Hirschsprung disease (HSCR, aganglionic megacolon) is a frequent congenital 
malformation regarded as a multigenic neurocristopathy. Two susceptibility genes 
have been recently identified in HSCR, namely the RET proto-oncogene and the 
endothelin B receptor (EDNRB) gene. Hitherto however, homozygosity for EDNRB 
mutations accounted for the HSCR-Waardenburg syndrome (WS) association. Here, we 
report heterozygous EDNRB missense mutations (G57S, R319W and P383L) in isolated 
HSCR. These data might suggest that EDNRB mutations could be dosage sensitive: 
heterozygosity would predispose to isolated HSCR with incomplete penetrance, 
while homozygosity would result in more complex neurocristopathies associating 
HSCR and WS features. In addition, the present data give further support to the 
role of the endothelin-signalling pathway in the development of neural 
crest-derived enteric neurons.