Beckwith Wiedemann syndrome (BWS) is a fetal overgrowth disorder involving 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

 renal anomalies (42%) (#12138139#)

• nephromegaly (25%)
• collecting system abnormalities (11%)
• renal cysts (10.5%)
• perilobar nephrogenic rests (perilobar nephroblastematosis)
• predisposition to Wilms tumor

 cardiac anomalies

• excess of cardiac malformation (#15608459#)
• epicardial angiofibroma (#15608459#)

 persistent hyperinsulinemic hypoglycemia (#11441340#)

• islet cell 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
 hemihypertrophy

 tumor predisposition (4-21%) (#15887271#)

• 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#)
  • nevus flammeus (#11424137#)

 Increased tumour risk

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

Molecular biology

 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

 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#

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