8 JMed Genet 1996;33:986-992

Williams-Beuren syndrome: phenotypicvariability and deletions of chromosomes 7, 1 1,and 22 in a series of 52 patients

C A Joyce, B Zorich, S J Pike, J C K Barber, N R Dennis

Wessex RegionalGenetics Laboratory,Salisbury DistrictHospital, SalisburySP2 8BJ, UKC A JoyceS J PikeJ C K Barber

Merton & SuttonCommunity NHSTrust, Orchard Hill,Carshalton, SurreySM5 4NR, UKB Zorich

Wessex ClinicalGenetics Service,Princess AnneHospital,SouthamptonS016 5YA, UKN R Dennis

Correspondence to:Dr Joyce.Received 1 April 1996Revised version accepted forpublication 15 July 1996

A

AbstractFluorescence in situ hybridisation (FISH)and conventional chromosome analysiswere performed on a series of 52 patientswith classical Williams-Beuren syndrome(WBS), suspected WBS, or supravalvularaortic stenosis (SVAS). In the classicalWBS group, 22123 (96%) had a sub-microscopic deletion ofthe elastin locus onchromosome 7, but the remaining patienthad a unique interstitial deletion of chro-mosome 11 (del(1l)(q13.5q14.2)). In thesuspected WBS group 2/22 (9%) patientshad elastin deletions but a third patienthad a complex karyotype including a ringchromosome 22 with a deletion ofthe longarm (r(22)(pll-ql3)). In the SVAS group,1/7 (14%) had an elastin gene deletion,despite having normal development andminimal signs of WBS.

Overall, some patients with sub-microscopic elastin deletions have fewerfeatures of Williams-Beuren syndromethan those with other cytogenetic ab-normalities. These results, therefore, em-phasise the importance of a combinedconventional and molecular cytogeneticapproach to diagnosis and suggest that thedegree to which submicroscopic deletionsofchromosome 7 extendbeyond the elastinlocus may explain some of the phenotypic

Bc

Figure 1 Patient 1 (A) at 14 months, (B) at 17years.

variability found in Williams-Beuren syn-drome.( Med Genet 1996;33:986-992)

Key words: Williams-Beuren syndrome; llq; 22q.

Williams-Beuren syndrome (WBS), first de-scribed by Williams et all in 1961 and in-dependently by Beuren et al2 in 1962, is acongenital developmental disorder involvingthe vascular, connective tissue, and centralnervous systems. It occurs with a frequency of1 in 20 000 livebirths and is almost alwayssporadic, although there are a few reports offamilial cases.35WBS is characterised by a distinct facial

appearance, including broad forehead, bi-temporal narrowness, periorbital fullness, widemouth, broad nasal tip, long philtrum, prom-inent ear lobules, full cheeks, and micrognathia(fig 1); mental retardation, mean IQ of 58;cardiovascular anomalies, characteristicallysupravalvular aortic stenosis (SVAS), which canalso be inherited as an autosomal dominanttrait, and peripheral pulmonary stenosis (PPS);infantile hypercalcaemia and hyperacusis.Other features of WBS include feeding diffi-culties during infancy, a gregarious personalitytogether with "cocktail party speech", poorvisual motor integration, hoarse voice, and jointlimitation.6'-l0

Hemizygosity of the elastin gene (ELN) onchromosome 7 has been shown to occur in thevast majority of WBS patients and mutationsat the 3' end of the ELN in some cases ofautosomal dominant SVAS.11-l9 It is nowthought that WBS is a contiguous gene syn-drome with the submicroscopic deletion at7q11.23 spanning at least 250kb2' and pre-sumably including additional as yet un-identified genes.

In the present study, we report the con-ventional and molecular cytogenetic (FISH)investigation of a series of 52 patients: 23 clas-sical WBS cases, 22 suspected WBS cases, andseven patients referred with SVAS or PPS.The results were used to establish phenotype-genotype correlations, which indicate a broadrange of phenotypes associated with WBS.

MethodsPATIENTSOur study population comprised three cat-egories: (1) 23 patients who, on the basis oftheir clinical features, had already been diag-

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987Williams-Beuren syndrome

nosed as having WBS. Of these, 21 were knownto the Clinical Genetics Service in Wessex andthe remaining two were referred to us in-dependently by a paediatrician and a car-

diologist; (2) 22 suspected WBS cases, ofwhichsix were referred by clinical geneticists, andthe remainder referred by paediatricians andcardiologists within Wessex; (3) seven patientsreferred primarily with SVAS or PPS or both,including two patients from autosomal dom-inant SVAS families.A clinical assessment of the patients was

carried out with emphasis on 18 features ofdevelopment and dysmorphology and in-dependent of the molecular cytogenetic results.Patients already known to the clinical geneticsservice were visited at home or seen at hospitalclinic appointments. For those who were re-

ferred to us by independent paediatricians or

cardiologists, clinical details were obtainedeither directly from the referring clinician or

from the patients' notes.

CYTOGENETIC AND MOLECULAR CYTOGENETIC

STUDIES

In all patients, GTL banded chromosomeswere prepared from peripheral blood after

semisynchronisation with FdU and release with

thymidine." These were then analysed at the

550 band level for structural chromosome ab-

normalities.FISH with the elastin Williams-Beuren syn-

drome chromosome region (WSCR) probe(Oncor®) was essentially by the method re-

commended by the probe supplier. Hy-bridisation sites were detected usingantidigoxigenin rhodamine and the chro-

mosomes were counterstained with DAPI.

Slides were viewed on a Zeiss Axiophot micro-

scope and images captured using a Pho-

tometrics cooled CCD camera and enhanced

using Digital Scientific Smart Capture soft-

ware. A minimum of 10 metaphases were

scored for a deletion of the 7q1 1.23 region in

each case. Only cells with a clear signal from

the control probe D7S427 at 7q36 on both

chromosome 7 homologues and a clear signalat 7ql1.23 on at least one chromosome 7 were

scored.

ResultsA summary of the clinical findings and labor-

atory results is presented in tables 1, 2, and 3

and in fig 2.

Table 1 Classical Williams syndrome category

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23

Developmental delay SD SD SD SD SD SD SD MD SD SD SD SD MD MD SD MD SD SD MD SD SD MD MDSVAS/PPS SP S SP S SP S S S S SP S SP P SP - S S P S -

Hypercalcaemia + - + . . . . . . + + - + + + - + + - - - + -

WS personality + + + + + + + + + + + + + + - + + + + - + + +Hoarse voice - + + + - + + + + - - - + + - + + + - + + +Feeding difficulties + + + + + + + ± + - + + - - + + + +Hyperacusis + + + - + - + + - + + - + - - + + - +Incoordination + + + + + + + + + + + + + + + - + +Joint limitation + + - + - + + +- - - + + - - + -_ _Full cheeks + + + + + + + + + + + + + + + + + + + + + + +Wide mouth + + + + + + + + + + + + + + + + + + + + + + +Broad forehead + + + + + + + + + + + + + + + + + + - + + +Broad nasal tip + + + + + + + + + + + + + + + + + + + + + + -

Prominent ear lobule + + - - + + + + - + + + + + + + - + - + + +Long philtrum + + + + + + + + + + + + + + + + + + + + + + +Bitemporal narrowness + + + + - + + + + + + + - + + + + + + + + + -

Periorbital fullness - + + + + + + + + + + + + + + + + + + + + + +Micrognathia + + - + - - + + + + + + - - + + + - +del(7)(qll.23) + + + + + + + + + + + + + + + + + + + + + + -

Other abnormality + +t

+ feature present.- feature absent.blank, information not available.SD, severe developmental delay.MD, moderate developmental delay.S, SVAS.P, PPS.* 47,XYY.t 46,XY,del(I 1)(q13.5q14.2).

Table 2 Suspected Williams syndrome category

24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45

Developmental delay MD MD MD MD MD MD MD MD MD - SD SD MD MD MDSVAS/PPS S P P - - P - - - - - -Hypercalcaemia - + + - - - + - - +WS personality + + + +Hoarse voice -Feeding difficulties -. . . .+ - + + + + - - - +Hyperacusis -+- - - +Incoordination - - + + + + - - - - _ _ + +Joint limitation --- - - - - +Full cheeks + + + + - - + - - + +Wide mouth + + + +Broad forehead + + + + - + - - - +Broad nasal tip + + + + - - + +Prominent ear lobule + + + - - - - - +Long philtrum + + + - + + -+Bitemporal narrowness + + - + - - - - - +Periorbital fullness + + + - + - - + - - +Micrognathia + + +- - - -del(7)(qll.23) + +Other abnormality +*

* Complex karyotype.

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88oyce, Zorich, Pike, Barber, Dennis

Table 3 SVAS/PPS category

46 47 48 49 50 51 52

Developmental delay - - - - -

SVAS/PPS S S P S S S SHypercalcaemiaWS personality + + -

Hoarse voice + + -

Feeding difficultiesHyperacusis +IncoordinationJoint limitationFull cheeks + +Wide mouthBroad forehead - - - - -Broad nasal tip + + +Prominent ear lobule - - -

Long philtrum - - -

Bitemporal narrowness - - -

Periorbital fullness - + -

Micrognathia - - -

del(7)(qll.23) + -

Other abnormality

CYTOGENETIC ANALYSISIn the classical WBS category 21/23 patientshad an apparently normal karyotype at theresolution available using conventional Gbanded analysis. Of the other two, one (patient13) had an XYY sex chromosome complementin addition to an elastin gene deletion, and theother (patient 23) was found to have a de novointerstitial deletion in the long arm of onechromosome 11 (46,XY,del(11)(q13.5q14.2)de novo) (fig 3A).

In the suspected WBS category 21/22patients had apparently normal karyotypes.The remaining case (patient 27) was shown byconventional and molecular cytogenetic in-vestigations to have a complex karyotype with

a ring chromosome 22 resulting in monosomyfor distal 22q (ql3-÷qter) and a whole armY;21 translocation resulting in monosomyfor the long arm of the Y (45,X,add(21p),r(22)de novo.ish 7ql1.23(WSCR x 2),der(Y;21)(plO;qlO) (wcpY+, SRY+, Y190+, DYZ3±+,D13Z1 +, wcp2l +), r(22)(wcp22 +, cH748 +,pH17-)) (fig 4A).

Finally, in the SVAS/PPS category no chro-mosome abnormalities were detected.

FISH ANALYSIS (FIG 5A, B)A total of 22/23 (96%) classical WBS caseswere shown to be hemizygous for the elastinlocus. The only patient from this category whodid not have a submicroscopic deletion at7q11.23 was patient 23 who had been shownto have the interstitial deletion of llq.Ofthe suspected WBS cases, 2/22 (9%) were

shown to be deleted at the elastin locus and 20did not have a submicroscopic deletion. Oneof these 20 cases (patient 26) was initiallythought to have a deletion at 7q11.23 in 5/30(17%) cells examined from a peripheral bloodsample. However, repeat investigations onblood lymphocytes and skin fibroblasts scoredblind alongside normal control samples didnot confirm the low level mosaicism originallydetected and we therefore interpret the deletedcells as artefacts.Among the patients referred with SVAS/PPS,

one out of seven (14%) also showed hemi-zygosity at the elastin locus and the remainingsix did not.

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1 ) uz k w ,;>s .d .'Y CL_. , q , . _ .r CE

. / - 'd' J. HL __.n r-.=I _o _

Nc-rideletion detected

Delet-I(o)i-n at -.lasti lo).I! hi-t t'

Figure 2 Phenotypic features of Williams syndrome and suspected Williams syndrome patients.

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Williams-Beuren syndrome

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I~~~~Figure 3 (A) GTL banded chromosomes 11 from patient 23 and schematic diagramshowing interstitial deletion of llq on one homologous del(ll) (q13.5q14.2). (B) Patient23 at 2 years 6 months. (C) Patient 23 at 5 years 6 months.

PHENOTYPE:GENOTYPE CORRELATIONSIn order to determine if there is a subset cWBS features which are present at a greatefrequency in those patients where a deletion athe elastin locus has been shown, the phenctypic characteristics of our deleted cases frorall three categories were compared with thosof the non-deleted cases from the classical ansuspected WBS categories (fig 2).Of those patients with a submicroscopic de

letion at 7q1 1.23, full cheeks and a broad nasatip were observed in 100% and several othefeatures were observed in 80% or more c

patients, including developmental delay, SVASPPS, WBS personality, wide mouth, broa(forehead, long philtrum, bitemporal narrowness, and periorbital fullness. In the nondeleted patients none of the listed featureswith the exception of developmental delay, waobserved in more than 50% of patients.Notable exceptions were patients 23, 27, anc

46. Patient 23, a 6 year old boy, had a deletiorof chromosome 11 and no submicroscopic deletion at 7ql 1.23 despite displaying the majority of Williams-Beuren characteristics. Hzhad originally been diagnosed as WBS by Eclinical geneticist at 2 years of age. This diagnosis was fully accepted by the paediatriciarover the next three years, and by the parentEwho met other children with WBS. He istherefore, included in our classical WBS cat-

egory. However, when assessed by a clinicalgeneticist at 5 years ofage, when the cytogeneticand elastin results were known, he was con-sidered to be atypical in some respects. He hasmoderate developmental delay and a gregariouspersonality but does not have disproportionateverbal facility. His facial features include abroad forehead, periorbital fullness, widemouth, full cheeks, prominent ear lobules, anda long philtrum (fig 3B, C).

Patient 27, a 22 month old boy referred tous by his paediatrician as ?Williams-Beurensyndrome, was also found to have no sub-microscopic 7q11.23 deletion but was shownto have a complex karyotype with deletions of22q and Yq. He has moderate developmentaldelay and poor growth. His motor developmentand performance are assessed to be at 15-16months and language skills at 10-12 months.His facial appearance was initially suggestiveofWilliams-Beuren syndrome (fig 4B). He hadperiorbital fullness, light irides, full cheeks,prominent nasal tip, and a long, well definedphiltrum. However, he had a high nasal bridgeand a small mouth, not typical of WBS. Fulldetails of this case will be presented elsewhere(Pike et al, in preparation).

Patient 46, a 6 year old girl, was originallyreferred to us with pulmanary stenosis as "?Turner syndrome, ?Noonan syndrome, ?22qdeletion". She was found to have an apparentlynormal female karyotype in 30 cells when ex-amined using conventional cytogenetics and noevidence of a submicroscopic deletion usingFISH with the H748 cosmid specific for theDiGeorge syndrome critical region in 22ql 1.2.However, a WSCR deletion was found whenher cardiac diagnosis was altered to SVAS. Sheis short, unlike her two sibs in appearance, andhas a gregarious personality, a hoarse voice, and

of hyperacusis. Mild developmental delay was re-:r ported early on but, while her development isat slightly delayed compared with her sibs, her IQ- is within the normal range and she is doing welln in a normal school. Her facial features are limited,e to full cheeks and a broad nasal tip (fig 6).d

Discussionil In our study, 96% of the classical WBS andr 9% of suspected WBS patients were shown to)f have a submicroscopic deletion at 7q1 1.23.W/ These figures are comparable with previousd reports.5-'9^- In this series, only full cheeks and a broadI- nasal tip were observed in all our patients with, elastin gene deletions. However, other featuresS frequently associated with a submicroscopic

deletion included developmental delay (96%),d SVAS/PPS (80%), WBS personality (88%),n wide mouth (96%), broad forehead (92%),- long philtrum (96%), bitemporal narrowness- (88%), and periorbital fullness (92%). Hyper-e calcaemia, often regarded as a good indicatora of WBS during early infancy, was almost as- frequent in the non-deleted as in the deletedi cases. Infantile hypercalcaemia was, therefore,s the poorest indicator of WBS in this study

population, consistent with other recent- reports.' 1619

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i

Figure 4 (A) Partial karyotype from patient 27 showing a ring chromosom6derived Y;21 chromosome from a whole arm translocation. (B) Patient 27 at

The only patient in the classical WBS cat-

egory who did not have a submicroscopic de-letion on chromosome 7 (patient 23) was

shown by routine cytogenetic analysis to have

a de novo interstitial deletion in the long arm

of one chromosome 11 resulting in monosomyfor 11qi4.1. Several chromosome abnormal-

-i-2z ities have previously been reported in isolatedcases of WBS, including a 15p deletion,22a balanced 9;17 translocation,23 a deletion ofthe long arm of chromosome 4,24 and an un-

balanced 13; 18 translocation.25 A furtherpatient with features of WBS was shown byTupler et alP6 in 1992 to have a complex un-

balanced chromosome rearrangement with 10breakpoints and monosomy for the region4q33-8q35.1. Two of the breakpoints were on

1 lq (1 1q13.1 and 1 q23), but neither of thesecorrespond to our patient's breakpoints. Weare unaware of any published cases with a

similar deletion of llq to our patient and,therefore, it is not yet possible to determine ifa deletion of this region consistently results ina phenotype remarkably similar to that ofWBS.Another interesting case in our series (patient27) was found to have a complex rearrangementincluding deletions of22q and Yq in associationwith a WBS-like phenotype. This 22 monthold boy had some ofthe facial features reportedin WBS including full cheeks, prominent nasaltip, and periorbital fullness. Overall, however,his phenotype was not typical of patients withclassical WBS and he was too young to beassessed for the "Williams syndrome per-sonality". Both these cases highlight theimportance of routine cytogenetic analysis inconjunction with FISH investigations.

Proximal 7q deletions detectable by con-

ventional cytogenetics are relatively rare. How-ever, at least 21 cases have been reported todate and the clinical findings associated withthese deletions have been reviewed by Zackow-

22 and a

ski et al27 and Gillar et al. 8 Of these 21 cases,e 2 years. 16 might be expected to include a deletion of

the elastin locus at 7q11.23. While WBS was

not considered as a diagnosis in these 16 cases,

Figure 5 Representative FISH results using the WSCR probe (7q11.23) and D7S427 control probe (7q36). (A)Normal sample showing two normal chromosomes 7, each with a clear signal at 7q11.23 and at 7q36. (B) Deleted

sample showing one normal chromosome 7 and one deleted chromosome 7 (arrowed) with only the control signal at 7q36.

A

B

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991Wlliams-Beuren syndrome

B

WBS clinical manifestations have been re-

ported in many of them, including shortbulbous nose, full cheeks, long philtrum, mi-crognathia, feeding difficulties in infancy, andcardiac defects. Noteable patients with sim-ilarities to WBS include a 14 year old boyreported by Frydman et al,29 a 4 year old girlreported by Klep-de Pater et al0 (case 2), anda 10 year old girl reported by Young et a!l(case 3). It would be of interest to reinvestigatethese patients using FISH in order to determinehow many of these proximal 7q deletions en-

compass the elastin locus and to what extentthe phenotypic outcome is dependent on de-letion of the WBS critical region.Of our seven patients referred with SVAS/

PPS where a diagnosis of WBS was not beingconsidered, one girl (patient 46) was shown tobe hemizygous at the elastin locus. As far as

we are aware, this is the first reported case ofa patient with normal development and an

elastin gene deletion detected by FISH. Inaddition, patient 47, from an autosomal dom-inant SVAS family, did not have a WSCRdeletion yet presented with some of the facialfeatures typical ofWBS, including full cheeks, a

broad nasal tip, and periorbital fullness togetherwith a hoarse voice. Subtle WBS facial featureswere present in her affected daughter. Thisis consistent with previous reports of some

subjects in autosomal dominant SVAS familieswho showed minor features of WBS.3 1332 Thisphenotypic overlap may not be unexpected ifhemizygosity for, or mutations within, the el-astin gene account for connective tissue ab-normalities including SVAS and some of thedysmorphic facial features but not other aspectsofWBS, such as the neurobehavioural features.If WBS is a contiguous gene disorder withdeletion ofgenes other than elastin contributingto mental retardation and the WBS personality,variability in the extent of the deletion couldbe a significant factor in determining the con-siderable phenotypic variability seen in this

syndrome. In our series the extremes wererepresented by patient 46 (fig 6) who had anormal IQ and relatively few WBS features,and patient 1 (fig 1) who had severe mentalretardation, no speech, and classical WBS fea-tures. Cases such as patient 32 and four of thepatients reported by Nickerson et al,'8 whohad many WBS features without SVAS andappeared normal with the WSCR probe, mayturn out to have deletions within the WBScritical region which do not involve the ELNgene.

In conclusion, we have seen a wide range ofphenotypes associated with a deletion at theelastin locus in this series. Since only full cheeksand a broad nasal tip were seen in all our deletedcases, the absence, even ofdevelopmental delayor the loquacious WBS personality, should notexclude a suspected WBS case from in-vestigation with FISH especially if SVAS orPPS is present. Molecular studies to determinethe size of deletions at the elastin locus cor-related to the phenotypic features of patientsshould be the next line of investigation andmay show the cause of the wide spectrum ofseverity observed in Williams-Beuren syn-drome. The occurrence of three different cyto-genetic abnormalities in this series, two ofthemapparently responsible for a WBS-like pheno-type, is a reminder that conventional cyto-genetics should not be omitted frominvestigations of WBS.

We would like to thank John Crolla for his assistance withfluorescent in situ hybridisation and Dr Karen Temple foradditional clinical assessments. We gratefully acknowledge thecooperation of the patients and their parents as well as theWellcome Foundation for supplying the image enhancementequipment used in this project.

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