Beckwith-Wiedemann Syndrome

Question 1

What is the mode of inheritance for BWS?

Answer 1

15% Familial autosomal dominant

Sporadic mostly

Question 2

What is the genetic defect for BWS?

Answer 2

Dysregulation of imprinted genes at chromosome 11p15.5
50% sporadic loss of methylation on maternal chromosome 11p15.5 at imprinting centre 2
20% sporadic parental uniparental disomy involving chromosome 11p15.5

Question 3

What are the associated medical findings with BWS?

Answer 3

1. Birth:
   a) LGA
   b) omphalocele or umbilical hernia
   c) macroglossia
   d) facial nevus flammeus
   e) posterior helical pits
   f) prominent eyes
   g) anterior ear lobe creases
2. Prenatal morbidity:
   a) preterm birth
   b) polyhdramnios
   c) large placenta and long umbilical cord
3. Perinatal mortality ~20%
4. Hypoglycemia ~30-50%
   - hyperinsulinemia with islet cell hyperplasia
5. Neonatal polycythemia, hypocalcemia, hypercholesterolemia, hypothyroidism
6. Cardiomegaly (common):
   a) HLH (rare)
   b) mild pulm stenosis
   c) PFO
7. Viscromegaly (liver, kidney, spleen)
   - nephromegaly and a wide range of other anomalies common
8. Increased risk for cancer, esp. <8yo (embryonal tumors)
   - 7.5 % risk for solid tumor
   - 5.9% risk of isolated hemihyperplasia
   a) Wilms
   b) hepatoblastoma
   c) rhabdomyosarcoma
   d) adrenocortical carcinoma
   e) neuroblastoma
9. Children with milder phenotype (i.e. macroglossia and umbilical hernia) may develop tumors
   a) Renal manifestations: HTN, nephrocalcinosis, medullary sponge kidney, medullary dysplasia, cystic changes
   b) cardiomyopathy (rare)
10. Dental malocclusion with tendency toward maxillary underdevelopment and mandibular prognathism

Question 4

What is idiopathic hemihyperplasia?

Answer 4

1. Asymmetric overgrowth of one-half of the body:
   a) single limb
   b) side of face incld. tongue asymmetry
   c) visceromegaly
2. Increased intra-abdominal tumors (kidney, liver, adrenal)

Question 5

What are the developmental outcomes in BWS?

Answer 5

1. Usually normal
2. Abnormal secondary to prolonged hypoglycemia (smaller OFC, lower IQ, poor neurodevelopmental prognosis if hypoglycemic seizures)
3. Abnormal if duplication of 11p15
4. Articulation maybe poor due to macroglossia and/or asymmetric facial muscles
5. Increased incidence of developmental delay (15-20%) in isolated hemihyperplasia (motor problems maybe seen if large discrepancy in extremities)

Question 6

What is the DDx of BWS?

Answer 6

1. Isolated hemihyperplasia (hemihypertryophy) for which abdominal embryonal
   tumor surveillance is also indicated.
2. Other overgrowth syndromes, especially:
   a) Perlman Syndrome (AR) – macrosomia and high risk of Wilms’ tumor.
   b) Simpson-Golabi-Behmel Syndrome (X-linked Recessive) – macrosomia
   +/- macrocephaly, visceromegaly, renal cystic dysplasia, and increased
   risk for Wilms’ tumor. Distinguished by different facial appearance,
   frequent polydactyly, cleft lip or cleft palate, cardiac conduction
   abnormalities, and developmental disabilities.

Question 7

What are the recommendations for BWS?

Answer 7

1. TREAT HYPOGLYCEMIA
2. Cardiac evaluation
3. Cancer screening
   a) Serum alphafetoprotein every 6 weeks until age 4
   b) Abdominal Ultrasounds every 3 months until age 8
4. Sleep Study, ENT consult
   a) Partial tongue resection (reduction glossoplasty) sometimes indicated for
   obstructive sleep apnea and severe articulation dysfunction associated with
   macroglossia
5. Orthodontics
6. Early Intervention for speech delay
7. Craniofacial and/or Orthopedic involvement
8. Consider need for adaptive equipment, shoe lift, Physical Therapy

Question 8

What are the major clinical manifestations for Beckwith-Wiedemann syndrome?

Answer 8

1. Macrosomia
2. Hemihyperplasia
3. Macroglossia
4. Organomegaly incld. omphalocele
5. Ear lobe pits
6. Predisposition to develop embryonal tumor (i.e. Wilms, hepatoblastoma)