The familial medullary thyroid carcinoma-associated RET E768D mutation in a multiple endocrine neoplasia type 2A case.

The clinical manifestations of the dominantly inherited multiple endocrine neoplasia type 2 (MEN 2) syndrome (familial medullary thyroid cancer [FMTC], MEN 2A or MEN 2B phenotypes) are determined by the transforming activity and penetrance of specific missense mutations in the “rearranged during transfection” (RET) proto-oncogene. 1 Ichihara M. Murakumo Y. Takahashi M. RET and neuroendocrine tumors. Cancer Lett. 2004; 204: 197-211 Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar In addition to medullary thyroid carcinoma (MTC), which is the common feature of all MEN 2 clinical variants and the only manifestation of FMTC, concurrent pheochromocytoma develops in the more aggressive MEN 2A and MEN 2B phenotypes. Pheochromocytoma has been described, although at variable frequencies, in carriers of most RET gene mutations except in those of base substitutions at codons 533, 630, and 768. 2 Brandi M.L. Gagel R.F. Angeli A. Bilezikian J.P. Beck-Peccoz P. Bordi C. et al. Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab. 2001; 86: 5658-5671 Crossref PubMed Scopus (1368) Google Scholar , 3 Scacheri P.C. Crabtree J.S. Kennedy A.L. Swain G.P. Ward J.M. Marx S.I. et al. V804M RET mutation in MEN 2A: first report. Intern Med. 2004; 255: 712 Google Scholar , 4 Jimenez C. Habra M.A. Huang S.C. El-Naggar A. Shapiro S.E. Evans D.B. et al. Pheochromocytoma and medullary thyroid carcinoma: a new genotype-phenotype correlation of the RET proto-oncogene 891 germline mutation. J Clin Endocrinol Metab. 2004; 89: 4142-4145 Crossref PubMed Scopus (34) Google Scholar , 5 Da Silva A.M. Maciel R.M. Da Silva M.R. Toledo S.R. De Carvalho M.B. Cerutti J.M. A novel germ-line point mutation in RET exon 8 (Gly(533)Cys) in a large kindred with familial medullary thyroid carcinoma. J Clin Endocrinol Metab. 2003; 88: 5438-5443 Crossref PubMed Scopus (92) Google Scholar Hence, the latter mutations have until now been associated exclusively with the FMTC phenotype.