Hirschsprung's disease

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]

Hirschsprung’s disease involves an enlargement of the colon caused by a bowel obstruction resulting from an aganglionic section of bowel. The condition, in which the normal enteric nerves are absent, begins from the anus and progresses proximally. The length of affected bowel varies, rarely extending more than approximately one foot

The disease is named after Harald Hirschsprung, the Danish physician who first described the disease in 1886 when describing two infants who had died with swollen bellies. The autopsies showed identical pictures with pronounced dilatation and hypertrophy of the colon as dominant features.

Hirschsprung’s disease may be classified as rectosigmoid disease, long segment disease, or ultrashort segment disease based on the extent of colon involvement.

Hirschsprung’s disease is a congenital disorder of colon in which certain nerve cells, called ganglion cells, are absent. This may lead to chronic constipation.^[1]

Hirschsprung’s disease is caused by a failure of the myentric and submucosal nerve plexuses to complete craniocaudal migration into the distal colon.

Hirschsprung’s disease must be differentiated from other diseases that cause meconium pass failure and abdominal distension in infants, such as meconium plug syndrome, small left colon syndrome, or congenital hypothyroidism.

The incidence of Hirschsprung’s disease is 20 per 100,000 newborns. Hirschsprung’s disease is three times more common in Asian Americans than the rest of the population. Males are more commonly affected than females.

The most potent risk factor for the development of Hirschsprung’s disease is a strong family history (i.e. involvement of multiple family members). Other risk factors include a family history of long segment disease and the proband being female.

According to the USPSTF, screening is not recommended for Hirschsprung’s disease.

If left untreated, Hirschsprung’s disease can lead to enterocolitis and even death. Common complications include enterocolitis, intestinal perforation, and short bowel syndrome. After appropriate surgical intervention, the odds of mortality drop significantly.

Hirschsprung’s disease is commonly diagnosed during the neonatal period. The cardinal symptoms of Hirschsprung’s disease include abdominal distension, delayed passage of meconium (i.e., after 24-48 hours from birth), and vomiting. ^[2][3]

Physical examination is nondiagnostic in newborns. It may reveal a distended abdomen and/or anal spasm. In older children, abdominal distension may result from the inability to release flatus.^[3]

There are no specific laboratory finding associated with Hirschsprung’s disease. All the pre-operation blood tests and coagulation tests will be within the reference range.^[3]

Abdominal X-ray is the modality of choice in diagnosing Hirschsprung’s disease. Major findings on abdominal X-rays in patients affected by Hirschsprung’s disease are decreased bowel caliber of the involved segment and colon distension.

There are no specific CT scan findings associated with Hirschsprung’s disease.

There are no specific MRI finding associated with Hirschsprung’s disease.

A barium enema is the mainstay of Hirschsprung’s disease diagnosis.

A rectal biopsy showing the absence of ganglion cells is the only definitive method of diagnosis.

Medical therapy only plays a supportive role in the management of Hirschsprung’s disease. Medical therapy indications include preventing disease complications, preventing post-operative infections, and managing post-operative bowel function. Intravenous fluid resuscitation and maintenance, nasogastric decompression, and the administration of intravenous antibiotics (as indicated) remain the cornerstones of initial medical management.^[4][5]

The usual treatment is pull-through surgery, in which the portion of the colon that has nerve cells is pulled through and sewn over the portion that lacks nerve cells (National Digestive Diseases Information Clearinghouse).

There are no primary preventive measures for Hirschsprung’s disease.

To prevent complications of Hirschsprung’s disease, diagnosis is required. Secondary preventive measures include the administration of laxatives and antibiotics to prevent obstruction and infection, respectively.

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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]

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.

• According to a study in 2002 and more recent studies, 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, leading to encoded protein function loss.^[1]
• The protein that RET proto-oncogene has to interact to develop Hirschsprung’s disease, is termed EDNRB.
• EDRB protein encoded by the gene EDNRB located on chromosome 13.
• Six other genes were discovered to be associated with Hirschsprung’s disease. These genes include: 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 in Hirschsprung’s disease is oligogenic. This means that two mutated genes interact to cause the disorder. Variations in RET and EDNRB have to coexist to involve a child with Hirschsprung’s disease.^[2]
• Although six other genes show to have an effect on Hirschsprung’s disease, the exact interaction mechanism with RET and EDNRB is unknown. Thus, the specifics of the disease’s origin are still not completely described.
• More recently, syndromic cases of Hirschprung’s disease (i.e. cases associated with other defects of the autonomic nervous system) were shown to be caused by mutations in the homeobox gene PHOX2B.
• RET codes for the proteins that help neural crest cells (which become ganglion cells) move through the digestive tract during the development of the embryo.
• EDNRB codes for the proteins that 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 mutation of these two genes, which would lead to the wrong proteins being produced.
• Research in June 2004 suggested 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 genes.
• RET mutates in different ways and is associated with Down syndrome. Since Down syndrome is co-morbid with two percent of Hirschsprung’s disease cases, it is assumed that RET is involved strongly in both Hirschsprung’s disease and Down syndrome.
• RET is also associated with thyroid cancer and neuroblastoma. Both of these disorders have also been seen among Hirschsprung’s disease patients with greater frequency than general population.
• In the developing fetus, RET controls the neural crest cells traveling through the intestines. When RET mutations occur, the cells that started traveling through the colon, stop immigration and cause Hirschsprung’s disease. The earlier the RET mutation occurs in Hirschsprung’s disease, the more severe the disorder becomes.
• While researchers remain uncertain about the exact genetic cause of Hirschsprung’s disease, Dr. Sawin notes that in familial cases (in which families have multiple affected members), Hirschsprung’s disease exhibits autosomal dominant transmission, with dominance of the RET. However, in sporadic cases, Sawin notes that there is no identified inheritance pattern.^[3][4][5][6]

• Biopsy shows absence of ganglionic cells.
• Presence of hypertrophied nerve trunks in the lamina propria demonstrated by acetylcholinesterase staining.^[7]
• Calretinin staining shows decreased immunofluorescence.

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