Lecture 21 Part I: Hirschsprung Disease

What is Hirschsprung Disease (HSCR) in a nutshell?

• Congenital aganglionosis (absence of ganglion cells) of the distal intestine.

• Inability to pass stool due to absent peristalsis → stool collection and bowel obstruction.

• Most common form of functional intestinal obstruction in neonates.

• Treated by surgical removal of affected intestinal segment.

What are the incidence and demographic features of HSCR?

• ~1/5,000 live births; 1.5–2.8/10,000 (varies by ethnicity).

• Strong male predominance (short-segment form: 5:1 male:female).

• Most cases are sporadic; familial in 5–20%.

• Can be inherited as autosomal dominant or autosomal recessive.

What is the underlying pathology of HSCR?

• Failure of neural crest cells (NCCs) to migrate, proliferate, differentiate, or survive during embryonic ENS development.

• Results in absence of ganglion cells along variable lengths of the distal GI tract.

• Without ganglia: no peristalsis → bowel cannot relax → obstruction.

What does HSCR anatomy look like: normal vs. diseased?

• Normal: nerves present throughout the colon, rectum, and anus → coordinate peristalsis to push waste out.

• HSCR: a segment lacks nerves entirely → that segment is narrow and collapsed (can't push) → proximal colon becomes enlarged from backed-up stool.

What are the three segment types of HSCR and their frequencies?

• Short-segment (missing only from last segment of large intestine): 80%; 5:1 male:female.

• Long-segment (missing from most or all of large intestine): 15–20%; equal sex ratio; more severe.

• Total colonic/small intestinal involvement: ~5%; most severe; nerve cells absent from entire large intestine, sometimes part of small intestine too.

What are the comorbid conditions associated with HSCR?

• Isolated in ~70% of cases; ~30% associated with other congenital syndromes.

• Down syndrome: ~1/20 HSCR patients.

• Also associated with urogenital (11%), cardiovascular (6%), and GI anomalies (6%).

• Prematurity in ~1/10 children with HSCR.

What are the symptoms of HSCR in newborns?

• No bowel movement within 48 hours of birth (key red flag).

• Swollen/distended abdomen from gas.

• Vomiting (may be yellow/green).

• Constipation.

What are the symptoms of HSCR in older children?

• Chronic constipation and distended abdomen.

• Fecal incontinence and gas.

• Failure to thrive, slower growth, fatigue.

• Anemia.

What is the pathophysiology/gross pathology of HSCR?

• Aganglionic segment: narrow, contracted, no peristalsis.

• Proximal bowel: dilated and hypertrophic from stool backup.

• Consequences: swollen abdomen, excessive flatulence, intestinal inflammation (enterocolitis).

• Fatal if untreated.

How is HSCR diagnosed?

• X-ray with barium contrast: shows narrow aganglionic segment vs. dilated normal bowel proximal to it.

• Rectal biopsy: definitive diagnosis → confirms absence of ganglion cells.

What genes are implicated in HSCR?

• RET (most common), EDNRB, and EDN3.

• Multiple gene mutations may be required; genetics are complex and incompletely understood.

• Autosomal dominant with incomplete penetrance (not all carriers develop disease).

What is the RET gene and its role?

• Location: 10q11.21; encodes a receptor tyrosine kinase.

• Critical for cell proliferation, differentiation, migration, and survival.

• Essential for neural crest and enteric nervous system development.

• Frameshift and missense mutations → loss of function of the tyrosine kinase domain.

What is the RET receptor complex?

• RET functions as a dimer; GDNF (ligand) first binds the co-receptor GFRα-1, which then activates the RET complex.

• RET mutation → loss of this signaling cascade → reduced ENCDC survival and proliferation.

• Degree of RET loss-of-function correlates with length of aganglionic segment.

How common are RET mutations in HSCR?

• 25–33% of sporadic cases; 40–60% of familial cases.

• 60+ alleles identified: frameshift, missense, nonsense, deletions, promoter mutations.

• Mutations in RET co-receptors can also contribute.

What is the molecular pathway from RET mutation to HSCR?

• GDNF → binds GFRα-1 → activates RET → promotes ENCDC survival and proliferation → bowel colonization.

• RET mutation → ↓ GDNF signaling → ↓ ENCDC proliferation → ↓ bowel colonization → aganglionosis → HSCR.

What are neural crest cells and which subtypes are relevant to HSCR?

• NCCs arise from ectoderm during neural induction; considered the fourth germ layer.

• Four subtypes: cranial, trunk, vagal & sacral, cardiac.

• Vagal and sacral NCCs specifically colonize the gut and form enteric ganglia → their failure to reach the distal intestine causes HSCR.

What is the role of neural crest cells in normal ENS development?

• NCCs migrate to the developing gut and differentiate into glial cells essential for peristalsis.

• GDNF/RET signaling drives their survival, proliferation, and bowel colonization.

• In HSCR: NCCs fail to colonize the distal intestine → no ganglion cells formed there.

What does pull-through surgery involve?

• Step 1: Identify the aganglionic (diseased) segment vs. the healthy proximal segment.

• Step 2: Surgically resect the aganglionic segment.

• Step 3: Pull the healthy bowel down and attach it directly to the remaining rectum/anus.

What are the other/supportive treatments for HSCR?

• Colostomy (temporary, if needed before definitive surgery).

• Antibiotics for enterocolitis.

• High-fiber diet, increased fluids, laxatives, physical activity.

What is the prognosis for HSCR after treatment?

• Generally excellent → most children pass stool normally after surgery.

• Some may have ongoing constipation, incontinence, or enterocolitis.

• Outcome depends on length of aganglionic segment and associated conditions.