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.

Classification

 Hirschsprung disease (isolated) (MIM.142263)
 short-segment Hirschsprung's disease

 Hirschsprung disease with mental retardation (MIM.235730)

• mutations of the ZFHX1B or SMADIP1 gene (MIM.605802)

Associations

 trisomy 21 (Down syndrome)
 mental retardation
 Waardenburg syndrome (MIM.277580)
 heart defects, laryngeal anomalies and preaxial polydactyly (MIM.604211)
 cardiac defects, craniofacial abnormalities and other dysmorphic features, and autonomic dysfunction - mutations in the ECE1 gene (#9915973#)
 polydactyly, renal agenesis and deafness (MIM.235740)
 hypoplastic nails and dysmorphic facial features (MIM.235760)
 type D brachydactyly (MIM.306980)
 ulnar polydactyly, polysyndactyly of big toes and ventricular septal defect (MIM.235750)
 severe hydrocephalus (mutations in the L1CAM gene (#11857550#)
 Smith-Lemli-Opitz syndrome (#3998935#, #6886911#)
 persistent Mullerian duct syndrome
 supernumerary digits
 segmental hypopigmentation

 Mowat-Wilson syndrome

• distinct facial appearance, microcephaly, agenesis of the corpus callosum and mental retardation (mutations in the ZFHX1B gene) (#14681759#)

 Goldberg-Shprintzen syndrome (GOSHS)

• germline mutations in KIAA1279

Etiology

 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)
 HSCR3
 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)

|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

References

 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#