Beckwith-Wiedemann and Russell-Silver Syndromes

Last Literature Review: June 2026 Last Update:

Beckwith-Weidemann syndrome (BWS) is a congenital overgrowth condition associated with neonatal hypoglycemia, macroglossia, macrosomia, hemihypertrophy, and an increased risk for embryonal tumors.  Russell-Silver syndrome (RSS) is a congenital condition characterized by pre- and postnatal growth deficiency, limb length asymmetry, relative macrocephaly at birth, feeding difficulties, and developmental delay.  Laboratory testing can confirm a suspected clinical diagnosis of BWS or RSS.

Disease Overview

Incidence

BWS: ~1/10,000-13,700 newborns 

RSS: ~1/30,000-100,000 newborns 

Symptoms

BWS (Major Findings)RSS

Macrosomia

Visceromegaly

Hemihyperplasia

Embryonal tumors in childhood (e.g., Wilms tumor, hepatoblastoma, neuroblastoma, rhabdomyosarcoma)

Macroglossia

Omphalocele

Renal abnormalities (cytomegaly of the adrenal cortex is considered pathognomonic)

Ear creases or pits

Pre- and postnatal growth deficiency

Proportionate short stature

Limb length asymmetry

Relative macrocephaly at birth

Feeding difficulties

Developmental delay and/or learning disabilities

Triangular facies, broad forehead, narrow chin

Sources: Shuman, 2023 ; Saal, 2025 

Genetics

Etiology

Causes of BWS

  • 50% have loss of maternal methylation on chromosome 11p15 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% of nonfamilial cases 
    • Approximately 40% of familial cases 
  • <1% cytogenetic abnormalities involving 11p15 

Causes of RSS

  • 35-67% have hypomethylation of paternal IC1 
  • 7-10% have maternal UPD of chromosome 7 
  • Approximately 40% have an unknown genetic mechanism 

Inheritance

  • 85% of BWS cases are sporadic. 
  • 15% of BWS cases are inherited.
  • Most cases of molecularly confirmed RSS are sporadic. 

Penetrance

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

Test Interpretation

Clinical sensitivity/specificity: 75% for BWS; 35-67% for RSS

Analytic sensitivity/specificity: 99%

Results

ResultBWSRSS
Positive

IC2 hypomethylation AND normal IC1 methylation

IC1 hypermethylation AND hypomethylation of ​IC2

IC1 hypermethylation AND normal methylation of IC2

IC1 hypomethylation
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, and low-level mosaicism may not be identified.

References