Case reports children. The recurrence of Down syndrome is probably 1 in 100 and will increase with age. The fact that clinical features of the two syndromes coexist in this patient shows the relative autonomy of these chromosomes in the determination of the processes of morphogenesis. Congenital dislocation of the knees is 80 times less common than congenital dislocation of the hips.8 The congenital anomalies most frequently associated with it are dislocated hips and talipes equinovarus. Except in Larsen syndrome, there does not appear to be a hereditary basis. Skeletal abnormalities such as short metacarpals, hypoplasia of the middle fifth phalanx, and clino- dactyly are seen in Down syndrome, whereas cubitus valgus, medial tibial exostosis, and short fourth metacarpal are seen in Turner syndrome. There is thus a possibility that the association of the knee abnormality with the Down-mosaic Turner syndrome may not be a chance occurrence, as other skeletal defects do occur in the two syndromes. I wish to thank Dr Saldafia-Garcia of Harperbury Hospital, Radlett, Herts, for his invaluable advice in the preparation of this manuscript, particularly in the analysis of the dermatoglyphs. I would also like to thank Dr M Super of the Department of Genetics, Royal Manchester Children's Hospital for his con- structive criticism and support. A R GATRAD Royal Manchester Children's Hospital, Pendlebury, Nr Manchester References 1Weiss L, Reynolds WA. Osseous malformations associ- ated with chromsomal abnormalities. Orthop Clin North Anm 1972;3:713-31. 2 Saldaina-Garcia P. Dermatoglyphs in sex chromosome anomalies. J Ment Defic Res 1977;23:91-104. 3Townes PL, White MR, Stiffler SJ, Kong-oo Goh. Double aneuploidy. Am J Dis Child 1975;129:1062-5. 4 Root AW, Bongiovanni AM, Briebarts S, Mellman WJ. Double aneuploidy: trisomy 21 and XO/XX sex chromo- some mosaicism. J Pediatr 1964;65:937-9. 5 Mikel'saar AVN, Blyumina MG, Kuznetsova LI, Mikel'saar RVA, Lur'e IV. A double chromosomal aberration of the 47,XX,21 + /47,XXp - q -,21 + type in a girl with features of Down's and Turner's syndromes. Genetika 1971;5:156-61. 6 Villaverde MM, Jacynths A, Da Silva A. Turner- mongolism polysyndrome, Review of the first eight known cases. JAMA 1975;234:844-7. 7Singh DN, Osborne RA, Hennigar GR, Bornett CD. Mosaic double aneuploidy of X and G chromosomes. Am J Ment Defic 1975;79:644-7. 8Kopits E. Beitrage zur Pathologic und Therapic der Angeboremen Kniegelenkssubluxatisen. Arch Orthop Unfallchir 1925 ;23 :593-609. Requests for reprints to Dr A R Gatrad, Department of Paediatrics, Oldham and District General Hospital, Rochdale Road, Oldham OLl 2JH. A new probably autosomal recessive cardiomelic dysplasia with mesoaxial hexadactyly SUMMARY A distinct probably autosomal re- cessive syndrome was ascertained in a 17-year-old boy and his deceased sister. The main features were cardiac dysplasia, peculiar facies, central bilateral (mesoaxial) hexadactyly, synmetacar- palia, short stature, ocular torticollis, and delayed puberty. We describe a patient with multiple congenital anomalies, some of which were indirectly ascer- tained in his deceased sister, suggesting autosomal recessive inheritance. Case report The proband, born in 1962, was the product of a term gestation and normal delivery. Birthweight and length were not recorded; however, he was smaller than his normal sibs. Bilateral hexadactyly, broad right hallux, acrocyanosis, the presence of teeth, and dyspnoea were observed at birth. Psychomotor retardation was evident from early infancy and he tilted his head to the left when he started walking at about 4 years of age. Excision of the supernumer- ary right finger was performed at 10 years of age. Physical examination at 131 years (fig 1) showed delayed development, a weight of 28-7 kg, a height of 134 cm (both below the 3rd centile), an upper-to- lower-segment ratio of 0 97 (66/68), an arm span of 127 cm, and a head circumference of 53 cm. Other features included normocephaly, wide and flat fore- head, hypotrichosis of the eyebrows distally (ulery- thema ophryogenes), telecanthus, ocular torticollis as a result of alternate exophoria-tropia, a winking tick, long prominent nose with lateral bossing, tented nares, lateral pits in the nasal alae, short philtrum, macrostomia, everted lower lip, down- turned mouth, multiple dental diastemata and mal- occlusion, large pinnae, prominent anthelix, two right Darwinian tubercles, short neck, prominent trapezius muscles, cylindrical thorax, hypoplastic nipples, underdeveloped external genitalia, normal spine, mesoaxial hexadactyly in both hands, digital clubbing and cutaneous syndactyly between digits 2 and 3, thenar and hypothenar hypoplasia, genu and pes valgus, right hallucal polysyndactyly, and mild flattening of toe nails. Dermatoglyphic analysis did not reveal extra triradii at the base of the super- numerary fingers. Received for publication 6 May 1980 151 on April 22, 2021 by guest. Protected by copyright. http://jmg.bmj.com/ J Med Genet: first published as 10.1136/jmg.18.2.151 on 1 April 1981. Downloaded from
Transcript
Case reports
children. The recurrence of Down syndrome isprobably 1 in 100 and will increase with age.
The fact that clinical features of the two syndromescoexist in this patient shows the relative autonomyof these chromosomes in the determination of theprocesses of morphogenesis.
Congenital dislocation of the knees is 80 timesless common than congenital dislocation of the hips.8The congenital anomalies most frequently associatedwith it are dislocated hips and talipes equinovarus.Except in Larsen syndrome, there does not appear
to be a hereditary basis.Skeletal abnormalities such as short metacarpals,
hypoplasia of the middle fifth phalanx, and clino-dactyly are seen in Down syndrome, whereascubitus valgus, medial tibial exostosis, and shortfourth metacarpal are seen in Turner syndrome.There is thus a possibility that the association of theknee abnormality with the Down-mosaic Turnersyndrome may not be a chance occurrence, as otherskeletal defects do occur in the two syndromes.
I wish to thank Dr Saldafia-Garcia of HarperburyHospital, Radlett, Herts, for his invaluable advice inthe preparation of this manuscript, particularly inthe analysis of the dermatoglyphs. I would also liketo thank Dr M Super of the Department of Genetics,Royal Manchester Children's Hospital for his con-
structive criticism and support.
A R GATRADRoyal Manchester Children's Hospital,
Pendlebury, Nr ManchesterReferences1Weiss L, Reynolds WA. Osseous malformations associ-
ated with chromsomal abnormalities. Orthop Clin NorthAnm 1972;3:713-31.
2 Saldaina-Garcia P. Dermatoglyphs in sex chromosomeanomalies. J Ment Defic Res 1977;23:91-104.
3Townes PL, White MR, Stiffler SJ, Kong-oo Goh. Doubleaneuploidy. Am J Dis Child 1975;129:1062-5.
4 Root AW, Bongiovanni AM, Briebarts S, Mellman WJ.Double aneuploidy: trisomy 21 and XO/XX sex chromo-some mosaicism. J Pediatr 1964;65:937-9.
5 Mikel'saar AVN, Blyumina MG, Kuznetsova LI,Mikel'saar RVA, Lur'e IV. A double chromosomalaberration of the 47,XX,21 + /47,XXp - q -,21 + typein a girl with features of Down's and Turner's syndromes.Genetika 1971;5:156-61.
6 Villaverde MM, Jacynths A, Da Silva A. Turner-mongolism polysyndrome, Review of the first eight knowncases. JAMA 1975;234:844-7.
7Singh DN, Osborne RA, Hennigar GR, Bornett CD.Mosaic double aneuploidy of X and G chromosomes. AmJ Ment Defic 1975;79:644-7.
8Kopits E. Beitrage zur Pathologic und Therapic derAngeboremen Kniegelenkssubluxatisen. Arch OrthopUnfallchir 1925 ;23 :593-609.
Requests for reprints to Dr A R Gatrad, Departmentof Paediatrics, Oldham and District GeneralHospital, Rochdale Road, Oldham OLl 2JH.
A new probably autosomalrecessive cardiomelic dysplasiawith mesoaxial hexadactyly
SUMMARY A distinct probably autosomal re-cessive syndrome was ascertained in a 17-year-oldboy and his deceased sister. The main featureswere cardiac dysplasia, peculiar facies, centralbilateral (mesoaxial) hexadactyly, synmetacar-palia, short stature, ocular torticollis, and delayedpuberty.
We describe a patient with multiple congenitalanomalies, some of which were indirectly ascer-tained in his deceased sister, suggesting autosomalrecessive inheritance.
Case report
The proband, born in 1962, was the product of aterm gestation and normal delivery. Birthweight andlength were not recorded; however, he was smallerthan his normal sibs. Bilateral hexadactyly, broadright hallux, acrocyanosis, the presence of teeth, anddyspnoea were observed at birth. Psychomotorretardation was evident from early infancy and hetilted his head to the left when he started walkingat about 4 years of age. Excision of the supernumer-ary right finger was performed at 10 years of age.Physical examination at 131 years (fig 1) showeddelayed development, a weight of 28-7 kg, a heightof 134 cm (both below the 3rd centile), an upper-to-lower-segment ratio of 0 97 (66/68), an arm span of127 cm, and a head circumference of 53 cm. Otherfeatures included normocephaly, wide and flat fore-head, hypotrichosis of the eyebrows distally (ulery-thema ophryogenes), telecanthus, ocular torticollisas a result of alternate exophoria-tropia, a winkingtick, long prominent nose with lateral bossing,tented nares, lateral pits in the nasal alae, shortphiltrum, macrostomia, everted lower lip, down-turned mouth, multiple dental diastemata and mal-occlusion, large pinnae, prominent anthelix, tworight Darwinian tubercles, short neck, prominenttrapezius muscles, cylindrical thorax, hypoplasticnipples, underdeveloped external genitalia, normalspine, mesoaxial hexadactyly in both hands, digitalclubbing and cutaneous syndactyly between digits2 and 3, thenar and hypothenar hypoplasia, genuand pes valgus, right hallucal polysyndactyly, andmild flattening of toe nails. Dermatoglyphic analysisdid not reveal extra triradii at the base of the super-numerary fingers.Received for publication 6 May 1980
FiG The proband aged 17 years. Note the infantile genitalia and the peculiar facies. In the upper left photograph the
patient had already had operations on both hands. In the lower left photograph the left hand still shows the mesoaxial
hexadactyly. Also niote the right hallucalpolysyndactyly.
Results of routine laboratory examinations, in-cluding blood cell count, glucose, urea, creatinine,plasma proteins, alkaline phosphatase, Ca and P,urine analysis, and screening tests for inborn errorsof metabolism, were either normal or negative. Thekaryotype processed forG bands was normal, 46,XY.Endocrinological studies included the followingnormal results: T3, T4, 17-ketosteroids, 17-hydroxy-corticoids, TSH and prolactin release after TRHstimulation, as well as basal and post-stimulation(insulin induced hypoglycaemia) HGH levels. At 17years of age, the plasma values of testosterone,dihydrotestosterone, total oestrogens, LH, and FSH(before and after stimulation with LH-RH) cor-respond to a prepubertal male.
X-ray examination disclosed a bone age delayed byabout 3 years (Greulich-Pyle), osteopenia, cervical
dextroconvex scoliosis, thinning of cortices, meta-carphophalangeal dysrhythmic growth, distal centralsynmetacarpalia and bilateral type A mesoaxialhexadactyly, right hallucal polysyndactyly, andenlarged first podal ray (fig 2). Urography wasnormal.
Cardiological evaluation, including haemodynamicstudies and direct visualisation during surgery,revealed pulmonary stenosis, persistent ductusarteriosus, single atrium, ventricular septal defect(20 mm), lower vena cava and persistent left uppervena cava draining into coronary sinus, and hepaticveins draining into left auricle (fig 3). Cardiac sur-gery at 11 years of age consisted of atrial and ven-tricular septal repair, pulmonary valvulotomy,and closure of the persistent ductus arteriosus.Cardiac failure was present for about one year after
surgery and required medical therapy. Neuro-ophthalmological evaluation supported a periphericorigin for the exophoria-tropia.At the age of 14, he had a mental age of 8 (IQ 57).
At 17 years of age, mild mental retardation, shortstature, and infantile genitalia were observed.
FIG 2 Radiographs of hands and feet. The right handhas already been operated upon. Note thesynmetacarpalia in the left hand as well as theunilateral hallucal polysyndactyly.
FAMILY DATAThe father and mother, aged 36 and 25 years, re-spectively, at the proband's birth, were clinicallyand radiologically normal. It was not possible toassess consanguinity. One sister, born with lowbirthweight and distally bifid 3rd fingers, who died6 days after birth with cardiorespiratory cyanogenicdistress, was considered to have had the same con-dition as the proband. Six other sibs, one femaleand five males, were normal. No relative as far asthe fourth degree was found to have this syndromeor constitutional short stature.
Discussion
The association of mental retardation, short stature,delayed puberty, mesoaxial polydactyly with centralsynmetacarpalia, ocular torticollis, oral and facialdysmorphism, and the cardiac malformations presentin the proband have not been previously reported.Although indirectly ascertained, the proband'sdeceased sister was also considered to have beenaffected, since she had mesoaxial hexadactyly(distally bifid 3rd fingers), which is a very rare mal-formation, as well as low birthweight and probablecardiac dysplasia as the cause of death. Differentialdiagnosis ruled out the cardiomelic dysplasiasI 2 andthe Ellis-van Creveld3 and Kaufman-McKusicksyndromes.4The lack of exposure to teratogenic factors, the
normal karyotype, the finding of the disease in twoof eight children of both sexes, and the lack ofphenotypic manifestations in the parents or relatives,strongly suggest autosomal recessive inheritance ofthis cardiomelic dysplasia.
This work was partially supported by a grant fromthe Ford Foundation. We thank Amado Barthel for
-.-~rAr,c
a r,er ,,
Pjnorr:-.orery
iLeft r>merccvc veir
vaive
FIG 3 Schematic representation of thecardiovascular malformations.
R MARTINEZ Y MARTiNEZ, E CORONA-RIVERA,M JIMiNEZ-MARTiNEz, R OCAMPO-CAMPOS,
S GARCiA-MARAVILLA, AND J M CANTODivision de Genetica, Subjefatura deInvestigacion Cientifica, Unidad de
Investigacion Biomedica y Hospital de Pediatria,Centro Medico de Occidente, Instituto Mexicano
del Seguro Social, Apartado Postal 1-3838,Guadalajara, Jalisco, Mexico.
ReferencesTamari I, Goodman RM. Upper limb-cardiovascularsyndromes. A description of two new disorders with aclassification. Chest 1974;65:632-9.
2 Cantu JM, Hernfndez A, Ramirez J, et al. Lethal facio-cardiomelic dysplasia. A new autosomal recessive dis-order. Birth Defects 1975;XI(5):91-8.
3 McKusick VA, Engeland JA, Elridge R, Krusen DE.Dwarfism in the Amish. I. The Ellis-van Creveld syndrome.Bull Johns Hopkins Hosp 1964;115:306-36.
4 Kaufman RL, Hartman AF, McAlister WM. Familystudies in congenital heart disease. II. A syndrome ofhydrometrocolpos, postaxial polydactyly and congenitalheart disease. Birth Defects 1972;VII(5):85-7.
Requests for reprints to Dr R Martinez, y Martinez,Division de Genetica, Unidad de InvestigacionBiom6dica, Apartado Postal 1-3838, Guadalajara,Jalisco, Mexico.
Prenatal diagnosis for adenosinedeaminase deficiency
SUMMARY Amniocentesis was performed in twosuccessive pregnancies of the mother of a childwith adenosine deaminase (ADA) deficientsevere combined immunodeficiency. Assay ofADA in amniotic fluid fibroblasts showed thepregnancies to be normal and homozygousdeficient, respectively. These findings were
confirmed by the demonstration of a normallevel of erythrocyte ADA in the cord blood ofthe healthy male born of the first pregnancy andby the demonstration of undetectable ADAactivity in cord erythrocytes, spleen, liver, andkidney of the abortus of the second pregnancy.Prenatal diagnosis of ADA deficiency appearsto be a reliable procedure.
Deficiency of the purine catabolic pathway enzymeADA represents the first inborn error of metabolism
Received for publication 4 June 1980
Case reports
to be associated with an immunodeficiency disorder.'The clinical significance of this association has beenexploited in a number of ways. Where a family hashad a child with severe combined immunodeficiency,the finding of ADA deficiency can be usefulfor genetic counselling, since it indicates an auto-somal recessive mode of inheritance. Enzyme re-placement appeared feasible since the enzyme isabundant in erythrocytes and successful correctionhas been achieved,2 3 though such success is notinvariable.45 Intrauterine diagnosis is possible sinceADA is widespread in tissues. Hirschhorn et a16reported the diagnosis of this deficiency in a 28-weekfetus. The pregnancy proceeded and the deficiencywas confirmed at delivery. The purpose of this com-munication is to report that prenatal diagnosis hasbeen performed successfully in two pregnancies of awoman who had previously born an ADA deficientchild.
Case report
The case history, clinical and laboratory findings,and details of management of the proband have beenreported elsewhere.5 Briefly, a first-born male wasreferred at 14 weeks with failure to thrive, recurrentbacterial infection, thrush, diarrhoea, and cough withrespiratory distress. Tonsillar and peripheral lym-phoid tissue were deficient. X-rays showed absentthymic shadow, interstitial pneumonitis, and skeletalfindings suggestive of ADA deficiency. Immuno-logical studies showed severe combined immuno-deficiency, ADA deficiency was shown in red bloodcells and leucocytes, and the parents were found tobe heterozygous deficient. A family study has beenreported elsewhere.7 Therapy included gamma-globulin replacement, erythrocyte and plasmainfusions, and fetal liver transplants, but was un-successful and the patient died at age 17 months of aparainfluenza pneumonitis. The mother of this childhas since had two pregnancies and prenatal diagnosiswas offered for both (see below). The first of theseproceeded to term and produced a healthy infant.The second was terminated at 22 weeks' gestation.
Methods
Amniotic fibroblast cultures were performed as de-scribed.8 Amniotic fluid was collected at 14 to 16weeks' gestation and set up in 25 cm2 flasks (FalconPlastics) in Ham's FIO medium buffered with 25mmol/l Hepes. For ADA assay, cells were lyseddirectly from the flask.ADA assay on all tissues examined was determined
by an isotopic method previously described in detail.9Tissue homogenate or cell suspensions in 10 mmol/l
