A Novel SDHB IVS2-2A>C Mutation Is Responsible for Hereditary Pheochromocytoma/Paraganglioma Syndrome.

Pheochromocytomas and paragangliomas are neuroendocrine tumors which arise from adrenal medulla, and sympathetic or parasympathetic nerves, respectively. Hereditary cases afflicted by both or either pheochromocytomas and paragangliomas have been reported: these are called hereditary pheochromocytoma/paraganglioma syndromes (HPPS). Many cases of HPPS are caused by mutations of one of the succinate dehydrogenase (SDH) genes; mainly SDHB and SDHD that encode subunits for the mitochondrial respiratory chain complex II. In this study, we investigated mutations of SDH genes in six HPPS patients from four Japanese pedigrees using peripheral blood lymphocytes (from one patient with pheochromocytoma and five patients with neck paraganglioma) and tumor tissues (from two patients with paraganglioma). Results showed that all of these pedigrees harbor germline mutations in one of the SDH genes. In two pedigrees, a novel IVS2-2A>C mutation in SDHB, at the acceptor-site in intron 2, was found, and the tumor RNA of the patient clearly showed frameshift caused by exon skipping. Each of the remaining two pedigrees harbors a reported missense mutation, R242H in SDHB or G106D in SDHD. Importantly, all these mutations are heterozygous in constitutional DNAs, and two-hit mutations were evident in tumor DNAs. We thus conclude that the newly identified IVS2-2A>C mutation in SDHB is responsible for HPPS. The novel mutation revealed by our study may contribute to improvement of clinical management for patients with HPPS.

Succinate Dehydrogenase Mutations as Familial Pheochromocytoma Syndromes.

It is recognized that a large portion of pheochromocytoma and paraganglioma cases will have an underlying germline mutation, supporting the recommendation for universal genetic testing in all patients with PPGLs. A mutation in succinate dehydrogenase subunit B is associated with increased rates of developing synchronous and/or metachronous metastatic disease. Patients identified with this mutation require meticulous preoperative evaluation, a personalized surgical plan to minimize the risk of recurrence and tumor spread, and lifelong surveillance.

Hereditary pheochromocytoma/paraganglioma syndrome with a novel mutation in the succinate dehydrogenase subunit B gene in a Japanese family: two case reports.

BACKGROUND: Pheochromocytoma and paraganglioma caused by succinate dehydrogenase gene mutations is called hereditary pheochromocytoma/paraganglioma syndrome. In particular, succinate dehydrogenase subunit B mutations are important because they are strongly associated with the malignant behavior of pheochromocytoma and paraganglioma . This is a case report of a family of hereditary pheochromocytoma/paraganglioma syndrome carrying a novel mutation in succinate dehydrogenase subunit B. CASE PRESENTATION: A 19-year-old Japanese woman, whose father died of metastatic paraganglioma, was diagnosed with abdominal paraganglioma, and underwent total resection. Succinate dehydrogenase subunit B genetic testing detected a splice-site mutation, c.424-2delA, in her germline and paraganglioma tissue. Afterwards, the same succinate dehydrogenase subunit B mutation was detected in her father's paraganglioma tissues. In silico analysis predicted the mutation as "disease causing." She is under close follow-up, and no recurrence or metastasis has been observed for 4 years since surgery. CONCLUSIONS: We detected a novel succinate dehydrogenase subunit B mutation, c.424-2delA, in a Japanese family afflicted with hereditary pheochromocytoma/paraganglioma syndrome and found the mutation to be responsible for hereditary pheochromocytoma/paraganglioma syndrome. This case emphasizes the importance of performing genetic testing for patients with pheochromocytoma and paraganglioma suspected of harboring the succinate dehydrogenase subunit B mutation (that is, metastatic, extra-adrenal, multiple, early onset, and family history of pheochromocytoma and paraganglioma) and offer surveillance screening to mutation carriers.