Knowledge on rare diseases and orphan drugs

Hirschsprung disease (HSCR) has an estimated prevalence at birth of 1/5,000-10,000 worldwide. In rectosigmoid HSCR, there is a male predominance of 4:1.

HSCR generally manifests shortly after birth with symptoms of lower intestinal obstruction such as failure to pass meconium within the first 48 hours of life, abdominal pain, constipation, progressive abdominal distention, vomiting, and occasionally diarrhea. Rarely, it presents later in childhood with symptoms of severe constipation and failure to thrive. Four forms of the disease are recognized on the basis of the extent of aganglionosis: in the classic form (HSCR; 80% of cases), aganglionosis is restricted to the rectosigmoid. In long-segment HSCR (15%), aganglionosis extends above the sigmoid colon, while in total colonic aganglionosis (5%), aganglionosis involves the entire large intestine. Total intestinal aganglionosis is the most severe form and is extremely rare.

HSCR is a neurocristopathy and is due to a defect in the development of the enteric nervous system. It is characterized by the absence of neuronal ganglion cells (aganglionosis) in the terminal part of the intestine. The affected bowel segment maintains a state of tonic contraction, resulting in a functional bowel obstruction. Genetic and environmental factors play a role in its pathogenesis. Several genes are associated with HSCR, particularly: the RET proto-oncogene (RET; 10q11.21), the glial cell derived neurotrophic factor gene (GDNF), the neurturin gene (NRTN), the endothelin B receptor gene (EDNRB), the endothelin-3 gene (EDN3), the endothelin-converting enzyme 1 gene ECE1, and the L1 cell adhesion molecule gene L1CAM.

Diagnosis is based on suction rectal biopsy of rectal mucosa and submucosa that shows aganglionosis, thickened extrinsic nerve fibers and overexpression of acetylcholinesterase. Recently, it has been shown that calretinin immunohistochemistry is useful. Assessment for associated anomalies allows the detection of syndromic HSCR. Plain abdominal radiography, lower gastrointestinal contrast studies, and ultrasound are useful in excluding alternative diagnoses.

Differential diagnosis includes gastrointestinal malformations such as anorectal malformation, chronic intestinal pseudo-obstruction, meconium ileus, anorectal stenosis and pelvic tumors. HSCR can also be associated with syndromes such neurologic Waardenburg-Shah syndrome, Bardet-Biedl syndrome, Mowat-Wilson syndrome, Haddad syndrome, or multiple endocrine neoplasia syndrome type 2A, Goldberg Shprintzen syndrome, Smith-Lemli-Opitz syndrome, Kaufman-McKusick syndrome, orofaciodigital syndrome type 5, PCWH syndrome, cartilage-hair-hypoplasia, and Down syndrome.

There are currently no practical capabilities for the prenatal diagnosis of HSCR, as abnormal sonographic findings are absent in the majority of fetuses with HSCR.

Most cases of non-syndromic HSCR are sporadic although familial cases are possible and thus genetic testing of both parents and the index patient may give a more accurate estimation of the risk of recurrence in future pregnancies. Genetic testing of RET to exclude the rare possibility of a MEN 2A associated RET mutation should be considered.

Treatment is surgical. It consists in resection of the aganglionic segment together with the transition zone followed by anastomosis of the proximal bowel to the anal margin. Different techniques including minimal invasive surgery as well as transanal surgery are applied. Type of surgery is dependent on the patient, length of aganglionosis and preference of the surgeon. Small bowel aganglionosis can lead to intestinal failure. In case of total intestinal aganglionosis, intestinal transplantation may be required.

Overall survival and functional prognosis are good in rectosigmoid or long-segment Hirschsprung, despite issues with constipation and continence even following surgical correction. Functional prognosis of total colonic Hirschsprung's is acceptable. The prognosis for children with small bowel or total intestinal aganglionosis leading to intestinal failure can be poor although intestinal transplantation is attempted to offer long term survival in complicated cases. Hirschsprung enterocolitis occurs in 30-50% of the cases but reacts well to treatment in most cases.

Last update: September 2021 - Expert reviewer(s): Dr A.S. [Alice] BROOKS | ERNICA* - Pr Mikko PAKARINEN | ERNICA* - Dr Pim SLOOTS | ERNICA* - Pr Tomas WESTER | ERNICA*

* European Reference Network