Hirschsprung's disease

Hirschsprung's disease, or aganglionic megacolon, involves an enlargement of the colon, caused by bowel obstruction resulting from an aganglionic section of bowel (the normal enteric nerves are absent) that starts at the anus and progresses upwards. The length of bowel that is affected varies but seldom stretches for more than a foot or so. more...

This disease is named for Harald Hirschsprung, the Danish physician who first described the disease in 1886, describing two infants who had died with swollen bellies. "The autopsies showed identical pictures with a pronounced dilatation and hypertrophy of the colon as the dominant features" (Madsen 17).

Hirschsprung’s disease is a congenital disorder of the colon in which certain nerve cells, known as ganglion cells, are absent, causing chronic constipation (Worman and Ganiats 487). The lack of ganglion cells, proven by Orvar Swenson to be the cause of the disease, disables the muscular peristalsis needed to move stool through the colon, thus creating a blockage. One in five thousand children suffer from Hirschsprung’s. Four times as many males get this disease than females. Hirschsprung’s develops in the fetus during the early stages of pregnancy. Typical symptoms for infants include not having their first bowel movement (meconium) within 48 hours of birth, and repeated vomiting. Some infants may have a swollen abdomen. Two thirds of the cases of Hirschsprung’s are diagnosed within three months of the birth. Occasionally symptoms do not appear until early adulthood. A barium enema is the mainstay of diagnosis of Hirschsprung’s.

The usual treatment is "pull-through" surgery where the portion of the colon that does have nerve cells is pulled through and sewn over the part that lacks nerve cells (National Digestive Diseases Information Clearinghouse). For a long time, Hirschsprung’s was considered a multi-factorial disorder, where a combination of nature and nurture were considered to be the cause (Madsen 19). However, in August of 1993, two articles by independent groups in Nature Genetics said that Hirschsprung’s disease could be mapped to a stretch of chromosome 10 (Angrist 351). This research also suggested that a single gene was responsible for the disorder. However, the researchers were unable to isolate the single gene that they thought caused Hirschsprung’s.

Genetic basis

In 2002, scientists thought they found the solution. According to this new research, the interaction of two variant genes caused Hirschsprung’s. RET was isolated as the gene on chromosome 10, and it was determined that it could have dominant mutations that cause loss of function (Passarge 11). An important gene that RET has to interact with in order for Hirschsprung’s to develop is EDNRB, which is 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. These scientists concluded that the mode of inheritance for Hirschsprung’s is oligogenic inheritance (Passarge 11). 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. 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.

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