What is the management and treatment of Beckwith-Wiedemann syndrome?

Management and Treatment of Beckwith-Wiedemann Syndrome

Patients with Beckwith-Wiedemann Syndrome (BWS) require standardized tumor surveillance with renal ultrasounds every 3 months from birth through age 7 for Wilms tumor detection and abdominal ultrasound with alpha-fetoprotein measurements every 3 months through age 4 for hepatoblastoma screening, regardless of molecular subtype. 1

Overview of BWS

Beckwith-Wiedemann Syndrome is a rare overgrowth syndrome characterized by:

• Pre- and postnatal constitutional and organ overgrowth 1
• Macroglossia (enlarged tongue) 1
• Omphalocele or umbilical hernia 1
• Facial nevus flammeus (port-wine stain) 1
• Hemihyperplasia (asymmetric growth) 1
• Predisposition to embryonal tumors 1

The incidence is approximately 1 in 10,500 births, though likely higher when including subtle cases with isolated hemihyperplasia 1.

Molecular Basis and Diagnosis

BWS is caused by dysregulation of imprinted growth genes on chromosome 11p15, with several molecular subtypes:

• Gain of methylation at imprinting control region 1 (IC1/H19/IGF2:IG-DMR) 1
• Loss of methylation at imprinting control region 2 (IC2/KCNQ1OT1:TSS-DMR) 1
• Paternal uniparental isodisomy (pUPD11) 1
• Maternal CDKN1C mutations 1
• Paternally inherited duplications of 11p15 region 1

Diagnostic approach:

• First-line testing should assess DNA methylation and copy number variation of the BWS region 2
• Tissue mosaicism can occur, requiring additional tissue samples if initial testing is negative 2
• Genetic counseling is recommended due to the complexity of inheritance patterns 1

Tumor Risk and Surveillance

Overall tumor risk is 5-10%, but varies significantly by molecular subtype:

• IC1 gain of methylation: 28% risk (primarily Wilms tumor) 1, 3
• IC2 loss of methylation: 2.6% risk 1
• Paternal UPD: 16% risk 1
• CDKN1C mutations: 6.7% risk 1

Standardized tumor surveillance recommendations:

• Wilms tumor screening: Renal ultrasounds every 3 months from birth (or time of diagnosis) through the 7th birthday 1
• Hepatoblastoma screening: Full abdominal ultrasound and alpha-fetoprotein (AFP) measurements every 3 months from birth through the 4th birthday 1
• Neuroblastoma screening: For patients with CDKN1C mutations, urine catecholamines and chest radiographs are recommended 1

These recommendations apply regardless of molecular subtype in the United States, though European centers may implement differential screening based on genetic/epigenetic causes 1.

Management of Clinical Features

• Macroglossia: May require surgical reduction if causing feeding difficulties, speech problems, or airway obstruction 2
• Abdominal wall defects: Surgical repair of omphalocele or umbilical hernia 1
• Neonatal hypoglycemia: Monitoring and management of hyperinsulinism 2, 4
• Hemihyperplasia: Regular monitoring for leg length discrepancies and orthopedic intervention if needed 4

Long-term Follow-up

• Children with BWS and Wilms tumor have excellent prognosis with modern treatment regimens (89% overall survival at 4 years) 5
• Adult height is often increased (mean 1.8 ± 1.2 SDS), with many patients having final height above +2 SDS 3
• Ongoing monitoring for psychosocial implications and adult health issues is recommended 4

Important Considerations and Pitfalls

• Bilateral Wilms tumor occurs in approximately 21% of BWS patients, either at diagnosis or as metachronous contralateral recurrence 5
• Tumor screening should be performed by specialists familiar with cancer predisposition syndromes 1
• Increasingly smaller tumors are being detected with modern imaging, suggesting benefit of early screening 5
• The molecular subtype not only influences overall tumor risk but also the likelihood of specific embryonal tumors 6
• Patients with BWS should be evaluated by a multidisciplinary team including geneticists, oncologists, and other specialists as needed 1