Beckwith-Wiedemann syndrome (BWS) is caused by epigenetic or genetic abnormalities at chromosome 11p15.5. Which combination of mechanisms correctly describes the two imprinting control regions (ICR1 and ICR2) and the pathogenesis of overgrowth in BWS?

• A Duplication of paternal ICR2 causes overexpression of KCNQ1OT1 (a non-coding RNA), which silences CDKN1C from both alleles; simultaneously, maternal ICR1 methylation is lost, increasing H19 expression which upregulates IGF2
• B Loss of maternal methylation at ICR1 causes biallelic expression of IGF2 (normally only paternally expressed) — IGF2 is a growth factor, causing overgrowth; gain of maternal methylation at ICR2 silences CDKN1C (p57KIP2, a growth suppressor) from the maternal allele — loss of this brake further drives overgrowth ✓
• C ICR1 regulates H19 exclusively; H19 loss causes reduced microRNA production, globally upregulating all growth factor transcripts including IGF2
• D UPD of paternal chromosome 11p15 provides two active IGF2 copies and two active KCNQ1OT1 copies; maternal ICR changes are irrelevant to the overgrowth phenotype

Explanation

At 11p15.5, two imprinting domains exist: ICR1 controls IGF2/H19 (normally maternal methylation suppresses H19, allowing paternal IGF2 expression) and ICR2 controls KCNQ1OT1/CDKN1C (normally maternal CDKN1C is expressed, paternal is silenced by KCNQ1OT1). In BWS: (1) Loss of maternal methylation at ICR1 causes biallelic IGF2 expression (growth promotion) and silencing of H19; (2) loss of maternal methylation at ICR2 allows paternal-pattern KCNQ1OT1 to silence CDKN1C (p57KIP2, a CDK inhibitor/growth suppressor) from the maternal allele too — removing the growth brake. The combination produces macrosomia, organomegaly, and predisposition to embryonal tumors. Paternal UPD(11p15) is one mechanism achieving these same epigenetic changes simultaneously.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

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Written and medically reviewed by the StethoPrep medical team.