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Familial Malignant Catecholamine-Secreting Paraganglioma with Prolonged Survival Associated with Mutation in the Succinate Dehydrogenase B Gene

Genetic Counseling Program (A.L.Y.), University of Minnesota, Minneapolis, Minnesota 55455; Departments of Psychiatry, Otolaryngology, and Human Genetics (B.E.B.), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213; and Division of Endocrinology, Metabolism, and Nutrition (W.F.Y.) and Department of Internal Medicine (A.D.), Mayo Clinic, Rochester, Minnesota 55905

Address all correspondence and requests for reprints to: William F. Young, Jr., M.D., Mayo Clinic, 200 First Street S.W., Rochester, Minnesota 55905. E-mail: . young.william{at}mayo.edu

Abstract

Approximately 10% of catecholamine-secreting tumors are malignant, and 10% are familial. These tumors have been associated with several hereditary syndromes, including multiple endocrine neoplasia type 2, von Hippel-Lindau syndrome, neurofibromatosis type 1, and familial paraganglioma. Mutations in succinate dehydrogenase (SDH) subunit genes have been identified in some kindreds with catecholamine-secreting tumors.

In 1972 at the Mayo Clinic, a metastatic catecholamine-secreting paraganglioma was diagnosed in a 32-yr-old man. In 1979, 7 yr after the initial surgical treatment, a lytic metastasis to the left femur was found and was treated with local external radiotherapy. Locally metastatic abdominal catecholamine-secreting paragangliomas were diagnosed in the patient’s 27-yr-old son.

Analyses of the VHL, RET, SDHD, and SDHC genes revealed no mutations. However, a missense point mutation was detected in the SDHB gene: c.725GA in exon 7, which alters a conserved arginine at amino acid position 242 to a histidine (R242H). Sequencing of the SDHB gene in the tumors did not reveal any somatic mutations or loss of heterozygosity of the remaining allele.

Thirty years after the initial diagnosis, the father is one of the longest living survivors of malignant catecholamine-secreting paraganglioma. Our findings indicate that mutations in SDHB may be associated with metastatic, yet clinically indolent, abdominal paraganglioma in some families.

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