A 2-day-old neonate presents with bilious vomiting and failure to pass meconium. AXR shows a 'double bubble' sign with no distal gas. The father had similar surgery as a neonate. Which genetic mutation is most strongly associated with familial Hirschsprung's disease?

• A CFTR mutation
• B APC gene mutation
• C RET proto-oncogene mutation ✓
• D MLH1 mutation

Explanation

Hirschsprung's disease (congenital aganglionosis) results from failure of neural crest cell migration into the distal bowel. RET proto-oncogene mutations account for approximately 50% of familial cases and 15–20% of sporadic cases. The RET gene encodes a receptor tyrosine kinase essential for enteric nervous system development. GDNF (RET ligand) mutations are also implicated. The 'double bubble' sign on AXR is classic for duodenal atresia (proximal plus gastric gas), which may be confused here — but the full question context of no distal gas and family history points to Hirschsprung's where suction rectal biopsy confirming absence of ganglion cells is diagnostic. APC mutations cause familial adenomatous polyposis; CFTR causes cystic fibrosis.

Reference: Bailey & Love's Short Practice of Surgery, 27th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.