Genetics of pheochromocytomas and paragangliomas

Pheochromocytoma and paraganglioma are tumors of the sympathetic or parasympathetic paraganglia. Pheochromocytoma is the tumor of the main sympathetic paraganglia, which is the adrenal medulla. The sympathetic paraganglioma secretes catecholamine while the parasympathetic do not. Both of them originate from neural crest cells and share similar mechanisms of tumor development. The same genetic alteration may predispose to the development of sympathetic and parasympathetic paraganglioma. The best known hereditary forms of pheochromocytoma and paraganglioma are the von Hippel-Lindau disease, in which pheochromocytoma may be associated with CNS hemangioblastoma, retinal angioma, pancreatic endocrine tumor/cysts and renal clear cell carcinoma/cysts; the multiple endocrine neoplasia type 2, in which pheochromocytoma is associated with medullary thyroid carcinoma and primary hyperparathyroidism, Type 1 neurofibromatosis, the most frequent hereditary cancer syndrome. Finally, it has been characterized the paraganglioma syndrome in which sympathetic and parasympathetic paraganglioma are variously associated. The list of predisposing gene is quite long and comprises VHL, RET, NF1, SDHB, SDHC, SDHD, SDHAF2. More rarely, two other genes may predispose to pheochromocytoma/paraganglioma development: KIF1Bbeta and PHD2. A mechanism conducing to a defective apoptosis is the common pathways of those genes. Finally, there is also good evidence of the role of other genes, not yet completely identified.