Syndrome of the month

Journal of Medical Genetics 1986, 23, 389-395

Williams syndromeJOHN BURNFrom the Department of Human Genetics, University of Newcastle upon Tyne, 19 Claremont Place,Newcastle upon Tyne NE2 4AA.

Williams et all in 1961 called attention to a syn-drome of supravalvular aortic stenosis, mentalretardation, and peculiar facial features. In 1962,Beuren et al2 described the syndrome independentlyand expanded it to include dental anomalies andperipheral pulmonary artery stenosis, as a result ofwhich some authors prefer the eponym Williams-Beuren syndrome.

Several earlier authors have a claim to posterity.The key cardiac defect, supravalvular aorticstenosis, was first described in 1842 by Chevers,3was named in 1930 by Mencarelli,4 and was shownto be a familial disorder in 1959 by Sissman.5Perhaps the strongest case can be made for Fanconiet at who described what is now known as Fanconitype idiopathic infantile hypercalcaemia (IIH) in1952, a condition associated with a characteristicdysmorphic syndrome and cardiac defects. Josephand Parrott7 in 1958 made particular reference tothe odd facies in these children.

In 1963 Black and Bonham Carter8 recognisedthat the 'elfin facies' of idiopathic infantilehypercalcaemia were the same as those described byWilliams et all and Beuren et al.2 In 1964, Garcia etal9 established this new combined entity with what isstill one of the very few fully documented examplesof IIH progressing to Williams-Beuren syndrome. Amajor factor in the preference for the latter termwas the recognition that overt hypercalcaemia is aninfrequent feature when large series of cases arereviewed. 10 "

Clinical features

GENERALThe classic syndrome is described in all dysmorph-ology texts: typical facies, supravalvular aortic steno-sis, and variable mental retardation with a friendly,outgoing personality. Infantile hypercalcaemia,

Received for publication 20 May 1986.Accepted for publication 30 May 1986.

when it occurs, may precipitate symptoms such asfailure to thrive, vomiting, constipation alternatingwith diarrhoea, and, in extreme cases, nephrocalci-nosis. If hypercalcaemia is overt, skeletal changes inadolescence and adulthood include osteosclerosis ofthe metaphyses of long bones, the skull vault, orlamina dura of the alveolar bone. Dental anomaliesare characteristic with late eruption, reduction insize, and general hypoplasia designated microdontiaand rhizomikry (small roots) together with invagina-tion of the incisors, malocclusion, and pathologicalfolding of the buccal mucosa.12

FACIAL FEATURESWhether or not these children have elfin facies isdifficult to establish, for while examples of thesyndrome are common, this author has never seenan elf. The term should be dropped.The facial dysmorphic features evolve with age as

shown in figs 1 to 4. The key features are a broadforehead, medial eyebrow flare, periorbital fullness,strabismus, stellate iris pattern, flat nasal bridge,malar flattening, full cheeks and lips, a long smoothphiltrum, a rather pointed chin, and a wide mouth.The face becomes more coarse with age. None ofthe features is constant but the characteristic com-bination for this author is the malar flattening withfull lower face, best shown in fig 3b.

CARDIOVASCULAR FEATURESCardiovascular anomalies are present in aboutthree-quarters of cases. Intracardiac anomalies,such as septal defects, have been described but areunusual. The characteristic abnormalities are supra-valvular aortic stenosis (SVAS) and peripheralpulmonary artery stenosis (PPAS) with othermuscular arteries involved less often.SVAS involves the ascending aorta above the

sinuses of Valsalva and, therefore, above the originsof the coronary arteries. These are exposed to theraised pressure and tend to become tortuous and

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FIG 1 A female infant at 3 months with typicalfacies,severe hypercalcaemia, peripheralpulmonary artery steno-sis, nephrocalcinosis, failure to thrive, and developmentaldelay.

thickened with an adverse effect on long termsurvival without surgery. Two-thirds of cases ofSVAS involve an hour glass deformity with the restdivided between a discrete membrane or diffusehypoplasia. In one-third, the aortic cusps arethickened and in the worst cases become adherent tothe area of disorganised aortic media and fibroticintima.13 Valve involvement may add the murmur ofaortic incompetence to the systolic murmur trans-mitted to the carotids. Folgerl showed the ascendingaorta to be unusually short which may be evidenceof common pathogenesis with the diffuse hypoplasiaof the pulmonary arteries beyond the bifurcation.Thisshorteningmay also be significant in embryology,since O'Connor et al13 noted that haemodynamicfactors may influence the site and nature of thenarrowing. Another factor of likely importance isthe observation that newborn infants may have aninfolding or plica at the upper margin of the sinusesof Valsalva which is conspicuous in some and almost

FIG 2 An older girl with classicfacies and moderatemental retardation.

absent in others. SVAS may be an exaggeration ofthis normal structure.15

Streaming of blood into the innominate arterymay give higher blood pressure in the right arm thanthe left. Clinical features correlate poorly withseverity though an ECG pattern of left ventricularhypertrophy with strain indicates a ventricularpressure above 200 mmHG16 and a worse outlook.

INTELLECTIntellectual development shows wide variation withmost cases falling in the mild to moderately retardedclass (mean IQ 56).10 Suggestions that perceptualand motor function are more impaired than verbalperformance were not corroborated by Kataria etal. 17 Martin et al, 18 in a review of 76 cases of IIH and41 cases of Williams syndrome, drew attention tohyperacusis which was found in 75% of their casesand proved disabling in some. These authors alsonoted that the failure to thrive of early months givesway to a tendency to obesity in later childhood, afeature evident in half the group studied.

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Syndrome of the month

OTHER FEATURESAmong the other general physical features noted byvarious authors, of particular value as 'make weight'

FIG 3 (a) A girl ofsimilar age with mild intellectualimpairment, outgoing personality, and mild supravalvularaortic stenosis.

findings are mild degrees of short stature andmicrocephaly, kyphoscoliosis, a long neck, inguinalor umbilical herniae, small nails, hallux valgus, anda hoarse voice. The long term outlook is dependent,usually, on the cardiovascular features dealt withabove, but Smith19 quotes, as a personal com-munication from B Hall, a tendency to degenerativerenal disease. This may be a late consequence ofdamage related to hypercalcaemia. The adult malereported by Dupont et a120 and by Jensen et a112 diedat 42 from pancreatic carcinoma. The latter authorsreported the postmortem discovery of calcium in theform of hydroxyapatite crystals in the cornea onelectron microscopy (EM), and in other tissues,despite the fact that hypercalcaemia had not beenreported in life. They suggested that EM of aconjunctival biopsy for calcium deposits may behelpful in diagnosis though this is unlikely to be usedoften.The various features of Williams syndrome are

arranged and weighted in a diagnostic index byPreus. 1 1

AETIOLOGY AND GENETICSIn the great majority of cases, Williams syndrome isa sporadic event of unknown cause. Two centralquestions are: first, how does the full syndromerelate to the variable autosomal dominant trait of'pure' SVAS and, second, is disturbance of fetalcalcium homeostasis by an inborn error or environ-mental stress or both of fundamental importance inits pathogenesis?The original report of familial SVAS by Sissman

et aP5 has been followed by several similarobservations.2126 Williams syndrome has been de-scribed in monozygotic twins27 and in secondcousins,28 and Cortada29 reviewed four sib reports

FIG 3 (b) Note malarflattening whichexaggerates the full cheeks and lips.

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FIG 4 (a) An adolescent with severe supravalvular aorticstenosis, moderate mental retardation, and typical, rathercoarse facialfeatures.

FIG 3 (c) Strabismus, telecanthus, slightstellate pattern and medial eyebrowflare.

and described an affected mother and twin daugh-ters, though the children look more like cases ofNoonan syndrome. The latter two reports notenormal karyotypes, but it remains possible that suchoccasional recurrences result from unrecognisedchromosome rearrangements.Many reports of Williams syndrome fail to men-

tion chromosome studies, including the report byMehes et a130 of IIH in a father and two children.Two small chromosome studies31 32 were done whentechniques were in their infancy. Fryns et a133described a possible case of Williams syndrome witha deletion of 15p. Martin et al18 found one case of abalanced 9;17 translocation, while Jefferson et a134report in this issue a female infant with features ofthe syndrome resulting from a deletion of the longarm of chromosome 4.While such cases may be nothing more than

phenocopies, it remains a distinct possibility thatWilliams syndrome results from a usually submicro-scopical deletion of a segment of the chromosomewhich includes the gene responsible for SVAS.Support for this view is given by the authors whocomment on 'elfin facies' in some of the patientswith familial SVAS. This case is put most forcefullyby Grimm and Wesselhoeft,26 whose major reviewof 128 families with SVAS or Williams syndromeidentified a number of family members in SVASpedigrees with features of Williams syndrome. Theyconcluded that these clinical phenotypes are ends ofa spectrum for an autosomal dominant gene defectof variable penetrance and expression whose genefrequency is at least 1 in 10 000. A criticism levelledat this and earlier reports is that their examples of

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the child illustrated in fig 5. His father and paternaluncle had the clinical features of PPAS and SVAS_ , ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~iFIG S A boy with SVAS whose brother, father, andpaternal uncle had either SVAS or PPAS or both. This childwas also hyperactive with mild developmental delay andsome ofthefacial features of Williams syndrome.

FIG 4 (b) Note the lacy stellate iris pattern andwide nose with bulbous tip.

respectively, while his brother had SVAS andPPAS. The proband had SVAS and was noted to behyperactive with evidence of mild developmentaldelay and facies which resemble the full Williamssyndrome. McKusick is sufficiently persuaded byGrimm and Wesselhoeft to have made the syndromea starred entry in the autosomal dominantcatalogue.3The remaining important issue is the role of

disturbed calcium homeostasis in the pathogenesis.Attention in the 1950s was focused on environmen-tal disturbance, in particular the role of maternalingestion of vitamin D. Following the recognition ofan apparent.epidemic of infantile hypercalcaemia,an association with vitamin D fortified milk wasproposed. Removal of this supplementation wasassociated with an apparent fall in birthprevalence.36 Persistence of the syndrome and itsoccurrence in infants definitely not exposed toexcess vitamin D led authors to conclude that thisteratogenic exposure had exposed fetuses in thepopulation with a pathological sensitivity to thevitamin.A series of animal experiments by Friedman et

a137 showed that very large doses of vitamin D inrabbits produced aortic lesions identical to thoseseen in SVAS, dental anomalies, strabismus, andcraniofacial changes closely resembling those seen inWilliams syndrome.38 Rather than the calciumdisturbances being an epiphenomenon due, forexample, to a neural crest abnormality affecting theface, heart, and the ultimobranchial body whichgives rise to thyrocalcitonin C cells, this studyshowed that a phenocopy could be produced by aprimary disturbance of fetal calcium homeostasis.Human studies support this interpretation; Becroftand Chambers39 found fibroblasts from affectedchildren to be hypersensitive to vitamin D2 (25

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John Burn

hydroxycholecalciferol) on the basis of excesscytoplasmic metachromasia, though this is a non-specific marker. Barr and Forfar,40 using an oralcalcium loading test, showed infants with IIH tohave exaggerated and prolonged rises in serumcalcium. Older cases with Williams syndrome wereless impressive. Forbes et al,41 however, used anintravenous calcium infusion of 10 mg/kg over onehour and found abnormally slow clearance in twocases of IIH and in five of six children with Williamssyndrome despite normal resting calcium levels.The precise defect of hormonal control remains

uncertain, and review of the expanding publicationson calcium metabolism is not appropriate here. Inbrief, vitamin D has three basic forms. Cholecal-ciferol, the dietary form, is converted in the liver to25 hydroxycholecalciferol which is, in turn, con-verted by the kidney to the highly potent 1,25hydroxycholecalciferol. This hormone sustainsserum calcium levels by enhanced absorption atbowel and kidney and at the expense of bone.Calcitonin, on the other hand, enhances clearanceof calcium from blood and tends to stabilise theimportant serum concentration while protecting theskeleton. Vitamin D binding protein has beenreported to be normal.42 Taylor et at3 foundabnormal regulation of circulating 25 hydroxy-cholecalciferol, following oral administration, in asmall group of patients and in two of four normalsibs. There is a report44 of a baby surviving intactingestion by the mother of massive doses of 1,25hydroxycholecalciferol though this might have beenthe result of the genetic resistance in the motherwhich necessitated the therapy. Forbes et at4l notedreports of normal parathyroid histology and con-cluded that a defect in calcitonin production, re-lease, or activity was most attractive. The recentlocalisation of the gene for calcitonin to chromo-some 1145 makes the possibility of an error in itsstructure of particular interest. Hutchins et ap6 haveobtained thyroid histology in an adult case ofWilliams syndrome who died at 30 years. There wasmarked hyperplasia of the C cells which producecalcitonin, which they interpreted as being secon-dary to chronic stimulation by a persistent error incalcium regulation. An alternative theory is that anabnormal product resulted in chronic feedbackstimulation to cell proliferation. The most recentreport47 is of a defect in calcitonin production incases of Williams syndrome. Culler et atP7 con-firmed, in their controlled investigation of fivechildren with Williams syndrome and no history ofhypercalcaemia, a raised baseline serum calciumand a delayed fall after an intravenous calciumbolus. The calcitonin response was blunted withsignificantly lower calcitonin levels. These authors

raise the possibility that a second product of thecalcitonin gene, the calcitonin gene related peptide,may be involved in the cause of retardation in viewof the substantial quantities found in normal braintissue.Whatever the precise defect, blind restriction of

dietary calcium and vitamin D is not advisable.Martin et al18 discovered 41% of their series hadbeen made hypocalcaemic and 9% had radiologicalevidence of rickets. They recommended reversion tonormal diet towards the end of the first year.

I am grateful for referral of the patients illustrated toDrs Fraser Alexander, Tony Goodwin, Philip Rees,and Elliot Shinebourne.

References

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2 Beuren AJ, Apitz J, Harmjanz D. Supravalvular aortic stenosisin association with mental retardation and certain facial appear-ance. Circulation 1962;26:1235-40.

3 Chevers N. Observations on the diseases of the orifice andvalves of the aorta. Guy's Hosp Rep 1842;7:387-421 (quoted byConnor WN et al. Arch Pathol Lab Med 1985;109:179-85).

4 Mencarelli L. Stenosi supravalvulare aortica ad anello. Arch ItalAnat Pathol 1930;1:829.

s Sissman NJ, Neill CA, Spencer FC, et al. Congenital aorticstenosis. Circulation 1959;19:458-68.

6 Fanconi G, Giardet P, Schlesinger Butler H, Black JS.Chronische hypercalcamie kambiniert mit osteosklerose,hyperazotamie minderwuschs und kogenital miss bildungen.Helv Paediatr Acta 1952;7:314-34.

7 Joseph MC, Parrott D. Severe infantile hypercalcaemia withspecial reference to the facies. Arch Dis Child 1958;33:385-95.

8 Black JA, Bonham Carter RE. Association between aorticstenosis and facies of severe infantile hypercalcaemia. Lancet1963;ii:745-9.

9 Garcia RE, Friedman WF, Kaback MM, Rowe RD. Idiopathichypercalcaemia and supravalvular aortic stenosis. Documenta-tion of a new syndrome. N Engl J Med 1964;271:117-20.

10 Jones KL, Smith DW. The Williams elfin facies syndrome. JPediatr 1975;86:718-23.

1 Preus M. The Williams syndrome-objective definition anddiagnosis. Clin Genet 1984;25:422-8.

12 Jensen OA, Warburg M, Dupont A. Ocular pathology in theelfin face syndrome (the Fanconi-Schlesinger type of idiopathichypercalcaemia of infancy). Ophthalmologica 1976;172:434-44.

13 O'Connor WN, Davis JB Jr, Geissler R, Cottrill CM, NoonanJA, Todd EP. Supravalvular aortic stenosis. Arch Pathol LabMed 1985;109:179-85.

14 Folger GM Jr. Further observations on the syndrome ofidiopathic infantile hypercalcemia associated with supravalvularaortic stenosis. Am Heart J 1977;93:455-62.

13 Perou ML. Congenital supravalvular aortic stenosis. ArchPathol 1961;71:453.

16 wesselhoeft H, Salomon F, Grimm T. Spektrum der supraval-vularen aortenstenose. Untersuchungsergebrisse bei 150 pa-tients mit Wifliams-Beuren-syndrom und der isolierten form dersupravalvularen aortenstenose. Z Kardiol 1980;69:131-40.

7 Kataria S, Goldstein DJ, Kushnick T. Developmental delay inWilliam's ("elfin facies") syndrome. Appl Res Ment Retard1984;5:419-23.

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19 Smith DW. Recognizable patterns of human malformation. 3rded. Philadelphia: Saunders, 1982:100-1.

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21 Eisenberg R, Young D, Jacobson B, Boito A. Familialsupravalvular aortic stenosis. Comments on the mechanisms ofangina pectoris. Am J Dis Child 1964;108:341-7.

22 Underhill WL, Tredway JB, D'Angelo GJ, Baay JEW. Familialsupravalvular aortic stenosis. Comments on the mechanisms ofangina pectoris. Am J Cardiol 1971;27:560-5.

23 Johnson LW, Fishman RA, Schneider B, Parker FB, Husson G,Webb WR. Familial supravalvular aortic stenosis. Report of alarge family and review of the literature. Chest 1976;70:494-500.

24 Dumoulin M, Van der Hauwaert L. Familial supravalvularaortic stenosis. Acta Paediatr Belg 1978;31:129-38.

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26 Grimm T, Wesselhoeft H. The genetic aspects of Williams-Beuren syndrome and the isolated form of the supravalvularaortic stenosis: investigation of 128 families. Z Kardiol1980;69:168-72.

27 Wiltse HE, Goldbloom RB, Antia AU, Ottesen OE, Rowe RD,Cooke RE. Infantile hypercalcemia syndrome in twins. N EnglJMed 1966;275:1157-60.

28 White RA, Preus M, Watters GV, Fraser FC. Familialoccurrence of the Williams syndrome. J Pediatr 1977;91:614-8.

29 Cortada X, Taysi K, Hartmann AF. Familial Williams syn-drome. Clin Genet 1980;18:173-6.

30 Mehes K, Szelid Z, Toth P. Possible dominant inheritance of theidiopathic hypercalcaemia syndrome. Hum Hered 1975;25:30-4.

31 Eberle P, Beuren AJ.. Chromosome studies in supravalvularaortic stenosis. Lancet 1963;iu:438.

32 Merritt AD, Palmer CG, Lurie PR, Petry EL. Supravalvularaortic stenosis: genetic and clinical studies. J Lab Clin Med1963;62:995.

33 Fryns JP, van der Hauwaert LG, Dumoulin M, van den BergheH. The elfin face syndrome and the short arm of chromosome15. Ann Genet (Paris) 1982;25:181-2.

34 Jefferson RD, Burn J, Gaunt KL, Hunter S, Davison EV. Aterminal deletion of the long arm of chromosome

4[46,XX,del(4)(q33)1 in a female infant with phenotypic fea-tures of Williams syndrome. J Med Genet 1986;23:474-7.

3 McKusick VA. Mendelian inheritance in man. 6th ed. Balti-more: Johns Hopkins University Press, 1983.

36 Oppe TE. Infantile hypercalcaemia, nutritional rickets andinfantile scurvy in Great Britain. Br Med J 1964;i:1659-61.

37 Friedman WF, Roberts WC. Vitamin D and the supravalvularaortic stenosis syndrome. The transplacental effects of vitaminD on the aorta of the rabbit. Circulation 1966;34:77-86.

38 Friedman WF, Mills LF. The relationship between vitamin Dand the craniofacial and dental anomalies of the supravalvularaortic stenosis syndrome. Pediatrics 1969;43:12-8.

39 Becroft DMO, Chambers D. Supravalvular aortic stenosis-infantile hypercalcaemia syndrome: in vitro hypersensitivity tovitamin D2 and calcium. J Med Genet 1976;12:223-8.

40 Barr DGD, Forfar JO. Oral calcium-loading test in infancy withparticular reference to idiopathic hypercalcaemia. Br Med J1969;i:477-80.

41 Forbes GB, Bryson MF, Mannig J, et al. Impaired calciumhomeostasis in the infantile hypercalcemic syndrome. ActaPaediatr Scand 1972;61:305-9.

42 Daiger SP, Miller M, Romeo G, Paisons M, Cavalli-Sforza LL.Vitamin-D-binding protein in the Williams syndrome andidiopathic hypercalcaemia. N Engl J Med 1978;298:687-8.

4 Taylor AB, Stem PH, Bell NH. Abnormal regulation ofcirculating 25-hydroxyvitamin D in the Williams syndrome. NEngl J Med 1982;306:972-5.

44 Marx SJ, Swart EG Jr, Hamstra AJ, Deluca HF. Normalintrauterine development of the fetus of a woman receivingextraordinarily high doses of 1,25-dihydroxy-vitamin D3. J ClinEndocrinol Metab 1980;51:1138-42.

45 Hoppener JWM, Steenbergh PH, Zandberg J, et aL Localisationof the polymorphic human calcitonin gene on chromosome 11.Hum Genet 1984;66:309-12.

46 Hutchins GM, Mirvis SE, Mendelsohn G, Bulkley BH. Supra-valvular aortic stenosis with parafollicular cell (C-cell) hyper-plasia. Am J Med 1978;64:967-73.

47 Culler FL, Jones KL, Deftos LJ. Impaired calcitonin secretionin patients with Williams syndrome. J Pediatr 1985;107:720-3.

Correspondence and requests for reprints to DrJohn Burn, Department of Human Genetics,University of Newcastle upon Tyne, 19 ClaremontPlace, Newcastle upon Tyne NE2 4AA.

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