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Hirschsprung disease (HSCR) is a congenital intestinal motility disorder that is characterized by signs of intestinal obstruction due to the presence of an aganglionic segment of variable extent in the terminal part of the colon.
ORPHA:388Classification level: Disorder
- Aganglionic megacolon
- Congenital intestinal aganglionosis
- Prevalence: 1-5 / 10 000
- Inheritance: Autosomal dominant or Autosomal recessive or Multigenic/multifactorial or Not applicable
- Age of onset: Infancy, Neonatal
- ICD-10: Q43.1
- OMIM: 142623 600155 600156 606874 606875 608462 611644 613711 613712
- UMLS: C0019569 C3661523
- MeSH: D006627
- GARD: 6660
- MedDRA: 10010539
HSCR has an estimated annual incidence of 1/5,000 births. Short segment HSCR is more frequent in males.
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. HSCR can also be associated with additional anomalies such as sensorineural hearing loss (neurologic Waardenburg-Shah syndrome), limb anomalies (Bardet-Biedl syndrome), intellectual deficit (Mowat-Wilson syndrome), central alveolar hypoventilation (Haddad syndrome), or medullary thyroid carcinoma (multiple endocrine neoplasia syndrome type 2B). HSCR is also associated with chromosomal abnormalities, mainly Down syndrome (see these terms).
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 (Cajal 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. 4 forms of the disease are recognized on the basis of the extent of aganglionosis: in the classic form (short segment HSCR; 80% of cases), aganglionosis is restricted to the rectosigmoid. In long-segment HSCR (15%), aganglionosis extends near 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. Genetic and environmental factors play a role in its pathogenesis. Several genes are associated with HSCR, particularly: the Ret proto-oncogene (RET), the glial cell derived neutrotrophic 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 fibres and overexpression of acetylcholinesterase. 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 atresia, chronic intestinal pseudoobstruction, meconium ileus (see these terms), anorectal stenosis and pelvic tumors.
No prenatal diagnosis is currently available. Abdominal distension is rarely seen on prenatal ultrasound in children with HSCR and is thus non-predictive.
Genetic counseling is difficult because HSCR is a polygenic disorder with incomplete penetrance and variable expressivity.
Management and treatment
Treatment is surgical. It consists in resection of the aganglionic segment followed by anastomosis of the proximal bowel to the anal margin (''pullthrough''). In case of total intestinal aganglionosis, intestinal transplantation may be required.
Overall prognosis is good in most cases, despite issues with constipation and continence even following surgical correction. The prognosis for children with total intestinal aganglionosis is poor although intestinal transplantation may offer long term survival. Hirschsprung enterocolitis, an inflammatory condition of the bowel which can be life-threatening, may also occur.
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