ABSTRACT
Multiple endocrine neoplasia type 2A (MEN2A), a dominantly inherited cancer syndrome, is defined by the presence of medullary thyroid carcinoma (MTC), pheochromocytoma (pheo), and primary hyperparathyroidism (p-HPT). Along with multiple endocrine neoplasia type 2B (MEN2B) and familial medullary thyroid carcinoma (FMTC), it is associated with germline mutations of the RETproto-oncogene localized in 10q11.2. In FMTC and MEN2A, point mutations result in the substitution of one of five Cys residues in the extracellular domain of RET. In a larger pedigree from Saarland, several individuals were observed with C-cell thyroid carcinoma. We screened 16 members of this extended family by single-strand conformation polymorphism analysis (SSCP), polymerase chain reaction (PCR), followed by restriction enzyme analysis, and by sequencing the mutated regions. In 7 family members, all of whom had been earlier operated on because of MTC, a DNA transition from T to C was observed, causing an amino acid substitution Cys(634)Arg. Nine members of the kindred did not carry the mutation and may be excluded from yearly biochemical testing. One of these persons seems to have been unnecessarily operated on owing to a borderline pentagastrin test.
