The pathogenesis of Hirschsprung disease.

Hirschsprung disease is the most common congenital malformation of the enteric nervous system. Phenotypic expression is variable because of incomplete penetrance, and the pathogenesis is multifactorial. Although mutations of the RET tyrosine kinase gene remain the most commonly identified cause, there are now eight separate human gene loci identified whose mutations result in this disease. Analysis of these gene products in experimental animal models and cell systems has led to an increasing elucidation of the signaling pathways that are in operation during specific embryonic time stages and that direct the spatial arrangements and differentiation of enteric neuroblasts. Mutation analysis through in vitro cell expression studies has led to detailed descriptions of the affected microdomains of signal pathway receptors and the cellular pathogenesis of abnormal signaling that leads to apoptosis of developing neurons before the completion of enteric nervous system development. The full description of the pathogenesis of this disorder awaits the definition of new genetic loci, multiple gene interactions, and the acknowledgment of random events that may lead to aganglionosis of the distal bowel.