Beckwith-Wiedemann and Russell-Silver Syndromes

Confirm diagnosis of BWS or RSS in individuals with a suspected clinical diagnosis

Beckwith-Weidemann syndrome (BWS) is a congenital overgrowth condition associated with neonatal hypoglycemia, macroglossia, macrosomia, hemihypertrophy and increased risk for embryonal tumors. Russell-Silver syndrome (RSS) is a congenital condition characterized by stunted grow, limb length asymmetry, and developmental delay. Testing can confirm a suspected clinical diagnosis of BWS or RSS.

Disease Overview

Incidence

BWS: ~1/10,000-13,700 newborns

RSS: ~1/100,000 newborns

Symptoms

BWS (Major Findings) RSS

Macrosomia

Visceromegaly

Hemihyperplasia

Embryonal tumors in childhood (eg, Wilms tumor, hepatoblastoma, neuroblastoma, rhabdomyosarcoma)

Macroglossia

Omphalocele

Renal abnormalities

Ear creases or pits

Pre- and postnatal growth deficiency

Proportionate short stature

Limb length asymmetry

Developmental delay and/or learning disabilities

Triangular facies, broad forehead, narrow chin

Genetics

Etiology

Causes of BWS

  • 50% have loss of maternal methylation on chromosome 15q11 imprinting center (IC)2
  • 20% have paternal uniparental disomy (UPD) for chromosome 11p15
  • 5% have gain of methylation in maternal IC1
  • Pathogenic sequence variants in CDKN1C 
    • 5-10% of nonfamilial cases
    • ~40% of familial cases
    • <1% cytogenetic abnormalities involving 11p15

Causes of RSS

  • 35-50% have hypomethylation of paternal IC1
  • 10% have maternal UPD of chromosome 7
  • ~40% have an unknown genetic mechanism

Inheritance

  • Sporadic in 85% of BWS cases and 60% of RSS cases
  • Autosomal dominant in 15% of BWS cases due to parent-of-origin transmission

Penetrance

  • Complete for RSS
  • Incomplete for BWS due to methylation (eg, individuals with a paternally inherited CDKN1C pathogenic variant will not show features of BWS)

Test Interpretation

Clinical sensitivity/specificity: 75% for BWS; 35-50% for RSS

Analytical sensitivity/specificity: 99%

Results

Result BWS RSS

Positive

IC2 hypomethylation AND normal IC1 methylation

IC1 hypomethylation

IC1 hypermethylation AND hypomethylation of ​IC2

IC1 hypermethylation AND normal methylation of IC2

Negative

Normal methylation patterns:

  • Risk reduced but not excluded
  • Consider CDKN1C gene sequencing and deletion/duplication
  • Consider chromosome analysis

Normal methylation patterns:

  • Risk reduced but not excluded
  • Consider UPD analysis of chromosome 7

Limitations

Molecular mechanisms causing BWS or RSS that do not affecting methylation patterns are not assessed, including:

  • Maternal UPD of chromosome 7
  • Chromosomal translocations, inversions, deletions, or duplications
  • Pathogenic CDKN1C sequence variants, deletions/duplications

Diagnostic errors can occur due to rare sequence variations.

Last Update: May 2019