In Hirschsprung disease, the migration is not complete and part of the colon lacks these nerve bodies that regulate the activity of the colon. The affected segment of the colon cannot relax and pass stool through the colon, creating an obstruction.The most accepted theory of the cause of Hirschsprung is a defect in the craniocaudal migration of neuroblasts originating from the neural crest that occurs during the first 12 weeks of gestation. Defects in the differentiation of neuroblasts into ganglion cells and accelerated ganglion cell destruction within the intestine may also contribute to the disorder.This lack of ganglion cells in the myenteric and submucosal plexus is well documented in Hirschsprungs disease. With Hirschsprungs disease, the segment lacking neurons (aganglionic) becomes constricted, causing the normal, proximal section of bowel to become distended with feces. This narrowing of the distal colon and the failure of relaxation in the aganglionic segment are thought to be caused by the lack of neurons containing nitric oxide synthase.The most cited feature is absence of ganglion cells: notably in males, 75% have none in the end of the colon (rectosigmoid) and 8% lack ganglion cells in the entire colon. The enlarged section of the bowel is found proximally, while the narrowed, aganglionic section is found distally, closer to the end of the bowel. The absence of ganglion cells results in a persistent overstimulation of nerves in the affected region, resulting in contraction.The equivalent disease in horses is lethal white syndrome. Diagnosis
Definitive diagnosis is made by suction biopsy of the distally narrowed segment.
Some of these occur in an autosomal dominant manner. The cause of the remaining cases is unclear. If otherwise normal parents have one child with the condition, the next child has a 4% risk of being affected. Genetics
Several genes and specific regions on chromosomes (loci) have been shown or suggested to be associated with Hirschsprungs disease:
The RET proto-oncogene accounts for the highest proportion of both familial and sporadic cases, with a wide range of mutations scattered along its entire coding region. A proto-oncogene  can cause cancer if it is mutated or overexpressed. RET proto-oncogene
RET is a gene that codes for proteins that assist cells of the neural crest in their movement through the digestive tract during the development of the embryo. Those neural crest cells eventually form bundles of nerve cells called ganglions. EDNRB codes for proteins that connect these nerve cells to the digestive tract. Thus, mutations in these two genes could directly lead to the absence of certain nerve fibers in the colon. Research suggests that several genes are associated with Hirschsprungs disease. Also, new research suggests that mutations in genomic sequences involved in regulating EDNRB have a bigger impact on Hirschsprungs disease than previously thought.RET can mutate in many ways and is associated with Down syndrome. Since Down syndrome is comorbid in 2% of Hirschsprungs cases, a likelihood exists that RET is involved heavily in both Hirschsprungs disease and Down syndrome. RET is also associated with medullary thyroid cancer and neuroblastoma, which is a type of cancer common in children.