Hereditary Paraganglioma and Pheochromocytoma

Paragangliomas (PGLs) and pheochromocytomas (PCCs) are rare neuroendocrine tumors, which predominantly occur in the head and neck. They can be part of a syndrome, such as multiple endocrine neoplasia (MEN), neurofibromatosis (NF) type 1, and von Hippel-Lindau syndrome (VHL). Hereditary PGLs/PCCs are caused by molecular defects in the mitochondrial respiratory chain complex II, also known as the succinate dehydrogenase (SDH) complex, which contains protein subunits and assembly factors encoded by the nuclear genes, SDHA, SDHB, SDHC, SDHD, and SDHAF2. This chapter focuses on molecular mechanisms, available clinical molecular tests, interpretation of test results, and the clinical utility of molecular testing for hereditary PGL/PCC caused by mutations in the SDH genes. In general, diagnosis can be achieved by immunohistochemical studies of tumors, sequence analysis of SDH genes in germline cells and tumor tissues, and detection of large heterozygous deletions or duplications by microarray-based technology. Detailed clinical evaluation and family history are vital to appropriate prioritization of the diagnostic testing and for interpretation of test results.