GERM-LINE MUTATION ANALYSIS IN FAMILIES WITH MULTIPLE ENDOCRINE NEOPLASIA TYPE 2A OR FAMILIAL MEDULLARY-THYROID CARCINOMA

The RET proto-oncogene has been identified as the multiple endocrine n eoplasia type 2 disease gene. An association between specific RET muta tion and disease phenotype has been reported. We present the phenotype -genotype of 12 Greek families with multiple endocrine neoplasia type 2A (MEN 2A) or familial medullary thyroid carcinoma (FMTC). Seventy me mbers were studied and DNA analysis for RET mutations was performed in fifty-eight of them. Exons 10, 11, 13, 14 and 16 of the RET protoonco gene were analyzed by single strand conformation polymorphism analysis , direct DNA sequencing and/or restriction enzyme analysis. No mutatio ns of the RET proto-oncogene were identified in 1 of 9 families with M EN 2A and in the 3 families with FMTC. In 7 MEN 2A families, the mutat ion was demonstrated in codon 634 and in 1 family it was demonstrated in codon 620. There was a low frequency, about 8%, of hyperparathyroid ism associated with MEN 2A. The specific causative mutations for parar thyroid disease were C634R or C634Y. Among the MEN 2A individuals ther e was one case with de novo C634R mutation and one case, C634Y, with c utaneous lichen amyloidosis which predated by 24 years the diagnosis o f MEN 2A. In 2 children who were MEN 2A gene carriers, microscopic med ullary thyroid carcinomas were found. These data show a low frequency of hyperparathyroidism in our cases and provide further evidence that individuals with C634R as well as with C634Y mutations of the RET prot o-oncogene could be at risk for parathyroid disease. Cutaneous lichen amyloidosis could be an early feature of MEN 2A. Additionally, direct DNA testing provided an opportunity to resect medullary thyroid carcin oma at an early stage.