.c. Hemimelia: total absence of entire fore-

arm/foreleg and hand or foot irrespectiveof the presence of digit-like structures atthe end of the limb.

2. Intercalary: absence or severe hypoplasiaof the proximal part of the limb with handor foot normal or near normal.


3. Preaxial longitudinal: absence or hy-poplasia of preaxial (radial/tibial) part ofthe limb.

4. Postaxial longitudinal: absence or hy-poplasia of postaxial (ulnar/fibular) part ofthe limb.

5. Split hand/foot: longitudinal terminal defi-ciency of rays, often associated with syndactyly.a. Typical split hand/foot: a cone-shaped

cleft tapering and dividing the hand/footinto two parts; absence or hypoplasia ofcentral ray (second, third, and fourthfingers/toes); the phalanges or metacarpal/metatarsal of the central rays may bemissing or reduced.

b. Monodactyly: merely one finger (defi-ciency of four fingers) in either hand orfoot.

6. Multiple type of reduction defects: in-clude infants with different types of limb re-duction defects in one limb or different limbs.


The overall prevalence of limb reduction de-fects is reported to vary from 2.5 to 7.06 per10,000 births in several population-based reg-istries.2–7 These variations in the reportedprevalence are probably related to differencesin definitions, case ascertainment, inclusion ofstillbirths and pregnancy termination in somestudies; and effect of environmental/genetic fac-tors. In a study of nearly three million newborninfants from South America, Castilla et al re-ported the overall prevalence rate of limb re-duction defects as 4.91 per 10,000 live birthsand 26.73 per 10,000 for stillbirths.8 Nearly 40%of live births and 80% of stillbirths with limb re-duction defects had associated congenital mal-formations.8 Since the thalidomide tragedy inthe early 1960s, no significant changes in theprevalence over time have been reported inmost studies.3,4 Infants with limb reduction de-fects are likely to have lower birth weight,lower gestational age, and intrauterine growth

restriction (IUGR). These differences are moreprominent in infants with limb reduction defectsand other associated malformations.4,6,7 No sexdifferences were reported in most studies but aslight male preponderance has been reportedby others. In a report from China, the preva-lence of limb reduction defects in rural areaswas reported to be significantly higher than inurban areas.7 Other reported risk factors arevaginal bleeding and threatened abortion in theindex pregnancy.9,10 A history of skeletal anom-alies among first degree relatives is reported in6.5–7.2% of all patients with limb reduction de-fects.7,9,11 The relationships between maternalage, ethnicity, and risk of limb reduction defectshave not been consistent.

Limb reduction defects are a diverse groupof birth defects which could be a result of errorsin the genetic control of limb development, dis-ruption of normal development by a teratogen,or intrauterine amputation of a normally devel-oping limb.5 McGuirk et al reported that the ap-parent causes of limb reduction defects in theirpopulation were genetic or teratogenic in 34%,vascular disruption in 35%, and unknown in theremaining 32% of the cases.5 Chromosomal ab-normalities have been reported in 6–13% of casesand single gene disorders have been identifiedin 15–43% of cases in other studies.5,6,11,12 Am-niotic disruption sequence was reported as sin-gle most common cause of limb reductiondefects by Evans et al.4 A significant proportionof all limb reduction defects occur sporadicallyand no specific cause can be ascertained in manyof these cases.

An increased incidence of limb reductiondefects has been reported among infants of dia-betic mothers, and after intrauterine exposure toalcohol, misoprostol, warfarin, phenytoin, val-proic acid, and retinoic acid, but none of theseassociations have been proven conclusively.13,14

A higher incidence of limb reduction defects isobserved in infants born to mothers who haveundergone chorionic villous sampling in earlypregnancy with the highest risk observed whenprocedures were performed prior to nineth


completed week of gestation.15,16 Periconcep-tional multivitamin use has been reported toreduce the risk for limb deficiency and this pro-tective effect was mainly for transverse limbdeficiency.17

� EMBRYOLOGY

The limbs begin to appear toward the end of thefourth week as small elevations of the ventrolat-eral body wall. The upper limb bud developsabout 2 days before the lower limb buds. The tis-sues of the limb buds are derived from two mainsources: somatic mesoderm and ectoderm. Theinteraction of apical epidermal ridge (AER) withthe underlying undifferentiated mesoderm is re-sponsible for limb development in a proximal todistal direction. Suppression of limb develop-ment during the fourth week results in completeabsence of a limb/limbs and results in amelia. Ar-rest or disturbance of differentiation or growth ofthe limbs over next 2 weeks can result in otherlimb reduction defects. All parts of the upper andlower limbs are essentially completely formed byeighth week of gestation. However, it is impor-tant to remember that certain limb reductiondefects such as amniotic band disruption se-quence can occur after normal limb development.


Most large studies of limb reduction defectshave shown that upper limb defects are morecommon than lower limb defects (60–80% versus25–40%).2,4,5,11 This preponderance of upperlimb involvement is more striking in isolatedcases and the frequency of lower limb involve-ment increases in infants with other non-limbcongenital malformations. 18 About 15–20% ofcases have both upper and lower limbs in-volvement.2,9,10 Overall unilateral involvementis more common but bilateral involvement ismore common in infants with other organ anom-alies.2,4 An increased incidence of right sideddefects has been reported in some studies and

this difference is particularly significant in caseswith longitudinal preaxial defects.

Lin et al in 1993 reported that terminal trans-verse defect was the most frequent type of limbreduction defect (35.1%), followed by split limbs(26.2%), longitudinal (25.1%), intercalary (9.6%),and multiple types (4.1%).2 However, more re-cent data indicate that longitudinal defects aremore common.3,5,19 In >9000 infants with limbreduction defects, longitudinal hand reductionswere most frequent, accounting for 46.4% ofupper limb defects and 27.2% of all limb de-fects.3 Longitudinal toe reductions were the mostcommon finding among newborns with lower-limb deficiencies.


Additional congenital malformations of otherorgans are reported in 30–50% of all infants withlimb reduction defects.4,6,11,18–20 However, ahigher incidence of nearly 80% has been re-ported among stillbirths with limb reductiondefects.8,21 Longitudinal preaxial limb defectsare the most common limb reduction defects ininfants with associated anomalies.4,22

Additional malformations are commonlyseen in infants with proximal terminal trans-verse defects (amelia, rudimentary limb), longi-tudinal preaxial defects (radial/tibial defects)followed by intercalary and split hand-foot de-fects. Additional malformations are rarely seenin infants with distal terminal transverse defectsand longitudinal postaxial or ulnar-fibulardefects.4 Major anomalies in three or more sys-tems are more common in cases of rudimentarylimb and radial/tibial defects.4 Additional mal-formations of cardiovascular, craniofacial, geni-tourinary, central nervous system (CNS), andgastrointestinal (GI) tract have been reported.Table 45-1 summarizes the various malforma-tions frequently seen in association with differ-ent types of limb reduction defects. The mostcommon anomalies seen in infants with limb

CHAPTER 45 LIMB REDUCTION DEFECTS 301

reduction defects are cryptorchidism, ventricu-lar septal defect, cleft lip with or without cleftpalate, club feet, syndactyly, renal agenesis, im-perforate anus, and hydrocephalus.4 A renalanomaly is reported to be present in about 8%of all cases of limb reduction defects and in 25%of infants with limb reduction defects and one ormore congenital anomaly of other organs.23

Twenty-five percent of these cases have VAC-TERL (vertebral, anal, cardiac, tracheal,esophageal, renal, and limb) association and theetiological diagnosis remain unknown in 50%. In-fants with limb reduction defects and other asso-ciated congenital anomalies have a significantlyhigher perinatal mortality rate and the risk of deathis reported to be highest among infants with preax-ial radial defects and humerus defects.4,11

About 15–30% of all cases with limb reductiondefects and 35–50% of all cases with limb reduc-tion defects with congenital anomalies of otherorgans have a recognizable syndrome. Trisomy18 followed by Trisomy 13 and 21 are the most

common chromosomal abnormalities reportedin infants with limb reduction defects. The mostcommonly encountered syndromes and associa-tions seen in these infants are Holt-Oram,Ectrodactyly-ectodermal dysplasia-clefting (EEC),Thrombocytopenia-absent-radius (TAR) syn-drome, and VACTERL association. Table 45-2summarizes other commonly associated syn-dromes seen in infants with limb reduction de-fects. The presence of congenital malformationsof other organs, preaxial defects of upper limb,bilateral limb involvement, and male gender arefactors that predict a high likelihood of an asso-ciated syndrome in these infants.24–27

� EVALUATION

A detailed family history, pregnancy history,and complete physical examination for accurateevaluation of the limb defects and other associ-ated malformations are important first steps in


� TABLE 45-1 Congenital Malformations in Associations with Different Limb Reduction Defects

Limb Defect Associated Congenital Malformations

Transverse• Amelia & rudimentary limb Gastroschisis, anorectal atresia, omphalocele unilateral renal

agenesis, anencephaly/encephalocele cleft lip, diaphragmatichernia, craniofacial defects

• Others Micrognathia and other craniofacial defects

Longitudinal• Preaxial

• Unilateral VACTERL association anomalies, facial, auricular, vertebralanomalies

• Bilateral VACTERL association anomaliesHydrocephalusCleft lip

• Postaxial Hypospadias• Central Axis EEC Syndrome anomalies,

Oro-mandibular and limb anomaly,HydronephrosisEncephalocele

Intercalary Omphalocele

Multiple Craniofacial defectsAxial skeleton defects

� TABLE 45-2 Syndromes Associated with Limb Reduction Defects


Adams-Oliver syndrome Mild IUGR, aplasia cutis congenita, encephalocele, Autosomalmicrocephaly, variable degree of terminal transverse dominantdefects of limbs, cleft lip and palate, cardiac defects

CHILD syndrome Congenital hemidysplasia, icthysiform erythroderma, X-linkedlimb defects, mild IUGR, cardiac defects, renal dominantagenesis, cleft lip

Cornelia de Lange IUGR, weak growling cry, synophrys, Autosomalsyndrome microbrachycephaly, long philtrum, thin upper lip, dominant

micrognathia, micromelia, phocomelia, cryptorchidismEctrodactyly-ectodermal Fair and thin skin, light colored sparse hair, hypoplastic Autosomal

dysplasia-clefting nipples, teeth anomalies, cleft lip with or without dominantsyndrome cleft palate limb anomalies, cryptorchidism,(EEC syndrome) holoprosencephaly, renal agenesis

Fanconi pancytopenia Short stature, microcephaly, eye anomalies, radial ray Autosomalsyndrome defects in upper limbs, pancytopenia, brownish recessive

pigmentation of skin cardiac, GI and CNS anomaliesGoltz syndrome Poikiloderma with focal dermal hypoplasia, sparse and X-linked

brittle hair, dystrophic nails, syndactyly and other dominantanomalies of hand/feet, eye colobomas, heart defects and

sporadicGerbe syndrome Marked distal limb reduction, short stature Autosomal

recessiveHolt-Oram syndrome Thumb anomalies and other skeletal anomalies of upper Autosomal

(Cardiac-Limb limbs, ostium secundum atrial septal defect and other dominantsyndrome) cardiac defects, narrow shoulders, hypertelorism,

vertebral anomalies, absent pectoralis majorMURCS association Müllerian duct aplasia, renal aplasia, cervicothoracic Unknown

somite dysplasia, upper limb defects, deafness,craniofacial anomalies

Nager syndrome Malar hypoplasia, radial limb anomalies, micrognathia, Autosomalear anomalies, cleft lip, hypoplasia of larynx or dominant,epiglottis Autosomal

recessivein somefamilies

Poland sequence Hypoplasia of pectoralis major muscle, nipple and Unknownareola, hemivertebrae, renal anomalies, dextrocardia,limb reduction defects of upper limb

Roberts-SC phocomelia Hypomelia limb reduction defects of both upper and Autosomallower limbs midfacial defects such as cleft lip and recessivepalate, microcephaly, severe IUGR, cryptorchidism,eye anomalies

Thrombocytopenia— Bilateral absence of radius, variable abnormalities of Autosomalabsent radii syndrome ulna and lower limbs, thrombocytopenia, anemia, recessive(TAR syndrome) cardiac defects

VACTERL association Vertebral, anal, cardiac, tracheal, esophageal, renal, and Unknownlimb anomalies, single umbilical artery, spinaldysraphia, genital abnormalities

IUGR, intrauterine growth retardation; GI, gastrointestinal; CNS, central nervous system.

303

all infants with limb reduction defects. A familyhistory of limb defects as well as history of anyother congenital malformations is important be-cause of the possibility of variability in pheno-typic expression in cases affected by the samesyndromes. A maternal history of threatenedabortion, vaginal bleeding, physical trauma, ex-posure to a teratogen, and chorionic villoussampling in the index pregnancy is particularlyimportant in these cases. A complete physicalexamination may also provide clues to the di-agnosis of amniotic band sequence. Radiographof the affected limbs as well as apparently nor-mal limbs may help in accurately defining theextent and type of defect. No further workupmay be necessary in an infant with a unilateral,isolated postaxial longitudinal, or distal trans-verse defect with a negative family history andotherwise normal physical examination. Simi-larly, an extensive work-up may not be indi-cated in infants suspected to have amniotic dis-ruption sequence.24,27 In contrast, imaging studiesof other organ systems such as renal/cranial ultra-sound, echocardiogram, and karyotype should bestrongly considered in all infants with bilaterallimb involvement, preaxial defects, and in pres-ence of congenital anomalies of other organsystems. A complete blood count and periph-eral smear should be obtained in all infants withradial defects. The diagnosis of Fanconi pancy-topenia syndrome should be considered in in-fants with longitudinal preaxial defects of theupper limb and chromosome breakage studiesfor this disorder should be considered in allcases suspected to have this serious disorder. Agenetic consult may be necessary in infants withassociated malformations and suspected syn-dromic defects.


The goals of treatment are improved function, ap-pearance, and social acceptance. The judicious useof prostheses with or without any surgery is themainstay of treatment but psychosocial support

for the patient and parents are equally important.Early introduction of prosthesis is vital for nor-mal development of the child and is recom-mended at about 6 months of age for a child withupper limb deficiency and by about 12 monthsof age for many lower limb deficiencies.

A higher perinatal and infant mortality rateshave been reported in infants with limb reduc-tion defects.4,11,25 These studies have reported amortality rate of 5–13% for all limb reduction de-fect cases and 21–56% for those with associatedmalformations.4 Risk of death is highest amonginfants with defects of humerus and preaxiallongitudinal defects; and is related to their as-sociation with other anomalies and syndromes.Most patients with isolated limb reduction de-fects have a normal life span.


There is very limited data on recurrence risk insubsequent pregnancies. Stoll et al reported arecurrence risk of about 3% while no recurrenceamong sibs was observed in a large study fromItaly.6,9 In another large population-based studyfrom Norway, children born to a mother withlimb defect had a relative risk of 5.6 of havingthe same defect as the mother and this relativerisk is much lower than the relative risk seen inmothers with cleft lip and palate and is similarto the risk observed for clubfoot.28 The recur-rence risk in infants with associated syndromeswould depend on the mode of inheritance ofthat syndrome.

REFERENCES

1. Frantz CH, O’Rahilly R. Congenital skeletal limbdeficiencies. J Bone Joint Surg. 1961;43A:1202–24.

2. Lin S, Marshall EG, Davidson GK, et al. Evaluationof congenital limb reduction defects in upstateNew York. Teratology. Feb 1993;47(2):127–35.

3. Dillingham TR, Pezzin LE, MacKenzie EJ. Limb am-putation and limb deficiency: epidemiology andrecent trends in the United States. South Med J.Aug 2002;95(8):875–83.


4. Evans JA, Vitez M, Czeizel A. Congenital abnor-malities associated with limb deficiency defects: apopulation study based on cases from the HungarianCongenital Malformation Registry (1975–1984).Am J Med Genet. Jan 1994;49(1):52–66.

5. McGuirk CK, Westgate MN, Holmes LB. Limb defi-ciencies in newborn infants. Pediatrics. Oct 2001;108(4):E64.

6. Stoll C, Calzolari E, Cornel M, et al. A study onlimb reduction defects in six European regions.Ann Genet. 1996;39(2):99–104.

7. Zhu J, Miao L, Xu C, Wang Y, et al. Analysis of 822infants with limb reduction defect in China. HuaXi Yi Ke Da Xue Xue Bao. Dec 1996;27(4):400–3.

8. Castilla EE, Cavalcanti DP, Dutra MG, et al. Limbreduction defects in South America. Br J ObstetGynaecol. May 1995;102(5):393–400.

9. Calzolari E, Manservigi D, Garani GP, et al. Limb re-duction defects in Emilia Romagna, Italy: epidemi-ological and genetic study in 173,109 consecutivebirths. J Med Genet. Jun 1990;27(6):353–7.

10. Goutas N, Simopoulou S, Petraki V, et al. Limb re-duction defects—autopsy study. Pediatr Pathol.Jan-Feb 1993;13(1):29–35.

11. Froster-Iskenius UG, Baird PA. Limb reduction de-fects in over one million consecutive livebirths.Teratology. Feb 1989;39(2):127–35.

12. Tayel SM, Fawzia MM, Al-Naqeeb NA, et al.A morpho-etiological description of congenitallimb anomalies. Ann Saudi Med. May-Jun 2005;25(3):219–27.

13. Froster UG, Baird PA. Congenital defects of thelimbs and alcohol exposure in pregnancy: datafrom a population based study. Am J Med Genet.Dec 1992;44(6):782–5.

14. Holmes LB. Teratogen-induced limb defects.Am J Med Genet. Oct 2002;112(3):297–303.

15. Firth HV, Boyd PA, Chamberlain PF, et al. Analysisof limb reduction defects in babies exposed tochorionic villus sampling. Lancet. Apr 1994;343(8905):1069–71.

16. Olney RS, Khoury MJ, Alo CJ, et al. Increased riskfor transverse digital deficiency after chorionic vil-lus sampling: results of the United States Multi-state Case-Control Study, 1988–1992. Teratology.Jan 1995;51(1):20–9.

17. Yang Q, Khoury MJ, Olney RS, et al. Does peri-conceptional multivitamin use reduce the risk forlimb deficiency in offspring? Epidemiology. Mar 1997;8(2):157–61.

18. Kallen B, Rahmani TM, Winberg J. Infants withcongenital limb reduction registered in the SwedishRegister of Congenital Malformations. Teratology.Feb 1984;29(1):73–85.

19. Makhoul IR, Goldstein I, Smolkin T, et al. Congen-ital limb deficiencies in newborn infants: preva-lence, characteristics and prenatal diagnosis. PrenatDiagn. Mar 2003;23(3):198–200.

20. Martinez-Frias ML, Bermejo E, Paisan L, et al. Chil-dren with limb reductions in a population of25,193 malformed newborns: the recognizedcauses. ECEMC. The Spanish Collaborative Studyof Congenital Malformations. An Esp Pediatr.Jan 1998; 48(1):49–53.

21. Froster UG, Baird PA. Congenital defects of thelimbs in stillbirths: data from a population-basedstudy. Am J Med Genet. Jun 1993;46(5):479–82.

22. Rosano A, Botto LD, Olney RS, et al. Limb defectsassociated with major congenital anomalies: clinicaland epidemiological study from the InternationalClearinghouse for Birth Defects Monitoring Systems.Am J Med Genet. Jul 2000;93(2):110–6.

23. Kroes HY, Olney RS, Rosano A, et al. Renal defectsand limb deficiencies in 197 infants: is it possibleto define the “acrorenal syndrome?” Am J MedGenet A. Aug 2004;129(2):149–55.

24. Czeizel AE, Vitez M, Kodaj I, et al. Causal study of iso-lated ulnar-fibular deficiency in Hungary, 1975–1984.Am J Med Genet. Jun 1993;46(4):427–33.

25. Froster UG, Baird PA. Upper limb deficiencies andassociated malformations: a population-basedstudy. Am J Med Genet. Dec 1992;44(6):767–81.

26. James MA, Green HD, McCarroll HR Jr, et al. The as-sociation of radial deficiency with thumb hypoplasia.J Bone Joint Surg Am. Oct 2004;86-A(10):2196–205.

27. Kozin SH. Upper-extremity congenital anomalies.J Bone Joint Surg Am. Aug 2003;85-A(8):1564–76.

28. Skjaerven R, Wilcox AJ, Lie RT. A population-basedstudy of survival and childbearing among femalesubjects with birth defects and the risk of recur-rence in their children. N Engl J Med. Apr 1999;340(14):1057–62.

CHAPTER 45 LIMB REDUCTION DEFECTS 305


Chapter 46

Skeletal DysplasiasPRAVEEN KUMAR

307

� INTRODUCTION

Skeletal dysplasias, also known as osteochon-drodysplasias, refer to a group of disorders whichare characterized by abnormalities in the devel-opment, growth, and maintenance of both boneand cartilage.1,2 The osteodysplasias are usuallycharacterized by osteopenia or osteosclerosis,whereas chondrodysplasias usually result inshort stature by affecting cartilage and thereforethe linear growth of bones.3 Some authors sub-divide these disorders into: dysplasias (abnor-malities of bone and/or cartilage growth) andosteodystrophies (abnormalities of bone and/orcartilage texture).4 Multiple bones of the axialand appendicular skeleton and bones develop-ing both from endochondral and membranousossification are involved and the abnormalitiesare intrinsic to bone and cartilage. The pheno-types in patients with these disorders continue toevolve throughout life and explain the fact thatmany cases of osteochondrodysplasia are diag-nosed later in life. It is important to differentiateosteochondrodysplasias from dysostoses whichoccur as a result of abnormalities of blastogenesis inthe first 6–8 weeks of life resulting in defective boneformation.4 Patients with dysostoses have re-gional bone abnormalities and the phenotyperemains static throughout life. The skeletal dys-plasias have been classified in many differentways over the years, but the most commonly used

classification is from the International WorkingGroup (IWG) on the Classification of Constitu-tional Disorders of Bone (CCDB). The last up-dated version was published in 2002 and in-cludes 33 groups of osteochondrodysplasias and3 groups of dysostoses.5 Although individualskeletal dysplasias are rare, they are relativelycommon as a group and have a significant effecton morbidity and mortality at all ages. Over 200skeletal dysplasias have been described andnearly half of these are lethal which account foralmost 9 per 1000 perinatal deaths.6 A completereview of all disorders in this category is beyondthe scope of this book. This chapter provides anapproach to evaluation of common skeletal dys-plasias presenting in perinatal period only.

� EPIDEMIOLOGY

Although individual skeletal dysplasias are rare,they are relatively common as a group with areported prevalence rate of 1.1–7.6 per 10,000births in previous epidemiologic studies.7 Thiswide range of prevalence in different studies isattributed to differences in case ascertainment,definition of dysplasias, inclusion age of patients,and differences in inclusion of still births, andpregnancy terminations after a prenatal diagnosis.The study reporting a prevalence rate of 7.6 per10,000 births was based on inclusion of cases


identified at any age.8 The most common skeletaldysplasias in this study were osteogenesis imper-fecta, multiple epiphyseal dysplasia, achondroge-nesis, osteopetrosis, thanatophoric dysplasia, andachondroplasia. The prevalence rate of skeletaldysplasias which present in the perinatal period isreported to be about 2.1–2.3 per 10,000 births andthe rate of lethal osteochondrodysplasia is about0.95 per 10,000 births.7,9 However, most of thesestudies concede that probably the true prevalencewas higher than captured in their databases. Pre-natal diagnosis of lethal skeletal dysplasia hasalso led to an increase in termination of affectedpregnancies and a corresponding decrease inthe number of infants born with these disorders.The most commonly reported skeletal dysplasiasand their prevalence at birth are thanatophoricdysplasia (0.09–0.60 per 10,000 births), osteogen-esis imperfecta (0.37–0.64 per 10,000 births),achondroplasia (0.13–0.64 per 10,000 births), andachondrogenesis (0.23–0.64 per 10,000 births).7,9

Other frequently observed skeletal dysplasias diag-nosed at birth include: camptomelic dysplasia,short-rib-polydactyly syndromes type I and II,chondrodysplasia punctata, asphyxiating thoracicdystrophy, spondyloepiphyseal dysplasia, anddiastrophic dysplasia.6,7 Based on a review of theliterature, Rasmussen et al reported that a spe-cific diagnosis could not be made in 7–21% ofall cases with osteochondrodysplasia.7 Increasedpaternal age is associated with higher risk ofachondroplasia and thanatophoric dwarfism.Maternal use of warfarin during pregnancy hasbeen reported to cause clinical picture similar tochondrodysplasia punctata. Osteogenesis imper-fecta is more common among Caucasians andchondroectodermal dysplasia (Ellis-van Crevelddisease) has a significantly higher incidence inthe Amish population. No gender predispositionand other risk factors have been reported.


The human skeletal system is divided into the ax-ial skeleton and the appendicular skeleton. The

axial skeleton includes the skull, vertebral column,ribs, and sternum; and the appendicular skeletonis composed of pectoral and pelvic girdles, andthe limb bones. The parts of axial skeleton, ver-tebrae and ribs, originate from the somites onboth sides of the neural tube while the craniofa-cial bones are of neural-crest origin. The appen-dicular skeleton originates from the lateral platemesoderm. The earliest event in skeletal devel-opment is the induction of undifferentiated mes-enchyme to form mesenchyme condensationwhich represents the outlines of future skeletalelements. Some bones, such as flat bones of theskull, develop from mesenchyme by intramem-branous ossification while in most other bonesmesenchyme is first transformed into cartilagebone models which later ossify by endochondralossification. The skeletal development begins atabout third week of gestation by mesenchymalcondensation and although most of the bonegrowth is complete by late adolescence, the in-ternal reorganization of bones continues through-out life. Skeletogenesis, the process of origin, for-mation, and development of the skeleton,requires close interaction between various regu-latory mechanisms that control cell determina-tion and differentiation, the orchestration of boneand cartilage-specific genes and other modifiers,and the influence of cell-cell and cell-matrix in-teractions.10 From the embryologic perspective,each osteochondrodysplasia is the result of an al-teration in any of these mechanisms by an ab-normal cellular product or process which in turnresults from a defective chromosome.11 How-ever, there is not always a clear correlation be-tween genetic defect and clinical phenotypes inall cases, indicating that other moderating factorsmay be involved.

In response to the rapid accumulation ofknowledge on genes and proteins responsiblefor various skeletal dysplasias, InternationalWorking Group on Constitutional Disorders ofBone added a classification of genetic disordersof the skeleton which divided these disordersinto the following seven groups based onmolecular-pathogenetic etiologies:12


Group 1: Defects in extracellular structural pro-teins as in osteogenesis imperfecta, achondro-genesis, and multiple-epiphyseal dysplasia

Group 2: Defects in metabolic pathways as inhypophosphatasia, infantile osteopetrosis,and chondrodysplasia punctata

Group 3: Defects in folding and degradation ofmacromolecules as in pycnodysostoses, andlysosomal storage diseases

Group 4: Defects in hormones and signal trans-duction mechanisms as in achondroplasia,thanatophoric dysplasia, hypochondropla-sia, and hypophosphatemic rickets

Group 5: Defects in nuclear proteins and tran-scription factors as in camptomelic dyspla-sia, and cleidocranial dysplasia

Group 6: Defects in oncogenes and tumor sup-pressor genes as in multiple exostosessyndrome

Group 7: Defects in RNA and DNA processingand metabolism as in cartilage-hair-hypoplasia


The spectrum of clinical presentation in thesepatients can range from early neonatal deathsecondary to respiratory failure to a normal-appearing infant with only subtle findings ofdisproportionate stature in the newborn period.Table 46-1 summarizes the important clinicalfeatures of common skeletal dysplasias present-ing in the perinatal period. The associatedanomalies of other organ systems are variablypresent and can help in establishing diagnosisin these patients.

� EVALUATION

Evaluation of an infant suspected to have skele-tal dysplasia is often challenging because of awide range of differential diagnosis, rarity ofcondition, and relative inexperience of physi-cians providing care. An accurate diagnosis iscritical to make appropriate decisions regarding

medical care and counseling of parents. Asystematic approach is crucial and should in-clude the following steps:

1. History: A complete three generation fam-ily history can provide important clues tothe diagnosis and should include history ofconsanguinity, ethnicity, unexplained peri-natal deaths, recurrent fractures, shortstature, and early arthritis in other familymembers. Maternal use of warfarins duringpregnancy is known to cause clinical pic-ture consistent with chondrodysplasia punc-tata. History of exposure to other teratogenssuch as alcohol, thalidomide, and maternalhistory of phenylketonuria or diabetes mel-litus should also be asked.

2. Physical examination: The accurate an-thropometric measurements are importantin deciding if an infant has short stature forgestational age and if it is proportionate ordisproportionate. In a normal infant, the fin-gertips of the hand fall between the iliaccrest and upper one-third of the thigh; there-fore fingertips above the iliac crest wouldsuggest short-limbed short stature. An in-creased upper segment to lower segment(US/LS) ratio will confirm the presence ofdisproportionate growth. The lower seg-ment is measured from the top of the sym-physis pubis to the sole of the foot and theupper segment is obtained by subtractingthe lower segment value from the totallength. A normal US/LS ratio in the new-born infant is 1.7. The measurement of armspan, the distance between the fingertips ofthe middle fingers of each hand with armsstretched out horizontally is also helpful.The normal arm span in an infant is about2–3 cm less than the total length. US/LS ra-tio is increased and arm span is decreasedin infants with short-limbed short staturesuch as in achondroplasia but infants withshort-trunk short stature such as in spondy-loepiphyseal dysplasia will have a normalarm span with reduced US/LS ratio.3,13 The

CHAPTER 46 SKELETAL DYSPLASIAS 309

� TABLE 46-1 Clinical Features of Common Skeletal Dysplasias Presenting in Perinatal Period

Associated RecurrenceDiagnosis Etiology Main Findings Findings Outcome Risk Comments

Thanatophoric Autosomal Extremely short Large head with Lethal in Very low Rare reports ofdysplasia (TD) dominant limbs depressed nasal perinatal survival beyond

New dominant Small chest with bridge period neonatal periodmutation in respiratory Bowing of femur Survivors haveFGFR3 gene failure (telephone receivers) profound growth

Sporadic and very flat vertebral andbodies in type I developmental

Craniosynostosis delay(Cloverleaf Skull intype II)

Osteogenesis Mutation in Prenatal diagnosis isimperfecta (OI) COL1A1 & possible

COL1A2 genesType I Autosomal 8% have fracture Bowing of femur/tibia Not lethal 50% Normal length

dominant at birth Blue sclerae at birthType II Autosomal Very short long Generalized Lethal in 6–8% Most survivors have

dominant bones hypomineralization perinatal associated hearingNew mutation Multiple fractures of all bones period loss, defective

in most cases Respiratory Broad, crumpled dentition,Rare autosomal failure femora with beaded hyperlaxity of

recessive ribs, wormian bones joints, and normaltransmission intelligence

Type III Autosomal Short stature Generalized Not lethal 50%dominant Multiple fractures hypomineralization in

Rarely Respiratory perinatalautosomal insufficiency +/– periodrecessive

Type IV Autosomal Fractures at Mild short stature Not lethal 50%dominant birth +/– at birth +/–

310

Achondrogenesis Autosomal Severe Macrocephaly Lethal Usually low Most infantsrecessive or micromelia Hydrops/cystic Could be as stillborn orsporadic Respiratory hygroma high as 25% die shortlymutation failure Generalized after birth

Mutation in hypomineralizationCOL2A1 Fractures +/–gene

Decreasedtype IIcollagen

Camptomelic Autosomal Short limbs, Club feet, short Usually Very low for Survivors havedysplasia dominant tibial bowing square hands lethal normal profound

Mutation in Respiratory Hypoplastic scapulae parents, growth andSOX9 insufficiency Cleft palate 50% if one developmentalgene on Heart defect parent is rare delay includingchromosome Hydronephrosis survivor with mild apneic spells17q24 Sex reversal (46XY manifestation

males present as of the diseasephenotypic female)

Asphyxiating Autosomal Narrow bell Postaxial polydactyly Usually 25% Progressive renalthoracic recessive shaped thorax of hand and feet+ lethal and hepaticdystrophy Respiratory (30%) dysfunction in(Jeune’s failure Chronic nephritis survivors whosyndrome) Short limbs Occasional situs may also

(rhizomelic inversus have retinalmicromelia) degeneration

Short rib- Autosomal Short limb Polydactyly of Invariably 25% Very rarepolydactyly recessive Respiratory hand and feet lethal Most infantssyndrome failure Cardiac defects, die shortly

e.g., TGV, DORV after birthPolycystic kidneysAmbiguous genitaliaCleft palate and CNS

anomalies +

(Continued)

311

� TABLE 46-1 Clinical Features of Common Skeletal Dysplasias Presenting in Perinatal Period (Continued)


Diastrophic Autosomal Short limb Club feet Variable but <25% due Most commondysplasia recessive Cervical kyphosis Malformed pinnae usually to wide in Finnish

Mutation in with calcifications nonlethal variability populationsulfate and cysts oftransporter Joint contractures expressiongene on Cleft palate,chromosome 5 Micrognathia +

“HitchhikerThumb”—bilateralabductiondeformityof thumbs

Airway anomaliesHypophosphatasia Autosomal Severe Very low or Lethal 25% Infantile form(Perinatal form) recessive hypomineralization undetectable present

Mutation in of bones levels of serum in first alkaline Fractures alkaline 6 monthsphosphatase Respiratory failure phosphatase with growthgene on Rhizomelic or failure,Chromosome asymmetric short childhood1p36.1 limbs form after

Blue sclera 6 months,and the adultform later in life

More common inMennonites inSouthernCanada

312

Chondrodysplasia X-linked Short stature Contractures Variable 25–50% Epiphyseal stipplingpunctata recessive and proximal of joints depending present in fetus

X-linked shortening of Depressed nasal on type of and infancydominant limbs bridge (saddle dysplasia but no longer

Autosomal Punctate nose) present afterdominant calcifications Cataracts 2 yrs of age

or epiphyseal Seizures and Same clinical picturestippling developmental due to maternal

delay use of warfarin,Hypoplasia of phenytoin, maternal

distal malabsorption ofphalanges vitamin K, or

Dermopathy maternal SLEHeart defects

Spondyloepiphyseal Autosomal Short stature Cleft palate Usually not 50% Severe myopiadysplasia dominant and limbs Platyspondyly lethal puts survivorscongenita Mutation in Kyphosis/scoliosis at risk of retinal

COL2A1 IUGR detachmentgene Talipes Spondyloepiphyseal

equinovarus, dysplasia tardaDislocation of presents later

hips in lifeChondroectodermal Autosomal Acromesomelia Postaxial Variable 25% Much higher incidence

dysplasia recessive polydactyly in in Amish and(Ellis-van Creveld Gene on all cases Australiansyndrome) chromosome 4 Cardiac defects aborigines

in 50% (ASD,single atrium)

Ectodermaldefects

Dysplastic nailsMultiple gingival

frenulae

(Continued)

313

� TABLE 46-1 Clinical Features of Common Skeletal Dysplasias Presenting in Perinatal Period (Continued)


Achondroplasia Autosomal Short stature and Macrocephaly, Usually not 50% if family Homozygous infantsdominant short limb frontal lethal history is born to

Mutations in the (rhizomelic bossing positive achondroplasicFGFR3 gene micromelia) Trident hand Low in others parents can haveon chromosome Prenatal severe lethal4p16.3 diagnosis is perinatal

possible by presentationDNA testing 75% of cases

remain undiagnosedin neonatal period

DNA testing can beeasily done becausethe involvedmutations areminimal in number

ASD, atrial septal defect; IUGR, intrauterine growth retardation; TGV, transposition of the great vessels; DORV, double outlet right ventricle.

314

length of the parts of the limb should bemeasured in infants with short-limbed shortstature skeletal dysplasias. If the humerusor femur is relatively shorter, the proximalshortening is called rhizomelia; dispropor-tionate shortening of middle bones (radius,ulna, tibia, and fibula) is called mesomelia;and disproportionate shortening of distal ex-tremities is called acromelia. The normalradius-humerus ratio is 75% and the normaltibia-femur ratio is 82%; and these ratios re-main constant in normal children regardlessof age or sex.13 Severe micromelia refers tolong bones that are four or more standard

deviations below the mean for gestationalage and is characteristic of thanatophoricdysplasia, achondrogenesis, and osteogen-esis imperfecta type II.

In addition, a complete physical exami-nation should be done to identify dysmor-phic features and other congenital anom-alies which can provide important clues tothe underlying diagnosis (Table 46-2). Thepresence of severe pulmonary insufficiencyis suggestive of pulmonary hypoplasia seenin many lethal forms of skeletal dysplasiasand may help in narrowing down the list ofdifferential diagnosis.


� TABLE 46-2 Clinical Clues to the Underlying Diagnoses in an Infant with Skeletal Dysplasia

• No malformation of other organs Achondroplasia, achondrogenesis, spondyloepiphysealexcept bones dysplasia, thanatophoric dysplasia, osteogenesis

imperfecta, hypophosphatasiaAssociated malformations of other Campomelic dysplasia, diastrophic dysplasia,

organs usually present chondro-ectodermal dysplasia, asphyxiating thoracicdystrophy, short rib polydactyly dysplasia,chondrodysplasia punctata

• Short limb—normal trunk Achondroplasia, thanatophoric dysplasia, osteogenesisimperfecta, chondrodysplasia punctata, campomelicdysplasia, diastrophic dyplasia, chondro-ectodermaldysplasia, asphyxiating thoracic dystrophy

Short trunk and short limbs Hypophosphatasia, osteopetrosis, achondrogenesis,spondyloepiphyseal dysplasia, hypochondrogenesis

• Craniofacial signsCloverleaf skull Thanatophoric dysplasiaNatal teeth, multiple frenulae Chondroectodermal dysplasiaCleft palate Campomelic dysplasia, diastrophic dysplasiaCataracts Chondrodysplasia punctataCystic ears Diastrophic dyplasia Blue sclerae Osteogenesis imperfecta

• LimbsHypoplastic/dysplastic nails Chondro-ectodermal dysplasia, Chondrodysplasia punctataJoint contractures Diastrophic dysplasia, chondrodysplasia punctataShort abducted thumbs Diastrophic dysplasia

(Hitchhiker’s thumbs)Polydactyly Chondro-ectodermal dysplasia, asphyxiating thoracic dystrophy,

short rib polydactyly dysplasiaClub feet Campomelic dysplasia, diastrophic dysplasia

• Congenital heart defects Chondro-ectodermal dysplasia, campomelic dysplasia,short rib polydactyly dysplasia

• Renal anomalies Asphyxiating thoracic dystrophy, short rib polydactyly dysplasia

3. Radiologic evaluation: The radiologic eval-uation has been extremely helpful in establish-ing a diagnosis in these infants. The skeletalsurvey in these infants should include: frontaland lateral views of vertebral column, lateralviews of the cervical spine and skull, antero-posterior views of chest and pelvis, and an-teroposterior views of one upper and onelower extremity. In cases with limb asym-metry, it may be necessary to obtain views ofboth upper and lower limbs. Imaging of otherfamily members suspected of having the samecondition as the proband may be helpful.Serial skeletal surveys may be necessary whenthe diagnosis is not certain on initial evaluationbut repeating the survey earlier than 12 monthsof initial survey is not likely to be helpful.4

These films are most helpful when reviewedby a pediatric radiologist with interest and ex-perience in this area. Table 46-3 summarizesthe important radiological findings in skele-tal dysplasias commonly presenting in theperinatal period.

4. Laboratory evaluation: Serum calcium,phosphate, and alkaline phosphatase levelsshould be measured and are more helpful ininfants with abnormal mineralization of thebones. The peroxisomal testing and sterolprofile may be helpful in infants with stip-pled epiphyses. Histopathological evaluationof chondro-osseous tissue can be particularlyhelpful in patients with no clear diagnosisbased on clinical and radiological evaluation.Testing for mutations in collagen genes canbe helpful in osteogenesis imperfecta.

5. Genetic testing: A karyotype should becarried out if there are associated malfor-mations of other organ systems and it canbe particularly helpful in the diagnosis ofcamptomelic dysplasia in which a 46XY in-fant frequently has a female phenotype onexamination. Molecular diagnosis utilizingDNA studies has become possible for mostof these disorders but may not be easilyavailable or be practical in many cases.Blood samples and fibroblast cultures from

skin biopsy or placental tissue can be storedto allow DNA analysis at a later date.

Figure 46-1 provides a systematic ap-proach to arrive at a diagnosis in infants withcommon skeletal dysplasias presenting inthe perinatal period.

� PROGNOSIS

Skeletal dysplasias are frequently classified aslethal or nonlethal. Lethality of a particular di-agnosis is mainly related to the associated pul-monary hypoplasia from an abnormally formedrestrictive thorax. The cause of death in someothers could be related to respiratory failuresecondary to brainstem compression due tothe stenosis of foramen-magnum or secondaryto severe airway anomalies. Several studies haveevaluated the ability of prenatal ultrasound find-ings to predict the neonatal outcome of affectedfetuses. Although only 48–65% of specific diag-noses are correct, the identification of a lethaldysplasia is highly accurate.11 The followingcriteria have been used to diagnose lethal skele-tal dysplasia on prenatal ultrasound: (1) earlysevere micromelia; (2) femur length: abdominalcircumference <0.16; (3) thoracic circumference<5th percentile for gestational age; (4) thoraciccircumference: abdominal circumference <0.79;and (5) cardiac circumference: thoracic circum-ference >0.60.11 Fetal femur length by itself hasalso been reported to distinguish among thefive most common skeletal dysplasias present-ing in the perinatal period.6 Fetuses with femurlength <40% of the mean for gestational ageare likely to have achondrogenesis, those withfemur length between 40% and 60% havethanatophoric dysplasia or osteogenesis imper-fecta type II, and those with femur length over80% have either achondroplasia or osteogenesisimperfecta type II. There are no similar reportsof criteria predicting outcome of neonates bornwith skeletal dysplasia but most infants withlethal forms of skeletal dysplasia have severepulmonary hypoplasia and die within first few



� TABLE 46-3 Summary of Radiological Findings in Patients with Skeletal Dysplasia

Finding Likely Diagnosis

A. Bone DensityGeneralized undermineralization or osteopenic Osteogenesis imperfecta

HypophosphatasiaAchondrogenesis

Overmineralization or osteosclerosis OsteopetrosisPyknodysostosisDysostosclerosis

B. Spine Frontal view

Progressively decreasing interpediculate distance Thanatophoric dysplasia AchondroplasiaDiastrophic dysplasia

Absence of pedicle ossification in lower thoracic spine Campomelic dysplasiaLateral view

Generalized vertebral dysplasia Spondyloepiphyseal dysplasiaHypochondroplasia

Coronal cleft vertebra Chondrodysplasia punctataWafer-thin vertebral bodies (severe platyspondyly) Thanatophoric dysplasiaHypoplastic odontoid Spondyloepiphyseal dysplasiaCervical kyphosis Diastrophic dysplasia

Campomelic dysplasiaC. Pelvis

Flat acetabular angle AchondroplasiaThanatophoric dysplasia

Hypoplastic square iliac bones AchondroplasiaThanatophoric dysplasia

Widened symphysis pubis Spondyloepiphyseal dysplasiaHypochondrogenesisAchondrogenesisCleidocranial dysplasia

D. ChestFrontal viewLong narrow chest (2° to rib shortening)

-Mild Achondroplasia-Severe Thanatophoric dysplasia

Asphyxiating thoracic dystrophyShort and wide chest (2° to short spine)

-Mild Spondyloepiphyseal dysplasia-Severe Achondrogenesis

Beading of ribs Osteogenesis imperfecta type IIAchondrogenesis

Absent or hypoplastic clavicles Cleidocranial dysplasiaHypoplastic scapulae Campomelic dysplasia

(Continued)

days of life. Infants with mild to moderate pul-monary insufficiency may survive neonatal pe-riod but may succumb to ongoing pulmonarymorbidity later in life. There are some recentreports of survival with aggressive perinatalmanagement in infants previously consideredto have a lethal skeletal dysplasia such as

thanatophoric dysplasia.14 These infants fre-quently have severe growth retardation andchronic respiratory insufficiency and some havemental retardation either secondary to underly-ing central nervous system anomalies or as aresult of chronic respiratory insufficiency.14 In-fants with nonlethal skeletal dysplasias such as


� TABLE 46-3 Summary of Radiological Findings in Patients with Skeletal Dysplasia (Continued)

Finding Likely Diagnosis

E. LimbsBowing

-Mild Achondroplasia-Severe Thanatophoric dysplasia

Campomelic dysplasiaOsteogenesis imperfecta

Epiphyseal stippling Chondrodysplasia punctataSmall or irregular epiphyses Multiple epiphyseal dysplasia

Spondyloepiphyseal dysplasiaTrident hand AchondroplasiaRhizomelic micromelia (humeri & femora)

Mild AchondroplasiaSpondyloepiphyseal dysplasiaHypochondrogenesis

Severe Thanatophoric dysplasiaAchondrogenesisChondrodysplasia punctata

(recessive type)Mesomelic micromelia Campomelic dysplasia

(ulna/radius and or tibia/fibula)Acromelic micromelia Asphyxiating thoracic dystrophy

Chondro-ectodermal dysplasiaNonspecific micromelia Osteogenesis imperfecta

Diastrophic dysplasiaChondrodysplasia punctata

(dominant type)Hypophosphatasia

F. SkullCloverleaf skull Thanatophoric dysplasiaWidening of cranial sutures and fontanelle Hypophosphatasia

AchondrogenesisCleidocranial dysplasia

G. Other findingsFractures Osteogenesis imperfecta

OsteopetrosisHypophosphatasiaAchondrogenesis

Figure 46-1. An approach to diagnosis in a newborn with skeletal dysplasia.∗

∗ This algorithm may not be applicable to all infants with skeletal dysplasias because of variations in clinical presentation and otherless common causes of skeletal dysplasia which are not included here.

Pathological Fractures or Abnormal Mineralization

Yes

Mineralization

DecreasedIncreased

Serum AlkalinePhosphatase

Osteopetrosis

Normal or IncreasedLow

Hypophosphatasia Micromelia

Less severe(Femoral Length 40–60% for gestational

age).

Severe(Femoral Length

<40%forgestational age)

Achondrogenesis OsteogenesisImperfecta

No

Respiratory Insufficiency

Severe

Family History of Achondroplasia inBoth Parents

Yes No

HomozygousAchondroplasia

Anomalies onexamination

Yes No

MineralizationPolydactyly

Yes No Decreased Normal

HeartDefect

Campomelic Dysplasia

Achondrogenesis

ThanatophoricDysplasiaYes No

Yes

Short RibPolydactylyDysplasia

AsphyxiatingThoracic

Dystrophy orShort Rib

PolydactylyDysplasia

HypoplasticScapulae,

NonmineralizedLower Thoracic

Pedicles

Mild to Moderate or None

Punctate Calcification on x-rays

Yes No

ChondrodysplasiaPunctata

Dysplastic Vertebrae and Long BoneEphiphyses

Yes + No

Spondylo-epiphysealDysplasia

DiastrophicDysplasia

Yes Anomalies on Exam

CysticPinnaeClubfeet jointcontractures

Yes

ChondroectodermalDysplasia

AchondroplasiaYes

Polydactyly,Heart DefectsDysplastic Nails

No

319

achondroplasia can expect normal or near nor-mal life span but require close medical follow-upand multidisciplinary care for various medical,orthopedic, and psychosocial issues related totheir underlying disorder.


An accurate clinical diagnosis is crucial to pro-vide appropriate genetic counseling. Table 46-1also includes the likely recurrence risk for commonskeletal dysplasias presenting in the perinatalperiod. Many cases of affected siblings born tounaffected parents in an autosomal dominant con-dition are most likely due to germ line mosaicismas in spondyloepiphyseal dysplasia congenitaand camptomelic dysplasia.

REFERENCES

1. Savarirayan R. RDL. Skeletal Dysplasias. AdvPediatr. 2004;51:209–29.

2. Baker ER, Goldberg MJ. Diagnosis and managementof skeletal dysplasias. Semin Perinatol. Aug 1994;18(4):283–91.

3. Mortier GR. The diagnosis of skeletal dysplasias: amultidisciplinary approach. Eur J Radiol. Dec 2001;40(3):161–7.

4. Offiah AC, Hall CM. Radiological diagnosis of theconstitutional disorders of bone. As easy as A, B,C? Pediatr Radiol. Mar 2003;33(3):153–61.

5. Hall CM. International nosology and classifica-tion of constitutional disorders of bone (2001).Am J Med Genet. Nov 2002;113(1):65–77.

6. Goncalves L, Jeanty P. Fetal biometry of skeletaldysplasias: a multicentric study. J Ultrasound Med.Dec 1994;13(12):977–85.

7. Rasmussen SA, Bieber FR, Benacerraf BR, et al.Epidemiology of osteochondrodysplasias: changingtrends due to advances in prenatal diagnosis.Am J Med Genet. Jan 1996;61(1):49–58.

8. Andersen PE, Jr., Hauge M. Congenital gener-alised bone dysplasias: a clinical, radiological,and epidemiological survey. J Med Genet. Jan 1989;26(1):37–44.

9. Orioli IM, Castilla EE, Barbosa-Neto JG. The birthprevalence rates for the skeletal dysplasias. J MedGenet. Aug 1986;23(4):328–32.

10. Francomano CA. HNC. Latest developments inskeletal dysplasia. Am J Med Genet. 2001;106:241–3.

11. Teele RL. A guide to the recognition of skeletal dis-orders in the fetus. Pediatr Radiol. Jun 2006;36(6):473–84.

12. Superti-Furga A, Bonafe L, Rimoin DL. Molecular-pathogenetic classification of genetic disordersof the skeleton. Am J Med Genet. Winter 2001;106(4):282–93.

13. Beals RK, Horton W. Skeletal dysplasias: an ap-proach to diagnosis. J Am Acad Orthop Surg.May 1995;3(3):174–81.

14. Baker KM, Olson DS, Harding CO, et al. Long-termsurvival in typical thanatophoric dysplasia type 1.Am J Med Genet. Jun 1997;70(4):427–36.


Chapter 47

ArthrogryposisPRAVEEN KUMAR

321

� INTRODUCTION

The term arthrogryposis is used to describe pre-natal onset of joint contractures with associatedlimitation of movements in two or more joints indifferent body areas. The term arthrogryposismeans “bent joint” (in Greek language “arthron”means joint and “gryposis” means hooking orbending). Over the years, the term arthrogryposishas been loosely used for a group of unrelateddiseases with the common phenotype of multiplecongenital contractures (MCC) with many differentetiologies. Nearly 150 specific entities include arthro-gryposis or multiple congenital contractures as aclinical feature. Since the final common pathwayleading to these contractures is the impaired in-trauterine mobility of the affected joints in theseconditions, some authors have used the term “fetalakinesia sequence” or “fetal akinesia deformationsequence” (FADS) to describe these infants.

� EPIDEMIOLOGY

The incidence of multiple congenital contracturesor arthrogryposis at birth has been reported torange from 1 in 3000 to 1 in 12,000 live births.1,2

These differences in the incidence are probablyrelated to the lack of consistent definition ofarthrogryposis, variable sources of data collec-tion, and reporting bias. It is suggested that the

incidence could be higher if miscarriages andstillbirths with congenital contractures were in-cluded. Based on data collected from three ortho-pedic centers in United States, United Kingdom,and Australia, Wynne-Davies et al had reporteda significantly higher incidence of arthrogryposisin all three countries in 1960s than either beforeor after that period.3 They attributed their find-ings to an unknown environmental agent. Moststudies have reported no sex predilection andany other identifying maternal or social charac-teristics among infants with arthrogryposis.

� EMBRYOLOGY

The development of synovial joints starts at about6 weeks of gestation with formation of interzone,an area of condensation of mesenchymal cells inprecartilaginous bones. These mesenchymal cellsfurther differentiate into chondrogenic cells, syn-ovial cells, and central cells which lead to the for-mation of articular cartilage, joint capsule withinner synovial membrane and the intra-articularstructures respectively. The anatomic develop-ment of joints is complete by seventh week ofgestation but the development of a joint cavityrequires mobility which occurs by about 8 weeks.The absence of joint movements disrupts the nor-mal development of joints and results in flatten-ing of the articular surfaces. The joint cavity fills


with fibrous tissue and the capsule thickens re-sulting in joint contractures and limb deformities.Although abnormal development of joints and itscontiguous soft tissue can lead to arthrogryposisin some cases, initial joint development is normalin a large majority of infants with arthrogryposis,and the changes secondary to immobility of anormally developed joint are responsible for thecontractures seen in these infants.

� ETIOPATHOGENESIS

The etiology of arthrogryposis is multifactorialand heterogenous. It is not unusual to be un-able to identify a specific cause despite exten-sive evaluation. Both animal and human studieshave shown that decreased joint movements inutero can lead to prenatal contractures of fetaljoints. It has also been reported that the fetuseswith earlier onset of immobilization of joints willhave more severe contractures. The causes fordecreased fetal movements can be divided intotwo broad categories:

1. Decreased movements secondary to abnormalfetal development with normal intrauterineenvironment. The fetal immobilization in thiscategory could be secondary to abnormaldevelopment of (a) central or peripheral ner-vous system, (b) abnormalities of muscledevelopment, or (c) abnormalities of con-nective tissue development including skin,bone, cartilage, and tendons. Both intrinsicfetal disorders and maternal factors such ashyperthermia, viral infections, medicationsand drug exposures, vascular accidents andhypotension, and maternal neuromusculardisorders such as myasthenia gravis havebeen reported to cause arthrogryposis in adeveloping fetus.

2. Decreased movements of a normally devel-oped fetus in an abnormal intrauterine envi-ronment such as oligohydramnios, uterinefibroids, multiple gestation, and uterine anom-alies such as bicornuate uterus.

The reported frequencies of different pathwaysleading to decreased fetal movements and subse-quent arthrogryposis either secondary to abnormalfetal development or an abnormal intrauterine en-vironment are summarized in Table 47-1.

The underlying genetic causes among infantswith arthrogryposis are equally heterogenous.In an analysis of 350 children with congenitalcontractures reported in 1985, chromosomal ab-normality or single gene genetic disorders wereidentified in 28%, known syndromes in 46%,environmental insult or maternal exposure to ateratogen in 6%, and the diagnosis remainedunknown in the remaining 20%.4 However ad-vances in genetics may identify a specific genefor many more disorders in the coming years.


The clinical presentation of an infant with arthro-gryposis or multiple congenital contractures canbe very variable depending on the underlyingcause as the diagnosis is part of over 150 syn-dromes and neuromuscular conditions that oftenare unrelated. In early 1980s, Hall proposed aclinical classification which separated infantswith multiple congenital contractures into threegroups: (1) those with primarily limb involvement;(2) those with limb involvement plus abnormalities


� TABLE 47-1 Etiopathogenic Mechanisms ofArthrogryposis

Neuropathic 65–85%Disorders of central nervous 15–35%

systemDisorder of (peripheral nervous ~30–65%

system or spinal cord)

Myopathic 5–15%Abnormal development

and function of muscles

Connective tissue disorders 5–10%

Fetal crowding <5%

in other body areas; and (3) those with limb in-volvement plus severe central nervous system(CNS) dysfunction.5 In a study from China, nearly65% of infants with arthrogryposis were placedin group 1, 20% in group 2, and 15% in group 3.6

Recently Aroojis’ et al proposed a new classifica-tion based on clinical presentation that will prob-ably make it easier to compare outcomes and re-sponse to different interventions in a systematicfashion.7 They classified patients with arthrogry-posis into the following five groups: Group I hadamyoplasia or classic arthrogryposis (56% of theirpatients); Group II had distal arthrogryposis(10.5% of patients); Group III had a specific syn-drome as a diagnosis (5.5% of patients); Group IVhad severe systemic or neurologic involvement(15% of patients); and Group V had unclassifiablecontracture syndromes (13% of patients).7


Since multiple congenital contractures are partof many different syndromes, it is not surprisingthat the congenital anomalies of other organsare frequently associated with arthrogryposis.The CNS malformations are most frequently as-sociated, followed by skeletal, renal, and cardiacanomalies. Nearly half of all patients with arthro-gryposis may have associated congenital mal-formations.7 In one report, 22% of infants hadabnormalities of the craniomaxillofacial area andin another report approximately 10% of all pa-tients with arthrogryposis had associated upperairway or other cranial nerve abnormalities.8,9

As noted earlier, arthrogryposis or multiplecongenital contractures are part of over 150 syn-dromes and a complete list of these disorders isout of the scope of this chapter. However, anabbreviated list of common disorders present-ing with joint contractures in neonatal period ispresented in Table 47-2. In addition, a brief dis-cussion of the following two major subgroupswill help in proper evaluation of an infant withmultiple congenital contractures.

� ARTHROGRYPOSIS MULTIPLEXCONGENITA/AMYOPLASIA

The terms arthrogryposis and arthrogryposis mul-tiplex congenita (AMC) have been used looselyand interchangeably to describe any infant withmultiple congenital contractures irrespective ofunderlying etiology and prognosis. Since diag-nostic accuracy is important for understandingand predicting the clinical course of an affectedpatient as well as for counseling the parents re-garding recurrence risk, the AMC committee ofthe International Federation of Societies forSurgery of the Hand (IFSSH) recently publishedrevised criteria for appropriate use of the termarthrogryposis multiplex congenita.10 Accordingto this report, AMC is a very specific, well-definedcondition and this diagnosis should be used onlyfor cases with the following characteristics:

1. Congenital, the full clinical expression ispresent at birth

2. Not genetically inherited and not due to anembryological malformation

3. Neuropathic etiology with likely cause be-ing patchy damage of the anterior horn cellsof the spinal cord in the developing fetus

4. Usually symmetric involvement of multiplejoints-both proximal and distal joints of allfour limbs

5. No systemic involvement or anomalies ofother organs

6. Normal intellect and normal sensation7. The muscles are fewer, smaller, and often

replaced by fibrous or fibrofatty tissue8. No progression after birth but changes may

occur over time due to growth and devel-opment or interventions

9. Joint deformities are due to secondarychanges as a result of lack of joint movements

10. Typically, these children are very adaptivein overcoming loss of normal function

AMC has no gender or racial predilectionand the life expectancy is not directly affectedby this disease. Although the exact cause remains

CHAPTER 47 ARTHROGRYPOSIS 323

� TABLE 47-2 Syndromes Associated with Arthrogryposis


Antley-Bixler syndrome Brachycephaly, craniosynostosis, midfacial hypoplasia, choanal atresia, Autosomal recessivedysplastic ears, radiohumeral synostosis

Chondrodysplasia punctata IUGR, cataracts, asymmetric limb shortening, flat facies, low nasal X-linked dominantbridge, punctate calcifications on x-rays Autosomal recessive

Cerebro-oculo-facio-skeletal Neurogenic arthrogryposis, microcephaly, agenesis of corpus Autosomal recessive(COFS) syndrome callosum, camptodactyly, renal anomalies

Cornelia de Lange syndrome IUGR, weak growling cry, synophrys, microbrachycephaly, long Unknownphiltrum, thin upper lip, micrognathia, micromelia, cryptorchidism

Fetal alcohol syndrome IUGR, microcephaly, maxillary hypoplasia, smooth philtrum with thin Prenatal alcoholand smooth upper lip, cardiac defects, cleft lip and palate exposure

FG syndrome Hypertelorism, downslanting palpebral fissures, imperforate anus, X-linked recessivebroad thumb and toes, cryptorchidism, craniosynostosis, cleft lip andpalate, cardiac defects

Kniest dysplasia IUGR, flat facial features, thick joints with contractures, cataracts, Autosomal dominanttracheomalacia, platyspondyly

Lethal multiple pterygium IUGR, hypertelorism, cleft palate, malformed ears, cryptorchidism, Autosomal recessivesyndrome diaphragmatic hernia, microcephaly X-linked recessive

Marden-Walker syndome IUGR, microcephaly, blepharophimosis, immobile facies, cleft palate, Autosomal recessivehypotonia, agenesis of corpus callosum, cardiac defects,cryptorchidism

Oligohydramnios sequence Flat facies, IUGR, pulmonary hypoplasia, renal anomalies SporadicPena-Shokeir phenotype IUGR, immobile facies, neurogenic arthrogryposis, hypertelorism, Autosomal recessive

micrognathia, pulmonary hypoplasia, cryptorchidism, cleft palate,cardiac defect

Popliteal Pterygium syndrome Cleft palate/lip, popliteal webs, syndactyly, cryptorchidism, Autosomal dominantgenital abnormalities

Roberts-SC phocomelia Hypomelia, limb reduction defects of both upper and lower limbs Autosomal recessivemidfacial defects such as cleft lip and palate, microcephaly,severe IUGR, cryptorchidism, eye anomalies

Trisomy 18 IUGR, low-set malformed ears, clenched hand, heart defects, Trisomy(Edwards syndrome) rocker bottom feet, microcephaly, genital anomalies

Zellweger syndrome Hypotonia, seizures, deafness, pachymicrogysia, heterotopias, Autosomal recessive(cerebro-hepato-renal anteverted nares, cataracts, hepatomegaly, cardiac defectssyndrome) camptodactyly, cryptorchidism


32

4

obscure, it should be distinguished from spinalmuscular atrophy (SMA) which has a well-definedgenetic basis and recurrence risk. Clinically,infants with AMC have reduced or absent skinfolds around affected joints and smooth skin withdimples is seen at the large joints. In a classicalcase, the limbs have a fusiform appearance. Theshoulder joints are held in adduction, the elbowjoints in extension, the wrists in flexion, thethumbs adducted, and the finger joints in flexion.Similarly, the common findings in the lower ex-tremities are hip subluxation, knee hyperexten-sion, and talipes equinovarus deformity of feet.The muscles are firmer than normal due to re-duced mass and an increase in fibrous tissue. Thespinal muscles are involved in more severe casesand this may make it difficult for the child to sit orstand upright. A similar clinical picture, musclebiopsy findings, disease course, and recurrence riskhas been reported in the past as amyoplasia.11,12

These authors estimated that nearly one-third ofall patients with arthrogryposis have amyoplasia.However, nearly 10% of these patients were alsoreported to have other anomalies such as bowelatresia and abdominal wall defects which wouldexclude them under the more strict definition ofAMC based on IFSSH report.

� DISTAL ARTHROGRYPOSIS

The term distal arthrogryposis is used to describepatients with congenital contractures of distaljoints of upper or lower extremities and sparing ofproximal joints. Initial classifications by Hall et al4,5

have been subsequently revised and expandedby other authors.13,14 Bamshad et al defined dis-tal arthrogryposis as “an inherited primary limbmalformation disorder characterized by congenitalcontractures of two or more different body areasand without primary neurologic and/or muscledisease that affects limb function.” This definitionexcludes all disorders in which structural CNSanomalies, cognitive delay, abnormal neurologictests, and/or abnormal muscle biopsies are pri-mary features. This new revised classification of

distal arthrogryposis includes nine distinct typeswhich are characterized by a common pattern ofcongenital distal joint contractures, minimal proxi-mal joint involvement, and an autosomal dominantinheritance pattern with reduced penetrance andvariable expressivity. A detailed description ofthese syndromes was recently published by Bealsin 2005 and a summary of important findings ispresented in Table 47-3.14

� EVALUATION

A detailed family history, pregnancy history, andcomplete physical examination to evaluate extentof joint involvement as well as to determine thepresence or absence of associated dysmorphicfeatures and systemic congenital malformationsare crucial in evaluating an infant with multiplecongenital contractures. An early evaluation bya geneticist, neurologist, orthopedic surgeon,and physical therapist is likely to be helpful inidentifying the underlying cause and in devel-oping a comprehensive management plan. Theinfants with the neuropathic type of arthrogry-posis have a higher likelihood of associated con-genital anomalies while infants with myopathicarthrogryposis have a high likelihood of a pos-itive family history of neuromuscular disease andhave few associated anomalies. Since the major-ity of these infants have a neuropathic etiology,all infants with multiple congenital contracturesshould be evaluated with a magnetic resonanceimaging (MRI) of brain and spinal cord. An elec-troencephalogram (EEG) has also been reportedto be helpful in predicting prognosis.15 Echocar-diogram and abdominal ultrasound may be nec-essary to exclude anomalies of other systemsand a hearing screen should be done on all in-fants. Serum creatine phosphokinase levels,electromyography, and muscle biopsy may helpto distinguish neuropathic from myopathic cases.However, their routine use and benefit is con-troversial. Generalized progressive weakness,myopathic facies, and abnormal muscle texturewould suggest need for workup for myopathic


32

6

� TABLE 47-3 Classification and Summary of Clinical Features of Distal Arthrogryposis Syndromes

Bamshad Other Upper Lower Facial OtherClassification Names Limbs Limbs Features Features Stature Intelligence

Type 1 Digitotalar Adducted thumbs, Club fect, Normal None Normal Normaldysmor- ulnar deviation vertical talus,phism of metacarpopha- metatarsus

langeal joints, varusclenched hands

Type 2A Freeman- Ulnar deviation at Club feet +/− Deep set Scoliosis, Mild short Normal, Sheldon metacarpopha- hip and knee eyes, Laryngo- stature Mild mentalsyndrome, langeal contractures hyper- malacia, retardation +/−or whistling joint, flexion of telorism, Pectusface fingers, and puckered excavatumsyndrome metacarpopha- mouth,

langeal joint of micrognathiathumb and long

philtrumType 2B Same as type 2A Vertical talus Triangular Cervical Normal Normal

face with webbingpointed chin,downwardpalpebralslant

Type 3 Gordon Proximal Talipes Cleft palate Hearing loss, Mild short Normal, syndrome interphalangeal equinovarus, short-neck, stature Mild mental

joint contracture, toe scoliosis, retardation +/−limitation of contracture, pectuspronation, hip and patellar excavatum,supination, dislocation omphalo-and elbow flexion coele

Type 4 Same as type 3 Usually normal Normal Scoliosis, Normal Normal, torticollis, Mild mentalfusion of retardation +/−cervicalvertebra,renalanomalies

32

7

Type 5 Proximal & distal Club feet, Limited Macular Mild short Normalinterphalangeal vertical talus, expression, pigmenta- staturejoint flexion, toe deep set tion,elbow, and wrist contractures eyes, abnormalcontracture ptosis, ERG,

opthalmo- scoliosisplegia

Type 6 Same as type Stiffness of Normal Hearing loss Normal Normal5 + ulnar toesdeviationof fingers

Type 7 Hecht Hyperextension Tight Trismus Mild short Normalsyndrome of metacar- hamstrings stature

Trismus- pophalangeal and calves,pseudocamp- joints, clubfeet, toetodactyly flexion contractures,syndrome contracture metatarsus

of fingers varusType 8 Dominant Ulnar deviation Tarsal coalition, Pterygium colli, Pterygium of Short Normal

pterygium of fingers, calcaneo- short neck, axilla, elbow,syndrome finger valgus, hip ptosis, low- knee,

contractures, dislocation set ears, scoliosismild syndactyly retrognathia,

down-slantingpalpebralfissures

Type 9 Beals Proximal Hip and knee Distortion and Scoliosis, Normal Normalsyndrome, interphalangeal contracture crumpling congenital

Congenital joint Calcaneal of ears heart defectscontractual contracture, deformity Micrognathiaarachn- elbow of foot,odactyly contracture curved toes

etiology. The use of age-appropriate referenceranges and specific diagnostic criteria for nerveconduction studies, electromyography, andmuscle biopsy are critical to the appropriate useof these diagnostic modalities and their inter-pretation. It is appropriate to restrict the use ofnerve conduction studies, electromyography,and muscle biopsy to the cases in whom his-tory, examination, and genetic evaluation havebeen unrevealing. Karyotpye evaluation shouldbe considered in infants with associated sys-temic malformations. Genetic testing for sur-vival motor neuron gene deletion, 22q11.2 dele-tion, and spinal muscular atrophy should beconsidered in selected cases based on clinicalpresentation. Ear, nose, and throat (ENT) evalu-ation including direct laryngobronchoscopy ororopharyngeal videofluoroscopy may be help-ful in selected patients with upper airwaysymptoms.


The joint contractures in these infants are non-progressive but they become more severe overtime if joint immobility is maintained. Thus themainstay of management is improved joint mobil-ity with the help of physiotherapy, splinting, andorthopedic surgery if necessary. The goals of treat-ment are to achieve lower-limb alignment andstability for ambulation and upper limb range ofmotion adequate for self-care. Recurrence of de-formities with growth is frequently seen becausethe dense periarticular inelastic soft tissues do notproperly elongate with growth. The managementof most distal deformities first and then moving ina proximal direction is the recommended approachfor lower extremities. It is strongly recommendedthat the treatment should not be delayed since re-sults are very disappointing if treatment is initiatedafter 12 months of age.10 The associated cran-iomaxillofacial anomalies, stiff jaw, and immobiletongue can result in feeding difficulties, recurrentrespiratory infections, and failure to thrive andmay benefit from early placement of tracheostomyand gastrostomy tubes.

The long-term needs of these infants andfamilies are best met by a comprehensive mul-tidisciplinary team comprised of primary carephysician, geneticist, neurologist, orthopedist,otolaryngologist, developmental pediatrician,dietician, physical and occupational therapist,psychologist, orthotist, speech therapist, and so-cial worker.

The prognosis of an infant with arthrogrypo-sis will largely depend on underlying cause, pres-ence or absence of associated syndrome, and thepathologic process. This emphasizes the need fora complete evaluation of all infants born withmultiple congenital contractures. Overall, nearly35–40% of all infants with multiple congenitalcontractures die during the neonatal period or in-fancy.2,16 Infants requiring more than transientrespiratory support have a high mortality.17 Majorcongenital anomalies of the CNS and polyhy-dramnios are also reported to be poor prognosticsigns for survival. Hall reported a mortality rate of1% for infants with primarily limb involvement,7% with limb and other organ involvement, andnearly 50% for those with limb and CNS involve-ment.5 Feeding difficulties are reported in nearlytwo-thirds of all patients and nearly half of thesepatients have dysarthria and nearly one in fourmay have general language delay.18 Among sur-vivors, patients with normal intelligence andmilder forms of contractures tend to have a betterquality of life. Long-term outcome is particularlyfavorable for infants diagnosed to have classicalarthrogryposis (AMC or amyoplasia) as these in-fants are reported to have normal to above normalintelligence. In a series of 38 patients, Sells et al re-ported that by the age of 5 years, 85% were ambu-latory and most were in regular classrooms at theappropriate grade level.11


The recurrence risk will depend on the underlyingetiology. In general, the recurrence risk is higherin the myopathic group than in the neuropathicgroup. Since amyoplasia or arthrogryposis mul-tiplex congenita is a sporadic condition with


unknown etiology, a couple with a child with thisdisorder has no increased risk over the generalpopulation risk.11 In the absence of a clear etiol-ogy, Hall and Reed reported the recurrence riskas 4.7% if only the limbs were involved, 1.4% ifthe limbs plus other areas were involved, and 7%if the central nervous system was involved.19 Inabsence of a complete workup and a specificdiagnosis, the recurrence risk of having anotheraffected child is reported to be about 3–5%.6

Serial ultrasounds can identify an affected fetusin early second trimester in many cases.

REFERENCES

1. Darin N, Kimber E, Kroksmark AK, et al. Multiplecongenital contractures: birth prevalence, etiology,and outcome. J Pediatr. Jan 2002;140(1):61–7.

2. Silberstein EP, Kakulas BA. Arthrogryposis multi-plex congenita in Western Australia. J PaediatrChild Health. Dec 1998;34(6):518–23.

3. Wynne-Davies R, Williams PF, O’Connor JC. The1960s epidemic of arthrogryposis multiplex con-genita: a survey from the United Kingdom, Australia,and the United States of America. J Bone Joint SurgBr. Feb 1981;63-B(1):76–82.

4. Hall JG. Genetic aspects of arthrogryposis.Clin Orthop Relat Res. Apr 1985(194):44–53.

5. Hall JG. Arthrogryposis multiplex congenita: etiol-ogy, genetics, classification, diagnostic approach,and general aspects. J Pediatr Orthop B. Jul 1997;6(3):159–66.

6. Wong V. The spectrum of arthrogryposis in 33Chinese children. Brain Dev. Apr 1997;19(3):187–96.

7. Aroojis AJ, King MM, Donohoe M, et al. Congenitalvertical talus in arthrogryposis and other contracturalsyndromes. Clin Orthop Relat Res. May 2005(434):26–32.

8. Steinberg B, Nelson VS, Feinberg SE, et al. Incidenceof maxillofacial involvement in arthrogryposis mul-tiplex congenita. J Oral Maxillofac Surg. Aug 1996;54(8):956–9.

9. Paugh DR, Koopmann CF Jr, Babyak JW. Arthro-gryposis multiplex congenita: otolaryngologicdiagnosis and management. Int J Pediatr Otorhi-nolaryngol. Oct 1988;16(1):45–53.

10. Mennen U, van Heest A, Ezaki MB, et al. Arthro-gryposis multiplex congenita. J Hand Surg [Br].Oct 2005;30(5):468–74.

11. Sells JM, Jaffe KM, Hall JG. Amyoplasia, the mostcommon type of arthrogryposis: the potential forgood outcome. Pediatrics. Feb 1996;97(2):225–31.

12. Bernstein RM. Arthrogryposis and amyoplasia.J Am Acad Orthop Surg. Nov–Dec 2002;10(6):417–24.

13. Bamshad M, Jorde LB, Carey JC. A revised and ex-tended classification of the distal arthrogryposes.Am J Med Genet. Nov 1996;65(4):277–81.

14. Beals RK. The distal arthrogryposes: a new classifica-tion of peripheral contractures. Clin Orthop Relat Res.Jun 2005(435):203–10.

15. Fedrizzi E, Botteon G, Inverno M, et al. Neurogenicarthrogryposis multiplex congenita: clinical and MRIfindings. Pediatr Neurol. Sep–Oct 1993; 9(5):343–8.

16. Hageman G, Willemse J, van Ketel BA, et al. Thepathogenesis of fetal hypokinesia. A neurologicalstudy of 75 cases of congenital contractures withemphasis on cerebral lesions. Neuropediatrics.Feb 1987;18(1):22–33.

17. Bianchi DW, Van Marter LJ. An approach toventilator-dependent neonates with arthrogryposis.Pediatrics. Nov 1994;94(5):682–6.

18. Robinson RO. Arthrogryposis multiplex congenita;feeding, language, and other health problems.Neuropediatrics. Nov 1990;21(4):177–8.

19. Hall JG, Reed SD. Teratogens associated with con-genital contractures in humans and in animals.Teratology. Apr 1982;25(2):173–91.



Part IX

MiscellaneousMalformations



Chapter 48

Single Umbilical ArteryPRAVEEN KUMAR

333

� INTRODUCTION

The umbilical cord is an important part of thefetoplacental unit and is vital to the growth andwell-being of the fetus. A normal umbilical cordis about 50–60 cm long at term and containstwo arteries and one vein which course throughWharton’s jelly in a helical fashion. Single um-bilical artery, a condition in which only oneumbilical artery is present, is one of the mostcommon congenital malformations in a humaninfant. Although presence of a single umbilicalartery was noted as early as the mid-sixteenth cen-tury, its association with various other congenitalmalformations was reported by Benirschke andBrown in 1955. Since then several reports fromdifferent parts of the world have confirmed ahigher incidence of associated malformations ininfants with single umbilical artery.

� EPIDEMIOLOGY

The incidence of single umbilical artery has beenreported to be 1.5–7% among abortuses, 0.2–1.6%among euploid fetuses, 9–11% among aneuploidfetuses, and 0.5–2.5% among uncomplicatedneonates.1–3 The overall incidence of single um-bilical artery in unselected populations has beenreported to range from 0.3% to 1.07%.4–6 These

differences in incidence rates are related tomethod of diagnosis such as, prenatal ultrasounddiagnosis or postnatal examination of the cordversus histopathological examination of the pla-centa or cord. The histopathological examinationof the cord is considered to be the gold standardbut it is important to note that the two arteriesmay fuse close to the placental insertion of thecord and examination at this point would over-estimate the incidence.1 The sensitivity of prena-tal ultrasound for diagnosis of single umbilicalartery has been reported to range from 30% to85% depending on the experience of the sonog-rapher as well as the indication for ultrasound,routine versus anatomic survey for congenitalmalformations.2,5,7 A study evaluating physician’sability to diagnose single umbilical artery on post-natal examination reported that the diagnosis ofsingle umbilical artery was missed by 24% ofobstetricians and 16% of pediatricians on exami-nation of cord.7

Single umbilical artery is reported to be lesscommon in patients with Japanese and Africanancestry and is more common in those fromEastern Europe.1,8 A significantly higher inci-dence has been noted in pregnancies associatedwith multiple gestations, maternal diabetes, andhypertension. A higher incidence of abnormalitiesof placenta such as marginal insertion and vela-mentous insertion of cord has also been noted.9


A six- to tenfold increase in perinatal mortalityrate has been reported in pregnancies associatedwith single umbilical artery.5,9–11 This increase inperinatal mortality was largely secondary to asso-ciated congenital malformations and intrauterinegrowth retardation (IUGR) but an increase in peri-natal mortality has been reported even in infantswith apparent isolated single umbilical artery.5,11

� EMBRYOLOGY

The umbilical cord and its elements are derivedearly in embryonic life from the primitive yolksac, connecting stalk, and amnion. Initially, twoparallel vascular systems develop from angio-genic mesenchyme that surrounds the vitellineduct and the allantoic duct. Two vitelline arteriesand two vitelline veins quickly regress and arenot identifiable by the end of pregnancy. Theumbilical arteries and veins develop from angio-genic mesenchyme around the allantoic duct.Initially, a single umbilical artery forms whichsubsequently bifurcates in two umbilical arteries.On the other hand, the umbilical veins are ini-tially paired structures but, the right umbilicalvein and a portion of the left umbilical vein de-generate early in gestation and the left umbilicalvein persists as a single umbilical vein during restof the gestation.12

Three mechanisms have been proposed toexplain the embryogenesis of single umbilicalartery: (1) persistence of the original single allan-toic artery of the body stalk, (2) primary agenesisof one umbilical artery, (3) secondary atrophy oratresia of a previously normal umbilical artery.12

Accumulating evidence in the literature stronglysuggests that secondary atrophy or atresia is themost likely mechanism in a large majority of in-fants with single umbilical artery.1,13,14 Based onthese different mechanisms, four possible typesof single umbilical artery have been described asfollows:1 (1) type I single umbilical artery is themost common form that has one umbilical arteryof allantoic derivation and a left umbilical vein;(2) type II single umbilical artery has one umbilical

artery of vitelline origin and a left umbilical vein.The umbilical artery frequently originates from thesuperior mesenteric artery. This type of SUA is al-most invariably associated with severe fetal mal-formations such as sirenomelia, caudal regression,and anal agenesis; (3) type III single umbilicalartery has one umbilical artery of either allantoicor vitelline origin and both, the left and an anom-alous persistent right, umbilical veins. This type isextremely rare and is associated with universallypoor prognosis and fetal malformations; (4) type IVsingle umbilical artery has one umbilical artery ofallantoic or vitelline origin and the right umbilicalvein. Only a few cases have been reported todate and these fetuses were lost early in thepregnancy.


The increased rate of congenital malformationsin association with single umbilical artery hasbeen reported by several studies and ranges from7% to 65% depending on the differences in thedefinition of malformation, methods used fordiagnosis and the reporting practices.1,8,14–16

These malformations occur in no consistent pat-tern and can occur in any organ system. No knownmalformation sequence or syndrome is consis-tently associated with single umbilical artery. Astudy based on birth registry data reported afourfold increase in the incidence of major con-genital malformations in babies with two-vesselumbilical cords (10% for infants with single um-bilical artery versus 2.6% for infants with three-vessel cord).17 The most prominent associations(odds ratio >5) in this study were with neural tubedefects, cardiovascular malformations, esophagealand anorectal atresia, polycystic kidneys, andlimb reduction defects. The mean numbers ofmalformations per infant have been reported torange from 2 to 5.1 Persutte and Hobbins di-vided single umbilical artery associated congen-ital malformations into three groups: (1) whichcan be identified with prenatal ultrasound;

334 PART IX MISCELLANEOUS MALFORMATIONS

(2) difficult to be diagnosed prenatally; and (3)unlikely to be diagnosed prenatally (Table 48-1).Using these criteria they concluded that nearlytwo-thirds of all congenital malformations associ-ated with single umbilical artery could be missedon a prenatal ultrasound examination.1

Trisomy 18 is the most common cytogeneticabnormality reported in infants with single um-bilical artery but, trisomy 13 and Turner syndromehave also been reported. Single umbilical arteryhas an incidence of 11.3% among cytogenetically

abnormal pregnancies and can be found in10–50% of trisomy 18 patients.18 Some othercommon syndromes associated with single um-bilical artery are listed in Table 48-2.

� EVALUATION

The guidelines for evaluation and managementof a fetus or newborn with single umbilicalartery have been controversial and limited by

CHAPTER 48 SINGLE UMBILICAL ARTERY 335

�TABLE 48-1 Reported Congenital Anomalies in Fetuses with Single Umbilical Artery and TheirLikelihood of Detection on Prenatal Ultrasound

System Expect to Detect Difficult to Detect Unlikely to Detect

Cardiovascular • Tetralogy of Fallot • Total anomalous • Patent ductus arteriosussystem • Truncus arteriosus pulmonary • Ventricular septal defect

• Dextrocardia venous return • Coarctation of aorta• Hypoplastic left heart • Transposition of

great vesselsCentral nervous • Anencephaly • Cranial nerve

system • Holoprosencephaly abnormalities• Hydrocephaly• Cerebellar anomalies• Meningomyelocoele

Gastrointestinal • Gastric atresia • Tracheoesophageal • Esophageal atresiasystem • Duodenal atresia fistula • Malrotation

• Abdominal wall • Liver anomalies • Imperforate anusdefects

Urogenital tract • Renal agenesis • Pelvic kidney Urorectal septum• Renal dysplasia • Horseshoe kidney malformation• Hydronephrosis • Malformed external • Urethral anomalies

genitaliaRespiratory system • Diaphragmatic • Pulmonary hypoplasia

hernia • Choanal artesia• Tracheal agenesis

Musculoskeletal • Sacral agenesis • Cleft lip/palate • High arched palatesystem • Amelia • Vertebral anomalies • Wrist and ankle

• Limb dysplasias • Hip dislocation deformities• Poly/syndactyly

Miscellaneous • Situs inversus • Pharyngeal teratoma • Endocrine gland• Sacrococcygeal abnormalities

Teratoma

(Adapted from Persutte WH, Hobbins J. Single umbilical artery: a clinical enigma in modern prenatal diagnosis.Ultrasound Obstet Gynecol. Sep 1995;6(3):216–29. Copyright 1995 International Society of Ultrasound inObstetrics & Gynecology. Reproduced with permission. Permission is granted by John Wiley & Sons Ltd. Onbehalf of the ISUOG)

the paucity of prospective studies and the smallsample size in the majority of retrospective re-ports. However, most authors support a detailedlevel II ultrasonographic evaluation of a fetuswith single umbilical artery to assess for thepresence of any associated congenital malforma-tions.1,13,19–23 Some studies have also supportedthe use of routine fetal echocardiogram.13,19,20,23

Genetic counseling, amniocentesis, and kary-otype evaluation is recommended if any addi-tional congenital malformations are identified.

However, the guidelines for management ofa neonate born with apparently isolated singleumbilical artery are even less clear. A meta-analysis published in 1998 concluded that exten-sive urologic radiographic investigation inasymptomatic newborns with “isolated” singleumbilical artery was not necessary.8 The diag-nosis of “isolated” single umbilical artery in thesestudies was primarily based on a normal physi-cal examination and absence of any symptomsat birth. However, several other authors have


� TABLE 48-2 Syndromes Associated with Single Umbilical Artery


Cloacal exstrophy Persistence of cloaca, omphalocele, hydromyelia, Unknownsequence cryptorchidism, pelvic kidneys, multicystic kidneys

Jarcho-Levin syndrome Short trunk dwarfism, prominent occiput, upslanting Autosomal (spondylothoracic palpebral fissures, short “crab-like” thorax, vertebral recessivedysplasia) anomalies, cleft palate, cryptorchidism neural tube

defects, genitourinary anomaliesLEOPARD syndrome Lentigenes, ECG abnormalities, ocular hypertelorism, Autosomal

(multiple lentigines pulmonic stenosis, abnormalities of genitalia, dominantsyndromes) retardation of growth, deafness

Meckel-Gruber syndrome Occipital encephalocele, polydactyly, cleft lip and/or Autosomalpalate, micropthalmia, ambiguous genitalia, IUGR, recessivemicrocephaly, cryptorchidism, cardiac defects

OEIS complex Omphalocele, exstrophy of bladder, imperforate anus, Unknownspinal defects

Sirenomelia sequence Single lower extremity, absence of sacrum, vertebral Unknowndefects, anorectal malformations, genitourinaryanomalies

Trisomy 13 Holoprosencephaly, micropthalmia, cyclopia, Trisomy(Patau syndrome) microcephaly, cleft lip and palate, heart defects,

IUGR, genital abnormalitiesTrisomy 18 IUGR, low-set malformed ears, clenched hand, heart Trisomy

(Edwards syndrome) defects, rocker bottom feet, microcephaly,genital anomalies

Urorectal septum Ambiguous genitalia, imperforate anus, rectal fistulas, Unknownmalformation sequence Müllerian duct defects

VACTERL association Vertebral, anal, cardiac, tracheal, esophageal, Unknownrenal and limb anomalies, single umbilical artery,spinal dysraphia, genital abnormalities

Zellweger Syndrome Hypotonia, seizures, deafness, pachymicrogyria, Autosomal(Cerebro-Hepato-Renal heterotopias, anteverted nares, cataracts, recessiveSyndrome) hepatomegaly, cardiac defects, camptodactyly,

cryptorchidism

IUGR, intrauterine growth retardation; ECG, electrocardiogram.

questioned these recommendations and recom-mend routine renal ultrasound with or withoutmicturating cystourethrogram in all infants withsingle umbilical artery.1,24,25 These recommen-dations are based on observations that nearly16% of infants with isolated single umbilicalartery have a renal anomaly and in half of thesecases, these malformations are severe and per-sistent on follow up.25 There are no existingrecommendations for cranial ultrasound,echocardiogram, or genetic evaluation of theseinfants. However, review of obstetric literatureclearly indicates that the incidence of associatedcongenital malformations is significantly higherin fetuses with single umbilical artery and 5–30%of fetuses with single umbilical artery and a nor-mal prenatal ultrasound are noted to have ma-jor congenital malformations at birth.5,15,20,22

IUGR is common among infants with single um-bilical artery and the incidence of associatedcongenital malformations is reported to be higherin fetuses with IUGR. Based on this data, it seemsappropriate that all neonates with single umbili-cal artery should be examined thoroughly at birthfor the presence of any dysmorphic features andminor or major external congenital malforma-tions. Tracheoesophageal fistula and loweranorectal anomalies should be excluded. The de-cision to perform cranial, renal ultrasound andechocardiography should be made based on theextent and reliability of prenatal evaluations andpostnatal examination. These noninvasive stud-ies should be strongly considered in an infantwith no prenatal evaluation, IUGR, and in infantswith other anomalies on exam; but could be de-ferred in asymptomatic, healthy infant with neg-ative level II USG and fetal echocardiography.Future studies will be necessary to answer thesequestions conclusively.

� PROGNOSIS

Low placental weight and IUGR are frequentlyseen in infants with single umbilical artery at birth.IUGR is reported to occur in 26–28% of all cases

of single umbilical artery and 15–20% of caseswhere no other associated congenital anomalieswere seen.1 Perinatal mortality rates are also sig-nificantly higher in these infants even in absenceof associated anomalies and range from 8% to60%, with a mean mortality rate of 20%.1,5 Theside of the missing artery has no predictive valuefor poor outcome.19 There are no recent long-term studies to evaluate the outcome of infantsborn with single umbilical artery beyond infancy.

REFERENCES

1. Persutte WH, Hobbins J. Single umbilical artery:a clinical enigma in modern prenatal diagnosis.Ultrasound Obstet Gynecol. Sep 1995;6(3):216–29.

2. Hill LM, Wibner D, Gonzales P, et al. Validity oftransabdominal sonography in the detection ofa two-vessel umbilical cord. Obstet Gynecol.Nov 2001;98(5 Pt 1):837–42.

3. Predanic M, Perni SC, Friedman A, et al. Fetalgrowth assessment and neonatal birth weight infetuses with an isolated single umbilical artery.Obstet Gynecol. May 2005;105(5 Pt 1):1093–7.

4. Blache G, Garba A, Frairot P, et al. Prognostic valueof a single umbilical artery. 87 cases. J GynecolObstet Biol Reprod (Paris). 1995;24(5):522–28.

5. Gornall AS, Kurinczuk JJ, Konje JC. Antenatal de-tection of a single umbilical artery: does it matter?Prenat Diagn. Feb 2003;23(2):117–23.

6. Volpe G, Volpe P, Boscia FM, et al. “Isolated” sin-gle umbilical artery: incidence, cytogenetic abnor-malities, malformation, and perinatal outcome.Minerva Ginecol. Apr 2005;57(2):189–98.

7. Jones TB, Sorokin Y, Bhatia R, et al. Single umbili-cal artery: accurate diagnosis? Am J Obstet Gynecol.Sep 1993;169(3):538–40.

8. Thummala MR, Raju TN, Langenberg P. Isolatedsingle umbilical artery anomaly and the risk forcongenital malformations: a meta-analysis. J PediatrSurg. Apr 1998;33(4):580–5.

9. Heifetz SA. Single umbilical artery. A statistical analy-sis of 237 autopsy cases and review of the literature.Perspect Pediatr Pathol. Winter 1984;8(4):345–78.

10. Clausen I. Umbilical cord anomalies and antena-tal fetal deaths. Obstet Gynecol Surv. Dec 1989;44(12):841–5.

11. Lilja M. Infants with single umbilical artery studiedin a national registry. 2: survival and malformations

CHAPTER 48 SINGLE UMBILICAL ARTERY 337

in infants with single umbilical artery. PaediatrPerinat Epidemiol. Oct 1992;6(4):416–22.

12. Monie IW. Genesis of single umbilical artery.Am J Obstet Gynecol. Oct 1970;108(3):400–5.

13. Abuhamad AZ, Shaffer W, Mari G, et al. Single um-bilical artery: does it matter which artery is missing?Am J Obstet Gynecol. Sep 1995;173(3 Pt 1):728–32.

14. Catanzarite VA, Hendricks SK, Maida C, et al. Pre-natal diagnosis of the two-vessel cord: implica-tions for patient counselling and obstetric man-agement. Ultrasound Obstet Gynecol. Feb 1995;5(2):98–105.

15. Chow JS, Benson CB, Doubilet PM. Frequency andnature of structural anomalies in fetuses with singleumbilical arteries. J Ultrasound Med. Dec 1998;17(12):765–8.

16. Sener T, Ozalp S, Hassa H, et al. Ultrasonographicdetection of single umbilical artery: a simple markerof fetal anomaly. Int J Gynaecol Obstet. Aug 1997;58(2):217–21.

17. Lilja M. Infants with single umbilical artery studiedin a national registry. General epidemiologicalcharacteristics. Paediatr Perinat Epidemiol.Jan 1991;5(1):27–36.

18. Saller DN Jr., Keene CL, Sun CC, et al. The associ-ation of single umbilical artery with cytogeneticallyabnormal pregnancies. Am J Obstet Gynecol.Sep 1990;163(3):922–5.

19. Budorick NE, Kelly TF, Dunn JA, et al. The singleumbilical artery in a high-risk patient population:what should be offered? J Ultrasound Med. Jun 2001;20(6):619–27; quiz 628.

20. Geipel A, Germer U, Welp T, et al. Prenatal diag-nosis of single umbilical artery: determination ofthe absent side, associated anomalies, Dopplerfindings, and perinatal outcome. Ultrasound ObstetGynecol. Feb 2000;15(2):114–7.

21. Jauniaux E. The single artery umbilical cord: it isworth screening for antenatally? Ultrasound ObstetGynecol. Feb 1995;5(2):75–76.

22. Lee CN, Cheng WF, Lai HL, et al. Perinatal man-agement and outcome of fetuses with single um-bilical artery diagnosed prenatally. J Matern FetalInvestig. Dec 1998;8(4):156–9.

23. Prucka S, Clemens M, Craven C, et al. Single um-bilical artery: what does it mean for the fetus?A case-control analysis of pathologically ascertainedcases. Genet Med. Jan–Feb 2004;6(1):54–7.

24. Pomeranz A. Anomalies, abnormalities, and care ofthe umbilicus. Pediatr Clin North Am. Jun 2004;51(3):819–27, xii.

25. Srinivasan R, Arora RS. Do well infants born withan isolated single umbilical artery need investigation?Arch Dis Child. Jan 2005;90(1):100–1.


Chapter 49

Sacral Dimple and OtherCutaneous Markers of Occult

Spinal DysraphismPRAVEEN KUMAR

339

� INTRODUCTION

The association between congenital cutaneouslesions and underlying dysraphic conditions ofthe spinal cord has been known for severaldecades. Spinal dysraphism is one of the mostcommon congenital malformations of the centralnervous system (CNS). The incidence of opendefects, such as meningomyelocele, is reportedto be up to 2 per 1000 live births and the occultlesions are likely to have an even higher inci-dence. Since a significant proportion of individ-uals with occult spinal dysraphism remainasymptomatic and are never diagnosed, the ex-act incidences of occult spinal dysraphism andcutaneous markers of occult spinal dysraphismare not entirely clear. Although as many as45–95% of infants with occult spinal dys-raphism have a cutaneous abnormality of thelumbosacral region, not all cutaneous lesionscan accurately predict the presence of an un-derlying occult spinal dysraphism.1,2

� EPIDEMIOLOGY

The incidence of potential dorsal cutaneousmarkers of occult spinal dysraphism in thehealthy neonatal population is reported to rangefrom 1.9% to 7.2%.3–6 North American andBritish studies have reported simple dimples asthe most common cutaneous marker and theselesions account for 75% of all infants presentingwith cutaneous markers of occult spinal dys-raphism.3,5 In contrast, a hair patch was the mostcommon finding in the only study from SouthAmerica, highlighting ethnic differences in thedistribution of these findings.6 Nearly 2–8% ofall infants with cutaneous markers are diag-nosed to have occult spinal dysraphism onspinal ultrasound and as many as 40% of all in-fants with atypical dimples and 60–70% of all in-fants with two or more cutaneous markers havebeen reported to have underlying occult spinaldysraphism on screening ultrasound.1,3,5,7 Morethan one cutaneous lesion suggestive of occult


spinal dysraphism are reported in about 5% of allinfants with cutaneous markers but are present innearly two-thirds of all infants with occult spinaldysraphism.8 No consistent risk factors or gen-der differences have been reported.

� EMBRYOLOGY

Both skin and nervous system share a commonectodermal origin during early embryogenesis.The separation of neural and cutaneous ecto-derm, a process called disjunction, occurs be-tween the third and fifth week of gestation andis one of the most vulnerable stages in the hu-man development. With complete separation ofneural and cutaneous ectoderm, mesoderm in-serts between these two layers and formsmeninges, vertebral column, and muscles. In-complete separation of neural and cutaneousectoderm results in abnormal development ofthe spinal cord with or without a persistent con-nection with the overlying skin and may alsoproduce abnormalities in the tissues derivedfrom mesoderm and cutaneous ectoderm.


The term occult spinal dysraphism includes avariety of spinal malformations which arecaused by imperfect fusion of midline neural,mesenchymal, and bony structures and are cov-ered by intact skin. In most cases, the neurallesion is often subtle, and the major overt ab-normality involves the vertebrae, the overlyingdermal structures, or both. The skin lesions as-sociated with occult spinal dysraphism have beenreported under many different names such as “der-mal stigmata,” “cutaneous markers,” and “cuta-neous signatures” among others, and usually arethe only clinical feature suggestive of occult spinaldysraphism in an otherwise healthy newborn.Cutaneous markers are present in nearly 45–95%of all patients with occult spinal dysraphism andmay occur alone or in combination.2,9,10 Most of

these lesions are seen in the lumbosacral regionbut may also be present in cervical or thoracicregion and have similar clinical significance.The following skin lesions have been describedin these patients.

� DIMPLES AND DERMAL SINUSES

Cutaneous dimples (Fig. 2-5) are commonly seenin lumbosacral area and are a common cause ofphysician anxiety. Although, these can be a signof occult spinal dysraphism, most infants arehealthy and do not require any imaging studies.A cutaneous dimple within the gluteal crease isusually benign and is also called a typical orsimple dimple or coccygeal pit, and may occur innearly 4–5% of normal infants.11,12 Lesions whichare >5 mm in diameter, >2.5 cm above the anusor cephalad to the gluteal crease or associatedwith other cutaneous markers are called atypi-cal dimples. Atypical dimples are associated withoccult spinal dysraphism in as many as 40% ofpatients and neuroimaging studies are indicatedin these infants. Dimples are sometimes referredto as “shallow” or “deep” dimples based onwhether the bottom of the canal is visible or not.This observation is not reliable and should notbe used as a criterion for further workup. Der-mal sinuses are epithelium-lined fistulae whichextend from the skin surface inward for a vari-able distance and connect to the meninges innearly 50% of cases.13 The incidence of dermalsinuses is reported as 1 in 2500 live births.11

A midline dimple may be an only finding onclinical examination. Associated vertebral anom-alies are not common but have been reported.Complications of dermal sinuses are related totheir association with dermoid or epidermoid tu-mors, association with other types of occultspinal dysraphism and the risk of infection. Teth-ered cord may be present in nearly 80% and in-tradural tumor in 50% of patients with dermal si-nuses.11 These lesions are located above thegluteal cleft and tract is directed superiorly andmay extend a considerable distance to terminate


several spinal segments above the cutaneousopening. All dermal sinuses above the glutealcrease should be presumed to have communi-cation with subarachnoid space until proven oth-erwise. The majority of all dermal sinuses occurin the lumbosacral area but can occur anywherealong the spine.

� HYPERTRICHOSIS/HAIRYPATCH

An unusual pattern of hair growth along themidline is another common cutaneous markerof occult spinal dysraphism. It is important todifferentiate abnormal hair patches from normalmild hypertrichosis seen in certain ethnic groupssuch as Mediterranean and Hispanic popula-tions. Hair growth in a normal infant is morediffuse, less thick, and has normal skin underthe hair. In contrast, abnormal hair growth is of-ten localized to the lumbosacral area and maypresent as a “silky down” or “faun tail.” Silkydown is a hairy line of fine, soft, lanugo hairlimited to a discrete midline area. A faun tail isa wide, often triangular or lozenge-shaped patchof coarse hair, usually several inches long andlocalized to the lumbosacral region (Fig. 49-1).The underlying skin in an infant with an abnor-mal hair patch is coarser than the surroundingskin. These hairy patches are frequently associ-ated with diastematomyelia and tethered cord.Cosmetic treatment of these lesions is con-traindicated before complete neurologic and ra-diologic evaluation has been completed.

� LIPOMAS

Lipomas either occurring alone or in combina-tion with other cutaneous markers are the mostcommon midline cutaneous lesions associatedwith occult spinal dysraphism and are reportedin nearly half of these patients.1 These lesionsare usually but not always located in the mid-line, can present as a subcutaneous mass or de-viated gluteal fold, and can go unnoticed foryears (Fig. 49-2).

CHAPTER 49 SACRAL DIMPLE AND OTHER CUTANEOUS MARKERS 341

Figure 49-1. Faun tail hypertrichosis (Reprintedwith permission from Guggisberg D, Hadj-RabiaS, Viney C, et al. Skin markers of occult spinaldysraphism in children: a review of 54 cases.Arch Dermatol. Sep 2004;140(9):1109–15.Copy-right 2004, American Medical Association. Allrights reserved.)

Figure 49-2. Sacral lipoma and deviatedgluteal fold (Reprinted with permission fromGuggisberg D, Hadj-Rabia S, Viney C, et al. Skinmarkers of occult spinal dysraphism in children:a review of 54 cases. Arch Dermatol. Sep2004;140(9):1109–15.Copyright 2004, AmericanMedical Association. All rights reserved.)

� HEMANGIOMA AND OTHERVASCULAR MALFORMATIONS

Midline, lumbosacral hemangiomas, and te-lengiectasias have also been reported as mark-ers of occult spinal dysraphism (Figs. 49-3 and49-4).14,15 Hemangiomas associated with occult

spinal dysraphism are usually >4 cm in size andare frequently associated with other cutaneousmarkers of occult spinal dysraphism.2,9 Theneed for neuroimaging studies in an infant withsolitary capillary malformation is less clear.16,17

� APLASIA CUTIS ANDCONGENITAL SCARS

Aplasia cutis is a congenital absence of skinand occurs most frequently on the scalp. Apla-sia cutis and its variant lesion in the lumbosacralarea have been reported in association with oc-cult spinal dysraphism.10 A small area of scari-fied loss of skin described as a “cigarette burn”in association with occult spinal dysraphismmay also be a variant of aplasia cutis.

� ACROCHORDONS, TAILS,AND PSEUDOTAILS

An acrochordon is a small flesh-colored or darkbrown papule or nodule which is skin covered,sessile, or pedunculated and is composed ofepidermis and dermal stalk. These lesions arealso described as “skin tags” sometimes. A true


A B

Figure 49-4. A. Lumbosacral port-wine stain, lipoma, dermal sinus, and deviated gluteal fold.B. Lumbosacral hamartoma (Reprinted with permission from Guggisberg D, Hadj-Rabia S, VineyC, et al. Skin markers of occult spinal dysraphism in children: a review of 54 cases. Arch Dermatol.Sep 2004;140(9):1109–15. Copyright 2004, American Medical Association. All rights reserved.)

Figure 49-3. Lumbosacral hemangioma(Reprinted with permission from Guggisberg D,Hadj-Rabia S, Viney C, et al. Skin markers of oc-cult spinal dysraphism in children: a review of 54cases. Arch Dermatol. Sep 2004;140(9):1109–15.Copyright 2004, American Medical Association.All rights reserved.)

or persistent vestigial tail is a caudal midline ap-pendage consisting of a central core of muscle,adipose tissue, connective tissue, blood vessels,and nerves (Fig. 49-5). A true tail may havespontaneous or reflex motion. In contrast, apseudotail is a caudal protrusion of normal orabnormal tissues such as adipose tissue, carti-lage, or teratoma. These lesions have been as-sociated with occult spinal dysraphism.

Hyper- and hypopigmented lesions havealso been reported in association with occultspinal dysraphism but these associations are lessclearly defined.

� SIGNIFICANCE OF AN EARLYDIAGNOSIS OF OCCULT SPINALDYSRAPHISM

The term occult spinal dysraphism includes manydifferent congenital malformations of the spine

such as spina bifida occulta, diastematomyelia,tethered cord, intraspinal lipoma, dermal sinus,dermoid cysts, and lipomyelomeningoceles amongothers. Abnormalities of the conus medullaris andfilum terminale are the most common findingsin infants with occult spinal dysraphism. Theconus is usually prolonged and filum terminaleis thickened and these structures may be “teth-ered” or fixed at their caudal end. Tethering ofthe cord can result in mechanical traction on thecord in some cases as the bony spine growsfaster than the spinal cord in early infancy. Thecord traction may also impair the microcircula-tion of the cord, causing progressive ischemiaand neural dysfunction.8 In other lesions, me-chanical pressure on the neural tissue or a combi-nation of both traction and pressure is responsiblefor neurological damage, which may be progres-sive and irreversible in some cases. Althoughearlier studies had suggested that early surgicalintervention may prevent neurological dysfunc-tion and improve long-term outcome in patientswith occult spinal dysraphism, these results havebeen questioned by some recent studies.8 How-ever, early detection and surgical excision of thedorsal dermal sinus can prevent recurrent in-traspinal infection and its associated morbidityand mortality.

� EVALUATION

Although early detection and prompt neurosur-gical intervention in patients with occult spinaldysraphism may be beneficial, it is equally im-portant to identify infants not at risk of associ-ated occult spinal dysraphism accurately toavoid parental anxiety and indiscriminate use oflimited resources. Several studies have shownthat a simple dimple or coccygeal pit is not as-sociated with occult spinal dysraphism and noworkup is necessary in these infants.3,5–7 Thesestudies have also reported that a combination oftwo or more congenital midline skin lesions isthe strongest marker of occult spinal dys-raphism. However, the relative significance ofeach cutaneous marker when present alone, has


Figure 49-5. A human tail (Reprinted withpermission from Guggisberg D, Hadj-Rabia S,Viney C, et al. Skin markers of occult spinal dys-raphism in children: a review of 54 cases. ArchDermatol. Sep 2004;140(9):1109–15.Copyright2004, American Medical Association. All rightsreserved.)

been a matter of dispute. It is recommended tohave a high index of suspicion in the presenceof a lipoma, true or pseudotails, a dermal sinus,aplasia cutis, or faun tail hypertrichosis. In contrast,the index of suspicion is lower for nonspecifichypertrichosis, isolated vascular malformations, orpigmentary abnormalities. It is also important toremember that dimples or sinuses should notbe probed because of the risk of injuring neuralstructures as well as the risk of introducing in-fection. Similarly, lumbar puncture should beavoided, if possible, to prevent inadvertenttrauma to a low-lying tethered cord.

Based on current evidence, Robinson et alproposed the following questionnaire to helpclinicians decide when to evaluate infants withcutaneous markers of occult spinal dysraphism.7

1. Was the antenatal scan abnormal?2. Is the cutaneous lesion other than a simple

dimple or pit? (Simple dimple was definedas ≤5 mm in diameter, in the midline and<2.5 cm from the anus)

3. Are there any other occult spinal dysraphismassociated congenital abnormalities such asgenitourinary malformations or the anom-alies associated with the CEARMS (cloacalexstrophy anorectal malforation-spectrum)or VACTERL (vertebral, anal, cardiac, tracheal,esophageal, renal, and limb) syndromes?

4. Are there any occult spinal dysraphism-associated neurologic, urologic, or orthopedicsigns or symptoms such as, urinary inconti-nence, weakness, spasticity, loss of sensation,scoliosis, talipes, congenital dislocation ofhip, or pes cavus?

If the answer is “yes” to any of these ques-tions, a screening ultrasound should be per-formed. An ultrasound of the spine should alsobe done in any infant with an infected dimpleor dermal sinus irrespective of the site of lesion.

Some recent studies have shown that a mag-netic resonance imaging (MRI) of the spine isthe best radiologic imaging modality in thesepatients.1,18 Because the posterior elements

of the spine are not ossified in the neonate,high-resolution spinal ultrasound allows quickand noninvasive evaluation of the spinal cord,costs less than MRI, and does not require anypremedication for sedation which makes it thepreferred method of screening newborns withcutaneous markers of occult spinal dysraphism.It is important to explore the entire spinal cordbecause the skin defect does not always overliethe underlying spinal dysraphism. An importantlimitation of ultrasound is interoperator variabil-ity based on their experience with this infre-quent test. The sensitivity of neonatal ultrasoundfor detection of occult spinal dysraphism is re-ported to be in 50–70% range.9,19 In view of theselimitations, some authors suggest that all infantswith two or more cutaneous markers or an iso-lated cutaneous marker in the high index of sus-picion group should get an MRI of the spine asinitial evaluation. For all other infants, MRI shouldbe done if the initial ultrasound is abnormal,equivocal, or technically difficult.


If proven to be associated with occult spinaldysraphism, these lesions should be consideredto be part of the neural tube defect spectrumand have similar recurrence risk and genetic im-plications, which are discussed in the chapteron spina bifida (Chap. 4). Recurrence risk datafor infants with these lesions in the absence ofassociated occult spinal dysraphism is not wellstudied but is likely to be same as in the generalpopulation.

REFERENCES

1. Guggisberg D, Hadj-Rabia S, Viney C, et al. Skinmarkers of occult spinal dysraphism in children: areview of 54 cases. Arch Dermatol. Sep 2004;140(9):1109–15.

2. Schropp C, Sorensen N, Collmann H, et al. Cuta-neous lesions in occult spinal dysraphism—correlation with intraspinal findings. Childs Nerv Syst.Feb 2006;22(2):125–31.


3. Gibson PJ, Britton J, Hall DM, et al. Lumbosacralskin markers and identification of occult spinaldysraphism in neonates. Acta Paediatr. Feb 1995;84(2):208–9.

4. Powell KR, Cherry JD, Hougen TJ, et al. A prospec-tive search for congenital dermal abnormalitiesof the craniospinal axis. J Pediatr. Nov 1975;87(5):744–50.

5. Kriss VM, Desai NS. Occult spinal dysraphism inneonates: assessment of high-risk cutaneousstigmata on sonography. AJR Am J Roentgenol.Dec 1998;171(6):1687–92.

6. Henriques JG, Pianetti G, Henriques KS, et al.Minor skin lesions as markers of occult spinaldysraphisms—prospective study. Surg Neurol.2005;63 (Suppl 1):S8–12.

7. Robinson AJ, Russell S, Rimmer S. The value of ul-trasonic examination of the lumbar spine in infantswith specific reference to cutaneous markers of oc-cult spinal dysraphism. Clin Radiol. Jan 2005;60(1):72–7.

8. Dick EA, de Bruyn R. Ultrasound of the spinalcord in children: its role. Eur Radiol. Mar 2003;13(3):552–62.

9. Drolet BA. Cutaneous signs of neural tube dys-raphism. Pediatr Clin North Am. Aug 2000;47(4):813–23.

10. McAtee-Smith J, Hebert AA, Rapini RP, et al. Skinlesions of the spinal axis and spinal dysraphism.Fifteen cases and a review of the literature.Arch Pediatr Adolesc Med. Jul 1994;148(7):740–8.

11. Ackerman LL, Menezes AH. Spinal congenitaldermal sinuses: a 30-year experience. Pediatrics.Sep 2003;112(3 Pt 1):641–7.

12. Schenk JP, Herweh C, Gunther P, et al. Imagingof congenital anomalies and variations of thecaudal spine and back in neonates and small in-fants. Eur J Radiol. Apr 2006;58(1):3–14.

13. Weprin BE, Oakes WJ. Coccygeal pits. Pediatrics.May 2000;105(5):E69.

14. Tubbs RS, Wellons JC III, Iskandar BJ, et al. Isolatedflat capillary midline lumbosacral hemangiomas asindicators of occult spinal dysraphism. J Neurosurg.Feb 2004;100(2 Suppl Pediatrics):86–9.

15. Ben-Amitai D, Davidson S, Schwartz M, et al. Sacralnevus flammeus simplex: the role of imaging.Pediatr Dermatol. Nov-Dec 2000;17(6):469–71.

16. Allen RM, Sandquist MA, Piatt JH Jr., et al. Ultra-sonographic screening in infants with isolatedspinal strawberry nevi. J Neurosurg. Apr 2003;98(3 Suppl):247–50.

17. Piatt JH Jr. Skin hemangiomas and occult dys-raphism. J Neurosurg. Feb 2004;100(2 Suppl Pedi-atrics):81–2; discussion 82.

18. Hughes JA, De Bruyn R, Patel K, et al. Evaluationof spinal ultrasound in spinal dysraphism. ClinRadiol. Mar 2003;58(3):227–33.

19. Drolet BA, Boudreau C. When good is not goodenough: the predictive value of cutaneous lesionsof the lumbosacral region for occult spinal dys-raphism. Arch Dermatol. Sep 2004;140(9):1153–5.



Chapter 50

Hemihyperplasia andOvergrowth Disorders

PRAVEEN KUMAR

347

� INTRODUCTION

An overgrowth disorder is defined as a condi-tion in which there is localized or generalizedexcessive growth and physical development forthe age and sex of the individual.1 Weaver clas-sified overgrowth syndromes in the followingthree broad categories:

1. Generalized overgrowth syndromes whichinclude conditions in which all or most para-meters of growth and physical developmentare in excess of two standard deviationsabove the mean for the person’s age andsex such as, Sotos syndrome. The condi-tions in this category could have either pre-natal or postnatal onset of overgrowth.

2. Regional overgrowth disorders includethose in which excessive growth is confinedto one or a few regions of the body such as,isolated hemihypertrophy; these disordersalso have their onset in either the prenatalor postnatal period.

3. Parameter-specific overgrowth disorders inwhich a single growth parameter is in excessof normal such as obesity or tall stature; mostof these disorders have a postnatal onset.

Most overgrowth disorders seen in a neonatehave prenatal onset and will fall into either thegeneralized or regional overgrowth disorder cat-egory. The following discussion will review theapproach to the evaluation of a neonate withgeneralized or regional overgrowth disordersand does not include large for gestational ageinfants of diabetic mothers.


The true prevalence of overgrowth disordersamong neonates is not clearly established. Theovergrowth syndromes are rare and only a hand-ful of cases have been reported for some syn-dromes. The incidence of Beckwith-Wiedemannsyndrome (BWS), one of the most common over-growth syndromes, is reported to be 1:14,000births.2,3 A recent series of observations havesuggested a link between assisted reproduc-tion and imprinting disorders such as BWS andAngelman syndrome.4 A retrospective study re-ported a risk of BWS in an in vitro fertilizationpopulation to be approximately 1 in 4000.5 Severalpopulation-based studies have reported a preva-lence rate of hemihypertrophy to range from 1 in


13,000 to 1 in 86,000 live births.6 However, thesestudies did not differentiate nonsyndromic hemi-hypertrophy from that occurring as part of a gen-eralized overgrowth syndrome.

The onset of prenatal overgrowth in mostcases can be attributed to hyperplasia (excessivecellular proliferation), hypertrophy (excessive cel-lular size), increase in interstitium, or some com-bination of these three factors.7,8 Although theprecise etiology and mechanism of overgrowthin many conditions is not completely under-stood, the recent advances in molecular geneticsand better understanding of factors controllingnormal fetal growth have provided a better in-sight into pathogenesis of overgrowth syn-dromes. It is likely that alterations of insulin-likegrowth factors, their cell-surface receptors,insulin-like growth factor-binding proteins, epi-dermal growth factors, human placental lacto-gen, and the regulators of these factors causemany of these disorders.1

� CLINICAL FEATURES ANDASSOCIATED SYNDROMES

As noted earlier, an overgrowth disorder canpresent either as excessive growth and physicaldevelopment of a localized part of the body oras a generalized disorder.

� GENERALIZED OVERGROWTHSYNDROMES

Generalized overgrowth syndromes include con-ditions in which all or most parameters of growthand physical development are in excess of twostandard deviations above the mean for the per-son’s age and sex such as in Soto’s syndrome.The conditions in this category could have ei-ther prenatal or postnatal onset of overgrowth.Various disorders of generalized overgrowth ofprenatal onset are listed in Table 50-1. The clin-ical features will vary depending on the under-lying disorder, but all infants with syndromic

generalized overgrowth disorders usually ex-hibit other anomalies, frequently have cognitivedelays, and often have a higher incidence ofcertain malignancies.

� REGIONAL OVERGROWTHSYNDROMES

These disorders with regional asymmetric over-growth were traditionally termed hemihyper-trophy but are more accurately referred to ashemihyperplasia in recent literature since theunderlying defect usually involves an abnormalproliferation of cells rather than an increase inthe size of existing cells. These disorders arecharacterized by asymmetric growth of cranium,face, trunk, limbs, and/or digits, with or withoutvisceral involvement.9 The overgrowth may in-volve an entire half of the body, a single limb,one side of the face, or combination thereof.Rowe (1962) proposed a classification systemfor hemihyperplasia, based on the anatomic siteof involvement:10

1. Complex hemihyperplasia—involvement ofhalf of the body (at least one arm and oneleg on the ipsilateral or contralateral side);

2. Simple hemihyperplasia—involvement of asingle limb;

3. Hemifacial hemihyperplasia—involvementof one side of the face.

Although the diagnosis of a generalizedovergrowth syndrome is easily suspected in alarge-for-gestational age infant, the diagnosis ofhemihyperplasia may be more difficult in the new-born period. The asymmetry is easily detected inits severe form but the smaller discrepancies inlimb length and circumference may not be eas-ily apparent in a newborn. It is also important todifferentiate between normal variation andpathological asymmetry. In the normal adultpopulation, extremities may differ in length andcircumference by as much as 1–2 cm comparedwith the contralateral limb.11 In a study of 1000


CHAPTER 50 HEMIHYPERPLASIA AND OVERGROWTH DISORDERS 349

� TABLE 50-1 Generalized Overgrowth Syndromes in Newborn

Syndrome Features Etiology

Beckwith-Wiedemann Macroglossia, infraorbital creases, ear lobe Autosomal dominant,creases and pits, abdominal wall defects, sporadicneonatal hypoglycemia, visceromegaly, riskfor abdominal neoplasms, hemihypertrophy,polyhydramnios, large placenta

Perlman Hypotonia, mental retardation, serration of upper Autosomal dominantalveolar ridge, nephromegaly, bilateral corticalhamartomas, and nephroblastomatosis

Sotos Macrocephaly, dolichocephaly, downslanting Sporadicpalpebral fissures, hypertelorism, prognathism,high narrow palate, premature eruption of teeth,large hands and feet, kyphoscoliosis, mentaldeficiency

Weaver Mental retardation, hypertonia, hoarse voice, Sporadicmacrocephaly, round face, ocular hypertelorism,down-slanting palpebral fissures, long philtrum,large ears, micrognathia, camptodactyly, thindeep-set nails, prominent fingertip pads

Bannayan-Riley- Delayed gross motor development, hypotonia, Autosomal dominantRuvalcaba speech delay, mental deficiency, macrocephaly,

pseudopapilledema, mesodermal hamartomas,lipid storage myopathy

Simpson-Golabi- Macrocephaly, ocular hypertelorism, short broad X-linked recessiveBehmel nose, large mouth, macroglossia, variable mental

retardation, hypotonia, postaxial polydactyly ofhands, nail hypoplasia, partial cutaneoussyndactyly, cryptorchidism, supernumerarynipples, cardiac defects, gastrointestinal defects,large cystic kidneys

Elejalde Craniosynostosis, gross edema, short limbs, Autosomal recessivepostaxial polydactyly, redundant neck skin, cysticrenal dysplasia, congenital heart defect, spleenanomaly, micromelia

Nevo Large, low-set malformed ears, cryptorchidism, Autosomal recessiveaccelerated osseous maturation, dolichocephaly,large extremities, clumsiness and retarded motorand speech development, generalized edema,hypotonia, contractures of the feet, wrist drop,clinodactyly

Marshall-Smith Accelerated linear growth, skeletal maturation, Sporadicpostnatal failure to thrive, hypotonia,development delay, structural brain anomalies,respiratory tract anomalies, recurrent pneumonia,pulmonary hypertension, dolichocephaly, coarseeyebrows, shallow orbits, blue sclerae, upturnednose, low nasal bridge, small mandibular ramus,hypertrichosis, umbilical hernia, choanal atresia,omphalocele

army recruits, only 23% were found to havelower extremities of equal length; and 15% hada discrepancy of 1.0 cm or more.6 Based on thesestudies, a threshold of a 5% difference was pro-posed to define abnormal asymmetry whichwould translate into a difference of <1 cm inlower extremity length in a young infant. Cur-rently, there are no well-accepted objective cri-teria for distinguishing hemihyperplasia from nor-mal variation in children. It is equally importantto differentiate if the larger side is hypertrophiedor the smaller side is atrophied. Hemihyperplasiamay be an isolated finding in some infants andis referred to as isolated hemihyperplasia whilein others it may be part of a multiple malfor-mation syndrome. Table 50-2 summarizes the

common malformation syndromes associatedwith hemihyperplasia.

� ISOLATED HEMIHYPERPLASIA

In a large multicenter series, the diagnosis ofisolated hemihyperplasia (IHH) was made in apatient with hemihyperplasia if multiple major orminor anomalies and a known overgrowth syn-drome were excluded.9 Females are affected morefrequently and a right preponderance has beenreported.3,9 Visceromegaly and medullary spongekidney are frequently reported associated findingsin these infants. Facial asymmetry and nervoussystem involvement such as hemimegalencephaly


� TABLE 50-2 Syndromes Associated with Hemihyperplasia at Birth

Syndrome Features Etiology

Beckwith-Wiedemann Omphalocele, hypoglycemia, generalized Heterogeneous; mostlyovergrowth, macroglossia, visceromegaly, sporadic, but Autosomalear lobe pits and creases, predisposition dominant in someto neoplasia families; gene on 11p15.5

Neurofibromatosisa Café-au-lait spots, hypopigmented patches, Autosomal dominantaxillary freckling, neurofibromas, iris Lischnodules, macrocephaly, scoliosis,hypertension, CNS tumors

Klippel-Trenaunay- Hemangiomata, lymphatic anomalies, Unknown; sporadicWeber poly/syndactyly, oligodactyly, macrocephaly,

glaucoma, cataractsProteus Lipomata, hemangiomata, macrocephaly, Unknown; sporadic

scoliosis, macrodactyly, gyriform changeson soles of feet

McCune-Albrighta Fibrous dysplasia of bones, irregular Unknown; sporadic;hyperpigmentation, precocious puberty, female predominancehyperthyroidism, hyperparathyroidism,other endocrinopathies

Epidermal nevus Epidermal nevi; pigmentary changes, mental Heterogenous; usuallydeficiency, seizures, CNS malformations, sporadickyphoscoliosis, potential for malignancy

Triploid/diploid Large placenta with hydatidiform changes, Chromosomal diploid/mixoploidy incomplete calvarial ossification, triploid mosaicism

microretrognathia, microphthalmia, (may be found onlycolobomata, cataracts, irregular skin in fibroblasts)pigmentation, syndactyly

CNS, central nervous system.aUsually presents later in life.

and unilateral peripheral nerve enlargementhave also been reported.9 Patients with centralnervous system (CNS) involvement are at risk ofdeveloping seizures and mental deficiency. IHHis assumed to be sporadic but familial cases havebeen reported.12 Hemihyperplasia occurs in ap-proximately 13% of patients with BWS and it hasbeen suggested that infants with IHH representa partial or incomplete expression of BWS insome cases.9


All infants suspected to have overgrowth syn-drome should have careful physical examinationto evaluate for associated major and minor anom-alies. It may be helpful to obtain a detailed familyhistory and to evaluate the parents and siblings ofthe affected infant as well. There may be a sig-nificant phenotype overlap between differentsyndromes and an early genetic evaluation isnecessary in all cases. All four limb lengths andcircumferences should be measured accuratelyto determine any asymmetry and for future com-parison. Blood sugar values should be monitoredclosely for first 3–7 days as untreated hypo-glycemia is an important cause of developmen-tal delay in many infants with BWS. A baselineskeletal survey for bone length, bone age, andscoliosis; and abdominal ultrasound to evaluatefor visceromegaly, anomalies, and to exclude anytumors should be done in all infants. An MRI ofbrain should be considered in all infants if the di-agnosis is not clear or craniofacial asymmetrywith or without neurological signs is present.

Conventional cytogenetic analysis of periph-eral blood lymphocytes should be done in allcases and high-resolution banding and in situfluorescence hybridization may be used in spe-cific cases. Further uniparental disomy analysisand methylation analysis for BWS should bedone in consultation with a geneticist in all casessuspected of BWS. Stratification of BWS casesaccording to the methylation pattern, also referredto as epigenotyping, can help in predicting the

risk for future tumor development.13,14 The af-fected children, particularly patients with IHH,require regular orthopedic follow-up to monitorfor limb length discrepancies and associated sco-liosis and gait abnormalities. Infants withmedullary sponge kidneys will require monitor-ing of their renal function every 6 months andperiodic nephrology follow up as necessary.

� PROGNOSIS

The long-term prognosis will depend on the un-derlying disorder and the presence or absence ofassociated congenital anomalies. Patients withisolated hemihyperplasia with no associated con-genital malformations are likely to have an aver-age life span.9 The cognitive outcome of infantswith overgrowth disorders is primarily related tothe underlying syndrome and was reviewed in arecent article by Cohen.15 The cognitive outcomeof infants with BWS, the most common cause ofgeneralized overgrowth in the newborn, corre-lates more to their neonatal course and episodesof untreated hypoglycemia. Patients with cranio-facial anomalies and hemimegalencephaly are athigher risk of developmental delays.

� RISK OF NEOPLASMS INOVERGROWTH SYNDROMES

Several reports have confirmed a significantlyhigher risk of neoplasms in infants with over-growth syndromes. Overgrowth disorders arecharacterized by dysregulation of normal cellu-lar growth-control mechanisms and it has beenproposed that the same abnormalities also pre-dispose these patients to future development ofneoplasms. These tumors may be present atbirth or may develop during childhood. Thegreatest risk for tumor development is in earlychildhood. The incidence of tumor develop-ment in BWS and IHH has been reported to beabout 7.5% and 5% respectively, which is severalhundred times higher than the incidence of


� TABLE 50-3 Reported Empiric Risk of Tumors in Some Overgrowth Syndromes

Ratio (Increased RiskFrequency of Malignant over the Risk of theNeoplasia (Approximately) General Population) Commonly Reported Tumors

Generalized overgrowthsyndromes

Bannayan-Riley-Ruvalcaba Limited data (but probably low) Limited data Lipoma, angiolipoma, thyroid carcinoma,syndrome ganglioneuroma

Beckwith-Wiedemann ~7.5% (5–10%) 1:12 (x600) Wilm’s tumor, hepatoblastoma,Syndrome adrenocortical carcinoma, rhabdomy

sarcoma, neuroblastomaMacrocephaly-cutis ~5–6% 1:20 (x300) Acute lymphoblastic leukemia, Wilm’s

marmorata syndrome tumor, meningioma, retinoblastomaMarshall-Smith syndrome No data available Probably not increased None to datePerlman syndrome 30–40% 1:2.5 (x2700) Wilms tumorSimpson-Golabi-Behmel ~7.5% (5–10%) 1:10 (x600) Wilms tumor, hepatoblastoma,

syndrome gonadoblastoma, neuroblastomaSotos syndrome ~4% (2.3–5%) 1:40: (x150) Acute leukemia, Wilm’s tumor,

Lymphoma, teratoma, neuroblastomaWeaver syndrome ~5–6% 1:20 (x300) Neuroblastoma, teratoma, endodermal

sinus tumor

Localized overgrowthsyndromes

Klippel Trenaunay No data available No data available Wilm’s tumor, carcinoma of esophagus,syndrome (but probably very low) astrocytoma

Isolated hemihyperplasia ~5% 1:25 (x200) Wilm’s tumor, adrenocortical carcinoma,hepatoblastoma, neuroblastoma

Proteus syndrome ~15% 1:7 (x1200) Meningioma, ovarian cysts, renal cyst,adenocarcinoma of testes

(Reprinted with modification from Lapunzina P. Risk of tumorigenesis in overgrowth syndromes: a comprehensive review. Am J Med Genet C Semin MedGenet. Aug 15, 2005;137(1):53–71. Reprinted with permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.)

35

2


these tumors in the general population. Themost common tumor in these infants is Wilmstumor followed by hepatoblastoma, adrenal cellcarcinoma, and others.3,9 BWS infants withhemihyperplasia are nearly five times morelikely to have a tumor compared to BWS infantswith no asymmetry of growth.16,17 Another riskfactor for future development of Wilms tumor inBWS is persistent nephromegaly.16

Based on a recent comprehensive review ofthe risk of tumorigenesis in overgrowth syn-dromes, Lapunzina reported the empiric risk oftumor development in various overgrowth syn-dromes (Table 50-3) and classified these disor-ders in high, mild/moderate, and very low/notumor risk categories (Table 50-4).3 Abdominallocation comprises >90% of all tumors in chil-dren with BWS, IHH, Perlman syndrome, andSimpson-Golabi-Behmel syndrome; patientswith these disorders need to be evaluated reg-ularly for intra-abdominal embryonal tumors.3

Extra-abdominal tumors account for 60–70% ofcases in children with other overgrowth syn-dromes and guidelines for their regular followup are less clear so far. Most studies have shownthat it is cost effective and prudent to performserial abdominal ultrasound in all infants withBWH and IHH every 3 months until 6–7 yearsof age.6,9,18,19 After that, recommendations vary

from follow up by physical examination to ser-ial abdominal ultrasound every 6 months untilpuberty or age 18 years or indefinitely.18,19 Ser-ial estimation of serum alpha fetoprotein (AFP)every 3 months up to age 3 or 4 years has beenreported to be helpful in early detection of he-patoblastoma.14,18,19 It is reported that tumorsurveillance may not have a significant impacton overall survival, but has the potential to re-duce morbidity due to early detection.19


The primary care physician and geneticist shoulddiscuss the long-term implications of this diagno-sis, the need for close follow-up, and recurrencerisk in future pregnancies which will depend onthe cause of overgrowth in the index patient. Therecurrence risk in BWS, the most common andwell-studied cause of hemihyperplasia of prena-tal onset, will depend on the molecular etiologyon genetic analysis but is low in large majority offamilies.19 However, it can be as high as 50% in5–10% of all BWS patients who are usually bornto mothers with a mutation in the CDKN1C gene.19

There are no well-documented reports of familialIHH and the recurrence risk is likely to be verylow in these families.9

� TABLE 50-4 Classification of Overgrowth Syndromes According to Tumor Risk

High tumor risk Malignant tumors Perlman syndrome, Simpson-Golabi-Behmel syndrome, Beckwith-Wiedemann syndrome, Isolated hemihyperplasia

Benign tumors Proteus syndrome, Bannayan-Riley-Ruvalcabasyndrome, Klippel-Trenaunay syndrome

Mild/moderate tumor risk Malignant tumor Bannayan-Riley-Ruvalcaba syndrome,Klippel-Trenaunay syndrome, Sotossyndrome, Weaver syndrome, Proteussyndrome, Macrocephaly-cutis marmorata

Benign tumors Isolated hemihyperplasia, Beckwith-Wiedemannsyndrome

Very low/no tumor risk Marshall-Smith syndrome

(Reprinted from Lapunzina P. Risk of tumorigenesis in overgrowth syndromes: a comprehensive review. Am J MedGenet C Semin Med Genet. Aug 15, 2005;137(1):53–71. Reprinted with permission of Wiley-Liss, Inc., a subsidiaryof John Wiley & Sons, Inc.)

REFERENCES

1. Weaver DD. Overgrowth syndromes and disor-ders: definition, classification and discussion.Growth Genetics & Hormones. 1994;10(1):1–4.

2. Gomes MV, Ramos ES. Beckwith-Wiedemannsyndrome and isolated hemihyperplasia. SaoPaulo Med J. May 2003;121(3):133–8.

3. Lapunzina P. Risk of tumorigenesis in overgrowthsyndromes: a comprehensive review. Am J MedGenet C Semin Med Genet. Aug 2005;137(1):53–71.

4. Cytrynbaum CS, Smith AC, Rubin T, et al. Advancesin overgrowth syndromes: clinical classification tomolecular delineation in Sotos syndrome andBeckwith-Wiedemann syndrome. Curr OpinPediatr. Dec 2005;17(6):740–6.

5. Halliday J, Oke K, Breheny S, et al. Beckwith-Wiedemann syndrome and IVF: a case-controlstudy. Am J Hum Genet. Sep 2004;75(3):526–8.

6. Ballock RT, Wiesner GL, Myers MT, et al. Hemihy-pertrophy. Concepts and controversies. J BoneJoint Surg Am. Nov 1997;79(11):1731–8.

7. Cohen MM Jr. A comprehensive and critical assess-ment of overgrowth and overgrowth syndromes.Adv Hum Genet. 1989;18:181–303, 373–186.

8. Cohen MM Jr. Perspectives on overgrowth syn-dromes. Am J Med Genet. Oct 1998;79(4):234–7.

9. Hoyme HE, Seaver LH, Jones KL, et al. Isolatedhemihyperplasia (hemihypertrophy): report of aprospective multicenter study of the incidence ofneoplasia and review. Am J Med Genet. Oct1998;79(4):274–8.

10. Rowe NH. Hemifacial hypertrophy. Review of theliterature and addition of four cases. Oral SurgOral Med Oral Pathol. May 1962;15:572–87.

11. Anderson M, Messner MB, Green WT. Distributionof lengths of the normal femur and tibia in childrenfrom one to eighteen years of age. J Bone JointSurg Am. Sep 1964;46:1197–1202.

12. Heilstedt HA, Bacino CA. A case of familial iso-lated hemihyperplasia. BMC Med Genet. Feb2004;5:1.

13. Rahman N. Mechanisms predisposing to childhoodovergrowth and cancer. Curr Opin Genet Dev.Jun 2005;15(3):227–33.

14. Bliek J, Gicquel C, Maas S, et al. Epigenotyping asa tool for the prediction of tumor risk and tumortype in patients with Beckwith-Wiedemann syn-drome (BWS). J Pediatr. Dec 2004;145(6):796–9.

15. Cohen MM Jr. Mental deficiency, alterations in per-formance, and CNS abnormalities in overgrowthsyndromes. Am J Med Genet C Semin Med Genet.Feb 2003;117(1):49–56.

16. DeBaun MR, Siegel MJ, Choyke PL. Nephromegalyin infancy and early childhood: a risk factor forWilms tumor in Beckwith-Wiedemann syndrome.J Pediatr. Mar 1998;132(3 Pt 1):401–4.

17. DeBaun MR, Tucker MA. Risk of cancer during thefirst four years of life in children from TheBeckwith-Wiedemann Syndrome Registry. J Pedi-atr. Mar 1998;132(3 Pt 1):398–400.

18. Beckwith JB. Children at increased risk for Wilmstumor: monitoring issues. J Pediatr. Mar 1998;132(3 Pt 1):377–9.

19. Tan TY, Amor DJ. Tumour surveillance inBeckwith-Wiedemann syndrome and hemihyper-plasia: a critical review of the evidence and sug-gested guidelines for local practice. J PaediatrChild Health. Sep 2006;42(9):486–90.


Chapter 51

Cystic HygromaPRAVEEN KUMAR

355

� INTRODUCTION

Cystic hygroma is a type of lymphangioma whichis a congenital malformation of lymphatic chan-nels. Initial classification of lymphangioma di-vided these malformations into three categorieson the basis of the size of the lymphatic spaces;(1) lymphangioma simplex is composed ofcapillary-sized thin-walled lymphatic channels;(2) cavernous lymphangioma is composed of di-lated lymphatic spaces; and (3) cystic hygromaor cystic lymphangioma is composed of cysts ofvariable sizes. Another classification of lymphaticmalformation divided these malformations intomicrocystic, macrocystic, or combined. Basedon this classification, macrocystic lymphatic mal-formations were referred to as cystic hygromasand microcystic lymphatic malformations as lym-phangiomas. Over the years, it has been notedthat these classifications are arbitrary and mostlesions are mixed. It has been suggested that thenature of surrounding tissue can determine thesecharacteristics and these classifications shouldbe abandoned in favor of lymphatic malforma-tions. Cystic hygromas can present as a single ormultiloculated fluid-filled cavity which is com-monly seen in the cervical region.


Cystic hygroma or lymphangioma is an uncom-mon congenital malformation at birth with a re-ported incidence ranging from 1 in 6000 to10,000 live births.1,2 However a much higher in-cidence of this malformation has been reportedamong spontaneous abortions and on first andsecond trimester ultrasounds. Cystic hygroma isnoted in as many as 0.5% of all spontaneousabortions and nearly 1 in 250 low-risk first trimesterpregnancies in population-based studies.3,4 Thereis no sex predilection and no secular trends buta higher incidence of cystic hygroma has beenreported among Far East Asians.

Both genetic and environmental factors havebeen implicated. Cystic hygroma is frequentlyassociated with other anomalies as part of amalformation syndrome. Both chromosomal ab-normalities such as Turner syndrome, Downsyndrome, and single gene disorders such asNoonan syndrome are frequently associatedwith this malformation. In addition, reports ofcystic hygroma in multiple siblings in a familysuggest a mendelian pattern of inheritance insome cases. Autosomal dominant with variableexpression, autosomal dominant with germline


mosaicism, or autosomal recessive modes of in-heritance have been suggested. Any relation-ships between specific environmental factors,teratogens, and cystic hygroma are not well es-tablished. However, development of cystic hy-groma after exposure to alcohol, aminopterin,and trimethadione has been suggested.5

� EMBRYOLOGY

The lymphatic system develops around the fifthweek of gestation and establishes connectionwith the venous system near the end of thesixth week. There are six primary lymph sacs;two jugular sacs drain the head, neck, and arms;two iliac sacs drain the legs and lower trunk; andthe remaining two, retroperitoneal lymph sacand cisterna chyli, drain the gut. The lymphaticvessels develop either as buddings from the pri-mary lymph sac or as endothelial outgrowthsfrom the venous system and lead to establishmentof communication between the lymphatic andvenous system. Lymphatic malformations are aresult of anomalous development of lymphaticchannels or a defect in connection between lym-phatic and venous systems. A large majority of alllymphatic malformations are seen in the headand neck area and result from a failure of theprimitive jugular lymphatic system to drain intothe jugular vein. The widespread use of earlyprenatal ultrasound and serial follow up of thelesions identified in early pregnancy suggest thatearly gestation lesions may have a differentetiopatho-logy and outcome as compared to thelesions diagnosed later in gestation or postna-tally. The developmental basis and reasons forappearance of these malformations in late gestationand postnatally are not completely understood.

� CLINICAL PRESENTATIONS

Cystic hygromas appear as painless, soft, doughy,freely mobile, and transilluminant masses. Upto 75% of all postnatal cystic hygromas are

diagnosed at birth and most are diagnosed bythe age of 5 years. A large majority of cystic hy-gromas are reported in the cervical region, thenext common site is the axilla but they have beenreported to occur in the groin, retroperitonealarea, mediastinum, trunk, and pelvis. Symptomsare related to the size, anatomic location, andextent of involvement. These lesions may vary insize from a few centimeters to a large mass com-pressing the surrounding structures which canlead to obstruction of the airway and difficulty inswallowing. Cervical cystic hygromas below thelevel of mylohyoid muscle are called type Ilesion. These are well circumscribed and easilyresectable. Type II cystic hygromas are above themylohyoid muscle and have poorly defined mar-gins; these lesions are considered invasive anddifficult to resect. Bleeding and infection are thetwo most common complications.

Associated Malformations andSyndromes

A higher incidence of other malformations hasbeen reported in association with cystic hygro-mas, both in the presence and absence of associ-ated chromosomal abnormalities. The disruptionof normal tissue migration or organ displacementsecondary to tissue edema has been proposedas an explanation for these associated anom-alies.6 Overall, two-thirds of all cases have eitherchromosomal or major structural fetal abnormal-ities and 20–35% of all cases with a normal kary-otype have been reported to have associatedmalformations.3,4,7 Cardiovascular and craniofa-cial anomalies are most common but pulmonary,genitourinary, central nervous system, and mus-culoskeletal anomalies have also been reportedwith increased frequency; no definite patternshave been identified.

The overall incidence of an abnormal fetalkaryotype in pregnancies with cystic hygromasranges from 50% to 75%.3,8 A higher incidence ofchromosomal abnormality is found in pregnan-cies with early gestation diagnosis of cystic hy-gromas compared to cystic hygromas that appear


in late gestation or the postnatal period. TurnerSyndrome, 45 XO, is the most common chromo-somal abnormality associated with cystic hygro-mas followed closely by Trisomy 21. It is estimatedthat 5% of fetuses with a cystic hygroma mayhave Down syndrome.9 Other karyotypic abnor-malities and syndromes associated with cystichygromas are listed in Table 51-1.

� EVALUATION

All fetuses with a prenatal diagnosis of cystic hy-groma should be evaluated by a detailed ultra-sound examination including echocardiogramto evaluate for associated structural malforma-tions and signs of hydrops fetalis. A detailedfamily and prenatal history, and karyotypeshould be obtained. These pregnancies shouldbe followed closely to monitor progression ofcystic hygromas and hydrops fetalis irrespectiveof karyotype results as there is no reliablemethod to predict which hygroma will regressor continue to progress. Initially it was consideredimportant to differentiate between septated andnonseptated forms as the latter lesion may havelower incidence of chromosomal abnormalitiesand a better outcome as compared to the sep-tated cystic hygromas, but several subsequentstudies have failed to show any difference inoutcome. However, it has been suggested thatthese nonseptated cystic hygroma should beconsidered a variant of increased nuchal translu-cency and are not included in some of the recentstudies of cystic hygroma.

If a diagnosis of cystic hygroma is first madeat birth, the evaluation of infant should include:

• Detailed family and prenatal history• Complete physical examination for dysmor-

phic features and signs of associated con-genital malformations

• Evaluation of the infant, parents, and thesiblings by a dysmorphologist/geneticist ifadditional finings are noted

• Echocardiogram and abdominal ultrasoundto exclude structural anomalies and effusions

• Chest radiographs and/or computed tomog-raphy (CT) to look for pleural effusion andsigns of mediastinal extension of hygroma

• Imaging of the lesion-preferably by mag-netic resonance imaging (MRI) but CT andultrasound can also be used

• Karyotype


Airway management at birth is crucial particu-larly in cases with a large cervical lesion. Theestablishment of airway access while placentalperfusion to the fetus is maintained as in Ex-utero Intrapartum Treatment (EXIT) or Opera-tion On Placental Support (OOPS) procedures,should be considered in these cases. Surgicalresection is the treatment of choice. Since this isa benign lesion, complete and total resection ofthe lesion is not necessary and sometimes notpossible. Aggressive resection may lead to in-jury to surrounding tissues and neurovascularstructures and may contribute to poor outcomeand long-term morbidities.

Alternative methods of treatment include in-jection of sclerosing agents, aspiration, laserdiathermy, and radiation. None of these thera-pies have been efficacious but use of a newersclerosing agent, OK-432 appears promising.OK-432, Picibanil, is derived from a low-virulentstrain of Streptococcus pyogenes and requiresseveral intralesional injections but appears to bea promising alternative to surgery. Spontaneousresolution of these lesions overtime has beenreported and observation should be consideredin absence of an urgent indication for interven-tion. Residual or recurrent hygroma is a frequentproblem and their incidence varies with treat-ment modality and the site of lesion.

� PROGNOSIS OF EARLYGESTATION CYSTIC HYGROMAS

Cystic hygromas have historically been associ-ated with a grim prognosis when diagnosed in

CHAPTER 51 CYSTIC HYGROMA 357

� TABLE 51-1 Syndromes Associated with Cystic Hygroma


Achondrogenesis Severe short stature, micrognathia, short ribs, ossification Sporadic or autosomalabnormalities of bones, cleft palate, short limbs dominant

Achondroplasia Short stature, midfacial hypoplasia, macrocephaly, Autosomal dominanttrident hands

Cornelia de Lange syndrome IUGR, weak growling cry, synophrys, microbrachycephaly, Autosomal dominantlong philtrum, thin upper lip, micrognathia, micromelia,cryptorchidism

Fryns syndrome Diaphragmatic defects, distal digital hypoplasia, pulmonary Autosomal recessivehypoplasia, Dandy-Walker malformation, agenesis ofcorpus callosum, ventricular septal defect

Klinefelter syndrome Hypogonadism, cryptorchidism, clinodactyly, long limbs Chromosomal abnormality,and behavioral problems later in life 47 XXY due to error in

meiosisNoonan syndrome Hypertelorism, ptosis, low-set ears, webbed neck, Autosomal dominant

low posterior hairline, shield chest, pulmonary stenosisand other cardiac defects, cryptorchidism, lymphaticdysplasia, hypogonadism

Roberts-SC Phocomelia Hypomelia limb reduction defects of both upper and lower Autosomal recessivelimbs midfacial defects such as cleft lip and palate,microcephaly, severe IUGR, cryptorchidism,eye anomalies

Short rib-polydactyly syndrome, Phocomelia, metaphyseal dysplasia, postaxial polydactyly, Autosomal recessivetype I (Saldino-Noonan type) syndactyly, cardiac defects, imperforate anus

Short rib-polydactyly syndrome, Short ribs and limbs, cleft lip and palate, pulmonary Autosomal recessivetype II (Majewski type) hypoplasia, hypoplasia of epiglottis and larynx,

pre/postaxial polydactylyThanatophoric dysplasia Severe micromelia, respiratory failure, craniosynostosis, Autosomal dominant

short flattened vertebrae, cardiac defect,renal anomalies

Trisomy 13 Holoprosencephaly, micropthalmia, cyclopia, microcephaly, Trisomycleft lip and palate, heart defects, IUGR, genitalabnormalities

35

8

Trisomy 18 IUGR, low-set malformed ears, clenched hand, heart Trisomydefects, rocker bottom feet, microcephaly,genital anomalies

Trisomy 21 Hypotonia, brachycephaly, brushfield spots in iris, Trisomyshort metacarpal and phalanges, simian creases,cardiac defects, loose skin folds, hyperlaxity of joints,flat facial profile with upslanting palpebral fissures andinner epicanthal folds

Turner syndrome IUGR, lymphedema, broad chest with widely spaced Aneuploidy, 45XOnipples, small maxilla and mandible, low hairline,webbed neck, redundant skin, heart defects, hearingimpairment


35

9

early gestation. However, most of these earlierreports were based on small number of casesand were performed retrospectively. Some ofthe recent prospective studies have reportedmore reassuring results. The first and secondtrimester evaluation of risk (FASTER) trial, aprospective multicenter study funded by Na-tional Institute of Health, recently reported onthe follow up of 134 cases of early gestationcystic hygroma.3 Half of these cases had associ-ated chromosomal abnormalities and one-thirdof the remaining cases had major structural mal-formations. Pregnancy was terminated electivelyin 60% and spontaneous fetal demise occurredin 15% of all cases. Nearly one-third of all caseshad no chromosomal or structural abnormalitieson prenatal evaluation and half of these preg-nancies resulted in a live birth. Only 17% of allcases with early gestation diagnosis of cystic hy-gromas but 95% of cases with cystic hygromaswith no chromosomal abnormalities and noassociated structural malformation were as-sessed to be normal on follow-up.3 Anotherstudy from the United States reported normaloutcome in nearly 30% of all cases with earlygestation cystic hygromas and 80% of all caseswith a normal karyotype had a normal out-come.10 In contrast, several European studieshave reported an overall “normal outcome” rate

for pregnancies with first and second trimesterdiagnosis of cystic hygromas to be <10%.4,7,11

Abnormal karytope, associated structural mal-formation, presence of hydrops, lack of resolu-tion by late second or early third trimester, largesize of hygroma (>6 cm), and a family history ofcystic hygroma in a previous pregnancy havebeen associated with a poor prognosis. The res-olution of cystic hygroma does not appear to bealways related to the karyotype or associatedstructural malformations.

� PROGNOSIS OF CYSTICHYGROMAS DIAGNOSED INLATE GESTATION AND AT BIRTH

The outcome data in cases when diagnosis ofcystic hygroma is made in the late thirdtrimester (after 30 weeks gestation) or at birthin a previously normal fetus is limited, but ingeneral is reported to be more favorable. Table51-2 summarizes the differences between thesetwo groups of patients with cystic hygroma.These lesions have also been referred to aslate-onset isolated cystic hygroma. Based oncurrent data, it seems appropriate to placecystic hygroma patients in the following threecategories for counseling regarding prognosis


� TABLE 51-2 Differences Between Early Gestation versus Late Gestation/Postnatal Cystic Hygroma

Early Gestation Late Gestation/Postnatal

Incidence High LowAssociated structural High Low

malformation andsyndromes

Chances for spontaneous High Lowresolution

Site Almost-always nuchal Commonly nuchal but atother sites also

Prognosis Guarded VariableRisk of chromosomal High ~1 in 250 Low ~1 in 6000

abnormalities

and outcome; (1) early gestation, normal kary-otype—good prognosis, (2) early gestation,abnormal karyotype—poor prognosis, (3) lategestation/postnatal-variable prognosis dependingon the size.


Genetic counseling and recurrence risk dependon the timing of appearance of cystic hygroma,associated chromosomal abnormality, identifi-cation of any associated syndromes, and familyhistory. If a chromosomal abnormality or syn-drome is identified, recurrence risk would bebased upon the pattern of inheritance of thatparticular disorder.

After an early gestation diagnosis of cystichygroma, the overall risk of fetal aneuploidy is50% and a residual risk of major structural mal-formation or spontaneous death in cases withnormal karyotype is also approximately 1 in 2.However, a nearly 90% chance of normal pe-diatric outcome can be anticipated in caseswith normal karyotype with no other struc-tural malformations on evaluation. The sur-vival rate at 1 year for the live-born infantswith cystic hygroma is close to 90%. The re-currence risk in cases with an abnormal kary-otype unrelated to a parental chromosomalrearrangement is low and is in the range of 1%.However, the risk in the presence of a sus-pected syndrome or in cases of isolated cystichygroma with a positive family history of cystichygroma could be as high as 25%. The recur-rence risk for a case with isolated cystic hy-groma and normal karyotype with negativefamily history is unknown but likely to be nodifferent than in the general population. Pre-natal ultrasound screening should be offeredin all subsequent pregnancies.

REFERENCES

1. Forrester MB, Merz RD. Descriptive epidemiologyof cystic hygroma: Hawaii, 1986 to 1999. SouthMed J. Jul 2004;97(7):631–6.

2. Chen CP, Liu FF, Jan SW, et al. Cytogenetic evalua-tion of cystic hygroma associated with hydrops fe-talis, oligohydramnios or intrauterine fetal death:the roles of amniocentesis, postmortem chorionicvillus sampling and cystic hygroma paracentesis.Acta Obstet Gynecol Scand. May 1996;75(5):454–8.

3. Malone FD, Ball RH, Nyberg DA, et al. First-trimesterseptated cystic hygroma: prevalence, natural history,and pediatric outcome. Obstet Gynecol. Aug 2005;106(2):288–294.

4. Howarth ES, Draper ES, Budd JL, et al. Population-based study of the outcome following the prenataldiagnosis of cystic hygroma. Prenat Diagn. Apr 2005;25(4):286–91.

5. Gallagher PG, Mahoney MJ, Gosche JR. Cystic hy-groma in the fetus and newborn. Semin Perinatol.Aug 1999;23(4):341–56.

6. Witt DR, Hoyme HE, Zonana J, et al. Lymphedemain Noonan syndrome: clues to pathogenesis andprenatal diagnosis and review of the literature.Am J Med Genet. Aug 1987;27(4):841–56.

7. Tanriverdi HA, Ertan AK, Hendrik HJ, et al. Out-come of cystic hygroma in fetuses with normal kary-otypes depends on associated findings. Eur J Ob-stet Gynecol Reprod Biol. Jan 2005;118(1):40–6.

8. Brumfield CG, Wenstrom KD, Davis RO, et al.Second-trimester cystic hygroma: prognosis of sep-tated and nonseptated lesions. Obstet Gynecol. Dec1996;88(6):979–82.

9. Nicolaides K, Shawwa L, Brizot M, et al. Ultra-sonographically detectable markers of fetal chro-mosomal defects. Ultrasound Obstet Gynecol. Jan1993;3(1):56–69.

10. Trauffer PM, Anderson CE, Johnson A, et al. Thenatural history of euploid pregnancies with first-trimester cystic hygromas. Am J Obstet Gynecol.May 1994;170(5 Pt 1):1279–84.

11. Ganapathy R, Guven M, Sethna F, et al. Natural his-tory and outcome of prenatally diagnosed cystic hy-groma. Prenat Diagn. Dec 2004;24(12):965–8.

CHAPTER 51 CYSTIC HYGROMA 361


Glossary of GeneticTerms

363

AAcquired mutations: Gene changes that arise withinindividual cells and accumulate throughout a person’slifetime; also called somatic mutations.

Additive genetic effects: When the combined effectsof alleles at different loci are equal to the sum of theirindividual effects.

Affected: An individual who manifests symptoms of aparticular condition.

Affected relative pair: Individuals related by blood,each of whom is affected with the same trait. Examplesare affected sibling, cousin, and avuncular pairs.

Alleles: Variant forms of the same gene. Different allelesproduce variations in inherited characteristics such aseye color or blood type.

Allele frequency: (Synonym: gene frequency) Theproportion of individuals in a population who have in-herited a specific gene mutation or variant.

Allelic heterogeneity: (Synonym: molecular hetero-geneity) Different mutations in the same gene at thesame chromosomal locus that cause a single phenotype.

Allogeneic: Variation in alleles among members of thesame species.

Alpha-fetoprotein (AFP): A protein excreted by thefetus into the amniotic fluid and from there into themother’s bloodstream through the placenta.

Alternate paternity: (Synonyms: false paternity, non-paternity) The situation in which the alleged father ofa particular individual is not the biological father.

Amino acid: Any of a class of 20 molecules that com-bine to form proteins in living things.

Amino acid sequence: The linear order of the aminoacids in a protein or peptide.

Amniocentesis: Prenatal diagnosis method using cellsin the amniotic fluid to determine the number and kindof chromosomes of the fetus and, when indicated, per-form biochemical studies.

Amniocytes: Cells obtained by amniocentesis.

Amplification: Any process by which specific DNAsequences are replicated disproportionately greaterthan their representation in the parent molecules.

Aneuploidy: State of having variant chromosomenumber (too many or too few) (i.e., Down syndrome,Turner syndrome).

Anticipation: The tendency in certain genetic dis-orders for individuals in successive generations topresent at an earlier age and/or with more severemanifestations; often observed in disorders resultingfrom the expression of a trinucleotide repeat mutationthat tends to increase in size and have a more signifi-cant effect when passed from one generation to thenext.

Autosome: Any of the non-sex-determining chromo-somes. Human cells have 22 pairs of autosomes.

Autosomal dominant: Describes a trait or disorder inwhich the phenotype is expressed in those who haveinherited only one copy of a particular gene mutation(heterozygotes); specifically refers to a gene on one ofthe 22 pairs of autosomes (nonsex chromosomes).


Autosomal recessive: Describes a trait or disorder re-quiring the presence of two copies of a gene mutationat a particular locus in order to express observablephenotype; specifically refers to genes on one of the22 pairs of autosomes (nonsex chromosomes).

Avuncular relationship: The genetic relationshipbetween nieces and nephews, and their aunts anduncles.

BBackground risk: (Synonym: population risk) Theproportion of individuals in a given population whoare affected with a particular disorder or who have mu-tations in a certain gene; often discussed in the geneticcounseling process as a comparison to the patient’spersonal risk given his/her family history or othercircumstances.

Barr body: The condensed single X-chromosome seenin the nuclei of somatic cells of female mammals.

Base pair: A pair of hydrogen-bonded nitrogenousbases (one purine and one pyrimidine) that join thecomponent strands of the DNA double helix.

Baysian analysis: A mathematical method to furtherrefine recurrence risk taking into account other knownfactors.

Birth defect: Any harmful trait, physical or biochemical,present at birth, whether a result of a genetic mutationor some other nongenetic factor.

CCandidate gene: A gene located in a chromosome re-gion suspected of being involved in a disease.

Carrier: A person who has a recessive mutated gene,together with its normal allele, also called heterozy-gous. Carriers do not usually develop disease but canpass the mutated gene on to their children.

Carrier rate: (Synonym: carrier frequency) The pro-portion of individuals in a population who have a singlecopy of a specific recessive gene mutation.

Carrier testing: Testing to identify individuals whocarry disease-causing recessive genes that could be in-herited by their children. Carrier testing is designed for

healthy people who have no symptoms of disease, butwho are known to be at high risk because of familyhistory.

Chimera (pl. chimaera): An organism that containscells or tissues with a different genotype. These can bemutated cells of the host organism or cells from a dif-ferent organism or species.

Chorionic villus sampling: An invasive prenatal di-agnostic procedure involving removal of villi from thehuman chorion to obtain chromosomes and cell prod-ucts for diagnosis of disorders in the human embryo.

Chromosomes: Structures found in the nucleus of acell, which contain the genes. Chromosomes come inpairs, and a normal human cell contains 46 chromo-somes, 22 pairs of autosomes, and 2 sex chromosomes.

Chromosome banding: A technique for stainingchromosomes so that bands appear in an unique pat-tern particular to the chromosome.

Chromosomal deletion: The loss of part of a chro-mosome’s DNA.

Chromosomal inversion: Chromosome segmentsthat have been turned 180 degrees. The gene sequencefor the segment is reversed with respect to the rest ofthe chromosome.

Chromosome painting: Attachment of certain fluo-rescent dyes to targeted parts of the chromosome. Usedas a diagnostic tool for particular diseases, e.g., typesof leukemia.

Chromosome region p: A designation for the shortarm of a chromosome.

Chromosome region q: A designation for the longarm of a chromosome.

Clone: A group of identical genes, cells, or organismsderived from a single ancestor.

Cloning: The process of making genetically identicalcopies.

Codominance: Situation in which two different allelesfor a genetic trait are both expressed.

364 GLOSSARY OF GENETIC TERMS

Codon: A sequence of three nucleotides in mRNA thatspecifies an amino acid.

Complex trait: Trait that has a genetic componentthat does not follow strict Mendelian inheritance. Mayinvolve the interaction of two or more genes or gene-environment interactions.

Comparative genomic hybridization: A molecularcytogenetic method for detecting loss and gain of chro-mosomal material; a map is produced showing DNAsequence copy number as a function of chromosomallocation.

Compound heterozygote: An individual who hastwo different abnormal alleles at a particular locus, oneon each chromosome of a pair; usually refers to indi-viduals affected with an autosomal recessive disorder.

Congenital: Any trait present at birth, whether the re-sult of a genetic or nongenetic factor.

Consanguinity: Genetic relatedness between individ-uals descended from at least one common ancestor.

Conservative change: An amino acid change thatdoes not affect significantly the function of the protein.

Consultand: The individual (not necessarily affected)who presents for genetic counseling and throughwhom a family with an inherited disorder comes tomedical attention.

Contiguous genes: Genes physically close on a chro-mosome that when acting together express a phenotype.

Crossovers: The exchange of genetic material be-tween two paired chromosome during meiosis.

Custom prenatal testing: Prenatal testing offered tofamilies in which disease-causing mutations have beenidentified in an affected family member in either a re-search or clinical laboratory; testing is not otherwiseclinically available for prenatal diagnosis.

Cytogenetics: The study of chromosomes.

DDeletion: The loss of a segment of the genetic materialfrom a chromosome.

de novo mutation: (Synonyms: de novo gene muta-tion, new gene mutation, new mutation) An alteration ina gene that is present for the first time in one familymember as a result of a mutation in a germ cell (egg orsperm) of one of the parents or in the fertilized egg itself.

Diploid: A full set of genetic material consisting ofpaired chromosomes, one from each parental set. Mostanimal cells except the gametes have a diploid setof chromosomes. The diploid human genome has46 chromosomes.

Disease: Any deviation from the normal structure orfunction of any part, organ, or system of the body thatis manifested by a characteristic set of symptoms andsigns whose pathology and prognosis may be knownor unknown.

Disease-associated genes: Alleles carrying particularDNA sequences associated with the presence of disease.

DNA fingerprint technique: A method employed todetermine differences in amino acid sequences be-tween related proteins; relies upon the presence of asimple tandem-repetitive sequences that are scatteredthroughout the human genome.

DNA hybridization: A technique for selectivelybinding specific segments of single-stranded (ss) DNAor RNA by base pairing to complementary sequenceson ssDNA molecules that are trapped on a nitrocel-lulose filter.

DNA probe: Any biochemical used to identify or iso-late a gene, a gene product, or a protein.

DNA sequencing: Plus and minus or primed synthesismethod, developed by Sanger, DNA is synthesized invitro in such a way that it is radioactively labeled and thereaction terminates specifically at the position corre-sponding to a given base; the chemical method, ssDNA issubjected to several chemical cleavage protocols that se-lectively make breaks on one side of a particular base.

Domain: A discrete portion of a protein with its ownfunction. The combination of domains in a single pro-tein determines its overall function.

Dominant: An allele that is almost always expressed,even if only one copy is present.

GLOSSARY OF GENETIC TERMS 365

Double heterozygote: An individual who is heterozy-gous for a mutation at each of two separate genetic loci.

Dysmorphology: The clinical study of malformationsyndromes.

EEuploid: Any chromosome number that is a multipleof the haploid number

Eugenics: The improvement of humanity by alteringits genetic composition by encouraging breeding ofthose presumed to have desirable genes.

Eukaryote: Cell or organism with membrane-bound,structurally discrete nucleus, and other well-developedsubcellular compartments.

FFamilial: A phenotype that occurs in more than onefamily member; may have genetic or nongeneticetiology.

Family history: The genetic relationships and med-ical history of a family; when represented in diagramform using standardized symbols and terminology, usu-ally referred to as a pedigree.

Fingerprinting: In genetics, the identification of mul-tiple specific alleles on a person’s DNA to produce aunique identifier for that person.

First-degree relative: Any relative who is one meio-sis away from a particular individual in a family (i.e.,parent, sibling, offspring)

FISH: Fluorescent in situ hybridization: a technique foruniquely identifying whole chromosomes or parts ofchromosomes using fluorescent-tagged DNA.

Flow cytometry: Analysis of biological material bydetection of the light-absorbing or fluorescing prop-erties of cells or subcellular fractions (i.e., chromo-somes) passing in a narrow stream through a laserbeam. An absorbance or fluorescence profile of thesample is produced. Automated sorting devices,used to fractionate samples, sort successive dropletsof the analyzed stream into different fractions de-pending on the fluorescence emitted by eachdroplet.

Flow karyotyping: Use of flow cytometry to analyzeand separate chromosomes according to their DNAcontent.

Founder effect: A gene mutation observed in highfrequency in a specific population due to the presenceof that gene mutation in a single ancestor or small num-ber of ancestors.

Fragile sites: A nonstaining gap of variable width thatusually involves both chromatids and is always at ex-actly the same point on a specific chromosome derivedfrom an individual or kindred.

Fraternal twin: Siblings born at the same time as theresult of fertilization of two ova by two sperm. Theyshare the same genetic relationship to each other asany other siblings.

Functional genomics: The study of genes, their re-sulting proteins, and the role played by the proteins inthe body’s biochemical processes.

GGamete: Mature male or female reproductive cell(sperm or ovum) with a haploid set of chromosomes(23 for humans).

Gel electrophoresis: The process by which nucleicacids (DNA or RNA) or proteins are separated by sizeaccording to movement of the charged molecules in anelectrical field.

Gene: A hereditary unit that occupies a certain positionon a chromosome; a unit that has one or more specificeffects on the phenotype, and can mutate to various al-lelic forms.

Gene amplification: Any process by which specificDNA sequences are replicated disproportionatelygreater than their representation in the parent mole-cules; during development, some genes become am-plified in specific tissues.

Gene expression: The process by which a gene’scoded information is converted into the structures pre-sent and operating in the cell. Expressed genes includethose that are transcribed into mRNA and then trans-lated into protein and those that are transcribed intoRNA but not translated into protein (e.g., transfer andribosomal RNAs).


Gene family: Group of closely related genes that makesimilar products.

Gene map: The linear arrangement of mutable siteson a chromosome as deduced from genetic recombi-nation experiments.

Gene markers: Landmarks for a target gene, eitherdetectable traits that are inherited along with the gene,or distinctive segments of DNA.

Gene pool: All the variations of genes in a species.

Gene therapy: Addition of a functional gene or groupof genes to a cell by gene insertion to correct a hered-itary disease.

Gene transfer: Incorporation of new DNA into anorganism’s cells, usually by a vector such as a modifiedvirus. Used in gene therapy.

Genetic code: The sequence of nucleotides, coded intriplets (codons) along the mRNA, that determines thesequence of amino acids in protein synthesis. A gene’sDNA sequence can be used to predict the mRNA se-quence, and the genetic code can in turn be used topredict the amino acid sequence.

Genetic counseling: The educational process that helpsindividuals, couples, or families to understand genetic in-formation and issues that may have an impact on them.

Genetic linkage map: A chromosome map showingthe relative positions of the known genes on the chro-mosomes of a given species.

Genetic marker: A gene or other identifiable portionof DNA whose inheritance can be followed.

Genetic mosaic: An organism in which different cellscontain different genetic sequence. This can be the re-sult of a mutation during development or fusion of em-bryos at an early developmental stage.

Genetic polymorphism: Difference in DNA se-quence among individuals, groups, or populations(e.g., genes for blue eyes versus brown eyes).

Genetic predisposition: Susceptibility to a geneticdisease. May or may not result in actual developmentof the disease.

Genetic screening: Testing groups of individuals toidentify defective genes capable of causing hereditaryconditions.

Genetic testing: Analyzing an individual’s geneticmaterial to determine predisposition to a particularhealth condition or to confirm a diagnosis of geneticdisease.

Genetic variation: A phenotypic variance of a trait ina population attributed to genetic heterogeneity.

Genetics: The study of inheritance patterns of specifictraits.

Genome: All the genetic material in the chromosomesof a particular organism; its size is generally given as itstotal number of base pairs.

Genome: All of the genes carried by a single gamete;the DNA content of an individual, which includes all 44autosomes, 2 sex chromosomes, and the mitochondrialDNA.

Genotype: Genetic constitution of an organism.

Germ cell: A sex cell or gamete (egg or spermatozoan).

Germ line: The cell line from which egg or spermcells (gametes) are derived.

Germline mosaicism: Two or more genetic or cyto-genetic cell lines confined to the precursor (germline)cells of the egg or sperm; formerly called gonadalmosaicism.

Germline mutation: The presence of an altered genewithin the egg or sperm (germ cell), such that the al-tered gene can be passed to subsequent generations.

HHaploid: A single set of chromosomes (half the full setof genetic material) present in the egg and sperm cells ofanimals and in the egg and pollen cells of plants. Humanbeings have 23 chromosomes in their reproductive cells.

Haplotype: A way of denoting the collective genotypeof a number of closely linked loci on a chromosome.

Hardy-Weinberg Law: The concept that both genefrequencies and genotype frequencies will remain


constant from generation to generation in an infinitelylarge, interbreeding population in which mating is atrandom and there is no selection, migration, or mutation.

Hemizygous: Having only one copy of a particulargene. For example, in humans, males are hemizygousfor genes found on the Y chromosome.

Heterozygote: Having two alleles that are different fora given gene.

Heterogeneity: The production of identical or similarphenotypes by different genetic mechanisms.

Homologous chromosome: Chromosome contain-ing the same linear gene sequences as another, eachderived from one parent.

Homozygote (Homozygous): An organism that hastwo identical alleles of a gene.

Housekeeping genes: Those genes expressed in allcells because they provide functions needed for suste-nance of all cell types.

Hybrid: The offspring of genetically different parents.

IIdentical twin: Twins produced by the division of asingle zygote; both have identical genotypes.

Imprinting: A chemical modification of a gene allelewhich can be used to identify maternal or paternal originof chromosome.

Incomplete penetrance: The gene for a condition ispresent, but not obviously expressed in all individualsin a family with the gene.

Inherit: In genetics, to receive genetic material fromparents through biological processes.

Insertion: A chromosome abnormality in which apiece of DNA is incorporated into a gene and therebydisrupts the gene’s normal function.

In situ hybridization: Hybridization of a labeledprobe to its complementary sequence within intact,banded chromosomes.

Interfamilial variability: Variability in clinical pre-sentation of a particular disorder among affected indi-viduals from different families.

Intrafamilial variability: Variability in clinical pre-sentation of a particular disorder among affected indi-viduals within the same immediate or extended family.

In vitro: Studies performed outside a living organismsuch as in a laboratory.

In vivo: Studies carried out in living organisms.

Isolated: An abnormality that occurs in the absence ofother systemic involvement.

KKaryotype: A photographic representation of the chro-mosomes of a single cell, cut and arranged in pairsbased on their size and banding pattern according to astandard classification.

Kindred: An extended family; term often used inlinkage studies to refer to large families.

Knockout: Deactivation of specific genes; used in lab-oratory organisms to study gene function.

LLinkage: The tendency for genes or segments ofDNA closely positioned along a chromosome tosegregate together at meiosis and therefore be in-herited together.

Linkage analysis: (Synonym: indirect DNA analysis)Testing DNA sequence polymorphisms (normal vari-ants) that are near or within a gene of interest to trackwithin a family the inheritance of a disease-causingmutation in a given gene.

Linkage disequilibrium: Where alleles occur togethermore often than can be accounted for by chance. In-dicates that the two alleles are physically close on theDNA strand.

Linkage map: A map of the relative positions of ge-netic loci on a chromosome, determined on the basisof how often the loci are inherited together. Distance ismeasured in centimorgans (cM).


Locus (pl. loci): The position on a chromosome of agene or other chromosome marker; also, the DNA atthat position. The use of locus is sometimes restrictedto mean expressed DNA regions.

Lod score: Logarithm of the odd score; a measure ofthe likelihood of two loci being within a measurabledistance of each other.

MMarker: A gene with a known location on a chromo-some and a clear-cut phenotype, used as a point of ref-erence when mapping a new mutant.

Maternal contamination: The situation which occursin prenatal testing in which a sample of chorionic villus,amniotic fluid, or umbilical blood becomes contami-nated with maternal (usually blood) cells, which canconfound interpretation of the results of genetic analysis.

Meiosis: The doubling of gametic chromosome number.

Mendelian inheritance: One method in which ge-netic traits are passed from parents to offspring.Named after Gregor Mendel, who first studied andrecognized the existence of genes and this method ofinheritance.

Methylation analysis: Testing that evaluates themethylation status of a gene (attachment of methylgroups to DNA cytosine bases); genes that aremethylated are not expressed; methylation plays arole in X-chromosome inactivation and imprinting.

Microarray: Sets of miniaturized chemical reactionareas that may also be used to test DNA fragments,antibodies, or proteins.

Microarray analysis: Often used with multiple DNAfragments to test for submicroscopic chromosome dele-tions or duplications.

Microdeletion syndrome: (Synonym: contiguousgene deletion syndrome) A syndrome caused by achromosomal deletion spanning several genes that istoo small to be detected under the microscope usingconventional cytogenetic methods. Depending on thesize of the deletion, other techniques, such as FISH orother methods of DNA analysis can sometimes be em-ployed to identify the deletion.

Missense mutation: A change in the base sequenceof a gene that alters or eliminates a protein.

Mitochondrial DNA: The mitochondrial genome con-sists of a circular DNA duplex, with 5–10 copies perorganelle.

Mitosis: Nuclear division.

Monogenic disorder: A disorder caused by mutationof a single gene.

Monosomy: Possessing only one copy of a particularchromosome instead of the normal two copies.

Mosaicism: Within a single individual or tissue, theoccurrence of two or more cell lines with different ge-netic or chromosomal constitutions.

Multifactorial inheritance: (Synonym: polygenic)The combined contribution of one or more often un-specified genes and environmental factors, often un-known, in the causation of a particular trait or disease.

Mutagen: An agent that causes a permanent geneticchange in a cell. Does not include changes occurringduring normal genetic recombination.

Mutagenicity: The capacity of a chemical or physicalagent to cause permanent genetic alterations.

Mutation: Any heritable change in DNA sequence.

Multifactorial: A characteristic influenced in its ex-pression by many factors, both genetic and environ-mental.

NNonsense mutation: A mutation in which a codon ischanged to a stop codon, resulting in a truncated pro-tein product.

Novel mutation: A distinct gene alteration that hasbeen newly discovered; not the same as a new or denovo mutation.

Null allele: A mutation that results in either no geneproduct or the absence of function at the phenotypiclevel.


OObligate carrier: (Synonym: obligate heterozygote)An individual who may be clinically unaffected butwho must carry a gene mutation based on analysis ofthe family history; usually applies to disorders inheritedin an autosomal recessive or X-linked recessive manner.

Obligate heterozygote: (Synonym: obligate carrier)An individual who may be clinically unaffected butwho must carry a gene mutation based on analysis ofthe family history; usually applies to disorders inheritedin an autosomal recessive and X-linked recessivemanner.

Oncogene: A gene, one or more forms of which is as-sociated with cancer. Many oncogenes are involved,directly or indirectly, in controlling the rate of cellgrowth.

PParent-of-origin studies: An analysis used to deter-mine whether a particular chromosome or segment ofDNA was inherited from an individual’s mother or fa-ther; helpful in the diagnosis of disorders in which im-printing or uniparental disomy is a possible underlyingetiological mechanism.

Parentage testing: (Synonyms: maternity testing, pa-ternity testing) The process through which DNA se-quences from a particular child and a particular adultare compared to estimate the likelihood that the twoindividuals are related; DNA testing can reliably ex-clude but cannot absolutely confirm an individual as abiological parent.

Parthenogenesis: The development of an individualfrom an egg without fertilization.

PCR: Polymerase chain reaction; a technique forcopying the complementary strands of a target DNAmolecule simultaneously for a series of cycles until thedesired amount is obtained.

Pedigree: A diagram of the heredity of a particular traitthrough many generations of a family.

Penetrance: The probability of a gene or genetic traitbeing expressed. Complete penetrance means the geneor genes for a trait are expressed in all the populationwho have the genes. Incomplete penetrance means the

genetic trait is expressed in only part of the population.The percent penetrance also may change with the agerange of the population.

Phenotype: Observable characteristics of an organismproduced by the organism’s genotype interacting withthe environment.

Pleiotropy: One gene that causes many different phys-ical traits such as multiple disease symptoms.

Polygenic disorder: Genetic disorder resulting fromthe combined action of alleles of more than one gene(e.g., heart disease, diabetes, and some cancers). Al-though such disorders are inherited, they depend onthe simultaneous presence of several alleles; thus thehereditary patterns usually are more complex thanthose of single-gene disorders.

Polymorphism: Difference in DNA sequence amongindividuals that may underlie differences in health. Ge-netic variations occurring in more than 1% of a popu-lation would be considered useful polymorphisms forgenetic linkage analysis.

Polyploidy: An increase in the number of haploid sets(23) of chromosomes in a cell. Triploidy refers to threewhole sets of chromosomes in a single cell (in humans,a total of 69 chromosomes per cell); tetraploidy refersto four whole sets of chromosomes in a single cell (inhumans, a total of 92 chromosomes per cell).

Population risk: (Synonym: background risk) Theproportion of individuals in the general populationwho are affected with a particular disorder or whocarry a certain gene; often discussed in the geneticcounseling process as a comparison to the patient’spersonal risk given his or her family history or othercircumstances.

Predisposition: To have a tendency or inclination to-wards something in advance.

Preimplantation diagnosis: (Synonym: preimplanta-tion testing) A procedure used to decrease the chance ofa particular genetic condition for which the fetus is specif-ically at risk by testing one cell removed from early em-bryos conceived by in vitro fertilization and transferringto the mother’s uterus only those embryos determinednot to have inherited the mutation in question.


Prenatal diagnosis: (Synonym: prenatal testing)Testing performed during pregnancy to determine if afetus is affected with a particular disorder. Chorionicvillus sampling (CVS), amniocentesis, periumbilicalblood sampling (PUBS), ultrasound, and fetoscopy areexamples of procedures used either to obtain a samplefor testing or to evaluate fetal anatomy.

Presymptomatic testing: Testing of an asymptomaticindividual in whom the discovery of a gene mutationindicates certain development of findings related to aspecific diagnosis at some future point. A negative re-sult excludes the diagnosis.

Probability: The long term frequency of an event rel-ative to all alternative events, and usually expressed asdecimal fraction.

Proband: (Synonyms: index case, propositus) The af-fected individual through whom a family with a geneticdisorder is ascertained; may or may not be the consul-tand (the individual presenting for genetic counseling).

Probe: Single-stranded DNA labeled with radioactiveisotopes or tagged in other ways for ease in identification.

Prognosis: Prediction of the course and probable out-come of a disease.

Pseudodominant inheritance: An autosomal reces-sive condition present in individuals in two or moregenerations of a family, thereby appearing to follow adominant inheritance pattern. Common explanationsinclude: (1) a high carrier frequency; (2) birth of an af-fected child to an affected individual and a geneticallyrelated (consanguineous) reproductive partner.

Pseudogene: A copy of a gene that usually lacks in-trons and other essential DNA sequences necessary forfunction; pseudogenes, though genetically similar to theoriginal functional gene, are not expressed and oftencontain numerous mutations.

RRecessive gene: A gene which will be expressed onlyif there are two identical copies or, for a male, if onecopy is present on the X chromosome.

Reciprocal translocation: When a pair of chromo-somes exchange a segment of DNA. Results in a shuf-fling of genes.

Recombinant DNA technology: Procedure used tojoin together DNA segments in a cell-free system (anenvironment outside a cell or organism). Under appro-priate conditions, a recombinant DNA molecule canenter a cell and replicate there, either autonomously orafter it has become integrated into a cellular chromosome.

Recombination: The process by which progeny derivea combination of genes different from that of eitherparent. In higher organisms, this can occur by crossingover.

Recurrence risk: The likelihood that a trait or disorderpresent in one family member will occur again in otherfamily members in the same or subsequent generations.

Reduced penetrance: Refers to the fact that some au-tosomal dominant disorders are not expressed in all in-dividuals who carry the dominant gene. Such disordersare said to exhibit reduced penetrance.

Restriction fragment length polymorphism(RFLP): Variation between individuals in DNA frag-ment sizes cut by specific restriction enzymes; polymor-phic sequences that result in RFLPs are used as markerson both physical maps and genetic linkage maps. RFLPsusually are caused by mutation at a cutting site.

Risk communication: In genetics, a process in whicha genetic counselor or other medical professionalinterprets genetic test results and advises patients ofthe consequences for them and their offspring.

SScreening: Testing designed to identify individuals ina given population who are at higher risk of having ordeveloping a particular disorder, or having a gene mu-tation for a particular disorder or looking for evidenceof a particular disease such as cancer in persons withno symptoms of disease.

Second-degree relative: Any relative who is twomeioses away from a particular individual in a pedi-gree; a relative with whom one quarter of an individual’sgenes is shared (i.e., grandparent, grandchild, uncle,aunt, nephew, niece, half-sibling).

Segregation: The normal biological process wherebythe two pieces of a chromosome pair are separatedduring meiosis and randomly distributed to the germcells.


Sex chromosome: The X or Y chromosome in humanbeings that determines the sex of an individual. Femaleshave two X chromosomes in diploid cells; males havean X and a Y chromosome. The sex chromosomescomprise the 23rd chromosome pair in a karyotype.See also: autosome.

Sex-linked: Traits or diseases associated with the X orY chromosome; generally seen in males.

Single-gene disorder: Hereditary disorder caused bya mutant allele of a single gene (e.g., Duchenne mus-cular dystrophy, retinoblastoma, sickle cell disease).

Somatic cell: Any cell in the body except gametes andtheir precursors.

Somatic mutation: A mutation occurring in any cellthat is not destined to become a germ cell; if the mu-tant cell continues to divide, the individual will cometo contain a patch of tissue of genotype different fromthe cells of the rest of the body.

Southern blotting: A technique for transferring elec-trophoretically resolved DNA segments from an agarosegel to a nitrocellulose filter paper sheet via capillary ac-tion; the DNA segment of interest is probed with a ra-dioactive, complementary nucleic acid, and its positionis determined by autoradiography.

Spectral karyotype (SKY): A graphic of all an or-ganism’s chromosomes, each labeled with a differentcolor. Useful for identifying chromosomal abnormalities.

Sporadic: The chance occurrence of a disorder or ab-normality that is not likely to recur in a family.

Substitution: In genetics, a type of mutation due to re-placement of one nucleotide in a DNA sequence byanother nucleotide or replacement of one amino acidin a protein by another amino acid.

Suppressor gene: A gene that can suppress the actionof another gene.

Susceptibility gene: A gene mutation that increasesthe likelihood that an individual will develop a certaindisease or disorder. When such a mutation is inher-ited, development of symptoms is more likely but notcertain.

Syndrome: A recognizable pattern or group of multiplesigns, symptoms, or malformations that characterize aparticular condition; syndromes are thought to arisefrom a common origin and result from more than onedevelopmental error during fetal growth.

TTeratogens: Any agent that raises the incidence ofcongenital malformations.

Trait: Any detectable phenotypic property of anorganism.

Translocation: A chromosome aberration which re-sults in a change in position of a chromosomal seg-ment within the genome. Translocation can be bal-anced or unbalanced. A balanced translocation doesnot change the total number of genes present and typ-ically is not associated with phenotypic abnormalities.An unbalanced translocation is associated with missingor extra chromosomematerial and usually is associatedwith phenotypic abnormalities.

Trisomy: Possessing three copies of a particular chro-mosome instead of the normal two copies.

UUniparental disomy: (Synonym: UPD) The situationin which both members of a chromosome pair or seg-ments of a chromosome pair are inherited from oneparent and neither is inherited from the other parent;uniparental disomy can result in an abnormal pheno-type in some cases.

VVariable expressivity: Variation in clinical features(type and severity) of a genetic disorder between af-fected individuals, even within the same family.

Vector: A self-replicating DNA molecule that transfersa DNA segment between host cells.

WWestern blotting analysis: A technique used to iden-tify a specific protein; the probe is a radioactively la-beled antibody raised against the protein in question.

Wild-type allele: The normal, as opposed to the mu-tant, gene, or allele.


XX chromosome: One of the two sex chromosomes,X and Y.

Xenograft: Tissue or organs from an individual of onespecies transplanted into or grafted onto an organismof another species, genus, or family. A common exampleis the use of pig heart valves in humans.

X-inactivation: The repression of one of the twoX-chromosomes in the somatic cells of females as amethod of dosage compensation; at an early embry-onic stage in the normal female, one of the twoX-chromosomes undergoes inactivation, apparently atrandom, from this point on all descendent cells willhave the same X-chromosome inactivated as the cellfrom which they arose, thus a female is a mosaic com-posed of two types of cells, one which expresses onlythe paternal X-chromosome, and another which ex-presses only the maternal X-chromosome.

X-linked dominant: Describes a dominant trait ordisorder caused by a mutation in a gene on the X chro-mosome. The phenotype is expressed in heterozygous

females as well as in hemizygous males (having onlyone X chromosome); affected males tend to have amore severe phenotype than affected females.

X-linked lethal: A disorder caused by a dominant mu-tation in a gene on the X chromosome that is observedalmost exclusively in females because it is almost al-ways lethal in males who inherit the gene mutation.

X-linked recessive: A mode of inheritance in whicha mutation in a gene on the X chromosome causes thephenotype to be expressed in males who are hemizy-gous for the gene mutation (i.e., they have only oneX chromosome) and in females who are homozygousfor the gene mutation (i.e., they have a copy of thegene mutation on each of their two X chromosomes).Carrier females who have only one copy of the mutationdo not usually express the phenotype, although differ-ences in X-chromosome inactivation can lead to varyingdegrees of clinical expression in carrier females.

YY chromosome: One of the two sex chromosomes,X and Y.



Web Resources

375

General Birth Defect Links:

Alliance of Genetic Support Groupshttp://www.geneticalliance.orgBirth Defect Research for Children, Inc.http://www.birthdefects.org Birth Defects Support Groupswww.ibis-birthdefects.org/Centers for Birth Defects Research and Preventionwww.cdc.gov/ncbddd/pub/cbdrpbk.pdfThe Family Villagehttp://www.familyvillage.wisc.eduGeneClinicshttp://www.geneclinics.orgGene Testswww.genetests.org Genetic Alliancehttp://www.geneticalliance.org Genetic Disorders & Birth Defects InformationCenterhttp://geneinfo.medlib.iupui.edu/Genetic Laboratorieswww.kumc.edu/International Clearinghouse for Birth DefectsMonitoring Systemshttp://www.icbd.orgInternet Resources for Special Children (IRSC)http://irsc.orgMarch of Dimes Birth Defects Foundationhttp://www.marchofdimes.com The National Association of Parents with Childrenin Special Education (NAPCSE)http://www.napcse.org National Birth Defects Prevention Network(NBDPN)http://www.nbdpn.org/NBDPNNational Organization for Rare Diseases(NORD) http://www.rarediseases.org/The National Rehabilitation InformationCenter http://www.naric.com/

National Society of Genetic Counselorshttp://www.nsgc.orgOMIM: Online Mendelian Inheritance in Manwww.ncbi.nlm.nih.gov/OMIMOrganization for Teratology InformationServices (OTIS)http://www.otispregnancy.orgSyndromes without a Namehttp://www.undiagnosed-usa.org Teratology Societyhttp://www.teratology.orgThe National Down Syndrome Societyhttp://www.ndss.org/The Noonan Support Group (TNSSG)http://www.noonansyndrome.orgTurner Syndrome Society of the United Stateshttp://www.turner-syndrome-us.org/

Central Nervous System Malformations:

About Face USA http://www.aboutfaceusa.org American Syringomyelia Alliance Projecthttp://www.asap.org/ Anencephaly Nethttp://www.anencephaly.net/ Anencephaly Support Foundationhttp://www.asfhelp.comChildren’s Craniofacial Association http://www.ccakids.com FACES: The National Craniofacial Association http://www.faces-cranio.org Forward Face, Inc. http://www.forwardface.orgHeadlines Craniofacial Support http://www.headlines.org.uk Holoprosencephalyhttp://hpe.home.att.net/Hydrocephalus Association http://www.hydroassoc.org/ The Hydrocephalus Foundation, Inc. www.hydrocephalus.org/


http://www.nsgc.org

http://www.geneticalliance.org

www.ncbi.nlm.nih.gov/OMIM

http://www.birthdefects.org

www.ibis-birthdefects.org/

http://www.otispregnancy.org

www.cdc.gov/ncbddd/pub/cbdrpbk.pdf

http://www.undiagnosed-usa.org

http://www.familyvillage.wisc.edu

http://www.teratology.org

http://www.geneclinics.org

http://www.ndss.org/

www.genetests.org

http://www.noonansyndrome.org

http://www.geneticalliance.org

http://www.turner-syndrome-us.org/

http://geneinfo.medlib.iupui.edu/

http://www.aboutfaceusa.org

www.kumc.edu/

http://www.asap.org/

http://www.icbd.org

http://www.anencephaly.net/

http://irsc.org

http://www.asfhelp.com

http://www.marchofdimes.com

http://www.ccakids.com

http://www.faces-cranio.org

http://www.napcse.org

http://www.forwardface.org

http://www.nbdpn.org/NBDPN

http://www.headlines.org.uk

http://www.rarediseases.org/

http://hpe.home.att.net/

http://www.hydroassoc.org/

http://www.naric.com/

www.hydrocephalus.org/

International Federation for Spina Bifidaand Hydrocephalushttp://www.ifglobal.org/National Hydrocephalus Foundationhttp://nhfonline.orgNIH/National Institute of Child Health and HumanDevelopment http://www.nih.gov/National Institute of Neurological Disordersand Stroke (NINDS) http://www.ninds.nih.gov/ National Organization of Disorders of the CorpusCallosumhttp://www.nodcc.org/Spina Bifida Association of Americahttp://www.sbaa.org/ Velo-Cardio-Facial Syndrome EducationalFoundation, Inc.http://www.vcfsef.org World Arnold Chiari Malformation Associationhttp://www.wacma.com/

Craniofacial Malformations:

American Cleft Palate-Craniofacial Association(ACPA)http://www.acpa-cpf.org American Foundation for the Blind http://www.afb.org American Speech-Language-Hearing Association http://www.asha.org The Arc (A National Organization on MentalRetardation) http://www.thearc.org/ CHARGE Syndrome Foundationhttp://www.chargesyndrome.org/Children’s Craniofacial Associationhttp://www.ccakids.com/ Cleft Plate Foundationhttp://www.cleftline.org/FACES the National Craniofacial Associationhttp://www.faces-cranio.org/ Helen Keller National Center for Deaf-BlindYouths and Adults http://www.hknc.org Let Them Hear Foundation http://www.letthemhear.org Micro and Anophthalmic Children’s Societyhttp://www.macs.org.uk/ National Association for Parents of Children withVisual Impairments (NAPVI) http://www.napvi.org

Pierre Robin Networkhttp://www.pierrerobin.org/ Wide Smileshttp://www.widesmiles.org/

Respiratory Malformations:

CHERUBShttp://www.cherubs-cdh.org/

Cardiac Malformations:

American Heart Association http://www.americanheart.org/ Congenital Heart Information Networkhttp://tchin.org/ Congenital Heart Defect Resourceshttp://www.congenitalheartdefects.com

Gastrointestinal Malformations:

EA/TEF Support Connectionhttp://www.eatef.org/ GEEPShttp://www.geeps.co.uk/The Pull-thru Network http://www.pullthrough.org/Tef Vater Webhttp://www.tefvater.org/ The International Ostomy Associationhttp://www.ostomyinternational.org/United Ostomy Associations of Americahttp://www.uoaa.org/VATER Connectionhttp://www.vaterconnection.org/

Renal Malformations:

American Association of Kidney Patientshttp://www.aakp.orgNational Kidney Foundationhttp://www.kidney.orgNIH/National Institute of Diabetes, Digestive &Kidney Diseaseshttp://www.niddk.nih.govPolycystic Kidney Disease Foundationhttp://www.pkdcure.org/site/PageServer Potter’s Syndromehttp://www.potterssyndrome.org/

Skeletal Malformations:

AMC Supporthttp://www.amcsupport.org/ Avenues-Arthrogryposis Multiplex Congenitahttp://www.avenuesforamc.com/

376 WEB RESOURCES

http://www.pierrerobin.org/

http://www.ifglobal.org/

http://www.widesmiles.org/

http://nhfonline.org

http://www.cherubs-cdh.org/

http://www.nih.gov/

http://www.ninds.nih.gov/

http://www.americanheart.org/

http://www.nodcc.org/

http://tchin.org/

http://www.sbaa.org/

http://www.congenitalheartdefects.com

http://www.vcfsef.org

http://www.eatef.org/

http://www.wacma.com/

http://www.geeps.co.uk/

http://www.pullthrough.org/

http://www.acpa-cpf.org

http://www.tefvater.org/

http://www.afb.org

http://www.ostomyinternational.org/

http://www.asha.org

http://www.uoaa.org/

http://www.vaterconnection.org/

http://www.thearc.org/

http://www.chargesyndrome.org/

http://www.aakp.org

http://www.ccakids.com/

http://www.kidney.org

http://www.cleftline.org/

http://www.faces-cranio.org/

http://www.niddk.nih.gov

http://www.pkdcure.org/site/PageServer

http://www.hknc.org

http://www.potterssyndrome.org/

http://www.letthemhear.org

http://www.macs.org.uk/

http://www.amcsupport.org/

http://www.napvi.org

http://www.avenuesforamc.com/

Children’s Brittle Bone Foundation http://www.cbbf.org Helping Hands Foundationhttp://www.helpinghandsgroup.org/ International Skeletal Dysplasia RegistryCedars-Sinai Medical Center 2004www.csmc.edu/Let Them Hear Foundation http://www.letthemhear.org Limb Differenceshttp://www.limbdifferences.org/

Little People of America http://www.lpaonline.org/NIH/National Arthritis and Musculoskeletal andSkin Diseases Informationhttp://www.niams.nih.gov Osteogenesis Imperfecta Foundation, Inc. http://www.oif.org STEPShttp://www.steps-charity.org.uk/home.php Superhands Networkhttp://www.superhands.us/

WEB RESOURCES 377

http://www.cbbf.org

http://www.lpaonline.org/

http://www.helpinghandsgroup.org/

http://www.niams.nih.gov

www.csmc.edu/

http://www.oif.org

http://www.letthemhear.org

http://www.steps-charity.org.uk/home.php

http://www.limbdifferences.org/

http://www.superhands.us/


AAarskog syndrome, 238tAbdominal wall defects.

See Gastroschisis;Omphalocele

Achondrogenesis, 311t, 358t. Seealso Skeletal dysplasias

Achondroplasia, 63t, 314t, 358t.See also Skeletal dysplasias

Acrocallosal syndrome, 46t, 79tAcrochordon, 342Acromelia, 315Adams-Oliver syndrome, 161t,

201t, 303tADPKD. See Autosomal dominant

polycystic kidney diseaseAdrenal hyperplasia, nonclassical,

31tAgenesis of corpus callosum,

77–81associated malformations and

syndromes, 78–81, 79–80t,80t

clinical presentation, 78epidemiology, 77etiology, 77–78evaluation, 80f, 81genetic counseling, 81management and prognosis, 81

Aicardi syndrome, 79tAlagille syndrome, 185t, 195, 195tAlcohol embryopathy. See Fetal

alcohol syndromeAmniocentesis, 32, 35fAmniotic band syndrome, 46t,

55t, 63tAndrogen embryopathy, 7tAnencephaly, 51–52

associated malformations andsyndromes, 46t, 51, 52t

embryology, 43f, 51epidemiology, 51etiology, 51evaluation, 52genetic counseling, 48–49prenatal diagnosis, 48treatment, 52

Angiotensin-converting enzyme(ACE) inhibitorsembryopathy, 7t

Anophthalmia, encephaloceleand, 54t

Anorectal malformations, 227–232associated malformations and

syndromes, 228–230, 229tclassification, 227, 228tclinical presentation, 228embryology, 228epidemiology, 227etiology, 228evaluation, 230genetic counseling, 232management and prognosis,

230–232Anotia, 52t, 111. See also Ear

anomaliesAnticoagulant embryopathy, 7tAntley-Bixler syndrome, 85t, 324tAortic valve defects

associated syndromes, 202clinical presentation, 199–200treatment and prognosis, 202,

203Apert syndrome

clinical features, 55t, 73t, 84t,220t, 296t

craniosynostosis syndromes in,84t

etiology, 55t, 73t, 220t, 296tsyndactyly in, 294

Aplasia, 8Aplasia cutis, 342ARPKD. See Autosomal recessive

polycystic kidneydisease

Arthrogryposis, 321–329associated malformations and

syndromes, 323, 324tclassification, 326–327tclinical features, 322–323,

326–327tdistal, 325, 326–327tembryology, 321–322epidemiology, 321etiology and pathogenesis,

322, 322tevaluation, 325, 328genetic counseling,

328–329management and prognosis,

328Arthrogryposis multiplex

congenita, 323–325Ashkenazi Jewish population,

29, 30tAsphyxiating thoracic dystrophy

(Jeune syndrome), 272t,311t

Asplenia syndrome, 176t, 206,206t

Association, 9Asymmetric crying facies,

105–107, 106fassociated malformations and

syndromes, 106etiology, 105evaluation, 106–107genetic counseling, 107incidence, 105prognosis, 107

Index

Page numbers followed by f or t indicate figures or tables, respectively.

379


380 INDEX

Atrial septal defectassociated malformations and

syndromes, 174–177tdiagnosis, 173etiology, 173, 177genetic counseling, 177incidence, 173treatment and prognosis, 177

Atrioventricular septal defect,180–181

associated malformations andsyndromes, 174–177t

diagnosis, 180etiology, 180genetic counseling, 181incidence, 180treatment and prognosis,

180–181Autosomal dominant disorders,

genetic counseling, 23, 23fAutosomal dominant polycystic

kidney disease (ADPKD)clinical presentation, 267t, 269tepidemiology, 265evaluation, 273–274, 273fgenetic counseling, 275management and prognosis,

274Autosomal recessive disorders,

genetic counseling, 23–25,24f

Autosomal recessive polycystickidney disease (ARPKD)

clinical presentation, 267t, 269tepidemiology, 265evaluation, 273–274, 273fgenetic counseling, 275management and prognosis,

274

BBaller-Gerold syndrome, 85tBanana sign, 45fBannayan-Riley-Ruvalcaba

syndrome, 349t, 352tBardet-Biedl syndrome, 238t,

272t, 289tBarth syndrome, 209–210, 211tBeals syndrome, 327t. See also

Arthrogryposis

Beare-Stevenson syndrome, 73t,84t

Beckwith-Wiedemann syndromeclinical features, 154t, 211t,

244t, 349t, 350tetiology, 244t, 350thypoglycemia in, 243inheritance pattern, 154t, 211tmanagement, 351neoplasm risk in, 351–353, 352tprognosis, 351

Bicuspid aortic valve, 199, 203Birth defects. See Congenital

malformationsBloom syndrome, 30tBochdalek hernia, 151. See also

Congenital diaphragmatichernia

Brachmann-de Lange syndrome,154t

Branchio-oto-renal (BOR)syndrome, 113–114, 257t,272t

Brushfield spots, 15f

C3 C syndrome, 68t, 174tCamptomelia, Cumming type,

167tCamptomelic dysplasia, 311t. See

also Skeletal dysplasiasCanavan disease, 30tCardiac-limb syndrome. See

Holt-Oram syndromeCardio-facio-cutaneous (CFC)

syndrome, 195t, 211tCardiomyopathy, 209–213

associated genetic disorders,211t, 212f

clinical presentation, 209–210,210f

diagnosis, 212epidemiology, 209etiology, 209–210evaluation, 212–213familial hypertrophic, 210, 212ftreatment, 213

Cardiovascular malformations.See also specificmalformations

anencephaly and, 52tanorectal malformations and,

229tCHARGE syndrome and, 118tcongenital diaphragmatic

hernia and, 155tduodenal atresia and, 224tencephalocele and, 54tesophageal

atresia/tracheoesophagealfistula and, 219t

Hirschsprung disease and, 237tincidence, 4tomphalocele and, 243tpolydactyly and, 288tprenatal diagnosis, 36renal agenesis and, 255, 255trenal cystic disease and, 271tsingle umbilical artery and,

335tCarnitine uptake defect, 211tCarpenter syndrome, 85t, 244t,

289t, 296tCarrier screening, 28–29Cartilage-hair hypoplasia

syndrome, 220t, 238tCat-eye syndrome, 185tCaudal regression syndrome,

231t, 257t, 279tCCAM. See Congenital cystic

adenomatoidmalformations

CDAGS, 231tCDG (congenital disorders of

glycosylation) syndromes,211t

Cenani-Lenz syndrome, 294Central nervous system

malformations. See alsospecific malformations

anorectal malformationsand, 229t

congenital diaphragmatichernia and, 155t

esophagealatresia/tracheoesophagealfistula and, 219t

Hirschsprung disease and, 237tincidence, 4tomphalocele and, 243t

INDEX 381

polydactyly and, 288trenal agenesis and, 255trenal cystic disease and, 271tsingle umbilical artery and,

335tCerebro-hepato-renal syndrome.

See Zellweger syndromeCerebro-oculo-facio-skeletal

(COFS) syndrome, 79t,324t

CFC (cardio-facio-cutaneous)syndrome, 195t, 211t

CHAOS. See Congenital highairway obstructionsyndrome

CHARGE syndrome/associationcardiac lesions, 174t, 185tclinical features, 118f, 118t,

174t, 185t, 220t, 244t, 257tdiagnostic criteria, 118–119ear anomalies, 118fetiology, 119, 174t, 220t, 244t

Chiari malformations, 71–75associated malformations and

syndromes, 72–73, 73tclinical presentation, 72epidemiology, 71etiology, 71evaluation, 72f, 73–74genetic counseling, 74–75management and prognosis,

74CHILD syndrome, 46t, 303tChoanal atresia, 117–120

associated anomalies andsyndromes, 117–119, 118f,118t

embryology, 117epidemiology, 117evaluation, 119, 119tgenetic counseling, 119–120management and prognosis,

119Chondrodysplasia punctata, 127,

130t, 313t, 324tChondroectodermal dysplasia.

See Ellis-van Creveldsyndrome

Chorionic villus sampling, 32–33,35f

Chromosome analysis, 32, 33f,34f

Cleft lip/palate, 93–99anencephaly and, 52tassociated anomalies and

syndromes, 94–97, 94f,94t, 95t

embryology, 94encephalocele and, 54tepidemiology, 93etiology, 93–94evaluation, 97–98, 97f, 98f, 98tgenetic counseling, 98–99, 99tmanagement and prognosis, 98

Cloacal exstrophy sequence,244t, 257t, 272t, 279t, 336t

Coarctation of the aorta, 200Coccygeal pit (cutaneous

dimple), 15f, 340Cockayne syndrome, 128, 130tCOFS (cerebro-oculo-facio-

skeletal) syndrome, 79t,324t

Coloboma, 121–124associated anomalies and

syndromes, 121–122, 122tin CHARGE syndrome, 118t,

122clinical presentation, 123fembryology, 121epidemiology, 121evaluation, 123, 123fgenetic counseling, 124management and prognosis,

124Complex, 9Computed tomography (CT)

in congenital pulmonarylymphangiectasia, 166

in neural tube defects, 44Congenital cataract, 125–130, 126f

classification, 125–129embryology, 125epidemiology, 125etiology, 125, 126tevaluation, 129, 129f, 130tgenetic counseling, 130isolated, 127management and prognosis,

130

in metabolic disease, 128–129other ocular abnormalities

and, 127in systemic disorders,

127–128Congenital contractual

arachnodactyly, 327t. Seealso Arthrogryposis

Congenital cystic adenomatoidmalformations (CCAM),147–149

associated malformations andsyndromes, 148

classification, 147clinical presentation, 148embryology, 148epidemiology, 147–148etiology, 148evaluation, 148–149genetic counseling, 149management and prognosis,

149Congenital diaphragmatic hernia,


syndromes, 154, 154t, 155tclinical presentation, 153–154embryology, 153epidemiology, 151etiology, 151, 152tevaluation, 154–155genetic counseling, 157management and prognosis,

155–157pathogenesis, 153types, 151

Congenital disorders ofglycosylation (CDGsyndromes), 211t

Congenital high airwayobstruction syndrome(CHAOS), 135–137

associated malformations andsyndromes, 136–137, 136t

clinical presentation, 136embryology, 135–136epidemiology, 135etiology, 135evaluation, 137genetic counseling, 137

382 INDEX

Congenital high airwayobstruction syndrome(CHAOS) (Cont.):

management and prognosis,137

Congenital hydrothorax, 159–163associated malformations and

syndromes, 160, 161tclinical presentation, 160epidemiology, 159etiology, 159–160evaluation, 160–161genetic counseling, 163management and prognosis,

161–163, 162fCongenital ichthyosis, 128, 130tCongenital intestinal

aganglionosis. SeeHirschsprung disease

Congenital limb deficiency. SeeLimb reduction defects

Congenital malformations. Seealso specificmalformations

assessment of infant withbiochemical testing, 18cytogenetic testing, 16, 17ffollow-up, 18–19history, 13–14molecular testing, 16–18physical examination, 14–16,

14f, 15fclassification systems

clinical, 9etiological, 10histological changes, 8–9medical consequences, 9–10timing of insult, 7–8

embryology, 5–6, 5fenvironmental factors, 6–7, 7tepidemiology, 3–4, 4tetiology, 6–7, 7tgenetic factors, 6infant mortality and, 4–5

Congenital pulmonarylymphangiectasia, 165–168


clinical presentation, 166embryology, 165

epidemiology, 165etiology, 166evaluation, 166forms, 165genetic counseling, 168management and prognosis, 168

Congenital scar, 342Cordocentesis, 33–34Cornelia de Lange syndrome,

303t, 324t, 358tCoronal synostosis, 83, 84tCorpus callosum, agenesis of. See

Agenesis of corpus callosumCostello syndrome, 195t, 211tCraniorachischisis, 43fCraniosynostosis, 83–88

associated malformations andsyndromes, 84t, 85t

clinical presentation,85–86, 86f

epidemiology, 83etiology, 83–85evaluation, 86–87genetic counseling, 88management and prognosis,

87–88Crouzon syndrome, 73t, 84tCT. See Computed tomographyCutaneous dimple (coccygeal

pit), 15f, 340Cystic fibrosis, 30tCystic hygroma, 355–361

associated malformations andsyndromes, 356–357,358–359t

categories, 355clinical presentation, 356early gestation vs. late

gestation/postnatal,360–361, 360t

embryology, 356epidemiology, 355etiology, 355–356evaluation, 357genetic counseling, 361management and prognosis,

357–360Cytogenetic testing, 16, 17fCytomegalovirus infection,

congenital, 63t

DDandy-Walker malformation,


syndromes, 68, 68t, 69fclinical presentation, 67epidemiology, 67etiology, 67evaluation, 68–69, 69fgenetic counseling, 70management and prognosis,

69–70Deformation, 8Deformational plagiocephaly, vs.

craniosynostosis, 87Denys-Drash syndrome, 154tDermal sinus, 340–341, 342fDextrocardia, 205–207

associated malformations andsyndromes, 206, 206t

epidemiology, 205etiology, 205evaluation, 206genetic counseling, 207prognosis and treatment, 206

Diaphragmatic hernia, congenital.See Congenitaldiaphragmatic hernia

Diastrophic dysplasia, 312tDiGeorge syndrome, 184, 201t,

202Digitotalar dysmorphism, 326t.

See also ArthrogryposisDisruption, 8Distal arthrogryposis, 325,

326–327t. See alsoArthrogryposis

Distraction osteogenesis, 102–103Dominant pterygium syndrome,

327t. See alsoArthrogryposis

Donnai syndrome, 154tDown syndrome. See Trisomy 21Duodenal atresia, 223–225

associated malformations andsyndromes, 224, 224t, 225t

clinical presentation, 224embryology, 223epidemiology, 223evaluation, 224t

INDEX 383

genetic counseling, 225management and prognosis,

225Dysplasia, 8–9Dyssegmental dysplasia

(Silverman-Handmakersyndrome), 55t

EEar anomalies, 111–115


in CHARGE syndrome, 118,118f, 118t

clinical presentation, 112f,113f, 115f

embryology, 111–112epidemiology, 111etiology, 111evaluation, 114, 115f, 116fgenetic counseling, 115management and prognosis,

114microtia, 113fpreauricular pit, 15f, 112fpreauricular tag, 112f

Ebstein anomalyassociated syndromes, 194clinical presentation, 193prognosis, 196recurrence risk, 196t

Echocardiography, fetal, 36Ectodermal dysplasias, cleft

lip/palate in, 94–95Ectrodactyly-ectodermal

dysplasia-clefting (EEC)syndrome, 257t, 296t, 303t

Edwards syndrome. See Trisomy18

Elejalde syndrome, 349tEllis-van Creveld syndrome

cardiac lesions, 175tclinical features, 145t, 175t,

257t, 289t, 313tetiology, 175t, 257t, 289t, 313tinheritance, 145trecurrence risk, 313t

Encephalocele, 53–55associated malformations and

syndromes, 54, 54t, 55t

clinical presentation, 53embryology, 53fepidemiology, 53tevaluation, 53–54genetic counseling, 54management and prognosis, 54

Epidermal nevus, 350tEsophageal

atresia/tracheoesophagealfistula, 217–221

associated malformations andsyndromes, 218–219, 219t,220t

clinical presentation, 218embryology, 217–218epidemiology, 217etiology, 217evaluation, 219–221genetic counseling, 221management and prognosis, 221variations, 217, 218f

Ex utero intrapartum treatment(EXIT) procedure

for congenital diaphragmatichernia, 155

for congenital high airwayobstruction syndrome, 137

Expressivity, 28

FFacial asymmetry

asymmetric crying facies,105–107, 105f

oculo-auriculo-vertebralsyndrome, 107–109, 107f

Factor XI deficiency, 30tFamilial dysautonomia, 30tFanconi anemia type C, 30tFanconi pancytopenia syndrome

clinical features, 220t, 225t,263t, 289t, 303t

etiology, 225t, 263tevaluation, 221inheritance, 220tpolydactyly and, 288

Faun tail hypertrichosis, 341, 341fFeingold syndrome (oculo-

duodeno-esophageal-digital syndrome), 220t,225t

Fetal akinesia deformationsequence. SeeArthrogryposis

Fetal alcohol syndromecardiac lesions, 177t, 185tclinical features, 7t, 79t, 177t,

185t, 324tetiology, 177t

Fetal nuchal translucency, 31–32Fetal surgery

for congenital diaphragmatichernia, 155

for congenital high airwayobstruction syndrome, 137

for hypoplastic left heartsyndrome, 203

Fetal trimethadione syndrome,185t

FG syndrome, 73t, 79t, 324tFibrochondrogenesis, 244tFluorescence in-situ hybridization

(FISH), 16, 17fFolic acid deficiency, neural tube

defects and, 42Fraser syndrome, 55t, 136, 296tFreeman-Sheldon syndrome,

326t. See alsoArthrogryposis

Frontonasal dysplasia, 55tFryns syndrome

cardiac lesions, 175tclinical features, 79t, 154t, 175t,

238t, 244t, 272t, 358tetiology, 244tinheritance, 79t

GGalactosemia, congenital

cataracts in, 128Gastrointestinal malformations.

See also specificmalformations

anencephaly and, 52tanorectal malformations and

other, 229tcongenital diaphragmatic

hernia and other, 155tHirschsprung disease and

other, 237tpolydactyly and, 288t

384 INDEX

Gastrointestinal malformations(Cont.):

renal agenesis and, 255trenal cystic disease and, 271tsingle umbilical artery

and, 335tGastroschisis, 247–250


clinical presentation, 248, 248fembryology, 247–248epidemiology, 247etiology, 247evaluation, 249genetic counseling, 250management and prognosis,

249–250vs. omphalocele, 249t

Gaucher disease type I, 30tGCKD (glomerulocystic kidney

disease), 268t, 269tGenetic counseling

definition, 21prenatal diagnosis

amniocentesis, 32, 35fchorionic villus sampling,

32–33, 35fchromosome analysis, 32,

33f, 34fcordocentesis, 33–34imaging, 34, 36preimplantation genetic

diagnosis, 36–37principles and practices, 21risk assessment

autosomal dominantdisorders, 23, 23f

autosomal recessivedisorders, 23–25, 24f

complex disorders, 27–28mitochondrial disorders,

26–27, 27fpenetrance and expressivity,

28sex-linked disorders, 25–26,

25f, 26fin unknown diagnosis, 28

screeningcarrier, 28–29fetal, 29–32

in specific disordersagenesis of corpus callosum,

81anencephaly, 48–49anorectal malformations, 232arthrogryposis, 328–329asymmetric crying facies, 107choanal atresia, 119–120cleft lip/palate, 98–99, 99tcoloboma, 124congenital cataract, 130congenital cystic

adenomatoidmalformations, 149

congenital diaphragmatichernia, 157

congenital high airwayobstruction syndrome, 137

congenital hydrothorax, 163congenital pulmonary

lymphangiectasia, 168conotruncal defects, 186,

188, 190–191craniosynostosis, 88cystic hygroma, 361Dandy-Walker malformation,

70dextrocardia, 207duodenal atresia, 225encephalocele, 54esophageal

atresia/tracheoesophagealfistula, 221

gastroschisis, 250Hirschsprung disease, 237,

239tholoprosencephaly, 59–60horseshoe kidney, 264hydrocephalus, 64–65, 65tleft ventricular outflow tract

obstructive defects, 203limb reduction defects, 304micrognathia, 103neural tube defects, 48–49occult spinal dysraphism,

344oculo-auriculo-vertebral

syndrome, 108omphalocele, 245overgrowth syndromes, 353

polydactyly, 290pulmonary agenesis, 141pulmonary hypoplasia, 146renal agenesis, 258–259renal cystic diseases, 274–275right ventricular outflow tract

obstructive defects, 196,196t

septal defects, 177, 179–180,181

skeletal dysplasias, 320syndactyly, 295

Genitourinary malformations. Seealso specificmalformations

anorectal malformationsand, 229t

CHARGE syndrome and, 118tcongenital diaphragmatic

hernia and, 155tesophageal

atresia/tracheoesophagealfistula and, 219t

Hirschsprung disease and, 237tomphalocele and, 243tpolydactyly and, 288trenal agenesis and, 255, 255trenal cystic disease and, 271tsingle umbilical artery and, 335t

Gerbe syndrome, 303tGerman syndrome, 167tGlomerulocystic kidney disease

(GCKD), 268t, 269tGoldenhar syndrome, 176t, 186t,

257tGoltz syndrome, 263t, 296t, 303tGordon syndrome, 326t. See also

ArthrogryposisGorlin-Chaudhry-Moss syndrome,

85tGreig cephalopolysyndactyly

syndrome, 289t, 296tGrowth retardation, in CHARGE

syndrome, 118t

HH-type fistula, 217. See also

Esophagealatresia/tracheoesophagealfistula

INDEX 385

Haddad syndrome, 238tHairy patch, 341, 341fHajdu-Cheney syndrome, 73tHearing loss, nonsyndromic, 31tHecht syndrome, 327t. See also

ArthrogryposisHemangioma, lumbosacral, 342,

342fHemihyperplasia, 348, 350–351,

350–351t, 352tHennekam lymphangiectasia,

167tHernia, congenital diaphragmatic.

See Congenitaldiaphragmatic hernia

Heterotaxy syndromes, 176t. Seealso Dextrocardia

High airway obstructionsyndrome, congenital. SeeCongenital high airwayobstruction syndrome

Hirschsprung disease (HSCR),233–239

assessment, 238tassociated malformations and

syndromes, 235–236, 237tclinical presentation, 235embryology, 235epidemiology, 233etiology, 233evaluation, 236–237, 236fgenetic counseling, 237, 239tgenetic mutations associated

with, 234tmanagement and prognosis,

237Holoprosencephaly, 57–60

associated malformations andsyndromes, 58, 95

autosomal dominant genes for,57, 58t

clinical presentation, 58, 58fepidemiology, 57etiology, 57evaluation, 59genetic counseling, 59–60management and prognosis, 59

Holt-Oram syndrome, 173, 175t,289t, 296t, 303t

Horseshoe kidney, 261–264


clinical presentation, 262embryology, 261–262epidemiology, 261evaluation and management,

262–263genetic counseling, 264prognosis, 264

HSCR. See Hirschsprung diseaseHydantoin embryopathy, 225tHydranencephaly, 61Hydrocephalus, 61–65


clinical presentation, 62epidemiology, 61etiology, 61evaluation, 62–64genetic counseling, 64–65, 65tmanagement and prognosis, 64

Hydrolethalus syndrome, 175tHydrops fetalis, idiopathic, 167tHydrothorax, congenital. See

Congenital hydrothoraxHyperplasia, 8Hypertrichosis, faun tail, 341,

341fHypertrophic cardiomyopathy,

familialdiagnosis, 212genetic defect in, 210, 212ftreatment, 213

Hypophosphatasia, 312tHypoplasia, 8Hypoplastic left heart syndrome,

200, 202–203Hypotrichosis-lymphedema-

telangiectasia syndrome,167t

IIchthyosis, congenital, 128, 130tIncontinentia pigmenti, 128, 130tInfant mortality, congenital

malformations and, 4–5Iniencephaly, 43fInterrupted aortic arch, 200, 202,

203Intestinal lymphangiectasia, 167t

Iris coloboma. See ColobomaIvemark syndrome, 176t, 257t

JJackson-Weiss syndrome, 84tJacobsen syndrome, 201tJarcho-Levin syndrome, 336tJeune syndrome (asphyxiating

thoracic dystrophy), 272t,311t

Johanson-Blizzard syndrome,231t

Juvenile nephronophthisis(JNPHP)

clinical presentation, 268t, 269tevaluation, 273, 273f

KKabuki syndrome, 175t, 185t,

201t, 263tKaufman-McKusick syndrome,

279tKleeblattschadel anomaly, 86Klinefelter syndrome, 358tKlippel-Feil anomaly, 73tKlippel-Trenaunay-Weber

syndrome, 350t, 352tKniest dysplasia, 97, 324tKnobloch syndrome, 167t

LLCHAD deficiency, 211tLeft ventricular outflow tract

obstructive defects,199–203

associated syndromes,200–202, 201t

clinical presentation, 199–200genetic counseling, 203treatment and prognosis,

202–203Lemon sign, 45fLEOPARD syndrome, 195t, 211t,

257t, 336tLethal multiple pterygium

syndrome, 324tLimb-body wall complex, 257t,

279tLimb reduction defects, 299–304

anencephaly and, 52t

386 INDEX

Limb reduction defects (Cont.):associated malformations and

syndromes, 301–302, 302t,303t

classification, 299–300clinical presentation, 301embryology, 301encephalocele and, 54tepidemiology, 300etiology, 300–301evaluation, 302–304genetic counseling, 304management and prognosis,

304Lipoma, sacral, 341, 341f, 342fLong chain fatty acid oxidation

disorders, 211tLong QT syndrome, syndactyly

and, 295Lowe syndrome, 127, 130tLymphedema/cerebral

arteriovenous anomaly, 167tLymphedema/hypoparathyroidism

anomaly, 167tLyon hypothesis, 25

MMacrocephaly-cutis marmorata

syndrome, 352tMagnetic resonance imaging

(MRI)in agenesis of corpus callosum,

78, 80fin Chiari malformation, 72fin Dandy-Walker malformation,

68, 69fin neural tube defects, 44for prenatal diagnosis, 36

Malformation, 7–8Marden-Walker syndrome, 324tMarshall-Smith syndrome, 349t,

352tMASA syndrome, 61, 63tMaternal diabetes embryopathy

cardiac lesions, 177t, 185t, 210clinical features, 7t, 46t, 177t,

185t, 225tetiology, 177tholoprosencephaly, 57neural tube defects, 42

Maternal PKU syndromecardiac lesions, 177t, 185t, 201tclinical features, 7t, 177t, 185t,

201tetiology, 177t, 201t

Maternal serum alpha-fetoprotein(MSAFP)

in gastroschisis, 249in neural tube defects, 48

McCune-Albright syndrome, 350tMCDK. See Multicystic dysplastic

kidneyMcKusick-Kaufman syndrome,

175tMeckel-Gruber syndrome, 54,

55t, 144, 244t, 336tMeningocele, 44–45, 45fMental retardation, in CHARGE

syndrome, 118tMesomelia, 315Metaphyseal dysplasia, 220t, 238tMicrognathia, 101–103, 102f

associated anomalies andsyndromes, 101–102

embryology, 101etiology, 101evaluation, 102genetic counseling, 103management and prognosis,

102–103, 103fMicrophthalmia, 54t, 63tMicrotia. See also Ear anomalies

anencephaly and, 52tclinical presentation, 111, 113fetiology, 111

Miller-Dieker syndrome, 79tMitochondrial disorders, 26–27, 27fMitochondrial respiratory chain

defects, 211tMitral stenosis, 199, 202Mohr syndrome. See Oral-facial-

digital syndromeMolecular testing, 16–18Morgagni hernia, 151. See also

Congenital diaphragmatichernia

Mowat-Wilson syndrome, 79t,238t

MRI. See Magnetic resonanceimaging

Mucolipidosis IV, 30tMucopolysaccharidoses, 211tMuenke syndrome, 84tMulticystic dysplastic kidney

(MCDK)clinical presentation, 267t, 269tepidemiology, 265evaluation, 273–274, 273fgenetic counseling, 274–275management and prognosis,

274Multiple endocrine neoplasia

type 2, 238tMultiple lentigines syndrome.

See LEOPARD syndromeMURCS association, 55t, 257t,

303tMusculoskeletal malformations.

See also specificmalformations

anorectal malformations and,229t


renal cystic disease and, 271tsingle umbilical artery and,

335tMyelomeningocele


clinical presentation, 44evaluation, 44–45, 45fgenetic counseling, 48–49management and prognosis,

45–47

NNager syndrome, 102, 238t, 303tNeu-Laxova syndrome, 79tNeural tube defects. See also

Anencephaly;Myelomeningocele


embryology, 42–43, 43fepidemiology, 41–42genetic counseling, 48–49prenatal diagnosis, 29, 31, 48

Neurofibromatosis, 350t

INDEX 387

Neurofibromatosis type I, 73tNevo syndrome, 349tNiemann-Pick disease, 31tNonclassical adrenal hyperplasia,

31tNonsyndromic hearing loss, 31tNoonan syndrome

cardiac lesions, 175t, 210, 211tclinical features, 63t, 112, 161t,

167t, 175t, 195t, 196f, 210,358t

ear anomalies, 112etiology, 63t, 161t, 167t, 175t,

195tinheritance pattern, 211t

Nuchal translucency, 31–32

OOctreotide, for congenital

hydrothorax, 163Oculo-auriculo-vertebral (OAV)

syndromeassociated malformations and

syndromes, 108cardiac lesions, 176tclinical features, 107–108, 107f,

176tetiology, 108, 176tevaluation, 108, 108tfacial asymmetry, 107fgenetic counseling, 108incidence, 108prognosis, 108

Oculo-duodeno-esophageal-digital (ODED) syndrome(Feingold syndrome),220t, 225t

Oculodentodigital syndrome, 296tOEIS complex, 231t, 244t, 336tOK-432, for cystic hygroma, 357Oligohydramnios sequence, 324tOmphalocele, 241–245


clinical presentation, 242, 242fembryology, 241–242epidemiology, 241etiology, 241evaluation, 243

vs. gastroschisis, 249tgenetic counseling, 245management and prognosis,

243–245Opitz C syndrome, 85tOpitz-Frias syndrome, 225tOpitz syndrome, 220t, 231tOral-facial-digital syndrome

(Mohr syndrome)cardiac lesions, 175tclinical features, 175t, 296tetiology, 175ttype I, 63t, 95, 272t, 289ttype II, 63t

Osteochondrodysplasias. SeeSkeletal dysplasias

Osteogenesis imperfecta, 310t.See also Skeletal dysplasias

Oto-palatal-digital syndrome, 97Overgrowth syndromes, 347–353

classification, 347clinical features, 348–350, 349tepidemiology, 347etiology, 347–348evaluation, 351genetic counseling, 353management, 351neoplasm risk in, 351–353,

352t, 353tprognosis, 351

P4p deletion syndrome (Wolf-

Hirschhorn syndrome), 95,174t

Pallister-Hall syndrome, 55t, 201t,231t, 263t, 289t

Patau syndrome. See Trisomy 13PEHO syndrome, 167tPena-Shokeir phenotype, 324tPenetrance, 28Pentalogy of Cantrell, 46t, 242,

244tPerlman syndrome, 154t, 349t,

352tPeters anomaly, 127Pfeiffer syndrome, 84t, 296tPGD (preimplantation genetic

diagnosis), 36–37PHACE syndrome, 68t, 201t

Phenytoin embryopathy, 7t, 93Pierre Robin syndrome, 96Plagiocephaly, deformational, vs.

craniosynostosis, 87Poland sequence, 296t, 303tPolycystic kidney disease. See

Renal cystic diseasesPolydactyly, 285–290

associated malformations andsyndromes, 287–288, 288t,289–290t

clinical presentation, 286–287embryology, 285–286, 286tencephalocele and, 54tepidemiology, 285evaluation, 288genetic counseling, 290management and prognosis,

290mesoaxial, 287postaxial, 286–287preaxial, 287

Polysyndactyly, 294. See alsoSyndactyly

Pompe disease, 210, 210f, 211tPopliteal pterygium syndrome,

324tPorencephaly, 61Port-wine stain, lumbosacral, 342fPostaxial polydactyly, 286–287,

286t. See also PolydactylyPosterior urethral valves, 277–280


classification, 277clinical presentation, 278embryology, 277–278epidemiology, 277evaluation, 279–280genetic counseling, 280–281management and prognosis,

280Potter syndrome, 145tPreauricular pit, 15f, 112fPreaxial polydactyly, 286t, 287.

See also PolydactylyPreimplantation genetic diagnosis

(PGD), 36–37Primary carnitine deficiency, 211tProteus syndrome, 350t, 352t

388 INDEX

Proud syndrome, 79tPseudotail, 343Pulmonary agenesis, 139–141


clinical presentation, 140embryology, 139–140epidemiology, 139etiology, 139evaluation, 140–141genetic counseling, 141management and prognosis, 141

Pulmonary atresiaclinical presentation, 194prognosis, 196recurrence risk, 196t

Pulmonary hypoplasia, 143–146associated malformations and

syndromes, 144, 145tclinical presentation, 144embryology, 143–144epidemiology, 143etiology, 143evaluation, 145genetic counseling, 146management and prognosis, 146

Pulmonary lymphangiectasia,congenital. See Congenitalpulmonarylymphangiectasia

Pulmonic stenosisassociated syndromes,

194–195, 195tclinical presentation, 193–194prognosis, 196trecurrence risk, 196t

Q22q11 deletion syndrome

cardiac lesions, 174t, 184, 185t,189

cleft palate and, 95–96clinical features, 73t, 95–96,

96t, 174t, 185t, 190fetiology, 73t, 174tfluorescence in-situ

hybridization testing, 16,17f

genetics, 96Quad screen, 31

RRacial/ethnic considerations, in

carrier screening, 28–29, 30tRenal agenesis, 253–259


clinical presentation, 254embryology, 254epidemiology, 253–254evaluation and management,

256, 258f, 258tgenetic counseling, 258–259prognosis, 256–258

Renal cystic diseases, 265–275associated malformations and

syndromes, 271, 271t,272–273t

classification, 265, 266tclinical presentation, 266,

267–270tembryology, 266epidemiology, 265–266evaluation, 271–274genetic counseling, 274–275management and prognosis,

274Respiratory system malformations

anorectal malformations and,229t


single umbilical artery and,335t

Retinoic acid embryopathy, 7t,185t

Rhizomelia, 315Rieger syndrome, 122, 127Right ventricular outflow tract

obstructive defects,193–196

associated syndromes,194–195, 195t

clinical presentation, 193–194genetic counseling, 196, 196tprognosis, 196

Ritscher-Schinzel syndrome, 68tRoberts SC-phocomelia, 55t, 263t,

303t, 324t, 358t

Robin sequence, 96Rubella embryopathy, 7t, 195tRubinstein-Taybi syndrome, 175tRussell-Silver syndrome, 279t

SSacral dimple, 15fSaethre-Chotzen syndrome, 84tSchinzel syndrome, 46tScimitar syndrome, 145tSeptic-optic dysplasia, 79tSequence, 9Setting sun sign, 62Sex-linked conditions, genetic

counseling, 25–26, 25f, 26fShah-Waardenburg syndrome,

234tShort rib-polydactyly syndrome

clinical features, 145t, 311tetiology, 311tinheritance, 145trecurrence risk, 311ttype I (Saldino-Noonan type),

272t, 289t, 358ttype II (Majewski type), 272t,

289t, 358tShprintzen-Goldberg syndrome,

85tSilverman-Handmaker syndrome

(dyssegmental dysplasia),55t

Simian crease, 15fSimple renal cysts, 268t, 269tSimpson-Golabi-Behmel

syndrome, 154t, 175t, 195t,349t, 352t

Single umbilical artery, 333–337associated malformations and

syndromes, 334–335, 335tembryology, 334epidemiology, 333–334evaluation, 335–337prognosis, 337

Sirenomelia sequence, 336tSitus inversus, 205, 206t. See also

DextrocardiaSkeletal dysplasias, 307–320

associated malformations andsyndromes, 315t

classification, 307

INDEX 389

clinical presentation, 309,310–314t, 315t

embryology, 308epidemiology, 307–308etiology, 308–309, 310–314tevaluation, 309, 315–316, 315t,

319fgenetic counseling, 320prognosis, 316radiological findings, 317–318trecurrence risk, 310–314t

Smith-Lemli-Opitz syndromebiochemical testing, 18cardiac lesions, 176t, 201tclinical features, 127, 176t,

201t, 238t, 257t, 272t, 289t,296t

diagnosis, 127–128, 130tetiology, 176t, 201t, 238t

Sotos syndrome, 349t, 352tSpina bifida. See Meningocele;

MyelomeningoceleSpina bifida occulta, 44Spinal dysraphism, occult

associated findings, 343clinical presentation, 44,

340–343, 341–343fembryology, 340epidemiology, 339–340evaluation, 343–344genetic counseling, 344

Spondyloepiphyseal dysplasiacongenita, 97, 313t

Spondylothoracic dysplasia, 336tStickler syndrome, 96–97Surfactant, for congenital

diaphragmatic hernia,156

Syndactyly, 293–296associated malformations and

syndromes, 295, 296tclinical presentation, 293–294embryology, 293epidemiology, 293evaluation, 295genetic counseling, 295management, 295types, 294

Synpolydactyly, 294. See alsoSyndactyly

TTACRD pattern/association, 136,

225tTail, 343, 343fTay-Sachs disease, 31tTBS. See Townes-Brocks

syndromeTeratogens, 6–7, 7t. See also

specific agentsTetralogy of Fallot, 188–191

associated malformations andsyndromes, 185–186t,189–190

clinical presentation, 189, 190fembryology, 188–189epidemiology, 189evaluation, 189–190genetic counseling, 190–191management and prognosis,

190Thanatophoric dysplasia, 310t,

358t. See also Skeletaldysplasias

Thoracentesisfor congenital hydrothorax,

161–162Thrombocytopenia-absent radius

(TAR) syndrome, 176t,303t

Toriello-Carey syndrome, 80t,176t

Townes-Brocks syndrome (TBS)cardiac lesions, 176tclinical features, 176t, 225t,

231t, 279t, 290tear anomalies, 114etiology, 176t, 225t, 231t

Toxoplasmosis, congenital, 63tTracheoesophageal fistula. See

Esophagealatresia/tracheoesophagealfistula

Transposition of the greatarteries, 186–188

associated malformations andsyndromes, 185t, 187–188

clinical presentation, 187embryology, 186–187epidemiology, 187evaluation, 188

genetic counseling, 188treatment and prognosis, 188

Treacher Collins syndrome, 102Tricuspid atresia

associated syndromes, 194clinical presentation, 193prognosis, 196recurrence risk, 196t

Trigonocephaly, 86Trimethadione syndrome, fetal,

185tTriple screen, 29Triploid/diploid mixoploidy, 350tTriploidy syndrome, 63t, 244t,

296tTrismus-pseudocamptodactyly

syndrome, 327t. See alsoArthrogryposis

Trisomy 8, partial, 185tTrisomy 13 (Patau syndrome)

cardiac lesions, 174t, 185t, 201tclinical features, 145t, 174t,

178f, 185t, 201t, 231t, 244t,263t, 272t, 289t, 336t, 358t

etiology, 174t, 201tlimb reduction defects, 302

Trisomy 18 (Edwards syndrome)cardiac lesions, 174t, 185t, 201tclinical features, 145t, 161t,

174t, 178f, 185t, 201t, 220t,231t, 244t, 263t, 272t, 289t,324t, 336t, 359t

etiology, 174t, 201t, 220tprenatal diagnosis, 29, 31

Trisomy 21 (Down syndrome)anorectal malformations, 230cardiac lesions, 174t, 185tclinical features, 14f, 15f, 161t,

174t, 185t, 220t, 225t, 231t,238t, 244t, 290t, 359t

duodenal atresia in, 224etiology, 185t, 220tlimb reduction defects, 302prenatal diagnosis, 29, 31–32

Truncus arteriosus, 183–186associated malformations and

syndromes, 184, 185tclinical presentation, 184embryology, 183epidemiology, 184

390 INDEX

Truncus arteriosus (Cont.):evaluation, 184genetic counseling, 186tmanagement and prognosis,

186tTuberous sclerosis, 272tTurner syndrome

cardiac lesions, 201t, 202clinical features, 161t, 201t,

202f, 263t, 359tetiology, 201t, 359tprenatal diagnosis, 29, 31

UUltrasonography

in neural tube defects, 44–45,45f

for prenatal diagnosis, 36Urioste syndrome, 167tUrorectal septum malformation

sequence, 231t, 279t, 336t

VVACTERL syndrome/association

anorectal malformations, 229cardiac lesions, 176t, 186tclinical features, 63t, 176t, 186t,

220t, 231t, 257t, 263t, 273t,279t, 303t, 336t

etiology, 63t, 220tlimb reduction defects, 302, 302t

Valproic acid embryopathycardiac defects, 177tcleft lip/palate, 93

clinical features, 7t, 46t, 177tetiology, 46tneural tube defects, 42

Van der Woude syndrome,94, 94f

Varicella zoster embryopathy, 7tVATER syndrome, 63tVelocardiofacial syndrome, 73t,

174t, 220t, 231t. See also22q11 deletion syndrome

Ventricular septal defectassociated malformations and

syndromes, 174–177tdiagnosis, 178–179etiology, 179genetic counseling, 179–180incidence, 179treatment and prognosis, 179

Ventriculomegaly in utero, 62Vestigial tail, 343, 343fVitamin A embryopathy, 46tVLCAD deficiency, 211t

WWaardenburg syndrome, 220tWaardenburg syndrome, type 1,

46tWalker-Warburg syndrome

clinical features, 55t, 63t, 68t,69f, 80t

coloboma in, 122etiology, 55t, 63t, 68t, 80t

Warfarin embryopathy, 7tWeaver syndrome, 349t, 352t

Whistling face syndrome, 326t.See also Arthrogryposis

Williams syndromecardiac lesions, 195t, 202clinical features, 73t, 195tetiology, 73t, 195t

Wilms tumorin Beckwith-Wiedemann

syndrome, 353horseshoe kidney and, 264

Wilms tumor-aniridia-genitalanomalies-retardation(WAGR) syndrome,121–122

Wolf-Hirschhorn syndrome(4p deletion syndrome),95, 174t

XX-linked disorders, 25–26, 25f, 26f

YYellow nail syndrome, 167t

ZZellweger syndrome

biochemical testing, 18clinical features, 127, 273t,

324t, 336tcongenital cataracts in, 127diagnosis, 130tgenetics, 130t

Zygodactyly, 294. See alsoSyndactyly

Date post:	02-Oct-2018
Category:	Documents
Upload:	lamphuc
View:	213 times
Download:	0 times

CONGENITAL MALFORMATIONS - … · Dandy-Walker Malformation 67 Barbara K. Burton vii For more...

Documents