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Research paper

Beckwith-Wiedemann Syndrome — GeneReviews

Authoritative BWS reference. Molecular subtypes: IC2 LOM (50-60%), paternal UPD 11p15 (20-25%, often mosaic), IC1 GOM (5-10%), CDKN1C variants. Classical features: overgrowth, macroglossia, macrosomia, omphalocele, neonatal hypoglycemia, hemihyperplasia, embryonal tumor risk (Wilms, hepatoblastoma). Development typically unaffected in classical BWS; neurodevelopmental risk is concentrated in 11p15 microdeletions encompassing ICR2 and extended CNVs. Tissue mosaicism is common; a single negative blood test does not exclude BWS.

Indexed context

Shuman C, Beckwith JB, Weksberg R

bwsbeckwith-wiedemann11p15imprintingmethylationgenereviews

Markdown path

content/research/papers/2019-bws-genereviews.md

Findings

Authoritative BWS reference. Molecular subtypes: IC2 LOM (50-60%), paternal UPD 11p15 (20-25%, often mosaic), IC1 GOM (5-10%), CDKN1C variants. Classical features: overgrowth, macroglossia, macrosomia, omphalocele, neonatal hypoglycemia, hemihyperplasia, embryonal tumor risk (Wilms, hepatoblastoma). Development typically unaffected in classical BWS; neurodevelopmental risk is concentrated in 11p15 microdeletions encompassing ICR2 and extended CNVs. Tissue mosaicism is common; a single negative blood test does not exclude BWS.

Why it may matter for Levi

Classical BWS is a poor phenotype match for Levi (no macroglossia, no omphalocele, no neonatal hypoglycemia, no hemihyperplasia, proportional rather than asymmetric overgrowth). Still worth including on MS-MLPA at zero marginal cost; closes the 11p15 imprinting branch cleanly whether positive or negative.

Paper text

Beckwith-Wiedemann Syndrome — GeneReviews

Shuman C, Beckwith JB, Weksberg R. — GeneReviews® (updated 2023). https://www.ncbi.nlm.nih.gov/books/NBK1394/

Findings summary

Authoritative reference on Beckwith-Wiedemann syndrome (BWS, OMIM 130650) and the BWS spectrum (BWSp). Key points relevant to Levi:

  • BWS is an imprinting / overgrowth disorder driven by genetic or epigenetic alterations at the 11p15.5 imprinted cluster, which contains IGF2, H19, KCNQ1OT1, and CDKN1C regulated by imprinting control regions IC1 (telomeric, H19/IGF2 DMR) and IC2 (centromeric).
  • Molecular subtypes and their approximate frequencies: IC2 loss of methylation (50–60%), paternal uniparental isodisomy of 11p15 (20–25%, often mosaic), IC1 gain of methylation (5–10%), autosomal dominant maternal CDKN1C point mutations (~5% of sporadic, ~40% of familial).
  • Clinical features classically include overgrowth, macroglossia, macrosomia, omphalocele / umbilical hernia, neonatal hypoglycemia (hyperinsulinism), ear creases / posterior helical pits, hemihyperplasia, visceromegaly, and predisposition to embryonal tumors (Wilms, hepatoblastoma, neuroblastoma, rhabdomyosarcoma, adrenocortical carcinoma). Tumor risk is highest in the first 7–8 years.
  • Development is typically unaffected in classical BWS. Two specific contexts carry neurodevelopmental risk: 11p15 microdeletions encompassing ICR2 (including CDKN1C) and chromosomal duplications or deletions that extend beyond the canonical imprinted domain.
  • Diagnosis requires demonstrating an 11p15.5 epigenetic or copy-number abnormality (methylation analysis ± CMA) or a pathogenic CDKN1C variant. Tissue mosaicism is common; a single negative blood test does not exclude BWS and additional tissue testing (e.g., buccal, fibroblast) is sometimes required.
  • Epilepsy is not a core feature of BWS. Seizures are most often secondary (neonatal hypoglycemia, hyperinsulinism) or reflect the atypical molecular subtypes (extended deletions/duplications).

Relevance to Levi

Levi's phenotype does not strongly match classical BWS: no macroglossia, no omphalocele, no neonatal hypoglycemia, no hemihyperplasia, no ear creases, and no documented hyperinsulinism in the current vault. His overgrowth is proportional and symmetric rather than hemihyperplastic. That substantially lowers the prior for a classical BWS presentation.

However, BWS is still worth including on the methylation / imprinting panel for three reasons:

  1. MS-MLPA at 11p15 is one of the standard assays bundled into methylation / imprinting panels (along with 5q35 for Sotos), so it is obtained at zero marginal cost when ordering the panel.
  2. Atypical / mosaic / extended-deletion BWS subtypes can present with intellectual disability and seizures without the classical BWS gestalt, making blood-based 11p15 methylation testing an appropriate screening component even in a non-classical presentation.
  3. A negative 11p15 result closes the branch cleanly and consolidates the epigenetic-overgrowth differential on the Sotos / TBRS / broader chromatinopathy axis.

Provenance