Beckwith-Wiedemann Syndrome

Background

Disorder characterized by overgrowth
Presents with variable severity
Caused by a wide range of genetic defects
- Greater than 85% of cases are sporadic
- Testing often does not reveal the specific defect, and genetic or epigenetic changes remain unknown in 1/5 or 1/3 of affected individuals
- Most patients have disruptions, rearrangements, mutations, paternal uniparental disomy, or methylation abnormalities involving chromosome 11p15
- Critical genes in the 11p15 region include insulin like growth factor (IGF2), cyclin-dependent kinase inhibitor 1C (CDKN1C), and imprinting centers 1 and 2 (IC1 and IC2)
  - IC1 and IC2 regulate expression of IGF2 and other pro-proliferation genes

Epidemiology

Prevalence of 1:13700 (may be an underestimation due to children with mild phenotypes who may go undiagnosed)

Clinical Features

Macrosomia (birth weights >90th percentile)
Macroglossia (present in 90% of children)
Red birthmark on forehead or eyes (Nevus flammeus)
Midline abdominal defects (most commonly omphalocele or umbilical heria)

Neonatal hypoglycemia (occurs in 1/2 of infants)
- Almost always asymptomatic, normalize within the first three days of life
Hemihypertrophy/hemihyperplaisa (can be isolated to one limb or body part, associated with an increased risk of cancer)
Organomegaly
Ear abnormalities (creases or pits in the ear)
Increased neoplasm risk (~600 times more):
- Wilms tumors or hepatoblastoma
- Greater than 80% of children do not develop cancer
- Risk is most elevated in childhood prior to age 10

Diagnosis

BWS is often suspected due to the presence of clinical features with or without hypoglycemia. Diagnosis is then confirmed with chromosomal studies for abnormalities in chromosome 11.

Pertinent tests include:

Blood glucose testing
Genetic testing
Abdominal MRI or CT followd by abdominal ultrasounds to screen for tumors every three months until age eight
Alpha-fetoprotein (AFP) to screen for tumors every six weeks until age four

Treatment:

Nonsurgical

Infants with BWS must have their blood glucose monitored at birth, and persistent hypoglycemia can be corrected with increased feedings or IV fluids.
- Children with persistent hypoglycemia after the neonatal (<5%) require more intensive treatment regimens
Increased cancer screenings

Surgical

Correction of abdominal defect
Reduction of macroglossia if indicated by feeding difficulties or airway obstruction
Children with BWS typically live normal lives and have not been shown to have significant cognitive delays compared to siblings