Phenotypic variation in a family with mutations in two Hirschsprung-related genes (RET and endothelin receptor B)

Hirschsprung disease is a congenital malformation affecting 1 in 5000 live births. The absence of parasympathetic neuronal ganglia (Meissner, Auerbach) in the hindgut results in poor coordination of peristaltic movement, and a varying degree of constipation. Four different genes have been implicated in the pathogenesis of Hirschsprung disease: the RET tyrosine kinase receptor gene; one of its ligands, the glial cell line-derived neurotrophic factor (GDNF) gene; the endothelin receptor B (EDNRB) gene; and its ligand, endothelin-3 (EDN3). Recently, combinations of mutations in two of these genes (RET and GDNF) have been reported in Hirschsprung patients. We report a family with missense mutations in both the RET gene (R982C) and the EDNRB gene (G57S). In this family, three out of five members have the two mutations, but only one, a boy, has the Hirschsprung disease phenotype. This illustrates the complexity of the molecular background of Hirschsprung disease.

Authors and Affiliations

1. Department of Molecular Medicine, Clinical Genetics Unit, CMM02, Karolinska Hospital, S-171 76 Stockholm, Sweden e-mail: Par-Johan.Svensson@cmm.ki.se, Fax: +46-8-5177-3620, , , , , , SE

   P.-J. Svensson, Maria Anvret & Agneta Nordenskjöld

2. Department of Pediatric Surgery, Karolinska/St Görans Hospital, Stockholm, Sweden, , , , , , SE

   Marie-Louise Molander

Received: 23 January 1998 / Accepted: 24 March 1998

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