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Beckwith-Wiedemann syndrome


Wednesday 17 September 2003

Definition: Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome characterized by macrosomia, macroglossia, omphalocele, hemihyperplasia, and increased tumor risk.

BWS can be associated with genetic and/or epigenetic alterations that modify imprinted gene expression on chromosome 11p15.5.

Somatic mosaicism for paternal uniparental disomy (UPD) of chromosome 11p15, found in 20% of BWS patients, is associated with specific features of BWS including hemihyperplasia, Wilms tumor, and hepatoblastoma.

The highly variable phenotypic spectrum of BWS associated with UPD may well reflect the level of UPD 11 cells in specific organs and tissues such that very high levels of UPD might produce a more severe phenotypic expression of BWS.

Beckwith Wiedemann syndrome (BWS) involves the deregulation of a number of genes, including IGF2 and CDKN1C, in the imprinted gene cluster on chromosome 11p15.5.

In sporadic BWS cases the majority of patients have epimutations in this region. Loss of imprinting of the IGF2 gene is frequently observed in BWS, as is reduced CDKN1C expression related to loss of maternal allele-specific methylation (LOM) of the differentially methylated region KvDMR1.

The causes of epimutations are unknown. To date the only genetic mutations described in BWS are in the CDKN1C gene.


- Frequency: 0.8% (USA)

Risk factors

- in vitro fertilization and assisted reproductive technology (ART) (4.6% vs 0.8% USA) (12439823)


- cardiac anomalies

  • excess of cardiac malformation (15608459)
  • epicardial angiofibroma (15608459)
  • focal giant cell cardiomyopathy (4095024)

- visceromegaly (unilateral or bilateral)

- hepatic anomalies in BWS

- adrenal anomaies in BWS

  • adrenomegaly
  • adrenal cytomegaly
  • adrenal macrocyst (unilateral or bilateral) (15539867)

- adrenal heterotopia

-  renal anomalies in BWS (42%) (12138139)

- persistent hyperinsulinemic hypoglycemia (11441340)

- infantile hamartomas

  • mixed hamartoma of the liver (MHL) (11441340)
  • left chest wall hamartoma (11424137)
  • vesical hamartoma (hamartoma of the urinary bladder) (2310920)
  • cardiac hamartoma (4343707)

- macroglossia
- omphalocele
- umbilical hernia
- diaphragmatic hernia (15517831)
- extralobar lung sequestration (15517831)
- hemihypertrophy

Tumor predisposition (4-21%) (15887271)

Patients with Beckwith-Wiedemann syndrome (BWS) have a risk of 7.5% to 10% of developing childhood tumors, 60% of which are Wilms’ tumors.

- vascular dysplasias (vascular malformations)

- Increased tumour risk

Molecular biology

Aberrant methylation of two distinct clusters of imprinted genes on chromosome 11p15 is detected in approximately 70% of BWS cases.

- sequence variants in the IGF2 gene (14645199)
- loss of imprinting of the IGF2 gene
- reduced CDKN1C expression related to loss of maternal allele-specific methylation (LOM) of the differentially methylated region KvDMR1
- germline mutations in the CDKN1C gene (MIM.600856) at 11p15.5
- germline mutations in the NSD1 gene (MIM.606681) at 5q35

See also

- overgrowth syndromes


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- Reik W, Maher ER. Imprinting in clusters: lessons from Beckwith-Wiedemann syndrome. Trends Genet. 1997 Aug;13(8):330-4. PMID: 9260520