A 2-week-old male neonate born to non-consanguineous parents presents with the clinical features shown in the diagram. The structure marked **A** (macroglossia) is causing difficulty with feeding and mild stridor. On examination, the infant also has an omphalocele and prominent ears with posterior helical pits. Serum glucose is 38 mg/dL despite early feeding. Which of the following genetic mechanisms is MOST likely responsible for this clinical presentation?

Explanation

## Why Mosaic paternal UPD or LOH affecting 11p15.5 is right Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome caused by dysregulation of the 11p15.5 imprinting region, which contains critical genes including IGF2, H19, CDKN1C, and KCNQ1OT1. The cardinal features—macroglossia (marked **A**), omphalocele, and neonatal hypoglycemia—are pathognomonic for BWS. Mosaic paternal UPD, loss of heterozygosity (LOH), and methylation defects are the primary molecular mechanisms driving this syndrome. The hypoglycemia results from transient hyperinsulinism (present in ~50% of BWS cases), requiring early feeding and glucose monitoring. This diagnosis directly explains all the clinical findings in this neonate (Nelson 21e, Ch 99). ## Why each distractor is wrong - **Maternal WT1 mutation on 11p13**: This causes Denys-Drash syndrome (Wilms tumor + congenital nephropathy + ambiguous genitalia), NOT macroglossia or omphalocele. While Denys-Drash increases Wilms risk, it does not present with the cardinal features of BWS shown here. - **Homozygous GPC3 mutation**: GPC3 mutations cause Simpson-Golabi-Behmel syndrome, an X-linked overgrowth disorder with visceromegaly and tumor risk, but NOT the characteristic macroglossia, omphalocele, and neonatal hypoglycemia pattern of BWS. - **Heterozygous NSD1 mutation**: NSD1 mutations cause Sotos syndrome, characterized by large head, advanced bone age, and learning disability—not macroglossia, omphalocele, or neonatal hypoglycemia. **High-Yield:** BWS = 11p15.5 imprinting dysregulation (paternal UPD/LOH/methylation) + macroglossia + omphalocele + neonatal hypoglycemia + Wilms tumor screening (abdominal ultrasound every 3 months until age 8). [cite: Nelson Textbook of Pediatrics, 21st edition, Chapter 99 — Beckwith-Wiedemann Syndrome and related overgrowth syndromes]