Clinical Information

Paragangliomas (PGL)and pheochromocytomas (PCC) are rare neuroendocrine tumors that arise from autonomous ganglia. Tumors located within the adrenal medulla (the largest sympathetic ganglion) are called pheochromocytomas, while those that stem from either parasympathetic or sympathetic ganglia are designated paragangliomas.

PGL/PCC have a germline genetic basis in up to 30% of cases.(1) The genes implicated in hereditary PGL/PCC syndrome include MAX, TMEM127, FH, and the SDHx genes.

The genes most frequently associated with hereditary PGL/PCC syndromes are the succinate dehydrogenase-associated genes SDHA, SDHAF2, SDHB, SDHC, and SDHD.

Germline alterations in the MAX gene are typically associated with increased risk for PCC, although some individuals have been identified with PGL. MAX variants occur in approximately 1% of patients with hereditary PGL/PCC syndromes.(2)

TMEM127 variants are associated most commonly with PCC and rarely PGL.(1) Alterations of TMEM127 account for approximately 2% of individuals with hereditary PGL/PCC.(2)

Recent evidence suggests that disease-causing variants in FH also increase risk for PGL/PCC.(3,4) Individuals with disease-causing FH variants carry a significantly increased risk for cutaneous or uterine leiomyomata and renal tumors.(5)

Alterations in VHL, NF1, and RET also increase risk for PGL/PCC, in addition to other types of tumors.(6)

Disease-causing variants in the VHL gene are associated with a syndrome called von Hippel Lindau (VHL) syndrome. In addition to PGL/PCC, individuals with VHL syndrome are at increased risk for hemangioblastomas, renal cell carcinoma, pancreatic cysts, neuroendocrine tumors, endolymphatic sac and epididymal tumors.(7)

NF1 gene variants are associated with neurofibromatosis type I (NF1). Individuals with NF1 are at increased risk for pheochromocytomas in addition to neurofibromas and central nervous system gliomas, such as optic nerve gliomas. NF1 is also characterized by other features such as cafe-au lait macules, axillary/inguinal freckling and Lisch nodules.(8)

Disease-causing RET variants result in a syndrome called multiple endocrine neoplasia type 2 (MEN2) or familial medullary thyroid cancer (FMTC). In addition to an increased risk for PGL/PCC, individuals with MEN2/FMTC have a very high risk of developing medullary thyroid cancer. Individuals with MEN2 may also have other features, such as primary hyperparathyroidism, mucosal neuromas, ganglioneuromatosis, and distinctive facial features.(9)

The National Comprehensive Cancer Network and the American Cancer Society provide recommendations regarding the medical management of individuals with hereditary PGL/PCC syndromes.(10)