Hirschsprung's disease pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]; Associate Editor(s)-in-Chief: Ahmed Younes M.B.B.CH [3] Aditya Ganti M.B.B.S. [4]
Overview
Hirschsprung’s disease is a congenital disorder of the colon; in which certain nerve cells, known as ganglion cells, are absent. It may cause chronic constipation.
Pathophysiology
Genetics
- According to a research in 2002 and also a newer one, the interaction between two proteins encoded by two variant genes may cause Hirschsprung’s disease.
- The RET proto-oncogene on chromosome 10 was identified as one of the involved genes; it was determined that dominant mutations may occur within this gene lead to a loss of function in the encoded protein.[1]
- The protein with which RET has to interact in order for Hirschsprung’s disease to develop is termed EDNRB, and is encoded by the gene EDNRB located on chromosome 13.
- Six other genes were discovered to be associated with Hirschsprung’s. According to the study, these genes are GDNF on chromosome 5, EDN3 on chromosome 20, SOX10 on chromosome 22, ECE1 on chromosome 1, NTN on chromosome 19, and SIP1 on chromosome 2.
- Scientists concluded that the mode of inheritance for Hirschsprung’s is oligogenic inheritance. This means that two mutated genes interact to cause a disorder. Variations in RET and EDNRB have to coexist in order for a child to get Hirschsprung’s.[2]
- However, although six other genes were shown to have an effect on Hirschsprung’s, the researchers were unable to determine how they interacted with RET and EDNRB. Thus, the specifics of the origins of the disease are still not completely known.
- More recently, syndromic cases of Hischprung's disease (that is, associated with other defects of the autonomic nervous system) were shown to be caused by mutations in the homeobox gene PHOX2B.
- RET codes for proteins that help the neural crest cells (which become ganglion cells) move through the digestive tract during the development of the embryo.
- EDNRB codes for proteins to actually connect these nerve cells to the digestive tract. This means that the absence of certain nerve fibers in the colon could be directly related to these two genes mutating so the wrong proteins are produced.
- Research published in June of 2004 suggests that there are actually ten genes associated with Hirschsprung’s disease. Also, new research suggests that mutations in genomic sequences involved in regulating EDNRB have a bigger impact on Hirschsprung’s disease than previously thought.
- Dr. Bob Sawin of Seattle’s Children's Hospital notes that it is generally accepted in the scientific community that the gene RET is the most important gene when looking for the genetic cause of Hirschsprung’s disease. RET can mutate in many ways and is associated with Down syndrome. Since Down Syndrome is comorbid in two percent of Hirschsprung’s cases, there is a likelihood that RET is involved heavily in both Hirschprung's disease and Down Syndrome.[3]
- RET is also associated with thyroid cancer and neuroblastoma. Both of these disorders have also been observed in Hirschsprung’s patients with greater frequency than in the general population.
- One function that RET controls is the travel of the neural crest cells through the intestines in the developing fetus. When RET mutations cause Hirschsprung’s disease, the cells start traveling through the colon, only to be stopped once the mutation occurs. The earlier the mutation of RET occurs in Hirschsprung’s disease, the more severe the disorder becomes.
- While researchers remain uncertain of the exact genetic cause of Hirschsprung’s disease, Dr. Sawin notes that in familial cases, (in which families have multiple affected patients) Hirschsprung’s disease exhibits autosomal dominant transmission, with the gene RET being dominant. However, in sporadic cases, Sawin notes that there has been no inheritance pattern identified.
Microscopic pathology
- Biopsy shows absence of ganglionic cells.
- Presence of hypertrophied nerve trunks using in the lamina propria on using acetylcholinesterase staining.[4]
- Calretinin staining shows decreased immunofluorescence.
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Video: Histopathological Findings
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References
- ↑ "Thieme E-Journals - European Journal of Pediatric Surgery / Abstract".
- ↑ "A gene for Hirschsprung disease (megacolon) in the pericentromeric region of human chromosome 10 - Nature Genetics".
- ↑ Elhalaby EA, Teitelbaum DH, Coran AG, Heidelberger KP (1995). "Enterocolitis associated with Hirschsprung's disease: a clinical histopathological correlative study". J. Pediatr. Surg. 30 (7): 1023–6, discussion 1026–7. PMID 7472925.
- ↑ Worman and Ganiats 1995, Am Fam Physician 51, 487-494 [1]