A DUPLICATION OF 12 BP IN THE CRITICAL CYSTEINE-RICH DOMAIN OF THE RET PROTOONCOGENE RESULTS IN A DISTINCT PHENOTYPE OF MULTIPLE ENDOCRINE NEOPLASIA TYPE 2A

Activating germline mutations in the cysteine-rich domain of the RET p roto-oncogene are found in >92% of the cases of multiple endocrine neo plasia type 2A (MEN2A) and 85% of familial medullary thyroid carcinoma (FMTC), In virtually 100% of patients with identified mutations one o f five cysteines is altered by a missense mutation. In a MEN2A family with 14 affected and 11 unaffected living members, hypercalcemia was d iagnosed in eight patients and histological evaluation revealed parath yroid hyperplasia in all cases examined (10/10). No member of this fam ily showed any evidence for the existence of pheochromocytoma, This is the first documentation of a family without pheochromocytoma but with a high incidence of parathyroid disease, Genetic analysis revealed th e presence of an unusual heterozygous mutation in exon 11 of the RET p roto-oncogene representing a duplication of 12 bp resulting in the ins ertion of four amino acids between codon 634 (Cys) and 635 (Arg), thus creating an additional cysteine residue.