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Germline Succinate Dehydrogenase Subunit D Mutation Segregating with Familial Non-RET C Cell Hyperplasia

Institute of Molecular Pathology and Immunology of the University of Porto (J.L., P.S., V.M., M.S.-S.), Porto 4200-465, Portugal; Faculdade de Medicina da Universidade do Porto (J.L., P.S., M.S.-S.), Porto 4200-319, Portugal; Hospital de Pedro Hispano (J.T.-G., M.H.), Matosinhos 4450, Portugal; Strangeways Research Laboratory (D.W.), University of Cambridge, Cambridge CB1 4RN, United Kingdom; and Hospital de S. João (M.S.-S.), Porto 4200-319, Portugal

Address all correspondence and requests for reprints to: Dr. M. Sobrinho-Simões, Institute of Molecular Pathology and Immunology of the University of Porto, Rua Dr. Roberto Frias s/n, 4200-465 Porto, Portugal. E-mail: ssimoes{at}ipatimup.pt.

C cell hyperplasia is associated with medullary carcinoma of the thyroid in the inherited MEN2 syndromes, in which the great majority of cases have been shown to be due to a mutation in the RET oncogene. We report a study of a family with C cell hyperplasia and hypercalcitoninemia in which no cases of medullary carcinoma have yet occurred and which lacked an identifiable causative RET mutation. Four of the family members showed hypercalcitoninemia, and marked C cell hyperplasia was present in each of the three in whom thyroidectomy has been performed. We investigated the possible involvement of the SDHD gene, because somatic and germline mutations in this gene have been found in a variety of tumors of neural crest-derived tissue. A germline mutation in exon 2 of the SDHD gene (c149 A-G, His 50 Arg) was found in six members of the family; all the four available members with hypercalcitoninemia possessed the mutation. One of the five available members without hypercalcitoninemia, an 18-yr-old female, also showed the mutation. We conclude that we have identified a new syndrome, characterized by familial non-RET C cell hyperplasia. Our studies suggest that a mutation in SDHD may be causative. These observations have implications for apparently incidental cases of hypercalcitoninemia or C cell hyperplasia.

This work was supported by a grant from "Fundação para a Ciência e Tecnologia" (Programa Operacional Ciência, Tecnologia, Inovação/Ciências Biomédicas e Oncológicas/43944/2001).

Abbreviations: CEA, Carcino-embryonic antigen; FMTC, familial MTC; H&E, hematoxylin and eosin; LOH, loss of heterozygosity; MEN, multiple endocrine neoplasia; MTC, medullary thyroid carcinoma; PGL1, paraganglioma; RET, rearranged during transfection; SDH A–D, succinate dehydrogenase subunits A–D; SSCP, single strand conformation polymorphism.

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