[Genetics of Hirschsprung disease]

Hirschsprung's disease (HD) is one of the commonest gastrointestinal malformations, as it affects one child out of 5,000 births. It classically induces severe neonatal intestinal obstruction requiring surgical treatment which currently ensures a favourable prognosis for most of the affected children. Although the great majority of cases are sporadic, the existence of familial forms (10% of cases) has allowed localization and then identification of an autosomal dominant gene on chromosome 10, the RET proto-oncogene, responsible for 50% of familial forms and 15% of sporadic cases. A second gene has been recently localized on chromosome 13, the endothelium beta receptor (EDNRB) gene. Two homozygous mutations of the EDNRB gene have been identified in two consanguineous families, in which HD is associated with Waardenburg's syndrome (WS). Other heterozygous mutations have been identified in patients presenting with isolated HD and an 5% of cases of HD can be considered to present mutations of this gene. Finally, the authors have recently identified a mutation of the endothelium gene 3 (EDN3), one of the EDNRB ligands in a patient presenting with a combination of HD and WS. This mutation, present at the homozygous state in this patient, is predictive of complete absence of EDN3 protein: this is therefore the third known gene responsible for HD.