560 Med Genet 1994;31:560-564 Syndrome of the month J Med Genet: first published as 10.1136/jmg.31.7.560 on 1 July 1994. Downloaded from Beckwith-Wiedemann syndrome Margaret Elliott, Eamonn R Maher In 1963 Beckwith' presented the necropsy find- features are most apparent before the age of 3 ings of three unrelated children with exompha- years, and after the age of 5 years there is often los, macroglossia, hyperplasia of the kidneys only minor dysmorphism. It is helpful to con- and pancreas, and adrenal cytomegaly, and sug- sider the complications of BWS by the age at gested that this might represent a new syn- presentation. drome. In 1964 Wiedemann2 published a case report of three sibs with exomphalos, macrog- lossia, and overgrowth. Subsequently more PRENATAL than 300 cases have been reported and the Exomphalos complicates approximately half incidence of Beckwith-Wiedemann syndrome the cases of BWS and will usually be picked up (BWS) has been estimated at 007 per 1000 on prenatal ultrasonography, but BWS is a births.34 rare cause of exomphalos (< 3% of all cases).6 Prenatal diagnosis of BWS has occasionally been reported after ultrasonographic detection Clinical features and natural history of a combination of abdominal wall defect, The clinical features of BWS are listed in the polyhydramnios, nephromegaly, and macro- table which is derived from the personal experi- glossia.7 BWS pregnancies are frequently com- ence of one of the authors (ME) of 69 cases in plicated by premature onset of labour. The risk the UK and 22 cases from the one other large of prematurity is associated with an increased clinical study published.5 Anterior abdominal incidence of polyhydramnios but not with fetal wall defects, macroglossia, pre- or postnatal overgrowth alone. Multiple births are more overgrowth, and characteristic facial dysmor- common in BWS, with an excess ofboth mono- phology occur in most cases (figs 1-3). Other zygotic and dizygotic twins. Twin pairs are common features are neonatal hypoglycaemia, invariably discordant for BWS, though the organomegaly, renal anomalies, and hemihy- second twin may occasionally show minor pertrophy. Neoplasia, developmental delay, features. There is an excess of female monozy- http://jmg.bmj.com/ and cardiac malformations may cause signific- gotic twins pairs among twin pairs with normal ant morbidity but are infrequent. The overall chromosomes (13 female, one male).89 mortality rate is about 10% with most deaths occurring early secondary to congenital malfor- mations or prematurity. Histopathology char- NEONATAL acteristically shows diffuse adrenal cytomegaly, Many BWS children will require surgery for islet cell hyperplasia, and nephrob- exomphalos in the neonatal period and this is pancreatic P on September 25, 2021 by guest. Protected copyright. lastomatosis.4 generally well tolerated. Hypoglycaemia also There are no fixed diagnostic criteria for occurs in the majority of BWS patients, but this BWS and no one feature is obligatory in making is usually mild and transient. In severe cases the diagnosis, but we have found the following hypoglycaemia may persist for months, and definition covers most cases: either (1) three early detection and treatment of hypoglycaemia major features (anterior abdominal wall defect, is important to prevent neurological damage. macroglossia, pre- or postnatal overgrowth) or Prematurity related pulmonary disease and (2) two major features plus three minor features congenital heart disease are the leading cause of (ear creases or pits, facial naevus flammeus, early death in BWS, although congenital car- hypoglycaemia, nephromegaly, hemihypertro- diac defects only occur in <10% of BWS phy). The craniofacial dysmorphological patients. Department of Clinicalfeatures of Beckwith-Wiedemann syndrome Clinical Genetics, Addenbrooke's Comlications Frequency (%) Hospital, Hills Road, Macroglossia 99 Cambridge CB2 2QQ, Pre- or postnatal gigantism (growth > 90th centile) 87 UK Abdominal wall defect (exomphalos, umbilical hernia, or diastasis recti) 77 M Elliott Ear creases or posterior helical ear pits 75 E R Maher Renal abnormalities (nephromegaly, multiple calyceal cysts, or hydropnephrosis) 62 Facial naevus flammeus 62 Cambridge University Hypoglycaemia 59 Department of Hemihypertrophy 23 Pathology, Cambridge Congenital cardiac malformations 9 CB2 lQP, UK Neoplasia 4 E R Maher Moderate/severe mental retardation 4 Polydactyly 3 Correspondence to Cleft palate 3 Dr Maher. Beckwith-Wiedemann syndrome 561 J Med Genet: first published as 10.1136/jmg.31.7.560 on 1 July 1994. Downloaded from Figure 1 An 8 month old boy with BWS. Macroglossia, maxillary hypoplasia, andfacial hemihypertrophy are present. x: t - \1t 't http://jmg.bmj.com/ Figure 2 A S year old girl with BWS after tongue reduction. Mild prognathism is present but dysmorphic features are much less apparent. on September 25, 2021 by guest. Protected copyright. Figure 3 Ear lobe creases and ear pits in BWS: posterior helical pits and pits on the posterior aspect of the ear lobe can be seen. CHILDHOOD Macroglossia is the most frequent manifes- The most frequent problems during childhood tation of BWS, and may cause feeding diffi- are related to macroglossia, overgrowth, hemi- culties, speech delay secondary to articulation hypertrophy, urological anomalies, and con- problems, and obstructive apnoea (during cerns about the risks of embryonal tumours sleep or feeding). Surgical tongue reduction is and psychomotor retardation. performed in up to 50% of cases (usually at 2 562 Elliott, Maher to 3 years of age, but earlier if there are increased risk of neoplasia, and a characteristic significant feeding problems or apnoea). craniofacial dysmorphism."4 15 As the pene- Untreated macroglossia that does not regress trance of familial BWS is more complete when spontaneously may lead to prognathism, open the mother is the transmitting parent,'216 the anterior bite, and dental problems. family history in BWS may occasionally re- J Med Genet: first published as 10.1136/jmg.31.7.560 on 1 July 1994. Downloaded from Growth patterns are very variable in BWS. semble X linked inheritance. Features to con- Often rapid growth occurs in early childhood sider in the differential diagnosis of BWS and and bone age is advanced. Growth rate tends SGS include the different facial dysmorphism, to slow down during late childhood and al- relative macrocephaly, and mild macroglossia though detailed information on adult height is in SGS, and the infrequency of exomphalos in sparse, most reported cases are 2 to 3 SD above SGS. Umbilical and inguinal herniae, and the mean. nephromegaly and renal malformations are Hemihypertrophy occurs in up to 25% of common to both. Cardiac malformations, cleft cases, is usually evident at birth, and often palate, glandular hypospadias, polydactyly, and becomes more marked as the child grows. Mild accessory nipples are seen occasionally in BWS, asymmetry may require physiotherapy and but are much more common in SGS. Perlman conservative orthopaedic management (for syndrome is a rare autosomal recessive disorder example, shoe raises). In more severe cases, with a high neonatal mortality, characteristic surgical intervention (to shorten the hypertro- facies, a high incidence of renal malformations phied side or lengthen the non-hypertrophied and Wilms' tumour, hypoglycaemia, and men- side) may be performed at puberty. tal retardation.'7 Exomphalos and macroglossia Organomegaly is common with nephrome- are not reported, and although there may be galy in 65%. In up to half of these cases there macrosomia at birth, postnatal overgrowth does may be an associated renal malformation and not occur. approximately 25% of children have recurrent urinary tract infections. Inguinal herniae and undescended testes are common in males. Neoplasia is generally estimated to occur in Genetics 7 5% of cases,'0 although this may be an overes- The genetics of BWS are complex and are the timate. The most common tumour is Wilms' subject of much current interest. Imprinted tumour, followed by adrenocortical carcinoma, genes in chromosome llpl5 have been impli- hepatoblastoma, and neuroblastoma. Screening cated in the pathogenesis of familial and spora- for tumours by three monthly abdominal ultra- dic BWS. A small number of patients (2 to 3%) sonography is frequently advocated." How- have cytogenetic abnormalities of chromosome ever, this has not yet been proven to improve 1pl5.p Paternally derived duplications of chro- the prognosis. Although the requirement for mosome 1 1p15 and maternally inherited inver- regular ultrasonography has been questioned, it sions or balanced translocations may be associ- is generally agreed that weekly abdominal pala- ated with BWS.'o20 Approximately 15% of http://jmg.bmj.com/ pation by parents can be helpful in detecting BWS patients have a positive family history, Wilms' tumours. Tumours rarely develop after and familial BWS is inherited as an autosomal the age of 10 years, but the risk of neoplasia dominant trait with incomplete penetrance. appears to be increased in children with hemi- Parent of origin differences in penetrance are hypertrophy.'0 well described, such that penetrance is more Most children with BWS develop normally, complete if the mother is the transmitting par- and the major risk factors for psychomotor Genetic linkage studies have mapped ent.'216 on September 25, 2021 by guest. Protected copyright. retardation are an unbalanced translocation, the BWS gene to chromosome 1 lp15.5.21 22 The