Penetrance of inherited medullary thyroid carcinoma and genotype-phenotype correlation in a large multiple endocrine neoplasia type 2A family with C634Y RET mutation.

Multiple endocrine neoplasia type 2A (MEN 2A) and familial medullary thyroid carcinoma (FMTC) are characterized by development of medullary thyroid carcinoma (MTC) and caused by germline RET mutations. Patients with MEN 2A also develop pheochromocytoma and/or hyperparathyroidism (HPT). However, MEN 2A-affected individuals could display the FMTC phenotype at first clinical manifestation. To establish the correct phenotype and improve clinical management of patients affected by hereditary MTC, clinical screening, RET mutational analysis, penetrance of MTC, and genotype-phenotype correlation were performed in a large, suspected FMTC kindred of 86 individuals. Germline C634Y RET mutation was confirmed in 22 individuals, 15 of whom were thyroidectomized when high serum calcitonin levels were detected. MTC was confirmed in 12 individuals and C-cell hyperplasia in 3. HPT was detected in two patients. High penetrance of MTC at young age (79% at 30 yr of age) was found. This family was considered to be affected by FMTC for several years because MTC was the sole clinical manifestation. However, our results allowed reclassifying the family as MEN 2A, thereby improving clinical management of family members. Our findings regarding penetrance and genotype-phenotype correlation suggest that patients considered to have FMTC may in fact have MEN 2A in some kindreds.