American Association of Endocrine Surgeon| Volume 146, ISSUE 6, P998-1005, December 2009

One hundred and seven family members with the rearranged during transfection V804M proto-oncogene mutation presenting with simultaneous medullary and papillary thyroid carcinomas, rare primary hyperparathyroidism, and no pheochromocytomas: Is this a new syndrome—MEN 2C?


      The rearranged during transfection (RET) V804M proto-oncogene mutation is rare and associated with medullary thyroid carcinoma (MTC). We present 40 members from a total cohort of 107 family members with this mutation.


      Family members were tested for RET mutations, calcitonin levels, and screened for pheochromocytoma and primary hyperparathyroidism (PHPT). Thyroidectomies were performed on 15 members. Surgery and pathology reports were obtained and reviewed. A pedigree was constructed.


      A high penetrance was found for MTC and simultaneous papillary thyroid carcinoma (PTC; 40%). The incidence of PHPT was low (13%). There were no findings of pheochromocytoma. The course in the first family generation was indolent, with late onset of MTC. The second generation experienced earlier disease development; onset occurred earliest in the third generation. The second generation experienced a higher incidence of PTC than the first.


      This is the largest family with this mutation reported to date. However, it does not fit the classic familial MTC or MEN 2A cancer syndrome. Considering that PTC is not an incidental finding, but the result of an inherited RET V804 M mutation, we propose to identify this phenotypic expression as a unique syndrome consistent with manifestations of MTC, PHPT, and PTC.
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        • Castellone M.D.
        • Santoro M.
        Dysregulated RET signaling in thyroid cancer.
        Endocrinol Metab Clin North Am. 2008; 37: 363-374
        • Takahashi M.
        • Ritz J.
        • Cooper G.M.
        Activation of a novel human transforming gene, ret, by DNA rearrangement.
        Cell. 1985; 42: 581-588
        • Donis-Keller H.
        • Dou S.
        • Chi D.
        • Carlson K.M.
        • Toshima K.
        • Lairmore T.C.
        • et al.
        Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC.
        Hum Mol Genet. 1993; 2: 851-856
        • Mulligan L.M.
        • Kwok J.B.
        • Healey C.S.
        • Elsdon M.J.
        • Eng C.
        • Gardner E.
        • et al.
        Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A.
        Nature. 1993; 363: 458-460
        • Eng C.
        • Smith D.P.
        • Mulligan L.M.
        • Nagai M.A.
        • Healey C.S.
        • Ponder M.A.
        • et al.
        Point mutation within the tyrosine kinase domain of the RET proto-oncogene in multiple endocrine neoplasia type 2B and related sporadic tumours.
        Hum Mol Genet. 1994; 3: 237-241
        • Carlson K.M.
        • Dou S.
        • Chi D.
        • Scavarda N.
        • Toshima K.
        • Jackson C.E.
        • et al.
        Single missense mutation in the tyrosine kinase catalytic domain of the RET protooncogene is associated with multiple endocrine neoplasia type 2B.
        Proc Natl Acad Sci U S A. 1994; 91: 1579-1583
        • Eng C.
        • Clayton D.
        • Schuffenecker I.
        • Lenoir G.
        • Cote G.
        • Gagel R.F.
        • et al.
        The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis.
        JAMA. 1996; 276: 1575-1579
        • 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
        • Fink M.
        • Weinhüsel A.
        • Niederle B.
        • Haas O.A.
        Distinction between sporadic and hereditary medullary thyroid carcinoma (MTC) by mutation analysis of the RET proto-oncogene. “Study Group Multiple Endocrine Neoplasia Austria (SMENA).”.
        Int J Cancer. 1996; 69: 312-316
        • Learoyd D.L.
        • Gosnell J.
        • Elston M.S.
        • Saurine T.J.
        • Richardson A.L.
        • Delbridge L.W.
        • et al.
        Experience of prophylactic thyroidectomy in multiple endocrine neoplasia type 2A kindreds with RET codon 804 mutations.
        Clin Endocrinol (Oxf). 2005; 63: 636-641
        • Gibelin H.
        • Bezieau S.
        • Misso C.
        • Bouin-Pineau M.H.
        • Maréchaud R.
        • Kraimps J.L.
        Germline RET V804M mutation associated with multiple endocrine neoplasia type 2A.
        Br J Surg. 2004; 91: 1458-1459
        • Pinna G.
        • Orgiana G.
        • Riola A.
        • Ghiani M.
        • Lai M.L.
        • Carcassi C.
        • et al.
        RET proto-oncogene in Sardinia: V804M is the most frequent mutation and may be associated with FMTC/MEN-2A phenotype.
        Thyroid. 2007; 17: 101-104
        • Feldman G.L.
        • Edmonds M.W.
        • Ainsworth P.J.
        • Schuffenecker I.
        • Lenoir G.M.
        • Saxe A.W.
        • et al.
        Variable expressivity of familial medullary thyroid carcinoma (FMTC) due to a RET V804M (GTG–>ATG) mutation.
        Surgery. 2000; 128: 93-98
        • Frohnauer M.K.
        • Decker R.A.
        Update on the MEN 2A c804 RET mutation: is prophylactic thyroidectomy indicated?.
        Surgery. 2000; 128: 1052-1057
        • Decker R.
        • Peacock M.
        Update on the profile of multiple endocrine neoplasia type 2a RET mutations.
        Cancer Supplements. 1997; 80: 557-568
        • Fattoruso O.
        • Quadro L.
        • Libroia A.
        • Verga U.
        • Lupoli G.
        • Cascone E.
        • et al.
        A GTG to ATG novel point mutation at codon 804 in exon 14 of the RET proto-oncogene in two families affected by familial medullary thyroid carcinoma.
        Hum Mutat. 1998; Suppl 1: S167-S171
        • Brauckhoff M.
        • Gimm O.
        • Hinze R.
        • Ukkat J.
        • Brauckhoff K.
        • Dralle H.
        Papillary thyroid carcinoma in patients with RET proto-oncogene germline mutation.
        Thyroid. 2002; 12: 557-561
        • Dionigi G.
        • Castano P.
        • Bertolini V.
        • Boni L.
        • Rovera F.
        • Tanda M.L.
        • et al.
        Simultaneous medullary and papillary thyroid cancer: two case reports.
        J Med Case Reports. 2007; 1: 133
        • Papi G.
        • Corrado S.
        • Pomponi M.G.
        • Carapezzi C.
        • Cesinaro A.
        • LiVolsi V.A.
        Concurrent lymph node metastases of medullary and papillary thyroid carcinoma in a case with RET oncogene germline mutation.
        Endocr Pathol. 2003; 14: 269-276
        • Foppiani L.
        • Forzano F.
        • Ceccherini I.
        • Bruno W.
        • Ghiorzo P.
        • Caroli F.
        • et al.
        Uncommon association of germline mutations of RET proto-oncogene and CDKN2A gene.
        Eur J Endocrinol. 2008; 158: 417-422
        • Shaha A.R.
        • Cohen T.
        • Ghossein R.
        • Tuttle R.M.
        Late-onset medullary carcinoma of the thyroid: need for genetic testing and prophylactic thyroidectomy in adult family members.
        Laryngoscope. 2006; 116: 1704-1707
        • Lecube A.
        • Hernandez C.
        • Oriola J.
        • Galard R.
        • Gémar E.
        • Mesa J.
        • et al.
        V804 M RET mutation and familial medullary thyroid carcinoma: report of a large family with expression of the disease only in the homozygous gene carriers.
        Surgery. 2002; 131: 509-514
        • Miccoli P.
        • Minuto M.N.
        • Galleri D.
        • D'Agostino J.
        • Basolo F.
        • Antonangeli L.
        • et al.
        Incidental thyroid carcinoma in a large series of consecutive patients operated on for benign thyroid disease.
        Aust N Z J Surg. 2006; 76: 123-126
        • Recasens M.
        • Oriola J.
        • Fernández-Real J.M.
        • Roig J.
        • Rodríguez-Hermosa J.I.
        • Font J.A.
        • et al.
        Asymptomatic bilateral adrenal pheochromocytoma in a patient with a germline V804M mutation in the RET proto-oncogene.
        Clin Endocrinol (Oxf). 2007; 67: 29-33
        • Sippel R.S.
        • Kunnimalaiyaan M.
        • Chen H.
        Current management of medullary thyroid cancer.
        Oncologist. 2008; 13: 539-547