A 2-week-old male infant born to non-consanguineous parents presents with macroglossia, exomphalos, and severe hypoglycemia requiring continuous intravenous dextrose infusion. Genetic testing reveals loss of methylation at the IC2 locus. The imprinting defect marked **A** in the diagram is responsible for this clinical phenotype. Which of the following best explains the molecular mechanism underlying the overgrowth and metabolic derangement in this infant?
A. Paternal deletion of the entire 11p15.5 region resulting in complete loss of growth-promoting genes
B. Gain of methylation at IC1 causing silencing of H19 and compensatory IGF2 upregulation
C. Increased IGF2 expression and loss of CDKN1C function leading to uncontrolled cell proliferation and hyperinsulinism
D. Maternal uniparental disomy of chromosome 11 leading to biallelic expression of imprinted growth suppressors
Explanation
Why option 1 is correct
Loss of methylation (LOM) at IC2 (the KCNQ1OT1/CDKN1C imprinting center) in Beckwith-Wiedemann syndrome results in aberrant silencing of the maternal CDKN1C allele, which encodes a CDK inhibitor critical for growth restraint. Simultaneously, the IC2 defect permits increased expression of IGF2 (insulin-like growth factor 2), a potent mitogen. The combined effect—loss of the growth brake (CDKN1C) and increased growth accelerator (IGF2)—produces the characteristic overgrowth phenotype (macroglossia, exomphalos, hemihypertrophy) and hyperinsulinism-driven neonatal hypoglycemia. This IC2 LOM subtype accounts for ~50% of BWS cases and is the most common molecular etiology (Nelson Textbook of Pediatrics 22e; 2018 International BWS Consensus).
Why each distractor is wrong
Option 2: Paternal deletion of 11p15.5 would result in loss of the paternal (normally expressed) IGF2 allele, producing intrauterine growth restriction and hypoglycemia—the opposite of the BWS overgrowth phenotype. Deletions account for only rare cases and do not explain IC2 LOM.
Option 3: Gain of methylation (GOM) at IC1 (H19/IGF2 center) is a distinct molecular subtype (~5–10% of BWS) that silences H19 and increases IGF2 expression. However, the clinical vignette explicitly states IC2 LOM, not IC1 GOM. GOM at IC1 does not directly involve CDKN1C loss.
Option 4: Maternal uniparental disomy (mUPD11) would result in biallelic maternal alleles, silencing paternal IGF2 and losing the paternal CDKN1C allele—producing growth restriction, not overgrowth. Paternal UPD (pUPD11, ~20% of cases) causes BWS; maternal UPD does not.
High-YieldNEET PG
IC2 LOM → loss of CDKN1C (growth brake) + increased IGF2 (growth accelerator) = overgrowth + hyperinsulinism; most common BWS subtype (~50%).
Nelson Textbook of Pediatrics 22e; 2018 International BWS Consensus
Practice similar questions
Sign up free to access AI-powered MCQ practice with detailed explanations and adaptive learning.
