Hereditary Paraganglioma-Pheochromocytoma Syndromes

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Paragangliomas (PGLs) and pheochromocytomas (PCCs) are rare neuroendocrine tumors that develop from specialized cells in the body’s neuroendocrine system. They can be benign or malignant. PGLs are nerve tumors that produce the hormone adrenaline, and PCCs are tumors of the adrenal gland.

Approximately 35 to 40% of all PGLs and PCCs are associated with a hereditary predisposition. A hereditary predisposition means there is a known genetic mutation that explains the diagnosis of the tumors. This mutation can be passed down from a parent to a child.

Mutations in several genes can predispose an individual to these hereditary syndromes:

  • Hereditary PGL/PCC is most often caused by mutations in the SDHASDHAF2, SDHBSDHC, and SDHD genes. Risk of these tumors being cancerous is low in tumors associated with mutations in the SDHASDHAF2, SDHC, and SDHD genes. But cancer risk is high in tumors associated with mutations in the SDHB gene.
  • TMEM127 gene mutations also lead to an increased risk for PGLs and PCCs.
  • MAX gene mutations lead to an increased risk for PCCs.

Other genetic conditions can also increase the risk for paraganglioma and pheochromocytoma:

  • Von Hippel-Lindau syndrome is caused by mutations in the VHL gene. People with this syndrome have an increased risk for developing PCCs, as well as for developing a type of kidney cancer called clear cell renal carcinoma, blood vessel tumors called hemangioblastomas, and pancreatic cysts or tumors.
  • Neurofibromatosis type 1 is caused by mutations in the NF1 gene. People with this syndrome commonly have skin pigmentation called café au lait spots and other skin changes. They are also at increased risk for PCCs as well as for other cancers and benign tumors of the nerves called neurofibromas.
  • Multiple endocrine neoplasia type 2 is caused by mutations in the RET gene. People with this syndrome are at an increased risk of PCCs as well as for a type of thyroid cancer called medullary thyroid cancer and parathyroid tumors.

Additional genes also may be associated with an increased risk for PGLs and PCCs. The list above represents the most common hereditary predispositions.