Beckwith-Wiedemann Syndrome

Beckwith-Wiedemann syndrome is an overgrowth disorder caused by abnormalities of imprinted genes at chromosome 11p15. It is characterised by macroglossia, abdominal wall defects, neonatal hypoglycaemia, lateralised overgrowth and an increased risk of embryonal tumours.

Its incidence is about 1 in 10 000 to 13 000 live births. Most cases are sporadic. About 50% have loss of methylation at imprinting centre 2 (KCNQ1OT1), about 20% have paternal uniparental disomy of 11p15, about 5% have gain of methylation at imprinting centre 1 (H19/IGF2), and 5 to 10% have CDKN1C variants (which are often inherited).

The risk of embryonal tumours (Wilms tumour, hepatoblastoma, neuroblastoma, adrenocortical tumour) is about 7 to 10% overall, highest with imprinting centre 1 gain of methylation and uniparental disomy, and lowest with loss of methylation at imprinting centre 2 and CDKN1C variants.

Pathophysiology.

Imprinting centres 1 and 2 control expression of growth promoting (IGF2) and growth suppressing (CDKN1C, H19) genes. Loss of normal imprinting increases IGF2 activity or reduces CDKN1C activity, which causes overgrowth and tumour predisposition.

Mosaicism explains lateralised overgrowth and variable features. Hyperinsulinism causes hypoglycaemia.

• Macrosomia, macroglossia, exomphalos (omphalocele), umbilical hernia or diastasis recti, and visceromegaly.
• Neonatal hypoglycaemia (in about 30 to 50%), which is often transient but may be prolonged.
• Lateralised overgrowth (hemihyperplasia), ear creases and pits, and naevus flammeus on the glabella or nape.
• Other: nephromegaly, renal anomalies, cardiomyopathy, embryonal tumours, and cleft palate in a few.

Red flags.

• Persistent hypoglycaemia or hyperinsulinism.
• Airway obstruction or feeding problems from macroglossia.
• New abdominal mass, haematuria, hypertension, abdominal distension, or precocious puberty.

• Diagnosis is clinical (macroglossia, abdominal wall defect, lateralised overgrowth, ear creases and pits, hypoglycaemia, nephromegaly, family history) and confirmed by molecular testing of 11p15 (methylation analysis, copy number analysis, uniparental disomy analysis) in blood, with testing of other tissue if mosaic. CDKN1C sequencing if familial.
• Glucose monitoring from birth, and for persistent hypoglycaemia, insulin, ketones and fatty acids.
• Abdominal and renal ultrasound, echocardiography, and alpha fetoprotein.

Differential diagnosis. Simpson-Golabi-Behmel syndrome, Sotos syndrome, Weaver syndrome, Perlman syndrome, infant of a diabetic mother, congenital hyperinsulinism and isolated hemihypertrophy.

• Hypoglycaemia: check glucose before feeds and treat with IV 10% glucose 2 mL/kg then 8 to 10 mg/kg/min, feeds, and if hyperinsulinism persists, diazoxide 5 to 15 mg/kg/day in 3 divided doses, with a thiazide diuretic. Maintain glucose over 2.6 mmol/L.
• Macroglossia: feeding support, speech therapy, airway assessment (sleep studies), and tongue reduction surgery for airway, feeding or dental problems.
• Abdominal wall defects: surgical repair. Treat hemihyperplasia by monitoring leg length and orthopaedic review. Check for scoliosis.
• Tumour surveillance: abdominal ultrasound every 3 months from diagnosis until 8 years of age, and alpha fetoprotein every 3 months until 4 years of age (for hepatoblastoma). Surveillance may be adjusted by molecular subtype. Parents should know to report an abdominal mass.
• Echocardiography and ECG at diagnosis, and renal follow up for nephrocalcinosis and anomalies.

Monitoring. Growth, glucose, ultrasound surveillance, blood pressure and development. Growth velocity normalises after the age of 7 or 8 years.

Referral and escalation. Refer to clinical genetics, endocrinology, a surgical team and, if a tumour is found, a paediatric oncology unit.