GENETICS OF HIRSCHSPRUNGS-DISEASE

Hirschsprung's disease (HD) is one of the commonest gastrointestinal m alformations, as it affects one child out of 5.000 births. It classica lly induces severe neonatal intestinal obstruction requiring surgical treatment which currently ensures a favourable prognosis for most of t he affected children. Although the great majority of cases are sporadi c, the existence of familial forms (10% of cases) has allowed localiza tion and then identification of an autosomal dominant gene on chromoso me 10, the RET proto-oncogene, responsible for 50% of familial forms a nd 15% of sporadic cases. A second gene has been recently localized on chromosome 13, the endothelin beta receptor (EDNRB) gene. Two homozyg ous mutations of the EDNRB gene have been identified in two consanguin eous families, in which HD is associated with Waardenburg's syndrome ( WS). Other heterozygous mutations have been identified in patients pre senting with isolated HD and an 5% of cases of HD can be considered to present mutations of this gene. Finally, the authors have recently id entified a mutation of the endothelin 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 predicti ve of complete absence of EDN3 protein: this is therefore the third kn own gene responsible for HD.