77 Med Genet 1993 30: 788-792

Congenital heart malformation in Yunis-Varonsyndrome

L C Ades, L L Morris, M Richardson, C Pearson, E A Haan

AbstractWe describe a male infant with Yunis-Varon syndrome who has tetralogy ofFallot. This appears to be the first case ofYunis-Varon syndrome associated withcongenital heart malformation.(J Med Genet 1993;30:788-92)

Department ofMedical Genetics andEpidemiology, (TheCentre for MedicalGenetics), AdelaideChildren's Hospital,72 King William Road,North Adelaide, SouthAustralia 5006,Australia.L C AdesE A Haan

Department of OrganImaging, Women'sand Children'sHospital (AdelaideChildren's HospitalDivision), NorthAdelaide, SouthAustralia 5006.L L Morris

Department ofCardiology, Women'sand Children'sHospital (AdelaideChildren's HospitalDivision), NorthAdelaide, SouthAustralia 5006.M Richardson

Department ofPaediatrics, Women'sand Children'sHospital (AdelaideChildren's HospitalDivision), NorthAdelaide, SouthAustralia 5006.C Pearson

Correspondence toDr Ades.Received 23 February 1993.Accepted 30 March 1993.

In 1980, Yunis and Var6n' reported five chil-dren from three Colombian families withsparse hair, cleidocranial dysostosis, severemicrognathia, bilateral absence of the thumbsand first metatarsal bones, and distal aphalan-gia. All five children died before the age of 10weeks. No additional abnormalities werefound at necropsy in three children but in afourth there was tracheal, laryngeal, and pul-monary hypoplasia. Chromosome studies intwo of the children were normal. Yunis andVar6n' suggested autosomal recessive inherit-ance since sibs of both sexes were affected, theparents were normal, and there was consan-guinity in two of three families.

Since the original report, seven further caseshave been described.2-5 In 1983, Hughes andPartington2 reported a mildly affected case,adding the features of prenatal and postnatalgrowth deficiency, prolonged survival, shortstature, and mental retardation to the clinicalpicture. Since that report, a further six caseshave been described, including another reportby Partington3 of one boy with the additionalfeatures of mild hypertelorism, midfacialhypoplasia, premature loss of deciduous teeth,dry skin, one foot smaller than the other, andcardiomyopathy. Garrett et al4 described cere-bral malformation, sclerocornea, cataracts,flared metaphyses, and pathological fracturesas new features of the syndrome.Yunis-Var6n syndrome appears to be a

generalised disorder with variable effects ongrowth and development of the skeletal, ecto-dermal, central nervous, and cardiovascularsystems. We report another case, which addscongenital cardiac malformations to the knownfeatures of this syndrome. In addition we re-view the neurological findings and discusstheir possible implications.

Case reportThe male proband was the first child born tounrelated Anglo-Saxon parents at 36 weeks'gestation after a normal pregnancy, labour,and delivery. Apgar scores were 4 and 6 at oneand five minutes respectively. Birth weightwas 2630 g (10th to 50th centile), length 44 cm(< 10th centile), and head circumference31 cm (< 10th centile). He was tachypnoeicfrom birth and had periods of desaturation

necessitating oxygen administration in the firstfew days of life. Acyanotic tetralogy of Fallotwas diagnosed by echocardiography. Therewas no family history of congenital heart dis-ease. The child was hypotonic and fed poorlynecessitating gavage feeding.

Craniofacial features (figs 1 to 4) includedredundant posterior neck skin, a flat occiput,prominent parietal bossing, bifrontal narrow-ing, fine, sparse scalp hair, low set and abnor-mally shaped ears, hypoplastic supraorbitalmargins giving the impression of mild prop-tosis, puffy upper eyelids, epicanthic folds,upward slanting palpebral fissures, a beakednose, mild micrognathia, thin lips, and anupper anterior gingivolabial fold. Funduscopyshowed anomalous take off of the retinal ves-sels from each optic disc. There was distaldigital hypoplasia of the thumbs, index, andlittle fingers (fig 5). The palmar creases wereabnormal with bilateral transverse palmarcreases and prominent creases perpendicularto the transverse crease. The big toes were heldin a cocked up position and there was distalphalangeal hypoplasia (fig 6). He had undes-cended testes, hypoplastic nipples, a left dislo-cated hip, and profound hypotonia.

Skeletal radiographs (figs 7 to 10) showedcentral defects in both clavicles, winged and

I

Figure 1 The proband aged 6 months showing sparsehair, upward slanting palpebral fissures, and epicanthicfolds.

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Congenital heart malformation in Yunis- Var6n syndrome

Figure4ITheproband aged12

Figure 4 The proband aged 12 months.O

ThLrbn

Figure 6 View of the toes showing distal phalangealhypoplasia.

Figure 3 The proband aged 12 months.

hypoplastic scapulae, a mild kyphosis at thecervicothoracic junction, broad sacrosciaticnotches, failure of ossification of the pubicbones and of the symphysis pubis, and left hipdislocation. The distal phalanx of the thumb,index, and little fingers were hypoplastic, thefirst metacarpal was short, and there was hypo-plasia of the middle phalanges of both littlefingers with clinodactyly. There was hypo-

plasia of the first metatarsal and proximalphalanx of both great toes and of the distalphalanges of the toes.A Nissen fundoplication and gastrostomy

were performed at 5 months of age because ofcontinued poor feeding. At the age of 1 1months he had become microcephalic and de-velopmental progress was assessed at a 3 to 4month level. Growth was retarded, with bothheight and weight remaining well below the3rd centile throughout the first year. At thattime the cardiac lesion had not required treat-ment because there was a nett left to rightshunt and the patient had not experienced anycyanotic attacks.

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Figure 7 Chest radiograph showing hyjclavicles.

Figure 8 Radiograph of the pelvis.

Figure 9 Hand radiograph showing distal phalangealhypoplasia.

poplasia of the

Figure 10 Foot radiograph showing distal phalangealhypoplasia.

Cranial ultrasound (fig 1 1) showed a largeinterthalamic adhesion and mild dilatation ofthe fourth ventricle associated with hypoplasiaof the inferior cerebellar vermis. Ultrasound ofthe urinary tract showed minor dilatation ofthe renal pelves.Chromosome studies showed a normal male

karyotype, 46,XY. Biochemical studies under-taken included serum creatine kinase, serumvery long chain fatty acids and amino acids,plasma lactate and pyruvate, lysosomal en-zymes, and urinary amino and organic acids.All results were normal.

DiscussionThe main characteristics of the Yunis-Var6nsyndrome include prenatal and postnatalgrowth deficiency, craniofacial disproportion,agenesis or hypoplasia of the clavicles, digitalanomalies especially extreme hypoplasia of thefirst rays, and, usually, death in the first weeksof life. The clinical and radiological features of

- ~~~our case are compared with the previouslyreported patients with Yunis-Var6n syndrome

Figure 11 Cranial ultrasound showing interthalamicadhesion and hypoplasia of the inferior cerebellarvermis.

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Congenital heart malformation in Yunis- Var6n syndrome

in tables 1 and 2 respectively. The facialfeatures were strikingly similar to those ofprevious cases, although our case lacked thecraniofacial disproportion, wide sutures andfontanelles, glossoptosis, and narrow/higharched palate described in most other cases.The pattern of abnormalities of the hands andfeet was characteristic although less severethan in some others. The clinical course of ourpatient is similar to that of most cases ofYunis-Var6n syndrome with severe failure tothrive and marked psychomotor delay domi-nating the clinical picture. Survival has beenpossible as a result of gavage feeding.A congenital heart malformation, present in

our patient, has not been described before inYunis-Var6n syndrome. Partington3 reporteddilated cardiomyopathy in one patient and case3 of Garrett et al,4 who died at the age of 3weeks, was found to have myocardial hyper-trophy at necropsy.Mental retardation, hypotonia, and hyperto-

nia have all been described in the Yunis-Var6n

Table 1 Clinical features of Yunis- Var6n syndrome.

SexBirth length < 3rd centileBirth weight < 3rd centileMicrocephalyWide sutures/fontanellesSparse scalp hairHypoplastic facial bonesSmall eyesProptosisAnteverted nostrilsShort upper lipLabiogingival retractionGlossoptosisNarrow/high arched palateMicrognathiaLow set/dysplastic earsLoose neck skinAbsent nipplesExternal genital anomaliesBilateral hip dislocationBilateral simian creaseAbsent/hypoplastic thumbsShort pointed fingersNail hypoplasia/agenesisAbsent/hypoplastic hallucesShort, pointed toesDeath in neonatal periodSclerocorneaCataractCNS malformationCardiomyopathyStructural cardiac malformation

Previous cases ofYunis-Var6n syndrome

(n= 12)

6M/6F6/87/94/1012/1211/119/95/77/9

10/1112/125/92/87/812/1212/125/62/123/95/86/911/1111/1110/1212/1210/127/91/41/42/41/120/12

Table 2 Radiological features of Yunis- Varon syndrome.

Previous cases ofYunis-Var6n syndrome

(n = 12)

Calvarial dysostosisWide suturesCraniofacial disproportionMicrognathiaAbsent/hypoplastic claviclesAbnormal scapulaeAbsent sternal ossificationPelvic dysplasiaHip dislocationCoxa valgaAgenesis/hypoplasia of thumbsAgenesis/hypoplasia of distal phalanges of fingersAgenesis/hypoplasia of middle phalanges of fingersAgenesis/hypoplasia of first metatarsalsHypoplasia of hallucal phalangesAgenesis/hypoplasia of distal phalanges of toesFlared metaphysesSubmetaphyseal constrictionThin, constricted diaphysesDelayed bone maturationPathological fractures

9/98/99/910/106/102/24/46/74/62/29/98/98/99/109/97/74/43/44/42/22/4

Present case

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Present case

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syndrome and structural brain abnormalitiesare likely to have contributed to these featuresin some cases. Garrett et al4 provided the firstdescription of central nervous system malfor-mations in two patients with Yunis-Var6nsyndrome. One patient with absence of theolfactory bulbs and tracts (arhinencephaly)and a hamartomatous lesion of the lateral vent-ricle had severe weakness and hypotonia anddied of pneumonia at the age of 4 months. Inthat case, neuropathological study confirmedneuronal loss and vacuolisation in cells of thecerebral cortex, dentate nuclei, basal ganglia,olives, and anterior horn cells. The secondcase, a fetus, had agenesis of the corpus callo-sum and dilatation of the lateral ventricles onultrasound at 18 weeks' gestation. The preg-nancy was terminated and no description ofthe histological appearance of the brain wasprovided. Our patient had a developmentalabnormality of the cerebellar vermis and alarge interthalamic adhesion, neither of whichhave been previously described in the Yunis-Var6n syndrome. It is clear that various brainmalformations can occur in Yunis-Var6n syn-drome but more detailed neuropathology willbe needed if the mechanism of severe centralnervous system dysfunction is to be under-stood.Yunis-Var6n syndrome is one of a small

number of defined multiple congenital anom-aly syndromes in which congenital clavicularhypoplasia/agenesis occurs.5 This finding sug-gested the diagnosis in our patient andprompted a full skeletal survey which allowedconfirmation. Garrett et a14 reported fourpatients with Yunis-Var6n syndrome who didnot have absent or hypoplastic clavicles. Thesepatients had metaphyseal and diaphyseal ab-normalities reminiscent of severe precociousosteodysplasty as described by Kozlowski etal6 and two had pathological fractures. Ourpatient had no skeletal features suggestive ofosteodysplasty.The presence and equal severity of the syn-

drome in sibs of both sexes, absence of reportsof the syndrome in more than one generation,and consanguinity in three of the nine familiesnow described point to an autosomal recessivemode of inheritance. Hennekam and Vermeu-len-Meiners7 reported shortening of thethumbs and distal phalanges in the mother of apatient but no such anomalies have been foundin the parents of the other described patients.Radiological investigations were not per-formed, however, so it remains unclearwhether these anomalies could occur moreoften. Hand radiographs of the parents of ourcase were normal.This report of another patient with the

Yunis-Var6n syndrome adds congenital heartdisease and new central nervous system mal-formations to the growing list of featuresaccompanying the condition.

We thank Dr M W Partington for reviewingthe case and the family for their cooperation.

1 Yunis E, Var6n H. Cleidocranial dysostosis, severe micro-gnathism, bilateral absence of thumbs and first metatarsalbone, and distal aphalangia. AmJ Dis Child 1980;134:649-53.

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2 Hughes HE, Partington MW. Brief clinical report. Thesyndrome of Yunis and Var6n. Report of a further case.Am Med Genet 1983;14:539-44.

3 Partington MW. Cardiomyopathy added to the Yunis-Var6nsyndrome. Proc Greenwood Genetic Center 1988;7:224-5.

4 Garrett C, Berry AC, Simpson RH, Hall CM. Yunis-Var6nsyndrome with severe osteodysplasty. J7 Med Genet1990;27:1 14-21.

5 Hall BD. Syndromes and situations associated with congen-

ital clavicular hypoplasia and agenesis. In: Papadatos CJ,Bartsocas CS, eds. Skeletal dysplasias. New York: Alan RLiss, 1982:279-88.

6 Kozlowski K, Mayne V, Danks DM. Precocious type ofosteodysplasty. A new autosomal recessive form. ActaRadiol 'Stockh/ 1973;14:171-6.

7 Hennekam RCM, Vermeulen-Meiners C. Further delinea-tion of the Yunis-Var6n syndrome. Med Genet1989;21:55-8.

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