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Hirschsprung disease

Monday 6 October 2003

Hirschsprung’s disease, congenital intestinal aganglionosis, digestive aganglionnosis; digestive aganglionoses


Definition: Aganglionic megacolon is associated with congenital absence of intrinsic ganglion cells in the myenteric (Auerbach) and submucosal (Meissner) plexuses of the gastrointestinal tract. The disorder is genetically heterogeneous.

Digital cases

- HPC:90 : rectal mucosa biopsies
- HPC:98 : rectal mucosa biopsies
- HPC:151 : Hirschsprung disease - Rectal mucosa biopsies
- HPC:228 : Hirschsprung disease - Rectal mucosa biopsies
- HPC:361 : Appendiceal Hirschsprung disease


- Hirschsprung disease (isolated) (MIM.142263)


- rectal Hirschsprung disease (short-segment Hirschsprung disease)
- colorectal Hirschsprung disease (long-segment Hirschsprung disease)


- chromosomal anomalies

  • trisomy 21 (Down syndrome)
  • del10q11 (RET)
  • del13q22 (EDNRB)
  • del2q22-q23 (ZFHX1B)
  • del 17q21
  • dup17q21-q23
  • tri22pter-q11 (Cat eye syndrome)

- syndromic neural crest disorders

- colorectal aganglionnosis mandatory

  • Goldberg-Sphrintzen syndrome (GOSHS) (KIAA1279 mutations) (MIM.235730)
  • Hirschsprung disease with limb anomalies
  • Hirschsprung disease with mental retardation (MIM.235730)
    • mutations of the ZFHX1B or SMADIP1 gene (MIM.605802)
    • Mowat-Wilson syndrome (distinct facial appearance, microcephaly, agenesis of the corpus callosum and mental retardation) (ZFHX1B mutations) (14681759)
    • HSAS/MASA spectrum with mutations in the X-linked L1CAM gene.

- colorectal aganglionnosis occasionally associated

  • ciliopathies
    • Bardet-Bield syndrome (BBS)
    • Kaufman-McKusick syndrome (MIM.236700)
    • Jeune syndrome (Jeune asphyxing thoracic dystrophia) (MIM.208500)
    • Joubert syndrome

- colorectal aganglionnosis rarely associated

- miscellaneous associations

- cardiac defects, craniofacial abnormalities and other dysmorphic features, and autonomic dysfunction (mutations in the ECE1 gene)(9915973)
- severe hydrocephalus (mutations in the L1CAM gene (11857550)
- persistent Mullerian duct syndrome

Associated anomalies

A wide spectrum of additional isolated anomalies have been described among HSCR cases, with an incidence varying from 5–30% according to series. No constant pattern is observed and these anomalies include distal limb, sensorineural, skin, central nervous system, genital, kidney and cardiac malformations.

However, cardiac defects, and mostly atrio- or ventriculoseptal defects, are found with an incidence of 5% of HSCR cases, once removed patients with trisomy 21 and HSCR.

Renal dysplasia or agenesis was reported in FMTC and found in 4.4% in a series of 160 HSCR cases and may still be underestimated. This is of interest since homozygous knock-out mice for genes involved in the Ret signalling pathway present with renal agenesia/dysplasia in addition to megacolon.

Genital anomalies including hypospadias are reported in up to 2–3% of HSCR patients.

Gastrointestinal malformations such as Meckel diverticulum, pyloric stenosis, single umbilical arteria, inguinal hernia or small bowel atresia are also found.

Facial dysmorphic features seem extremely frequent when looked for.


Hirschsprung disease genes


- HSCR1: dominant mutations in the RET gene (MIM.164761) in 3% of isolated sporadic Hirschsprung’s disease
- HSCR2 at 13q22: recessive mutation in the EDNRB gene coding for the endothelin receptor type B (MIM.131244) - Hirschsprung disease-2 (MIM.600155)
- Locus 5p13-p12: mutations in gene GDNF coding for glial cell line-derived neurotrophic factor (MIM.600837)
- mutations in ECE1 gene coding for endothelin converting enzyme-1 (MIM.600423)

- 19p13.3: mutations in the NRTN gene coding for neurturin (MIM.60201)
- 21q22
- 20q13: mutations in gene EDN3 coding for endothelin-3 (MIM.131242)
- 22q13: mutations in the SOX10 gene (22q13) (MIM.602229)

S-HSCR 3p21 10q11 19q12
10q11 HSCRS2 RET
3p21 HSCRS2 - MIM.606874
19q12 HSCRS3 - MIM.606875

Etiology by subtypes

- short-segment Hirschsprung disease 1 - 10q11.2 - RET
- short-segment Hirschsprung disease 2 (MIM.606874) - 3p21
- short-segment Hirschsprung disease 3 (MIM.606875) - 19q12


- Hirschsprung disease by Washington deceit

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- Chakravarti A. Endothelin receptor-mediated signaling in hirschsprung disease. Hum Mol Genet. 1996 Mar;5(3):303-7. PMID: 8852653

- Qualman SJ, Murray R. Aganglionosis and related disorders. Hum Pathol. 1994 Nov;25(11):1141-9. PMID: 7959658

- Ariel I, Vinograd I, Lernau OZ, Nissan S, Rosenmann E. Rectal mucosal biopsy in aganglionosis and allied conditions. Hum Pathol. 1983 Nov;14(11):991-5. PMID: 6195084


- Histopathological and immunohistochemical study of the enteric innervations among various types of aganglionoses including isolated and syndromic Hirschsprung disease. Matsuda H, Hirato J, Kuroiwa M, Nakazato Y. Neuropathology. 2006 Feb;26(1):8-23. PMID: 16521475