Beckwith-Wiedemann Syndrome

The underlying cause is unclear. 80% of cases have genotypic abnormalities on the distal portion of chromosome 11p. The reported pattern of inheritance is autosomal dominance with variable expression. There is contiguous gene duplication at band 11p.15.5.³ This is always derived from the patients father, whereas translocation and inversion is invariably derived from the mother. There appears to be aberrant genomic imprinting resulting from a defective or absent copy of the maternally derived gene - uniparental disomy.

Most sporadic cases lack apparent cytogenetic abnormalities. Only 2% carry inversions, translocations or deletions. 20% of sporadic cases have uniparental disomy.⁴ 50% have loss of methylation.
Most patients with BWS show biallellic expression of IGF2 (insulin-like growth factor 2) in various tissues - see below.

Incidence

Clusters in families in 15% of cases. Most are sporadic.
1 in 15,000 in USA.⁵
Approx. 1 in 13,700 for rest of Western world. There is no predilection for race or gender.

Recent work has suggested an association between genetic imprinting disorders (such as BWS and Angelman syndrome) and children conceived with assisted reproduction techniques (ART) such as IVF and ICSI.^6,7 1-3% of births result from these techniques, and the figure is rising. Studies from Britain, France and the USA showed unexpectedly high numbers of BWS cases in children conceived this way.^8,9

Increasingly commonly diagnosed at prenatal ultrasound.¹⁰ Suspicious features include:

• Increased abdominal circumference
• Large kidneys
• Large placenta, raised amniotic fluid volume
• Protruding tongue
• Large for gestational age fetus
• Raised alpha-fetoprotein with omphalocoele

Symptoms

• Hypoglycaemia
• Poor feeding
• Lethargy
• Problems with breathing, eating and speech, relating to the severity of macroglossia

Signs

• Growth
  • Large for gestational age; the overgrowth in BWS is often the result of increased IGF 2 action in the tissues. Birth weight and length are increased. Hemihypertrophy can be seen, where one part of the body, or usually all or part of one side of the body is enlarged. This often becomes apparent in later childhood.
  • Accelerated growth (on 90th centile or above)
• Abdominal wall defects
  • Omphalocoele¹¹ and umbilical hernia
  • Diastasis recti causing a 'pot-belly' appearance
• Visceromegaly
  • Enlarged liver, kidneys, pancreas and spleen are found
• Facial abnormalities
  • Large, prominent eyes
  • Creases in ear lobes and pit behind the upper ear
  • Pinna abnormalities, low set ears
  • Raised fontanelle, prominent occiput
  • Metopic ridge, prominent on forehead due to early closure of fontanelle
• Others
  • Seizures
  • Cryptorchidism
  • Early bone maturation
  • Naevus flammeus - stork bite mark over eyelids and forehead
  • Renal structural anomalies, nephrocalcinosis

• Fetal overgrowth syndromes e.g. Simpson-Golabi-Behmel syndrome, Perlman syndrome, Costello syndrome
• Glycogen storage disorders; type 0 or 1
• Hyperinsulinaemia
• Hyperpituitarism
• Hypoglycaemia
• Nesidioblastosis
• Obesity

• X-ray long bones
• Blood sugar
• X-ray, Ultrasound, CT /MRI of abdomen
• Chromosome analysis

There is an increased risk of tumour development in children with BWS. The incidence of malignant tumours in reported cases is 5-10%. The commonest of these is Wilms nephroblastoma. This occurs in 5-7%. The risk of cancer is age-dependent with most occurring by age 4 years. 95% have occurred by the age of 8 years.¹² Others are hepatoblastoma and adrenal tumours. Neuroblastomas are less common. Asymmetrical overgrowth is associated with increased risk of tumour development.

Non-Drug

Screening for tumours.^8,13 The child should have alpha-fetoprotein levels (marker for hepatoblastoma) measured every 6 weeks until 3 years old.¹⁴ Also abdominal ultrasound scan every 3 months until 8 years old.^15,16

Drugs

Hypoglycaemia should be rigorously avoided and treated, when necessary.
Diazoxide, to inhibit insulin secretion. Paediatric dose of 5-15mg/kg per day, divided 8-12 hourly.

Surgical

If the tongue protrudes and interferes with speech and dental development, the child should be considered for reduction surgery before 4 years old. Abdominal wall defects will need early neonatal repair. Testes may need bringing down within the scrotum.

Most, already mentioned, can be anticipated and managed:

• Premature delivery
• Monozygotic twinning (usually female and discordant)
• Neonatal hypoglycaemia; uncontrolled hypoglycaemia in infancy is thought to be the major aetiological factor in the reported low IQ in BWS, rather than congenital malformation.

Children who survive infancy do well. There is a 20% infant mortality rate⁹ from complications of prematurity, hypoglycaemia and more rarely cardiomyopathy. The older the child becomes, the more normal they appear. Most children have very subtle problems, which do not affect their quality of life.