A 2-day-old term male infant presents with abdominal distention, bilious vomiting, and failure to pass meconium. Contrast enema shows a narrow distal colonic segment (marked **C** in the diagram) with a transition zone to a dilated proximal colon. Rectal suction biopsy of the narrow segment confirms absence of ganglion cells in both Meissner and Auerbach plexuses. Which of the following best explains the pathophysiology of the narrow distal segment marked **C**?
A. Abnormal smooth muscle development in the distal colon with secondary loss of myenteric plexuses due to chronic obstruction
B. Failure of neural crest cell migration into the distal hindgut during weeks 5–12 of gestation, resulting in absence of inhibitory ganglion cells and unopposed tonic contraction
C. Premature apoptosis of ganglion cell precursors in the distal bowel caused by mutations in the EDNRB gene alone
D. Failure of the internal anal sphincter to relax due to defective parasympathetic innervation from the sacral spinal cord
Explanation
Why option 1 is correct
The narrow distal aganglionic segment marked C results from failure of craniocaudal migration of neural crest-derived ganglion cell precursors into the distal hindgut between weeks 5–12 of gestation. This produces complete absence of ganglion cells in both Meissner (submucosal) and Auerbach (myenteric) plexuses. Loss of inhibitory neurotransmission (nitric oxide and VIP from these plexuses) leads to unopposed tonic contraction of the aganglionic bowel, creating a functional obstruction. This is the fundamental pathophysiology of Hirschsprung disease and explains why the distal segment is narrow and contracted, not dilated (Nelson Textbook of Pediatrics 22e, APSA Guidelines).
Why each distractor is wrong
Option 2: Abnormal smooth muscle development is not the primary pathology in Hirschsprung disease. The smooth muscle itself is normal; the defect is neuronal (absence of ganglion cells). The proximal dilated megacolon is normal ganglionic bowel that dilates secondary to the functional obstruction created by the aganglionic segment.
Option 3: While EDNRB mutations are associated with Hirschsprung disease, they are not the sole cause. The RET protooncogene accounts for ~50% of familial cases and is the most common genetic association. Moreover, this option incorrectly attributes the pathology to apoptosis rather than failure of migration, which is the core mechanism.
Option 4: The internal anal sphincter dysfunction is not the primary pathology. Although anorectal manometry shows absent rectoanal inhibitory reflex (RAIR) in Hirschsprung disease, this is a consequence of the absent ganglion cells in the rectum, not the cause of the narrow distal segment. The defect is in the enteric nervous system of the distal bowel, not in sacral parasympathetic innervation.
High-YieldNEET PG
Hirschsprung disease = failure of neural crest migration → absent ganglion cells → loss of inhibitory tone → tonic contraction of distal segment (narrow, not dilated). The dilated proximal colon is normal bowel proximal to a functional obstruction.
Nelson Textbook of Pediatrics 22e, Chapter on Hirschsprung Disease; APSA Guidelines for Hirschsprung Disease Management
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