Med Genet 1994;31:560-564

Syndrome of the month

Beckwith-Wiedemann syndrome

Margaret Elliott, Eamonn R Maher

In 1963 Beckwith' presented the necropsy find-ings of three unrelated children with exompha-los, macroglossia, hyperplasia of the kidneysand pancreas, and adrenal cytomegaly, and sug-

gested that this might represent a new syn-

drome. In 1964 Wiedemann2 published a case

report of three sibs with exomphalos, macrog-

lossia, and overgrowth. Subsequently more

than 300 cases have been reported and theincidence of Beckwith-Wiedemann syndrome(BWS) has been estimated at 007 per 1000births.34

Clinical features and natural historyThe clinical features of BWS are listed in thetable which is derived from the personal experi-ence of one of the authors (ME) of 69 cases inthe UK and 22 cases from the one other largeclinical study published.5 Anterior abdominalwall defects, macroglossia, pre- or postnatalovergrowth, and characteristic facial dysmor-phology occur in most cases (figs 1-3). Othercommon features are neonatal hypoglycaemia,organomegaly, renal anomalies, and hemihy-pertrophy. Neoplasia, developmental delay,and cardiac malformations may cause signific-ant morbidity but are infrequent. The overallmortality rate is about 10% with most deathsoccurring early secondary to congenital malfor-mations or prematurity. Histopathology char-acteristically shows diffuse adrenal cytomegaly,pancreatic P islet cell hyperplasia, and nephrob-lastomatosis.4There are no fixed diagnostic criteria for

BWS and no one feature is obligatory in makingthe diagnosis, but we have found the followingdefinition covers most cases: either (1) threemajor features (anterior abdominal wall defect,macroglossia, pre- or postnatal overgrowth) or

(2) two major features plus three minor features(ear creases or pits, facial naevus flammeus,hypoglycaemia, nephromegaly, hemihypertro-phy). The craniofacial dysmorphological

Department ofClinical Genetics,Addenbrooke'sHospital, Hills Road,Cambridge CB2 2QQ,UKM ElliottE R Maher

Cambridge UniversityDepartment ofPathology, CambridgeCB2 lQP, UKE R Maher

Correspondence toDr Maher.

features are most apparent before the age of 3years, and after the age of 5 years there is oftenonly minor dysmorphism. It is helpful to con-

sider the complications of BWS by the age at

presentation.

PRENATALExomphalos complicates approximately halfthe cases ofBWS and will usually be picked upon prenatal ultrasonography, but BWS is a

rare cause of exomphalos (<3% of all cases).6Prenatal diagnosis of BWS has occasionallybeen reported after ultrasonographic detectionof a combination of abdominal wall defect,polyhydramnios, nephromegaly, and macro-

glossia.7 BWS pregnancies are frequently com-

plicated by premature onset of labour. The riskof prematurity is associated with an increasedincidence of polyhydramnios but not with fetalovergrowth alone. Multiple births are more

common in BWS, with an excess of both mono-zygotic and dizygotic twins. Twin pairs are

invariably discordant for BWS, though thesecond twin may occasionally show minorfeatures. There is an excess of female monozy-gotic twins pairs among twin pairs with normalchromosomes (13 female, one male).89

NEONATALMany BWS children will require surgery forexomphalos in the neonatal period and this isgenerally well tolerated. Hypoglycaemia alsooccurs in the majority ofBWS patients, but thisis usually mild and transient. In severe cases

hypoglycaemia may persist for months, andearly detection and treatment of hypoglycaemiais important to prevent neurological damage.Prematurity related pulmonary disease andcongenital heart disease are the leading cause ofearly death in BWS, although congenital car-

diac defects only occur in <10% of BWSpatients.

Clinical features of Beckwith-Wiedemann syndromeComlications Frequency (%)

Macroglossia 99Pre- or postnatal gigantism (growth > 90th centile) 87Abdominal wall defect (exomphalos, umbilical hernia, or diastasis recti) 77Ear creases or posterior helical ear pits 75Renal abnormalities (nephromegaly, multiple calyceal cysts, or

hydropnephrosis) 62Facial naevus flammeus 62Hypoglycaemia 59Hemihypertrophy 23Congenital cardiac malformations 9Neoplasia 4Moderate/severe mental retardation 4Polydactyly 3Cleft palate 3

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Beckwith-Wiedemann syndrome

Figure 1 An 8 month old boy with BWS.Macroglossia, maxillary hypoplasia, and facialhemihypertrophy are present.

x:

Figure 2 A S year old girl with BWS after tongue reduction. Mild prognathism ispresent but dysmorphic features are much less apparent.

Figure 3 Ear lobe creases and ear pits in BWS: posterior helical pits and pits on theposterior aspect of the ear lobe can be seen.

CHILDHOODThe most frequent problems during childhoodare related to macroglossia, overgrowth, hemi-hypertrophy, urological anomalies, and con-cerns about the risks of embryonal tumoursand psychomotor retardation.

Macroglossia is the most frequent manifes-tation of BWS, and may cause feeding diffi-culties, speech delay secondary to articulationproblems, and obstructive apnoea (duringsleep or feeding). Surgical tongue reduction isperformed in up to 50% of cases (usually at 2

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Elliott, Maher

to 3 years of age, but earlier if there are

significant feeding problems or apnoea).Untreated macroglossia that does not regress

spontaneously may lead to prognathism, open

anterior bite, and dental problems.Growth patterns are very variable in BWS.

Often rapid growth occurs in early childhoodand bone age is advanced. Growth rate tendsto slow down during late childhood and al-though detailed information on adult height issparse, most reported cases are 2 to 3 SD abovethe mean.Hemihypertrophy occurs in up to 25% of

cases, is usually evident at birth, and oftenbecomes more marked as the child grows. Mildasymmetry may require physiotherapy andconservative orthopaedic management (forexample, shoe raises). In more severe cases,

surgical intervention (to shorten the hypertro-phied side or lengthen the non-hypertrophiedside) may be performed at puberty.Organomegaly is common with nephrome-

galy in 65%. In up to half of these cases theremay be an associated renal malformation andapproximately 25% of children have recurrenturinary tract infections. Inguinal herniae andundescended testes are common in males.

Neoplasia is generally estimated to occur in7 5% of cases,'0 although this may be an overes-timate. The most common tumour is Wilms'tumour, followed by adrenocortical carcinoma,hepatoblastoma, and neuroblastoma. Screeningfor tumours by three monthly abdominal ultra-sonography is frequently advocated." How-ever, this has not yet been proven to improvethe prognosis. Although the requirement forregular ultrasonography has been questioned, itis generally agreed that weekly abdominal pala-pation by parents can be helpful in detectingWilms' tumours. Tumours rarely develop afterthe age of 10 years, but the risk of neoplasiaappears to be increased in children with hemi-hypertrophy.'0Most children with BWS develop normally,

and the major risk factors for psychomotorretardation are an unbalanced translocation,ineffective treatment of hypoglycaemia, andsevere prematurity related complications.

ADOLESCENCE AND ADULTHOODLess information is available, but it seems thatnew complications are infrequent after child-hood. An increased incidence of infertility hasbeen reported in males with BWS, in some

cases possibly related to cryptorchidism.'2 Per-sonal experience suggests an apparent excess ofendocrinopathies, but further information isrequired.

Differential diagnosisBWS should be distinguished from Simpson-Golabi syndrome (SGS), Perlman syndrome,and overgrowth disorders such as Sotos andWeaver syndromes.'3 The most common mis-diagnosis is with SGS, an X linked recessivecondition characterised by overgrowth, mildmacroglossia, umbilical and inguinal her-niae, cleft palate, cardiac malformations, an

increased risk of neoplasia, and a characteristiccraniofacial dysmorphism."4 15 As the pene-trance of familial BWS is more complete whenthe mother is the transmitting parent,'216 thefamily history in BWS may occasionally re-semble X linked inheritance. Features to con-sider in the differential diagnosis of BWS andSGS include the different facial dysmorphism,relative macrocephaly, and mild macroglossiain SGS, and the infrequency of exomphalos inSGS. Umbilical and inguinal herniae, andnephromegaly and renal malformations arecommon to both. Cardiac malformations, cleftpalate, glandular hypospadias, polydactyly, andaccessory nipples are seen occasionally in BWS,but are much more common in SGS. Perlmansyndrome is a rare autosomal recessive disorderwith a high neonatal mortality, characteristicfacies, a high incidence of renal malformationsand Wilms' tumour, hypoglycaemia, and men-tal retardation.'7 Exomphalos and macroglossiaare not reported, and although there may bemacrosomia at birth, postnatal overgrowth doesnot occur.

GeneticsThe genetics of BWS are complex and are thesubject of much current interest. Imprintedgenes in chromosome llpl5 have been impli-cated in the pathogenesis of familial and spora-dic BWS. A small number of patients (2 to 3%)have cytogenetic abnormalities of chromosomep1pl5. Paternally derived duplications of chro-

mosome 1 1p15 and maternally inherited inver-sions or balanced translocations may be associ-ated with BWS.'o20 Approximately 15% ofBWS patients have a positive family history,and familial BWS is inherited as an autosomaldominant trait with incomplete penetrance.Parent of origin differences in penetrance arewell described, such that penetrance is morecomplete if the mother is the transmitting par-ent.'216 Genetic linkage studies have mappedthe BWS gene to chromosome 1 lp 15.5.21 22 Theparent of origin effects in familial BWS andpatients with chromosome 11 aberrationssuggest that the BWS gene(s) is imprinted.Further evidence for genomic imprinting is theobservation that about 20% of patients withsporadic BWS have unipaternal isodisomy ofchromosome 112324 (unpublished observations).Detailed analysis has shown that (1) uniparentaldisomy in BWS patients arises as a postzygoticmitotic event so that affected persons are mosaicfor normal and disomic cell lineages, and (2) thecritical region of paternal isodisomy includeschromosome 1 lpl5.5. There is a strong associ-ation between uniparental disomy and hemihy-pertrophy (and possibly Wilms' tumour) inBWS, and the hemihypertrophy presumablyreflects the variation in the proportion of dis-omic cells between the two sides of the body.25Although not proven, it is hypothesised thatmonozygotic twins discordant for BWS mayreflect differing degrees of mosaicism for UPD.The excess of female monozygotic twins mightresult from the delayed development of femalecompared to male embryos.

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Beckwith-Wiedemann syndrome

AetiologyCandidate BWS genes from chromosome11p15 should be imprinted. BWS could beexplained by (1) an excess of an imprintedgrowth promoter expressed from the paternalallele, or (2) a deficiency of an imprinted growthsuppressor expressed from the maternal allele.25In BWS patients with duplications of chromo-some 1lpl5 only the former mechanism wouldfit, while either or both mechanisms could beoperative in disomic persons. Maternally inher-ited chromosome 11 inversions and balancedtranslocations would appear to involve a loss offunction mutation in an imprinted growth sup-pressor which is expressed from the maternalallele, but could cause BWS by disruptingnormal imprinting of a growth promoter so thatthere was now activation of the silenced mater-nal allele. Familial BWS could result fromsimilar mechanisms. Comparative studies inman and mice have identified two genes (IGF2and H19) within the target region (distal chro-mosome 7p in the mouse and chromosome1lpl5 in man are homologous) which areimprinted in both species. Insulin-like growthfactor 2 (IGF2) is an imprinted growth pro-moter which is expressed from the paternalallele.'6'8 Mice with inactivating mutations ofthe paternal IGF2 allele are small,29 and chi-meric mouse embryos with paternal disomy ofdistal chromosome 7p are larger than controls.27H19 is widely expressed during embryonal de-velopment, is closely linked to IGF2, but isoppositely imprinted to IGF2 (H19 isexpressed from the maternal allele) in man andmouse. 1'2 Determining the function of H19has been enigmatic and the absence of a con-served open reading frame between mouse andman suggests that H19 may not encode a pro-tein product.3 However, a recent studysuggests that H19 expression can suppressgrowth in an embryonal tumour cell line andsuppress tumour formation in nude mice.34Both IGF2 and H19 have been suggested ascandidate BWS genes. BWS patients withpaternally derived chromosome 11 duplicationsand paternal UPD would be predictedto have increased expression of IGF2 (the mini-mally duplicated/disomic region includesIGF2), and recently Weksberg et al35 havereported four non-disomic BWS patients inwhich there was disruption of maternal repres-sion of IGF2 resulting in biallelic IGF2expression. These findings clearly implicateIGF2 overexpression in the pathogenesis of asubset of patients with BWS, but whether thisresults from mutations in the IGF2 gene or inan imprinting control gene is not known. Relax-ation of IGF2 imprinting has been reported insporadic Wilms tumour,3637 and supports theconcept that IGF2 overexpression wouldpromote cellular growth and predispose totumour development. Familial BWS couldresult from mutations which directly orindirectly disrupt normal imprinting of theIGF2 gene leading to expression of the mater-nal IGF2 allele. Such families would only beexpected to show matemal transmission of thedisease phenotype. An alternative explanationinvokes maternally inherited inactivating muta-

tions of a paternally repressed growth suppres-sor gene such as H19. Molecular mapping ofthe balanced translocation and inversion break-points associated with maternally inheritedBWS have identified two breakpointcluster regions.38 The most telomeric is closeto IGF2 and might disrupt normal IGF2imprinting. The proximal breakpoint cluster (atchromosome 1lpl5.4) might indicate the pres-ence of a second BWS gene.'8 Alternatively, it isconceivable that the translocation would have along range effect on IGF2 imprinting.A variety of genetic mechanisms may pro-

duce BWS. Overexpression of IGF2 appears tobe the primary abnormality in some patientswith BWS. However, the report of a patientwith gigantism, Wilms' tumour, and biallelicexpression of IGF2, but no other evidence ofBWS suggests that other factors may beinvolved.39 Further research should elucidatewhether IGF2 is the cause of BWS in all cases,and whether other genes, such as H19, areinvolved. Furthermore, such studies shouldidentify the molecular mechanisms underlyingthe loss of repression of the maternal allele ofIGF2 in BWS.

We thank Dr Anne Ferguson-Smith for helpful advice, and themany families and their doctors who have helped with ourresearch.

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