Background Germline RET gene mutations are causative of MEN 2 and may be identified by genetic screening. Three different syndromes are distinguished: MEN 2A when MTC is associated with PHEO and/or parathyroid adenomas, MEN 2B when accompanied by a marfanoid habitus and/or a PHEO, and FMTC when only MTC is present.

Patients and methods During the last 13 years, we performed RET genetic screening in 807 subjects: 481 with apparently sporadic MTC, 37 with clinical evidence of MEN 2 and 289 relatives. Genomic DNA was extracted from the blood of all subjects and exons 10, 11, 13, 14, 15 and 16 were analysed by direct sequencing after PCR.

Results We unexpectedly discovered a germline RET mutation in 35/481(7.3%) apparently sporadic MTC patients. A germline RET mutation was also found in 36/37 patients with clinical evidence of hereditary MTC. The distribution of RET mutations in cysteine and non-cysteine encoding codons was significantly different in the two groups of patients with the prevalence of RET mutations in non-cysteine codons being higher in MTC that presented as apparently sporadic (p<0.0001). Thirty four FMTC (75.5% of all FMTC) arrived with apparent sporadic MTC, with no familial history of other MTC cases. According to genetic screening and clinical data, our 72 families were classified as follows: 45 FMTC (62.5%), 22 MEN 2A (30.5%) and 5 MEN 2B (7%).

Conclusions In this large series of MTC, hereditary forms, mainly FMTC, were clinically unsuspected in 7.3% of apparently sporadic cases. As a consequence, the prevalence of FMTC in our series is higher than that previously reported (60% versus 10%). In these cases, RET mutations were more prevalently located in non-cysteine codons. Data derived from our series helped elucidate the role of RET genetic screening for the identification of all forms of MEN 2 and especially for FMTC which are frequently clinically misdiagnosed as non-hereditable, sporadic cases.