J Am Acad Audiol 6 : 15-27 (1995) Nosology of Deafness John T . Jacobson* Abstract It is estimated that about one half of all congenital deafness and/or hearing impairment is inherited and that approximately one third of this communicative disorder is associated with syndromic abnormalities . The remainder of inherited deafness occurs as an isolated entity, independent of alterations in physical status or any disease process. This latter group typi- cally presents with no clinical signs or symptoms or other dysmorphic stigmata that might help in the early identification of hearing loss . As contemporary advances in genetic testing and therapy emerge, there is an ever-increasing opportunity to provide improved diagnosis and counseling to those with inherited disorders . Over the past 3 decades, there have been several distinct categorical systems introduced to define deafness . Most often, the nosology of deafness is described by either origin, onset, degree and type of severity, and/or struc- tural pathology. Therefore, understanding the cause and nature of hearing loss is the first measure in the accurate diagnosis and management of patient care . This article describes several classification schemata, citing examples of numerous congenital syndromes and other disorders that contribute to deafness . Key Words : Autosomal dominant, autosomal recessive, congenital, deafness, hearing impair- ment, inheritance, syndrome, X-linked R egardless of the etiology or onset, new- born and/or childhood hearing impair- ment has significant long-term conse- quences for the affected infant and family mem- bers, as well as for society in general . Unequiv- ocal evidence supports the relationship between deafness and deficits in speech, language, and cognitive development, limitations in educa- tional and socioeconomic opportunities, and dis- crimination in work-related placement. As a result, the importance of early identification and early management has been universally advocated . Recently, the Joint Committee on Infant Hearing (1994) and the National Institute of Health Consensus Development Conference Statement on Early Identification of Hearing Impairment in Infants and Young Children (National Institutes of Health, 1993) have rec- ognized and acknowledged these principles of early identification and have recommended uni- *Department of Otolaryngology-Head and Neck Surgery, Division of Audiology, Eastern Virginia Medical School, Norfolk, Virginia Reprint requests : John T. Jacobson, Eastern Virginia Medical School, Department of Otolaryngology-Head and Neck Surgery, 825 Fairfax Ave ., Suite #510, Norfolk, VA 23507 versal infant hearing screening . Recommenda- tions include not only the hearing screening of infants at risk for hearing loss, as determined by a high-risk register, but also all normal healthy, term babies . These recommendations take into account that only about one half of all hearing-impaired infants are identified through the implementation of risk factors ; the remain- der of infants and children identified with hear- ing loss result from genetic factors with a neg- ative family history (Rose et al, 1977) . Because as many as one third of all patients with hereditary hearing loss are associated with other syndromic abnormalities, medical man- agement, including newly developed genetic techniques, is a priority in the overall health care strategy. With recent advances in genetic map- ping of the human genome and the ability to determine its DNA sequence, there is an increas- ing opportunity to provide improved counsel- ing and other available medical management alternatives to individuals of the more than 4000 inherited diseases . To address this formidable task, hearing health care professionals require, in addition to their specific area of expertise, broad-based knowledge in such areas as genetics, craniofa- cial embryology, and normal growth and devel-
Transcript
J Am Acad Audiol 6 : 15-27 (1995)
Nosology of Deafness John T. Jacobson*
Abstract
It is estimated that about one half of all congenital deafness and/or hearing impairment is inherited and that approximately one third of this communicative disorder is associated with syndromic abnormalities. The remainder of inherited deafness occurs as an isolated entity, independent of alterations in physical status or any disease process. This latter group typi-cally presents with no clinical signs or symptoms or other dysmorphic stigmata that might help in the early identification of hearing loss . As contemporary advances in genetic testing and therapy emerge, there is an ever-increasing opportunity to provide improved diagnosis and counseling to those with inherited disorders. Over the past 3 decades, there have been several distinct categorical systems introduced to define deafness . Most often, the nosology of deafness is described by either origin, onset, degree and type of severity, and/or struc-tural pathology. Therefore, understanding the cause and nature of hearing loss is the first measure in the accurate diagnosis and management of patient care . This article describes several classification schemata, citing examples of numerous congenital syndromes and other disorders that contribute to deafness .
egardless of the etiology or onset, new-born and/or childhood hearing impair-ment has significant long-term conse-
quences for the affected infant and family mem-bers, as well as for society in general. Unequiv-ocal evidence supports the relationship between deafness and deficits in speech, language, and cognitive development, limitations in educa-tional and socioeconomic opportunities, and dis-crimination in work-related placement. As a result, the importance of early identification and early management has been universally advocated. Recently, the Joint Committee on Infant Hearing (1994) and the National Institute of Health Consensus Development Conference Statement on Early Identification of Hearing Impairment in Infants and Young Children (National Institutes of Health, 1993) have rec-ognized and acknowledged these principles of early identification and have recommended uni-
*Department of Otolaryngology-Head and Neck Surgery, Division of Audiology, Eastern Virginia Medical School, Norfolk, Virginia
Reprint requests : John T. Jacobson, Eastern Virginia Medical School, Department of Otolaryngology-Head and Neck Surgery, 825 Fairfax Ave ., Suite #510, Norfolk, VA 23507
versal infant hearing screening. Recommenda-tions include not only the hearing screening of infants at risk for hearing loss, as determined by a high-risk register, but also all normal healthy, term babies. These recommendations take into account that only about one half of all hearing-impaired infants are identified through the implementation of risk factors ; the remain-der of infants and children identified with hear-ing loss result from genetic factors with a neg-ative family history (Rose et al, 1977).
Because as many as one third of all patients with hereditary hearing loss are associated with other syndromic abnormalities, medical man-agement, including newly developed genetic techniques, is a priority in the overall health care strategy. With recent advances in genetic map-ping of the human genome and the ability to determine its DNA sequence, there is an increas-ing opportunity to provide improved counsel-ing and other available medical management alternatives to individuals of the more than 4000 inherited diseases .
To address this formidable task, hearing health care professionals require, in addition to their specific area of expertise, broad-based knowledge in such areas as genetics, craniofa-cial embryology, and normal growth and devel-
Journal of the American Academy of Audiology/Volume 6, Number 1, January 1995
opment. Advance knowledge should lead to an improved comprehensive service through the recognition, diagnosis, and eventual auditory management of the patient. The information found within the article summarizes multidis-ciplinary efforts that have added to and eluci-date both inherited and acquired factors asso-ciated with deafness and hearing impairment . Several fundamental genetic concepts were dis-cussed in the article by Smith (1995) in this issue and are an integral part of discussions that fol-low in this special issue on hereditary syn-dromes and other childhood auditory disorders. The following is a review of existing classifica-tion schemes of deafness and hearing impair-ment that also includes their diverse modes of inheritance. For an excellent, comprehensive, readable review of genetics, the reader is referred to and encouraged to examine Smith's Recognizable Patterns of Human Malformation (Jones, 1988).
CLASSIFICATION
T here are several methods of classifying hearing impairment and/or deafness, but most often they are described in terms of either their origin (e .g ., hereditary, acquired), onset (e.g ., congenital, delayed), degree and type of severity (e.g ., mild-to-profound sensory, con-ductive, or mixed), and/or structural pathology (e.g ., inner ear congenital anomaly types: Michel, Mondini, Scheibe, etc.) . Although there are other descriptive nomenclature, these four classifica-tions or combinations of these four are most commonly found in the literature .
Intrinsically, within each classification cat-egory there may be several descriptive subsets and, as a result, interrelationships between cat-egories and their subsets often introduce more confusion than clarification. As an example, McKusick (1992) has listed seven distinct meth-ods of describing genetic disorders, suggesting that the naming of syndromes is, at best, dis-orderly. He argues that the name for a genetic trait should have some relation to the basic defect, should be imaginative, and should pre-sent an image of the phenotype. McKusick states that terminology should be appropriate for trans-mittal to patients but readily admits that there is little sense to the use of disorder, disease, syndrome, and anomaly. The terms association and anomalad were proposed (Smith, 1974) for some birth defects but, according to McKusick, are of limited use in connection with Mendelian phenotypes . Often, the terms malformation,
deformation, and disruption have been used interchangeably, but they express specific dis-tinctions in birth defects. The term malforma-tion refers to a basic abnormality in embryologic development; deformation connotes intrauterine pressure effects, whereas the effects of abnormal vascular supply to developing structures are best described as a disruption . In short, Diefendorf and colleagues (1993) have correctly pointed out that the best interests of the patient are served when intervention strategies embrace common goals and when a common terminology is optimized.
The causes of deafness tend to be broadly classified into three primary categories : genetic (hereditary disorder), nongenetic (acquired), and unknown causes . It is estimated that about one half of all congenital deafness is hereditary, that is, the genetic trait of deafness is passed from parent(s) to offspring (Beighton, 1983 ; NIDCD, 1989). The remainder of hearing impair-ment appears equally represented by either causative (nongenetic) factors or by those of unknown origin .
The ability to hear is a genetic predisposi-tion and therefore is present in the majority of live births ; however, if an inherited auditory deficit is identified at birth, three recognized genetic forms of inheritance may be considered as potential contributing factors. They include single gene abnormalities, chromosomal aber-rations, and disorders due to multifactoral inher-itance . Of noteworthy clinical significance, hered-itary hearing loss may be congenital (present at birth) or may manifest at a later period in life . Importantly, regardless of the descriptive clas-sification scheme employed, a thorough knowl-edge of the nosology of deafness is a prerequi-site to correct medical and audiologic manage-ment of hearing impairment . This article addresses two commonly referred classification systems, inherited hearing loss and congenital hearing loss . Acquired hearing loss that results from environmental factors is described later in this issue (by Strasnick and Jacobson, 1995).
Inherited Hearing Loss
To review, Mendelian laws describe genetic traits (physical characteristics) of inheritance that are passed from one generation to another. These fundamental physical and functional units of inheritance are called genes and con-sist of segments of deoxyribonucleic acid (DNA) that encode the blueprint for every living thing. DNA is structurally packaged within chromo-
16
Nosology of Deafness/Jacobson
somes. Each human cell contains 46 chromo-somes in 23 pairs. Twenty-two of the pairs are identical in the male and female and are des-ignated as autosomes. The remaining pair are called the sex chromosomes and are represented by two X chromosomes in the female and one X and one Y chromosome in the male . One chro-mosome of each pair is inherited from each par-ent and, with the exception of the XY male chromosome, each genetic determinant is pre-sent in two doses (Jones, 1988). Pairs of genes are called alleles and occupy the identical site on homologous chromosomes . Unless there is a structural anomaly, each pair of homologous chromosomes is identical with respect to its locus. A gene that alters normal characteristics is referred to as a mutant gene . The full com-plement of genetic material in the set of chro-mosomes of an organism is called its genome .
One method of describing a chromosome is by its structural morphology ; its narrowest point is called a centromere . Each chromo-some has a characteristic length and position of the centromere, allowing each projection to be called an arm. At metaphase, each chromo-some has paired long and short arms . The short arms are designated as "p" (petite) and the long arms as "q." Reference to a specific arm of chromosome 1 would be to lp or 1q, to chro-mosome 2 as 2p and 2q, and so forth. The des-ignation of a + or - sign before a chromosome number is indicative of the addition or absence of an entire chromosome . This represents a numeric chromosomal aberration . An example of this is the karyotype 47, XY, +21, which is that of a male with an extra number 21 chro-mosome (i .e ., trisomy 21 - Down syndrome). In contrast, the designation of a + or - sign fol-lowing a chromosome number represents an increase or decrease in chromosome length . This represents a structural chromosomal anomaly. Such an example is Cri-du-chat syn-drome, represented as 46,YX,5p-, meaning 46 chromosomes, in a female with deletion of the short arm of the #5 chromosome . This basic form of descriptive reference is referred to as karyotype nomenclature .
Normal
Dominant
Heterozygous Recessive
Homozygous Recessive
X-linked Recessive
Except for the XY, there is a pair of genes for each function, located at the same loci on sister chromosomes . One pair of normal genes is represented as dots on a homologous pair of chromosomes.
Single Gene Mutation
Single gene (monogenic) mutations that cause changes in the normal sequence of DNA base pairs are associated forms of Mendelian inheritance that are designated as autosomal dominant, autosomal recessive, and sex (X)-linked patterns . X-linked inherited disorders
A single mutant (changed) gene is dominant if it causes an evident abnormality. The chance of inheritance of the mutant gene (M) is the same as the chance of inheriting a particular chromosome of the pair: 50 per cent .
A single mutant gene is recessive (1) if it causes no evident abnormality, the function being well covered by the normal partner gene (allele) . Such an individual may be referred to as a heterozygous carrier.
When both genes are recessive mutant ()o.) the abnormal effect is expressed . The parents are generally carriers, and their risk of having another affected offspring is the chance of receiving the mutant from one parent (50 per cent) times the chance from the other (50 per cent) or 25 per cent for each offspring .
An X-linked recessive will be expressed in the male because he has no normal partner gene . His daughters, receiving the X, will all be carri-ers, and his sons, receiving the Y, will all be normal .
An X-linked recessive will not show overt expression in the female because at least part of her "active" X's will contain the normal gene . The risk for affected sons and carrier daugh-ters will each be 50 per cent.
Figure 1 Diagram of normal and major mutant gene Mendelian inheritance. (Jones KL . [19881 . Smith's Recog-nizable Patterns of Human Malformations. 4th ed . Phila-delphia: WB Saunders, 646. Reprinted with permission from the publisher.)
may be either recessive or dominant (addressed in the following discussion). A diagrammatic representation of Mendelian inheritance is illus-trated in Figure 1 . Single gene mutations may cause about 1500 rare syndromes, diseases, and morphologic traits that are associated with a high risk of recurrence (Jones, 1988). The term syndrome is used to describe a pattern of mul-tiple anomalies that are pathogenetically related, that is, attributable to a specific etiology. Syn-dromes are either known-genesis (e.g ., Turner syndrome, a chromosomal aberration causing external and middle ear abnormalities and sen-sory and mixed hearing loss) or unknown-gen-esis types (e.g ., Goldenhar syndrome, affecting the development of the first and second branchial arch derivatives, causing a multitude of facial deformities and malformations, including inner ear anomalies), having several subcategories (Cohen, 1982).
Autosomal-Recessive Inheritance. Auto-somal-recessive inheritance requires a pair of
Journal of the American Academy of Audiology/Volume 6, Number 1, January 1995
genes for hearing loss, one recessive gene from each parent to produce the disorder. The mutant gene must be present in a double dose for abnor-mal characteristics to present. The term reces-sive applies only to homozygous (a condition having similar genetic patterns at both alle-les) expressed traits . Parents are heterozygous, having one normal and one abnormal allele, and clinically asymptomatic . Recessive inher-ited hearing loss is by far the largest of the sin-gle gene mutations, consisting of about 80 per-cent of this genetic trait. Although usually unaf-fected, these carriers will pass a copy of the identical recessive gene for hearing loss to about 25 percent of their children . Infants with reces-sive inherited hearing deficits that are first born to families comprise the largest percent-age of neonatal hospital-discharged, unidenti-fied, hearing-impaired babies, since there are no associated abnormalities and generally no other recognized familial hearing loss . With minor exception, these otherwise healthy babies are typically not screened for hearing loss and are discharged with no confirmed knowledge or even suspicion of possible auditory deficits .
Autosomal-Dominant Inheritance. About 20 percent of genetic hearing loss is attrib-uted to autosomal-dominant inheritance (Rose et al, 1977). The term dominant applies to a genetic pattern that is expressed when only one gene from either parent is dominant for hear-ing loss (heterozygous state) . In this condi-tion, an affected parent need pass only a sin-gle mutant gene in a single dose to cause the trait. Thus, the trait is manifested in every infant who inherits the gene, irrespective of the condition (normal) of the other allele . The affected offspring will either be the product of an affected parent who expresses the gene or the result of a new mutation dominant trait (Nora and Fraser, 1989). From this inheri-tance pattern, the risk for hearing impair-ment is 50 percent for each pregnancy. The car-rier is almost always hearing impaired . The term penetrance refers to the proportion of individuals who have clinical expression of the gene in some form or another and trans-mit it to their offspring; 100 percent pene-trance suggests that all individuals with the gene have symptoms of the disorder. The degree of clinical manifestation varies greatly between individuals with a specific disorder. The term expressivity describes the degree of clinical variability encountered from mild to
severe . In Waardenburg syndrome, an auto-somal-dominant disorder, 50 percent of the offspring are affected but only 20 percent have deafness (Jones, 1988). Often in the same fam-ily, the expressivity differs substantially (e.g., see Treacher Collins Syndrome in this issue [Jahrsdoerfer and Jacobson, 1995]) .
X-Linked Inheritance. X-linked inherited hearing loss accounts for the remaining 1 to 2 percent of this genetic trait (Nance and Sweeney, 1975). X-linked genes can be either recessive or dominant. Because of the XX (female)/XY (male) chromosomal relationship, a female with a recessive gene for hearing loss on one of her two X chromosomes will have normal hearing. Only males are affected with offspring having a 50 percent chance of hear-ing loss, whereas each daughter has a 50 per-cent chance of carrying the affected gene and, in turn, transmitting the X-linked trait to 50 percent of her sons . A male with the gene can-not pass the trait on to his sons (since they will have inherited his Y chromosome), but all of his daughters will be carriers . Further, the poten-tial for a new mutation in X-linked disorders also exists . Two well-known, X-linked, recessive gene disorders are Hunter and Alport syn-dromes (the latter is described in detail by Wester [1995] in this special issue) .
In contrast, X-linked dominant disorders are generally expressed in hemizygous males (a condition where only one allele of a specific gene locus is present) and is only relevant for X-linked recessive inheritance, since the reces-sive allele appears because there is no corre-sponding allele on the Y chromosome . There-fore, since a dominant allele will be expressed with just one "dose," it does not matter if the individual is a heterozygous female or hem-izygous male . The pedigree pattern of X-linked dominant traits differs from that of autosomal dominance only in that all of the daughters and none of the sons of affected males will be affected, since a male gives his X chromosome only to his daughters (Nora and Fraser, 1989). One example of an X-linked, dominant, inher-ited trait is otopalatodigital syndrome (Gorlin et al, 1973). Otopalatodigital syndrome, types I and II (a more severe skeletal manifestation of type I, with a life expectancy of about 5 years), includes auditory abnormalities usu-ally limited to conductive pathology due to mid-dle ear ossicular anomalies (Dudding et al, 1967). Recently, Brunner (1991) reported nearly
18
Nosology of Deafness/Jacobson
30 distinct X-linked conditions that have hear-ing loss as an associated anomaly.
Chromosomal Aberrations
Genetic hearing loss may also be the result of chromosomal or cytogenetic (the study of chromosomes) abnormalities such as numeric distribution errors that may consist of the pres-ence (e.g., trisomy 18 [47,XX,+18] represent-ing chromosome 18 in triplicate rather than in duplicate) or absence (e.g., Turner syndrome ; 45,X) of an additional chromosome . Chromoso-mal aberrations may also present as structural errors in which deletions, additions, duplica-tions, translocations, and inversions may occur (Rollnick and Smith, 1986 ; Jung, 1989). Chromo-somal disorders account for about 1 percent of the total newborn population (Jacobs, 1977). Down syndrome (trisomy 21) is the most famil-iar and common chromosomal abnormality, hav-ing an incidence of about 1 :600 live births (de Grouchy and Truleau, 1984) and producing a high incidence of conductive hearing loss (Balkany et al, 1979) and, to a lesser degree, associated auditory sensory pathology. In Down syndrome, there is evidence that sensory audi-tory pathology worsens with age, suggesting a possible acquired component (Keiser et al, 1981). For an in-depth review, see Diefendorf et al (1995), in this special issue.
Multi factorial Inheritance
Deafness due to multifactoral (polygenic) inheritance refers to the additive effects of sev-eral minor gene pair abnormalities in associa-tion with nongenetic environmental interactive factors (McKusick, 1992). In these cases, genetic inheritance is difficult to ascertain; however, there remains a familial predisposition for a disorder to occur at a greater incidence than that found in the general population. In addition to hearing loss within this category, a higher inci-dence of craniofacial birth defects may occur, including cleft lip and palate . For example, Pierre Robin sequence is a triad of micrognathia, cleft palate, and glossoptosis (Gorlin et al, 1990). A sequence is considered a multiple pattern of anomalies, but unlike a syndrome, a sequence results from a primary anomaly such as micro-gnathia, as in the case of Robin sequence . In this sequence, the presence of mandibular hypopla-sia has not been accurately traced and the under-lying cause could be a combination of genetic fac-tors or a secondary effect of in utero compression
of the mandible, limiting its growth and devel-opment (Jung, 1989). Robin sequence may also be a feature of a genetic syndrome such as Beck-with-Wiedemann in rare cases, Catel-Manzke, Donlan, Myotonic dystrophy, otopalatodigital type II, or velocardiofacial . It may also be iden-tified in a chromosomal syndrome such as del(4p) or dup(llq) . Robin sequence has been reported as the result of fetal exposure to a teratogen as in fetal alcohol or fetal trimethadione syndromes or in conditions of unknown etiology, such as CHARGE association (see Toriello [1995], in this special issue) and Moebius sequence . Auditory abnormalities include low-set and malformed ears and mixed hearing loss (Smith and Stowe, 1961). Its most common association, however, is with Stickler syndrome (Turner, 1974 ; Cohen et al, 1990 ; Gorlin et al, 1990). Stickler syndrome is an autosomal-dominant hereditary condition that presents with pathognomonic facial fea-tures, bone dysplasia, myopia, and auditory deficits (Stickler et al, 1965 ; Stickler and Pugh, 1967 ; Gorlin et al, 1990). This skeletal disorder has been linked to chromosome 12q, close to the structural gene for type II collagen (Fran-comano et al, 1987). There is evidence, how-ever, that mutations in the collagen gene itself are the cause of the syndrome in some but not in all cases, whereas other cases do not show linkage to that region . These findings led to a syndrome that produces expressive variability and high but incomplete penetrance (Weingeist et al, 1982 ; Suslak and Desposito, 1988). Because such similar clinical traits are reported between Pierre Robin sequence and Stickler syndrome, Herrmann and colleagues (1975) have suggested that as many as half of those with the Pierre Robin sequence may have the inherited disorder, Stickler syndrome . The degree and type of hear-ing loss has been variable in these disorders (Jacobson et al, 1990a) .
Multifactoral risk characteristics are depen-dent on ethnic origin, gender, the number of affected relatives and their relationship in any one family, and the severity of the defect (Roll-nick and Smith, 1986). Table 1 lists some com-mon, inherited hearing disorders based on sin-gle gene abnormalities (autosomal dominant, autosomal recessive, and X-linked), chromoso-mal aberrations, and disorders due to multi-factoral inheritance.
The majority of inherited hearing loss occurs as an isolated entity, independent of other changes in physical status or disease processes. Typically, there are no additional clinical signs or symptoms or other dysmorphic stigmata
Journal of the American Academy of Audiology/Volume 6, Number 1, January 1995
Table 1 Classification of Primary Categories of Common Inherited Hearing Loss
Numerical van der Woude Trisomy (13, 18 & 21, Down) Waardenburg Turner
Structural Multifactorial Inheritance (single or Cri du chat multiple gene abnormality with possible DiGeorge sequence nongenetic environmental factors) Prader-Willi Cornelia de Lange Wolfe-Hirshhorn DiGeorge sequence
Specific syndromes may be listed in more than one category because more than one type may exist,
associated with this type of hearing loss, often making early identification of hearing loss prob-lematic. However, about one third of all genetic hearing loss accompanies syndromes having physical characteristics such as craniofacial anomalies or multiple congenital organ system malformations. Specific examples include hear-ing impairment with craniofacial and muscu-loskeletal disease (e.g ., Crouzon syndrome, an autos omal-dominant disorder), eye disease (e.g ., Alstrom syndrome, an autosomal-recessive disorder), skin disease (e.g., Leopard syndrome, an autosomal-dominant disorder), and meta-bolic abnormalities (Hurler and Hunter syn-dromes, autosomal recessive and X-linked, respectively) . The most common metabolic disorder with hearing loss is Pendred syndrome, having an incidence of about 1:200,000 . This autosomal-recessive endocrine-metabolic trait, which usually presents with hypothyroidism,
goiter abnormality, severe sensory hearing loss, and often defective vestibular function, may account for up to 10 percent of all congen-ital deafness (Batsakis and Nishiyama, 1962 ; McKusick, 1992)..Van Wouwe et al (1986) have linked Pendred syndrome to duplication defi-ciency, that is, duplication in 10p and deficiency in distal 8q.
This classification system, which combines hearing loss with an organ system defect caused by the same gene, was described by Konigs-mark and Gorlin (1976) . Table 2 lists inherited syndromes by their major physical organ abnor-mality, each having some degree of hearing loss as a component of the disorder. At present, over 90 different types of hereditary deafness have been identified and their degree of severity varies dramatically (Konigsmark and Gorlin, 1976; McKusick, 1992).
20
Nosology of Deafness/Jacobson
Table 2 Classification of Genetic Hearing Loss Incorporating Major System Defects
No Associated Abnormalities External Ear Abnormalities Dominant congenital severe sensory Atresia Dominant progressive early-onset sensory Otofaciocervical syndrome Dominant unilateral sensory Lacrimoauriculodentodigiral syndrome Otosclerosis (conductive or mixed loss) Lop ears, micrognathia, and conductive hearing loss Recessive congenital severe sensory Malformed low-set ears Recessive congenital moderate sensory Microtia Recessive early-onset sensory Preauricular pits, branchial fistulas X-linked congenital sensory Thickened ear lobes X-linked early-onset sensory X-linked moderate sensory Integumentary (Skin) System Disease Atresia of auditory canal - conductive Dominant onychodystrophy
Dominant piebald trait Musculoskeletal Disease Fragile X Albers-Schonberg disease (osteopetrosis) Leopard syndrome Apert syndrome (type I) Pili Torti and sensory hearing loss Cornelia de Lange Recessive onychodystrophy Crouzon syndrome Recessive piebaldness Forney syndrome Waardenburg syndrome (types I, II) Goldenhar Juvenile Paget's disease Eye Disease Karmondy-Feingold Alstrom syndrome Klippel-Feil syndrome Cockayne syndrome Kniest syndrome Cryptophthalmia syndrome Mohr syndrome Hallgren syndrome Osteogenesis imperfecta (types I-IV) Harboyan syndrome Otopalatodigital syndrome Laurence-Moon-Biedl syndrome Pierre Robin sequence Marshall syndrome Sanfilipo (type III) Mobius syndrome Stickler syndrome Norrie syndrome Treacher Collins syndrome Optic atrophy, juvenile diabetes van Buchem's disease Refsum syndrome Wildervanck syndrome Rosenberg-Chutorian syndrome
The term congenital is used to describe a condition or symptom, the onset of which occurred at (perinatal) or before (prenatal) birth. Congenital birth defects imply that during cer-tain critical periods of the pregnancy, changes
in normal morphologic and functional develop-ment have occurred that are recognized at birth or manifest and progress later in life . Impor-tantly, there is a systematic pattern of embry-ologic development that exists within the human auditory system . Consider the external ear, which consists of the pinna and external audi-
Journal of the American Academy of Audiology/Volume 6, Number 1, January 1995
tory canal (EAC). By the fourth gestational week, the pinna begins to develop around the first branchial groove from first (mandibular) and second (hyoid) branchial arch mesoderm . Within 2 weeks, these arches divide into six hillocks, each contributing to a specific structural com-ponent of the pinna. Williams (1994) reports that the first three hillocks are formed from the mandibular arch and the remaining three are derived from the hyoid arch . By the twentieth fetal week, the pinna has reached adult shape and location (Kenna, 1990). The developmental pattern of the EAC is similar in that by the fourth gestational week, it begins its maturation from the first branchial groove between the mandibular and hyoid arches . By the eighth week, a tube is shaped from the branchial groove, ultimately forming the outer one third (primary meatus) of the EAC. Simultaneously, a dense epi-dermal plug extends medial, reaching the pri-mary tympanic cavity to cast the meatal plate. Mesenchyme then begins to constitute a bridge between the epithelial cells and the meatal plate. Absorption of epithelial cells takes place by the fifth month, establishing a canal and leaving only an ectodermal plug. Eventually, the medial bony two-thirds portion of the EAC is derived from this ectodermal tube (Schuknecht and Gulya, 1986). Importantly, any alteration to normal fetal development of the external ear within this critical time frame may result in congenital malformations to either the pinna or the EAC. Take, for instance, malformations of the branchial sinus and/or cyst, which result in defects in the resolution of the branchial cleft. Primary causes usually occur prior to the eighth week, resulting in preauricular malformations (Jones, 1988). Because anatomic structures com-prising the auditory system have independent developmental archetype, congenital anomalies may be independent, as in first and second branchial arch disorders that directly involve the external and middle ear, leaving the inner ear predominantly unscathed. Therefore, in the clin-ical analysis of patients who present with cran-iofacial anomalies, an expanded knowledge of the developmental patterns of the auditory system may help to support and explain findings that are associated with congenital ear abnormalities and provide realistic management strategies in this population base .
The incidence of total deafness represents less than 1 percent of infants and children with congenital auditory deficits, thus leaving the vast majority with some degree of residual hear-ing. The term congenital hearing loss is often lim-
ited to that population with severe-to-profound sensory auditory deficits . This description is somewhat restrictive and should be expanded to include those with conductive as well as mixed hearing loss of all degrees of severity, since hear-ing loss at birth is congenital by definition.
Congenital hearing loss may result from either genetic and/or other factors such as pre-natal viral infection, anoxia, trauma, or other perinatal insults of known or unknown origin . Therefore, congenital hearing impairment may not necessarily be genetically based. Further, a congenital syndrome may also have later-onset hearing loss . For example, congenital syphilis (nongenetic disorder), which has shown sub-stantial increases of occurrence over the past decade, is present at birth because it is a pre-natal event, but hearing loss is delayed, since symptoms are usually not demonstrated until the teenage years. Alport syndrome is a het-erogenetic kidney disease often progressing to renal failure (Barker et al, 1990). It has six subtypes and two modes of inheritance: auto-somal dominant (types I, V, and VI) and X-linked dominant (types II, III, and IV) (Atkin et al, 1986). With the exception of type IV (X-linked adult, purely renal disease; McKusick [1992]), all are reported to have deafness as a characteristic trait. Although congenital, Alport syndrome usually presents as a preadolescent progressive sensory impairment affecting males and females in successive generations (McKu-sick, 1992). (See Wester [1995], for a compre-hensive review of Alport syndrome in this spe-cial issue.) Two examples of variable onset are branchio-oto-renal syndrome (described in this special issue) and Klippel-Feil sequence, a pri-mary skeletal abnormality with fused cervical vertebrae. Klippel-Feil sequence is considered to be a morphologically and etiologically het-erogeneous disorder with five patterns and two modes of inheritance, autosomal recessive and autosomal dominant . It has been reported that between one quarter to one half present with associated sensory and/or conductive hearing loss that may be present at birth or delayed in its onset (Palant and Carter, 1972 ; Helmi and Pruzansky, 1980; Shaver et al, 1986 ; Stewart and O'Reilly, 1989). Anomalies include preau-ricular appendages, microtia, and stenosis or atresia of the EAC, whereas sensory pathology is attributed to a rudimentary cochlea, although syndromic dependent (Sando et al, 1990). The degree, severity, and acceleration of auditory ero-sion vary considerably in delayed hearing impairment, and its onset may be observed dur-
22
Nosology of Deafness/Jacobson
ing the neonatal or early childhood period (Bergstrom, 1984) .
These examples of congenital conditions with delayed onset having hearing loss are gen-erally the exception rather than the rule . Typi-cally, infants with congenital syndromes have
auditory deficits that are identifiable at birth. Such an example is Jervell and Lange-Nielsen syndrome, an autosomal-recessive hereditary condition that presents with cardiac abnormal-ities characterized by a prolonged Q-T electro-cardiographic pattern. Although milder states of
Table 3 Classification System of Hearing Disorders by Type and Major System Dysfunction
Craniofacial and Skeletal Disorders Nervous System Disorders Endocrine and Metabolic Disorders
Modified from Bergstrom et al, 1971 . R = autosomal recessive, D = autosomal dominant, X = X-linked, C = chromosomal .
Journal of the American Academy of Audiology/Volume 6, Number 1, January 1995
hearing sensitivity have been reported (Corcos et al, 1989), infants routinely present with con-genital severe-to-profound bilateral sensory hearing loss . This disorder affects about 0.3 per-cent of the congenitally deaf with the cases of deafness representing 6 percent to 30 percent of all the patients with a prolonged Q-T pattern (Schwartz et al, 1975; Moss et al, 1985). Early identification through the use of electrocardio-graphic and auditory brainstem response screen-ing has helped to identify this potentially life-threatening condition (Jacobson et al, 1990b) . In all cases of congenital hereditary hearing loss that are identified, appropriate referral sources including genetic counseling must be strongly underscored.
As early as 1971, Bergstrom and associates adapted a classification scheme based on con-genital hearing loss, major system dysfunction, and type of auditory deficit, that is, conductive, sensory, mixed, and progressive. This complex myriad is similar to that fashioned by Konigs-mark and Gorlin (1976; Table 2) and provides the added benefit of type of hearing loss as an addi-tional descriptor. For example, a congenital "sen-sory" hearing loss with integumentary disorder includes Waardenburg syndrome, type I (with lateral displacement of the inner canthi) and type II (without dystopia), an autosomal-dominant pattern with variable expressivity (Arias, 1971). About half of type I families have been linked to chromosome 2q (Asher and Friedman, 1990 ;
Grundfast and San Agustin, 1992) . The fre-quency of sensory deafness is greater in type II (McKusick, 1992). Syndromes of congenital "con-ductive" hearing loss with craniofacial and skele-tal disorders include Apert syndrome (autosomal dominant) and Goldenhar syndrome, a form of hemifacial microsomia including microtia and preauricular tags (Rollnick and Kaye, 1985). The latter is considered a form of heterogeneous inheritance including teratogenic, chromosomal anomalies and evidence that about 2 percent of the syndrome present as autosomal-dominant inheritance (Regenbogen et al, 1982). Finally, a "progressive" sensory hearing loss of delayed onset and nervous system disorder includes neu-rofibromatosis (autosomal dominant, types I and II ; see Pikus [19951, in this special issue) and Friedreich's ataxia (autosomal recessive) . This multifaceted classification system provides a complex yet precise method of describing audi-tory disorders and is illustrated in Table 3.
Another method of classifying deafness was reported by Glasscock et al (1988) and is pre-sented in Table 4. This eclectic approach syn-thesizes both onset and origin as follows: (1) con-genital nongenetic, (2) congenital genetic, (3) delayed-onset nongenetic, and (4) delayed-onset genetic. Glasscock and colleagues reasoned that the use of origin (genetic versus nongenetic) descriptors independent of onset was confin-ing since parents may not be aware of the spe-cific familial hearing history, and only follow-
Table 4 Classification of Hearing Loss by Origin and Onset
Alport syndrome Alstrom syndrome Branch io-oto-renal Crouzon syndrome Freidreich ataxia Hunter syndrome Hurler syndrome Laurence-Moon-Biedl Mucopolysaccharidoses Noorie syndrome Neurofibromatoses II Neurofibromatoses II Osteogenesis imperfecta I Otosclerosis Pyle disease
Modified from Glasscock et al, 1988 .
Nosology of Deafness/Jacobson
ing the detection of family members or affected offspring would the nature of the genetic hear-ing loss be accurately identified . Conversely, using only onset as the exclusive method of classification is also self-constraining, that is, infants born severely physically compromised are often too ill and/or neurologically premature to be screened for hearing loss prior to hospital discharge. Frequently, these same infants are released from the hospital with potentially unrecognized auditory deficits . In such cases in which hearing impairment is eventually rec-ognized, hearing loss may have been truly con-genital but undetected. Thus, auditory disorders tend to be lost in the larger picture of morbid-ity and, subsequently, deafness and/or hearing loss when discovered may be misclassified as acquired . The value of this four-component interactive classification system is simplicity.
Finally, Jones (1988) ascribes to a genetic classification system that uses recognizable pat-terns of malformation . Each anomaly includes syndromes in which defects are listed as either the frequent or occasional feature. Two cate-gories pertinent to this discussion are deafness and external ears (low-set ears, malformed auri-cles, and preauricular tags or pits). For a cata-logue of this application, see Hall et al (1995) in this special issue, specifically Table 2.
and manage inherited syndromes and other auditory deficits in infants and children .
Acknowledgment. The author would like to acknow-ledge Shelley Smith, Ph.D . FACMG, Boys Town National Research Hospital and Marie T. Greally, M.D ., Eastern Virginia Medical School for their review of and thought-ful suggestions on earlier versions of this manuscript.
REFERENCES
Arias S. (1971) . Genetic heterogeneity in the Waardenburg syndrome . Birth Defects 7(4) :87-101.
Asher JH Jr., Friedman TB . (1990) . Mouse and hamster mutants as models for Waardenburg syndromes in humans . J Med Genet 27 :618-626 .
Atkin CL, Gregory MC, Border WA. (1986) . Alport syn-drome . In: Schrier RW Gottschalk CW eds. Strauss and Welt's Disease of the Kidney. 4th ed . Boston: Little, Brown, 249-273 .
Balkany T, Downs M, Jafek B, Krajicek M. (1979) . Hearing loss in Down's syndrome . Clin Pediatr 18:116-118 .
Barker DF, Hostikka SL, Zhou J, Chow LT, Oliphant AR . (1990). Identification of mutations in COL4A5 collogen gene in Alport syndrome . Science 248:1224.
Batsakis J, Nishiyama R . (1962). Deafness with sporadic goitre . Arch Otolaryngol 76:401-406 .
Beighton P (1983) . Hereditary deafness . In : Emery AEH, Rimoin DL, eds. Principles and Practice of Medical Genetics . New York: Churchill Livingstone, 562-575.
SUMMARY
t is beyond the expectations of any hearing health care professional to commit to mem-
ory every auditory disorder that causes hear-ing loss . Suffice it to say that this article is intended to provide only a brief introduction to the nosology of deafness and hearing loss . The listing of various classification schemes found within the tables contained in this article should not be considered inclusive but rather as a quick reference to be used as a first, not pri-mary, source of information. It is important to recognize that many books and articles are currently available that provide specific details regarding auditory deficits, their origin, and onset. The reader is encouraged to review sev-eral excellent sources, including Pediatric Oto-laryngology (Bluestone and Stool, 1990), Syn-dromes of the Head and Neck (Gorlin et al, 1990), Smith's Recognizable Patterns of Human Malformations (Jones, 1988), and Mendelian Inheritance in Man (McKusick, 1992). As our knowledge of new technology in human genet-ics improves, so will our ability to diagnose
Bergstrom L, Hemenway WG, Downs MP. (1971) . A high-risk registry to find congenital deafness . Otolaryngol Clin North Am 4:369-399 .
Bergstrom L. (1984) . Congenital hearing loss . In : North J, ed . Hearing Disorders. Boston : Little, Brown, 153-160.
Bluestone CD, Stool SE . (1990) . Pediatric Otolaryn-gology. Philadelphia : WB Saunders .
Brunner H . (1991) . X-linked hearing impairment in man . Hereditary Deafness Newsletter 6:28-29 .
Cohen MM Jr. (1982) . The Child with Multiple Birth Defects . New York : Raven Press .
Cohen MM Jr., Stool SE, Marasovich WA. (1990) . Craniofacial anomalies and syndromes . In : Bluestone CD, Stool SE, eds . Pediatric Otolaryngology . Philadelphia : WB Saunders .
Corcos AP, Tzivoni D, Medina A. (1989) . Long QT syn-drome and complete situs inversus . Preliminary report of a family. Cardiology 76 :228-233 .
De Grouchy J, Turleau C. (1984) . Clinical Atlas of Human Chromosomes. New York : John Wiley & Sons .
Diefendorf AO, Bull MJ, Casey-Harvey D, Miyamoto RT, Pope ML, Renshaw JJ, Schriener RL, Wagner-Escobar M. (1995) . Down syndrome : multidisciplinary perspective. J Am Acad Audiol 6 :39-46 .
Journal of the American Academy of Audiology/Volume 6, Number 1, January 1995
Dudding BA, Gorlin R, Langer L . (1967) . The oto-palato-digital syndrome . Am J Dis Child 113:214-221 .
Francomano CA, et al. (1987). The Stickler syndrome : evi-dence for close linkage to the structural gene for type II collagen . Genomics 1 :293-296.
McKusick VA. (1992) . Mendelian Inheritance in Man . 10th ed . Vols . 1 & 2. Baltimore: The Johns Hopkins University Press.
Moss AJ, Schwartz PJ, Crampton RS, Locate E, Carleen E. (1985) . The long QT syndrome . A prospective inter-national study. Circulation 71:17-21 .
Nance WE, Sweeney A . (1975). Genetic factors in deaf-ness of early life . Otolaryngol Clin North Am 8:19-48 .
Glasscock ME, McKennan KX, Levine SC . (1988) . Differential diagnosis of sensorineural hearing loss in children . In : Bess F, ed. Hearing Impairment in Children . Parkton, MD: York Press.
Gorlin RJ, Poznanski AK, Hendon 1 . (1973) . The oto-palato-digital (OPD) syndrome in females . Oral Surg Oral Med Oral Pathol 35:218-224 .
Gorlin RJ, Cohen MM, Levin LS. (1990). Syndromes of the Head and Neck . New York : Oxford University Press.
Grundfast KM, San Agustin TB . (1992) . Finding the gene(s) for Waardenburg syndrome(s). Otolaryngol Clin North Am 25:935-951 .
Hall JW III, Prentice CH, Smiley G, Werkhaven J. (1995). Auditory dysfunction in selected syndromes and patterns of malformations : review and case findings . J Am Acad Audiol 6:81-94 .
Helmi C, Pruzansky S. (1980) . Craniofacial and extracra-nial malformations in the Klippel-Feil syndrome . Cleft Palate J 17:65-88 .
Herrmann J, France TD, Spranger JW Opitz JM, Wiftler C . (1975) . The Stickler syndrome (hereditary arthro-oph-thalmopathy) . Birth Defects 11:76-103 .
Jacobs PA. (1977) . Epidemiology of chromosome abnor-malities in man. Am J Epidemiol 105:180 .
Jacobson JT, Jacobson CA, Gibson W. (1990a) . Stickler's syndrome: a family case study. JAm Acad Audiol 1:37-40.
Jacobson JT, Jacobson CA, Francis P. (1990b). Congenital hearing loss in Jervell and Lange-Nielson syndrome . J Am Acad Audiol 1:171-173.
Jahrsdoerfer RA, Jacobson JT. (1995) . Treacher Collins syndrome : otologic and auditory management. JAm Acad Audiol 6:95-102 .
Joint Committee on Infant Hearing Screening. (1994) . Position statement. Audiology Today 6:6-9 .
Jones KL . (1988). Smith's Recognizable Patterns of Human Malformations . 4th ed . Philadelphia : WB Saunders .
Jung JH . (1989) . Genetic Syndromes in Communication Disorders. Boston: Little, Brown.
Keiser H, Montague J, Wold D, Maune S, Pattison D. (1981) . Hearing loss of Down syndrome adults . Am J Ment Defic 85:467-472 .
Kenna MA. (1990) . Embryology and developmental anatomy of the ear. In : Bluestone CD, Stool SE, eds. Pediatric Otolaryngology . Philadelphia : WB Saunders, 77-87.
Konigsmark BW Gorlin RJ . (1976) . Genetic and Metabolic Deafness . Philadelphia : WB Saunders .
National Institute on Deafness and Other Communication Disorders. (1989) . Report of the Task Force on the National Strategic Research Plan . Washington, DC : US Government Printing Office .
National Institutes of Health . (1993) . NIH Consensus Development Conference Statement, Early Identification of Hearing Impairment in Infants and Children . Washington, DC : US Government Printing Office.
Nora JJ, Fraser FC . (1989) . Medical Genetics: Principles and Practice . 3rd ed . Philadelphia : Lea & Febiger.
Palant DI, Carter BL . (1972). Klippel-Feil syndrome and deafness : a study in polytomography. Am J Dis Child 123:218-221 .
Pikus AT. Pediatric audiologic profile in type 1 and type 2 neurofibromatosis . J Am Acad Audiol 6:54-62 .
Regenbogen L, Goodel V, Goya V (1982) . Further evidence for an autosomal dominant form of ocloauriculovertebral dysplasia. Clin Genet 21:161-167 .
Rollnick BR, Kaye CI . (1985) . Hemifacial microsomia and the branchio-oto-renal syndrome. Am J Med Genet Suppl 1:287-295 .
Rollnick BR, Smith ACM. (1986). Birth defects and genetic counseling in pediatric otolaryngology. In : Balkany TJ, Pashley NRT, eds. Clinical Pediatric Otolaryngology . St . Louis: CV Mosby, 33-51.
Rose SP, Conneally PM, Nance WE. (1977). Genetic analy-sis of childhood deafness . In : Bess FH, ed . Childhood Deafness . New York: Grime and Stratton, 19-35.
Sando I, Shibahara Y, Wood RP 11 . (1990) . Congenital anomalies of the external and middle ear. In : Bluestone CD, Stool SE, eds . Pediatric Otolaryngology. Philadelphia: WB Saunders, 271-304.
Schuknecht HF, Gulya AJ . (1986) . Anatomy of the Temporal Bone with Surgical Implications . Philadelphia : WB Saunders .
Schwartz PJ, Periti M, Malliani A. (1975) . The long Q-T syndrome . Am Heart J 8:378-390 .
Shaver KA, Proud VK, Shaffer MC, Meyer JM, Nance WE. (1986) . Deafness, facial asymmetry and Mippel-Feil syndrome in five generations. [Abstract] . Am J Hum Genet 39:A81 .
Smith SD . (1995) . Overview of genetic auditory syn-dromes . J Am Acad Audiol 6:1-14 .
Smith DW (1974) . Nomenclature of syndromes . Birth Defects 7:65-67 .
Smith JL, Stowe FR. (1961) . The Pierre Robin syndrome: a review of 39 cases with emphasis on associated ocular lesions . Pediatrics 27:128-133.
26
Nosology of Deafness/Jacobson
Stewart EJ, O'Reilly BF (1989) . Klippel-Feil syndrome and conductive deafness . J Laryngol Otol 103:947-949 .
Stickler GB, Belau PG, Farrell FJ, Jones JD, Pugh DG, SteinbergAG, Ward LE . (1965) . Hereditary progressive arthro-ophthalmopathy. Mayo Clin Proc 40:433-477 .
Stickler GB, Pugh DG. (1967) . Hereditary progressive arthro-ophthalmolopathy. II. Additional observations on vertebral abnormalities, a hearing defect and a report of a similar case . Mayo Clin Proc 42:495-500 .
Strasnick B, Jacobson JT. (1995). Teratogenic hearing loss . J Am Acad Audiol 6:28-38 .
Suslak L, Desposito F. (1988) . Infants with cleft lip/palate. Pediatr Rev 9:331-334 .
Toriello HV (1995) . CHARGE Association . J Am Acad Audiol 6:47-53 .
Turner G. (1974) . The Stickler syndrome in a family with the Pierre Robin syndrome and severe myopia . Aust Paediatr J 10:103-108 .
van Wouwe JP, Wijnands MC, Mourad-Baars PEC, Geraedts JPM. (1986) . A patient with dup(10p)del(8q) and Pendred syndrome . Am J Med Genet 24:211-217 .
Weingeist TA, Hermsen V, Hanson JW Bumsted RM, Weinstein SL, Olin WH. (1982) . Ocular and systemic manifestations of Stickler's syndrome : a preliminary report . Birth Defects 18:539-560 .
Wester DC, Atkin CL, Gregory MC . (1995) . Alport syn-drome : clinical update. J Am Acad Audiol 6:73-79 .
Williams GH . (1994). Developmental anatomy of the ear. In : English GM, ed . Otolaryngology . Revised ed . Philadelphia : JB Lippincott, 1-67 .
