Redefining the prevalence of different clinical variants in MEN2A and their correlation with RET germline mutations: a single-center series and experience

Multiple endocrine neoplasia type 2 (MEN2) is caused by germline RET mutations and is characterized by the presence of medullary thyroid cancer (MTC) associated or not with other endocrine neoplasias. MEN2 is classified as MEN2A, including different variants, and MEN2B. The aim of the present study was to evaluate the impact of the RET genetic screening in redefining the prevalence of the different MEN2 variants inside the MEN2A group. This study included 223 MEN2 families: 202 MEN2A (55 MEN2A classical, 3 MEN2A + lichen cutaneous amyloidosis (CLA), 5 MEN2A + Hirschsprung disease (HD) and 139 FMTC variants) and 21 MEN2B. RET germline mutations found in MEN2A classical variant, as well as in MEN2A + CLA and MEN2A + HD, were the 'high-risk' category in most cases, while only 5/139 RET-mutated FMTC families showed a 'high-risk' category mutation. The most frequent mutation in the FMTC variant was the p.Val804Met (62/139). Among all, 116 families had a known history of hereditary disease (group A) at diagnosis and 107 had an apparently sporadic form of MTC (group B). Different MEN2A variants and RET ATA risk level category mutations were observed in the two groups. In conclusion, we demonstrated that the FMTC is the most prevalent MEN2A variant; 'moderate-risk' RET mutations, particularly non-cysteine mutations, are almost exclusively present in the FMTC variant; about 50% of hereditary MTC kindreds are primarily discovered by the RET genetic screening, confirming the clinical utility of performing this analysis in all cases of MTC.