Background: Multiple endocrine neoplasia type 2 (MEN 2) is a group of related autosomal dominant cancer syndromes caused by mutations in the RET protooncogene. A subset of familial Hirschsprung's disease, aganglionic megacolon, is also caused by mutations in this gene.
Methods: The authors performed mutation analysis of exons 10, 11, 13, and 16 of the RET gene is six established MTN 2 kindreds and in six patients with apparent sporadic disease, in order to correlate their genotypes and phenotypes.
Results: One of these kindred's carried both Hirschsprung's disease and MEN 2A in conjunction with a cysteine-to-arginine substitution of codon 620 of the RET gene. One patient with apparently sporadic disease was found to have a germline M918T mutation. Patients with confirmed familial disease all carried pathologic germline mutations of RET.
Conclusions: Several lines of evidence support a gain of function mechanism for tumorigenesis in the MEN 2 syndromes but a loss of function mechanism for aganglionosis in Hirschsprung's disease. The authors propose that a multihit mechanism can reconcile the apparent paradox of a single mutation that gives rise to both gain and loss of function disorders in a single patient.