RET codon 804 mutations in multiple endocrine neoplasia 2: genotype-phenotype correlations and implications in clinical management.

Multiple endocrine neoplasia type 2 (MEN 2) is a genetic syndrome caused by germline mutations in the RET proto-oncogene. These mutations cause changes in either the cysteine-rich extracellular domain or, less commonly, the non-cysteine intracellular domains of the RET protein. The genotype-phenotype correlations of classical cysteine RET mutations have been the subject of several comprehensive reviews. Less is known about the characteristics of the non-cysteine RET mutations. Studies of familial medullary thyroid cancer and MEN 2A kindreds carrying non-cysteine RET mutations have revealed a wide array of phenotypes, variable penetrance, and a diverse clinical course. The observed heterogeneity in disease expression has important diagnostic, therapeutic and prognostic implications. This review summarizes the genotypic and phenotypic characteristics of RET codon 804 mutation, a prototype for the less well-defined non-cysteine RET mutations associated with MEN 2.