Beckwith-Wiedemann syndrome

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.

Epidemiology

 Frequency: 0.8% (USA)

Risk factors

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

Synopsis

 cardiac anomalies

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

 visceromegaly (unilateral or bilateral)

• nephromegaly (tumoral risk factor) (9544890)
• hepatomegaly
• adrenomegaly

 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

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

 adrenal heterotopia

• pulmonary adrenal heterotopia (6465087)
• heterotopic adrenal cortex with cytomegaly in lateral ventricle choroids plexus (17162526)

  renal anomalies in BWS (42%) (12138139)

• 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)

 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.

• Wilms tumor
• hepatoblastoma
• neuroblastoma
• embryonal rhabdomyosarcoma (11826361)
• corticoadrenal adenoma and corticoadrenal carcinoma
• angiofibroma (15608459)
• hemangiomas
  • splenic hemangioma (9094248)
  • multiple hepatic hemangioendotheliomas (1570237)
  • placental chorangioma (10191350)
  • juvenile hemangioma (15509684)

 vascular dysplasias (vascular malformations)

• nevus flammeus (11424137)
• large congenital arteriovenous malformations (AVM) (17162526)

 Increased tumour risk

• hemihypertrophy
• nephromegaly (9544890)
• aberrant H19 and not KCNQ1OT1 methylation (11181570, 15580204)

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

References

 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

 Cohen MM Jr. Beckwith-Wiedemann syndrome: historical, clinicopathological, and etiopathogenetic perspectives.
Pediatr Dev Pathol. 2005 May-Jun;8(3):287-304. PMID: 16010495

 Weksberg R, Smith AC, Squire J, Sadowski P. Beckwith-Wiedemann syndrome demonstrates a role for epigenetic control of normal development. Hum Mol Genet. 2003 Apr 1;12 Spec No 1:R61-8. PMID: 12668598

 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

 Steenman M, Westerveld A, Mannens M. Genetics of Beckwith-Wiedemann syndrome-associated tumors: common genetic pathways.
Genes Chromosomes Cancer. 2000 May;28(1):1-13. PMID: 10738297

 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

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