Understanding the development of congenital defects of the enteric nervous system, such as Hirschsprung’s disease, was, until recently, an intractable problem. The analysis of transgenic mice, however, has now led to the discovery of a number of genetic abnormalities that give rise to aganglionic congenital megacolon or neuronal intestinal dysplasia. The identification of the responsible genes has enabled the developmental actions of their protein products to be investigated, which, in turn, has made it possible to determine the causes of aganglionoses. Two models of pathogenesis have emerged. One, associated with mutations in genes encoding endothelin-3 or its receptor, endothelin B, posits the premature differentiation of migrating neural crest-derived progenitors, causing the precursor pool to become depleted before the bowel has been fully colonized. The second, associated with mutations in genes encoding glial cell line-derived neurotrophic factor (GDNF), its preferred receptor GFRα1, or their signaling component, Ret, appears to deprive a GDNF-dependent common progenitor of adequate support and/or mitogenic drive. In both cases, the terminal bowel becomes aganglionic when the number of colonizing neuronal precursors is inadequate.
A case of fulminant diversion pan-colitis presenting 19 years after colonic diversion for neuronal intestinal dysplasia
