Pathophysiology Hirschsprung's disease

1 pathophysiology

1.1 genetic basis
1.2 ret proto-oncogene
1.3 other genes

pathophysiology

the accepted theory of cause of hirschsprung defect in craniocaudal migration of neuroblasts originating neural crest occurs during first 12 weeks of gestation. defects in differentiation of neuroblasts ganglion cells , accelerated ganglion cell destruction within intestine may contribute disorder.

this lack of ganglion cells in myenteric , submucosal plexus documented in hirschsprung s disease. hirschsprung s disease, segment lacking neurons (aganglionic) becomes constricted, causing normal, proximal section of bowel become distended feces. narrowing of distal colon , failure of relaxation in aganglionic segment thought caused lack of neurons containing nitric oxide synthase.

the equivalent disease in horses lethal white syndrome.

genetic basis

several genes , specific regions on chromosomes (loci) have been shown or suggested associated hirschsprung s disease:

hirschsprung s disease can present part of multisystem disorder, such down syndrome, bardet–biedl syndrome, waardenburg–shah syndrome, mowat–wilson syndrome, goldberg–shprintzen megacolon syndrome, cartilage–hair hypoplasia, multiple endocrine neoplasia type 2, smith-lemli-opitz syndrome, , congenital central hypoventilation syndrome.

the ret proto-oncogene accounts highest proportion of both familial , sporadic cases, wide range of mutations scattered along entire coding region. proto-oncogene gene can cause cancer if mutated or over-expressed.

research published in 2002 suggested hirschsprung s may caused interaction between 2 proteins encoded 2 variant genes. ret proto-oncogene on chromosome 10 identified 1 of 2 genes involved. other protein ret must interact cause hirschsprung’s disease termed ednrb, , encoded gene ednrb located on chromosome 13.

hirschsprung s disease, hypoganglionosis, gut dysmotility, gut transit disorders, , intussusception have been recorded dominantly inherited neurovisceral porphyrias (acute intermittent porphyria, hereditary coproporphyria, variegate porphyria). children may require enzyme or dna testing these disorders, may not produce or excrete porphyrins before puberty.

ret proto-oncogene

ret gene codes proteins assist cells of neural crest in movement through digestive tract during development of embryo. neural crest cells form bundles of nerve cells called ganglions. ednrb codes proteins connect these nerve cells digestive tract. thus, mutations in these 2 genes directly lead absence of nerve fibers in colon. research suggests several genes associated hirschsprung’s disease. also, new research suggests mutations in genomic sequences involved in regulating ednrb have bigger impact on hirschsprung’s disease thought.

ret can mutate in many ways , associated down syndrome. since down syndrome comorbid in 2% of hirschsprung’s cases, likelihood exists ret involved heavily in both hirschsprung s disease , down syndrome. ret associated medullary thyroid cancer , neuroblastoma, type of cancer common in children. both of these disorders more common in hirschsprung’s patients in general population. 1 function ret controls travel of neural crest cells through intestines in developing fetus. earlier ret mutation occurs in hirschsprung’s disease, more severe disorder becomes.

other genes

common , rare dna variations in neuregulin 1 (nrg1) , nrg3 (nrg3) first shown associated disease in chinese patients through genome wide association study hong kong team in 2009 , 2012, respectively subsequent studies in both asian , caucasian patients confirmed initial findings university of hong kong. both rare , common variants in these 2 genes have been identified in additional chinese, thai, korean, indonesian , spanish patients. these 2 genes known play role in formation of enteric nervous system; thus, involved in pathology of hirschsprung s disease, @ least in cases.