Pathogenesis of Hirschsprung's disease

Hirschsprung's disease is an inherited disorder showing incomplete penetran ce and variable expressivity. Genetic mapping and mutation screening of can didate genes, together with the study of several natural and knockout anima l models, clearly have shown the involvement of several different genes in the pathogenesis of Hirschsprung's disease. Among these genes, the RET prot o-oncogene accounts for the highest proportion of both familial and sporadi c cases, with a wide range of mutations scattered along its entire coding r egion. The low detection rate of RETmutations in Hirschsprung patients also led to different hypotheses, such as the existence of additional Hirschspr ung genes. Different animal and human genetic studies have identified 6 Hir schsprung 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 trans cription factor SOX10 (SOX10). Microenvironmental factors also can play a r ole in the pathogenesis of aganglionosis. The developmental process of the crest-derived progenitor cells is sensitive to the level of different molec ules. The expression deficit of different factors (GDNF, NTN) in the hindgu t, in the absence of genetic mutations, could determine a missed activation of the receptor system, causing enteric neuroblast migration arrest. Copyr ight (C) 2000 by W.B. Saunders Company.