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)
Localization
rectal Hirschsprung disease (short-segment Hirschsprung disease)
colorectal Hirschsprung disease (long-segment Hirschsprung disease)
Associations
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
- SHAH-Waardenburg syndrome (WS4) (MIM.277580)
- Yemenite deaf-blind-hypopigmentation (MIM.601706)
- BADS (MIM.227010)
- piebaldism (MIM.172800)
- Haddad syndrome (MIM.209880)
- MEN2A (MIM.)
- Riley-Day syndrome (MIM.223900)
- familial neuroblastoma (association Hirschsprung disease-neuroblastoma) (8950328)
- segmental hypopigmentation
colorectal aganglionnosis mandatory
- Goldberg-Sphrintzen syndrome (GOSHS) (KIAA1279 mutations) (MIM.235730)
- BRESHEK
-
Hirschsprung disease with limb anomalies
- polydactyly, umilateral renal agenesis, hypertelorism, deafness (MIM.235740)
- postaxial polydactylt, ventricular septal defect (MIM.235750)
- heart defects, laryngeal anomalies and preaxial polydactyly (MIM.604211)
- 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)
- polydactyly (supernumerary digits)
-
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
- Smith-Lemli-Opitz syndrome (3998935, 6886911)
- cartilage-hair hypoplasia (MIM.250250)
- HSAS/MASA (MIM.307000)
colorectal aganglionnosis rarely associated
- Fukuyama congenital muscular dystrophy (MIM.253800)
- Clayton-Smith syndrome (MIM.258840)
- Kaplan syndrome (MIM.304100)
- Okamoto syndrome (MIM.308840)
- Werner mesomelic dysplasia (MIM.188770)
- Pitt-Hopkins syndrome (MIM.610954)
miscellaneous associations
- Pallister-Hail syndrome (CAVE) (MIM.140510)
- Fryns syndrome (MIM.229850)
- Aarskog syndrome (MIM.100050)
- fronto-nasal syndrome (MIM.136760)
- osteopetrosis
- Goldenhar syndrome (MIM.164210)
- Lesch-Nyhan syndrome (MIM.308000)
- Rubinstein-Taybi syndrome (MIM.180849)
- Toriello-Carey syndrome (MIM.217980)
- SEMDJL (MIM.271640)
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.
Etiology
Hirschsprung disease genes
| RET | GDNF | NTRN | SOX10 | EDNRB | EDN3 | ECE1 | ZFHX1B | phox2b | TCF4 |
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)
| 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
Videos
Hirschsprung disease by Washington deceit
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