Wednesday 17 September 2003
Definition: Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome characterized by macrosomia, macroglossia, omphalocele, hemihyperplasia, and increased tumor risk.
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)
in vitro fertilization and assisted reproductive technology (ART) (4.6% vs 0.8% USA) (12439823)
- excess of cardiac malformation (15608459)
- epicardial angiofibroma (15608459)
- focal giant cell cardiomyopathy (4095024)
visceromegaly (unilateral or bilateral)
hepatic anomalies in BWS
- focal nodular hyperplasia (15965690)
- hepatoblastoma predisposition (14692643, 12970646, 12721741, 10573588)
- biliary dysgenesis (proliferation of abnormally shaped ducts in the portal tracts) (2371181)
- mixed hamartoma of the liver (11441340)
- hepatic hemangioendotheliomas [1570237)
adrenal anomaies in BWS
- adrenal cytomegaly
- adrenal macrocyst (unilateral or bilateral) (15539867)
- pulmonary adrenal heterotopia (6465087)
- heterotopic adrenal cortex with cytomegaly in lateral ventricle choroids plexus (17162526)
- bilateral nephromegaly (25%)
- clusters of immature tubules (1570237)
- foci of dysplastic medullary ducts (1570237)
- collecting system abnormalities (11%)
- renal medullary dysplasia (17172498)
- renal cysts (10.5%)
- perilobar nephrogenic rests (perilobar nephroblastematosis)
- predisposition to Wilms tumor
persistent hyperinsulinemic hypoglycemia (11441340)
- islet cell hyperplasia (endocrine pancreas hyperplasia) (11441340)
- mixed hamartoma of the liver (MHL) (11441340)
- left chest wall hamartoma (11424137)
- vesical hamartoma (hamartoma of the urinary bladder) (2310920)
- cardiac hamartoma (4343707)
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.
- Wilms tumor
- embryonal rhabdomyosarcoma (11826361)
- corticoadrenal adenoma and corticoadrenal carcinoma
- angiofibroma (15608459)
vascular dysplasias (vascular malformations)
Increased tumour risk
- nephromegaly (9544890)
- aberrant H19 and not KCNQ1OT1 methylation (11181570, 15580204)
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
Bliek J, Gicquel C, Maas S, Gaston V, Le Bouc Y, Mannens M. Epigenotyping as a tool for the prediction of tumor risk and tumor type in patients with Beckwith-Wiedemann syndrome (BWS). J Pediatr. 2004 Dec;145(6):796-9. PMID: 15580204
Smith AC, Shuman C, Chitayat D, Steele L, Ray PN, Bourgeois J, Weksberg R. Severe presentation of Beckwith-Wiedemann syndrome associated with high levels of constitutional paternal uniparental disomy for chromosome 11p15. Am J Med Genet A. 2007 Dec 15;143(24):3010-5. PMID: 18000906
Drut R, Quijano G, Altamirano ME, Jones MC, Maffessoli OB. Vascular malformation and choroid plexus adrenal heterotopia: new findings in Beckwith-Wiedemann syndrome? Fetal Pediatr Pathol. 2006 Jul-Aug;25(4):191-7. PMID: 17162526
Weksberg R, Shuman C, Smith AC. Beckwith-Wiedemann syndrome. Am J Med Genet C Semin Med Genet. 2005 Aug 15;137(1):12-23. PMID: 16010676
Goldman M, Smith A, Shuman C, Caluseriu O, Wei C, Steele L, Ray P, Sadowski P, Squire J, Weksberg R, Rosenblum ND. Renal abnormalities in beckwith-wiedemann syndrome are associated with 11p15.5 uniparental disomy. J Am Soc Nephrol. 2002 Aug;13(8):2077-84. PMID: 12138139
DeBaun MR, Siegel MJ, Choyke PL. Nephromegaly in infancy and early childhood: a risk factor for Wilms tumor in Beckwith-Wiedemann syndrome. J Pediatr. 1998 Mar;132(3 Pt 1):401-4. PMID: 9544890