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A Novel Case of Multiple Endocrine Neoplasia Type 2A Associated with Two de Novo Mutations of the RETProtooncogene¹

Dipartimento di Biochimica e Biotecnologie Mediche e Ceinge, Centro di Ingegneria Genetica, Università degli Studi di Napoli Federico II (A.T., M.C., D.V., V.C.), e Istituto di Endocrinologia, Seconda Università di Napoli (A.A.S., D.P., A.B.), 80131 Naples; and Facoltà di Scienze, Università del Sannio (V.C.), 82100 Benevento, Italy

Address all correspondence and requests for reprints to: Vittorio Colantuoni, M.D., Department of Biochemistry and Medical Biotechnologies, Via Sergio Pansini 5, 80131 Naples I, Italy. E-mail: colantuoni{at}dbbm.unina.it

We report a novel case of multiple endocrine neoplasia type 2A (MEN 2A) associated with two mutations of the protooncogene RET. One affects codon 634 and causes a cysteine to arginine substitution; the second at codon 640 causes an alanine to glycine substitution in the transmembrane region. The two mutations were present on the same RET allele and were detected in germline and tumor DNA. Both mutations were de novo, i.e. they were not found in the DNA of the parents or relatives. Immunohistochemical and RT-PCR analysis showed that the pheochromocytoma expressed calcitonin as well as both RET alleles. A cell line established from the tumor and propagated in culture sustained the expression of RET and calcitonin, as did the original pheochromocytoma. Because the patient presented with medullary thyroid carcinoma and pheochromocytoma without parathyroid gland involvement, we speculate that this clinical picture could be correlated with the two RET mutations and to the unusual calcitonin production. This is the first report of a MEN 2A case due to two mutations of the RET gene and associated with a calcitonin-producing pheochromocytoma.

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