Pathogenesis of Hirschsprung's disease

Giuseppe Martucciello, Isabella Ceccherini, Margherita Lerone, Vincenzo Jasonni

Research output: Contribution to journalArticlepeer-review


Hirschsprung's disease is an inherited disorder showing incomplete penetrance and variable expressivity. Genetic mapping and mutation screening of candidate genes, together with the study of several natural and knockout animal models, clearly have shown the involvement of several different genes in the pathogenesis of Hirschsprung's disease. Among these genes, the RET proto-oncogene accounts for the highest proportion of both familial and sporadic cases, with a wide range of mutations scattered along its entire coding region. The low detection rate of RET mutations in Hirschsprung patients also led to different hypotheses, such as the existence of additional Hirschsprung genes. Different animal and human genetic studies have identified 6 Hirschsprung genes: RET proto-oncogene (RET), endothelin 3 (EDN3), endothelin B receptor gene (EDNRB), glial-cell-line-derived neurotrophic factor (GDNF), endothelin converting enzyme (ECE1), gene encoding the Sry-related transcription factor SOX10 (SOX10). Microenvironmental factors also can play a role in the pathogenesis of aganglionosis. The developmental process of the crest-derived progenitor cells is sensitive to the level of different molecules. The expression deficit of different factors (GDNF, NTN) in the hindgut, in the absence of genetic mutations, could determine a missed activation of the receptor system, causing enteric neuroblast migration arrest. Copyright (C) 2000 W.B. Saunders Company.

Original languageEnglish
Pages (from-to)1017-1025
Number of pages9
JournalJournal of Pediatric Surgery
Issue number7
Publication statusPublished - Jul 2000


  • Gene mutation
  • Genetic mapping
  • Hirschsprung's disease

ASJC Scopus subject areas

  • Surgery


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