Болезнь Гиршпрунга: генетика, патогенез и современные исследования.

The disorder may occur by itself or in association with other genetic disorders such as Down syndrome or Waardenburg syndrome. Males are more often affected than females. and is named after Danish physician Harald Hirschsprung following his description in 1888.

The disorder may occur by itself or in association with other genetic disorders such as Down syndrome. A proto oncogene can cause cancer if it is mutated or overexpressed.

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 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. RET can mutate in many ways and is associated with Down syndrome. Since Down syndrome is comorbid in 2% of Hirschsprung's cases, a likelihood exists that RET is involved heavily in both Hirschsprung's disease and Down syndrome. RET is also associated with medullary thyroid cancer and neuroblastoma, which is a type of cancer common in children. Both of these disorders are more common in Hirschsprung's patients 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. The earlier the RET mutation occurs in Hirschsprung's disease, the more severe the disorder becomes.

Common and rare DNA variations in the neuregulin 1 (NRG1) and NRG3 (NRG3) were first shown to be associated with the disease in Chinese patients through a Genome Wide Association Study by the Hong Kong team in 2009 and 2012, respectively Subsequent studies in both Asian and Caucasian patients confirmed the initial findings by the University of Hong Kong. Both rare and common variants in these two genes have been identified in additional Chinese, Thai, Korean, Indonesian, and Spanish patients. These two genes are known to play a role in the formation of the enteric nervous system; thus, they are likely to be involved in the pathology of Hirschsprung's disease, at least in some cases. Another gene associated with this condition is NADPH oxidase, EF hand calcium binding domain 5 (NOX5). This gene is located on the long arm of chromosome 15 (15q23).

During normal prenatal development, cells from the neural crest migrate into the large intestine (colon) to form the networks of nerves called the myenteric plexus (Auerbach plexus) (between the smooth muscle layers of the gastrointestinal tract wall) and the submucosal plexus (Meissner plexus) (within the submucosa of the gastrointestinal tract wall). 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 Hirschsprung's disease.

Definitive diagnosis is made by suction biopsy of the distally narrowed segment. A histologic examination of the tissue would show a lack of ganglionic nerve cells. Diagnostic techniques involve anorectal manometry, barium enema, and rectal biopsy. The suction rectal biopsy is considered the current international gold standard in the diagnosis of Hirschsprung's disease. Radiologic findings may also assist with diagnosis. An abdominal x ray can reveal a lack of stool in the large intestine or a bulging caused by blocked stool. Cineanography (fluoroscopy of contrast medium passing anorectal region) assists in determining the level of the affected intestines.

Treatment of Hirschsprung's disease consists of surgical removal (resection) of the abnormal section of the colon, followed by reanastomosis.

The first stage of treatment used to be a reversible colostomy. In this approach, the healthy end of the large intestine is cut and attached to an opening created on the front of the abdomen. The contents of the bowel are discharged through the hole in the abdomen and into a bag. Later, when the patient's weight, age, and condition are right, the "new" functional end of the bowel is connected with the anus. The first surgical treatment involving surgical resection followed by reanastomosis without a colostomy occurred as early as 1933 by Doctor Baird in Birmingham on a one year old boy.

The Swedish American surgeon Orvar Swenson (1909–2012), who discovered the cause of Hirschsprung's, first performed its surgical treatment, the pull through surgery, in 1948. The pull through procedure repairs the colon by connecting the functioning portion of the bowel to the anus. The pull through procedure is the typical method for treating Hirschsprung's in younger patients. Swenson devised the original procedure, and the pull through surgery has been modified many times.' Currently, several different surgical approaches are used, which include the Swenson, Soave, Duhamel, and Boley procedures. The Duhamel procedure, named for the French pediatric surgeon Bernard Duhamel (1917–1996), uses a surgical stapler to connect the good and bad bowel. For the 15% of children who do not obtain full bowel control, other treatments are available. Constipation may be remedied by laxatives or a high fiber diet. In those patients, serious dehydration can play a major factor in their lifestyles. A lack of bowel control may be addressed by an ileostomy – similar to a colostomy, but uses the end of the small intestine rather than the colon. The Malone antegrade colonic enema (ACE) is also an option. In a Malone ACE, a tube goes through the abdominal wall to the appendix, or if available, to the colon. The bowel is then flushed daily. Children as young as 6 years of age may administer this daily flush on their own. If the affected portion of the lower intestine is restricted to the lower portion of the rectum, other surgical procedures may be performed, such as a posterior rectal myectomy. The prognosis is good in 70% of cases. Chronic postoperative constipation is present in 7 to 8% of the operated cases. Postoperative enterocolitis, a severe manifestation, is present in the 10–20% of operated patients.

According to a 1984 study conducted in Maryland, Hirschsprung's disease appears in 18.6 per 100,000 live births. It is more common in male than female (4.32:1) and in white rather than nonwhite. Nine percent of the Hirschsprung cases were also diagnosed as having Down syndrome. Most cases are diagnosed before the patient is 10 years of age.

The first report of Hirschsprung's disease dates to 1691, when it was described by Dutch anatomist Frederik Ruysch. However, the disease is named after Harald Hirschsprung, the Danish physician who first described two infants who died of this disorder in 1888. In patients with Hirschsprung disease, both myenteric and submucosal plexuses are absent. A barium enema is the mainstay of diagnosis of Hirschsprung's, though a rectal biopsy showing the lack of ganglion cells is the only certain method of diagnosis. The first publication on an important genetic discovery of the disease was from Martucciello Giuseppe et al. in 1992. The authors described a case of a patient with total colonic aganglionosis associated with a 46, XX, del 10 (q11.21 q21.2) karyotype. The major gene of Hirschsprung disease was identified in this chromosomal 10 region, it was the RET proto oncogene. 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. For a long time, Hirschsprung's was considered a multifactorial disorder, where a combination of nature and nurture was considered to be the cause. However, in August 1993, two articles by independent groups in Nature Genetics said that Hirschsprung's disease could be mapped to a stretch of chromosome 10. This research also suggested that a single gene was responsible for the disorder. However, the researchers were unable to isolate it.