A heterozygous endothelin 3 mutation in Waardenburg-Hirschsprung disease: is there a dosage effect of EDN3 / EDNRB gene mutations on neurocristopathy phenotypes?

Editor—Hirschsprung disease and Waardenburg syndrome are congenital malformations involving neural crest derivatives. Several genes are involved in these diseases, defining a complex pattern of inheritance. Hirschsprung disease (HSCR) is characterised by the absence of intramural ganglia in the distal bowel. This lack of enteric innervation results in intestinal obstruction or severe constipation. The incidence of HSCR is 1 per 5000 live births and both genetic and environmental factors are thought to contribute to the phenotype. The mode of inheritance is dominant in some families and recessive or multifactorial in others.1 In a number of cases, mutations of the RET proto-oncogene, a tyrosine kinase receptor, result in a dominant disease with incomplete penetrance.2-4 Mutations in the RET ligand GDNF (glial cell line derived neurotrophic factor) may also affect the phenotype.5-7 A few patients with HSCR were found to have heterozygous mutations in the genes encoding the endothelin B receptor ( EDNRB )8-10 or its ligand endothelin 3 ( EDN3 ).11 12 Waardenburg syndrome (WS) is characterised by a combination of sensorineural deafness and abnormal pigmentation, including a white forelock and eyelashes, heterochromia irides, and areas of skin depigmentation. Four subtypes of WS have been described on the basis of clinical features.13 Types 1 and 3 and type 2 are associated with mutations in the PAX3 and microphthalmia associated transcription factor ( MITF ) genes,14 respectively. Patients with type 4 WS (WS4, Waardenburg-Hirschsprung disease or Shah-Waardenburg syndrome) have features of both WS and HSCR.15 Several WS4 subjects have homozygous EDNRB or EDN3 gene mutations,12 16-19 whereas other patients have heterozygous mutations in the gene encoding SOX10,20 a transcription factor expressed in emerging neural crest cells. Endothelins are a family of three vasoactive peptides recognised by two G protein coupled heptahelical receptors. Endothelin 3 preferentially …