When Genetics Matter Most: Understanding Hereditary in Pheochromocytomas and Paragangliomas

Genetic Syndromes Association with Pheochromocytomas and Paragangliomas

From Jennifer Perkins, MD, MBA,  Co-director of UCSF’s endocrine neoplasia program, Executive Medical Director ambulatory, and PWN contributor – Pheochromocytomas (PCCs) are catecholamine-secreting tumors arising from chromaffin cells of the adrenal medulla, the center part of the adrenal gland. Paragangliomas (PGLs) arise from extra-adrenal paraganglia and may be sympathetic (often catecholamine-secreting) or parasympathetic (often non-secreting, typically located in the head and neck). The annual incidence of PCC/PGL is approximately 2–8 cases per million, but up to 30–40% are associated with germline pathogenic variants, making them among the most heritable tumors in endocrinology. Genetic testing is therefore recommended in most patients with PCC/PGL. Typically, genetic testing is considered in most patients with these tumors, but especially in those less than 45-50 years old, those with extra-adrenal paragangliomas or bilateral/multifocal tumors, presence of metastatic disease, head and neck PGLs, family history of PCC/PGLs or like syndromes or syndromic features suggesting a higher risk for PCC/PGL. The preferred approach to genetic testing is a comprehensive multi-gene panel testing that includes SDHx, RET, VHL, NF1, TMEM127 and MAX mutations when there is not a known familial mutation.

Succinate Dehydrogenase (SDHx)–Related Syndromes

• Genes: SDHA, SDHB, SDHC, SDHD, SDHAF2 accounting for about 20% of all PCCs
• Tumors: PCCs and PGLs (head/neck and abdominal); SDHB more associated with aggressive, metastatic disease in up to 25%
• Associated features: Renal cell carcinoma up to 3-5% risk (more common in SDHB patients), gastrointestinal stromal tumors (Carney–Stratakis), pituitary adenomas (rare)
• Key clues: Young age, extra-adrenal PGLs, head/neck PGLs, malignancy, multifocal disease, family history
• Testing: SDHx panel testing recommended for nearly all PCC/PGL patients

 

 Multiple Endocrine Neoplasia Type 2 (MEN2)

• Gene: RET proto-oncogene accounting for about 5.4% of all PCCs
• Tumors: Pheochromocytomas (often bilateral, adrenal); rarely PGLs. Rate of occurrence depends on which RET mutation is found, but roughly occurs in 40-50% of affected individuals
• Associated features: Medullary thyroid carcinoma (nearly universal in >98%), hyperparathyroidism (MEN2A), mucosal neuromas and marfanoid habitus (MEN2B)
• Key clues: PCC with medullary thyroid cancer (MTC), family history of medullary thyroid cancer
• Testing: RET sequencing in PCC with MTC or MEN2 features

Von Hippel–Lindau (VHL) Syndrome

• Gene: VHL (a critical tumor suppressor gene)
• Tumors: Pheochromocytomas (often bilateral), paragangliomas, accounting for about 10-18% of PCCs
• Associated features: Hemangioblastomas (retinal/central nervous system), clear cell renal carcinoma, pancreatic NETs and cysts, endolymphatic sac tumors
• Key clues: PCC at young age, bilateral adrenal disease, CNS/retinal lesions
• Testing: VHL sequencing in PCC/PGL with syndromic features or young onset

 

Neurofibromatosis Type 1 (NF1)

• Gene: NF1 (Neurofibromatosis 1) tumor suppressor gene on chromosome 17
• Tumors: Pheochromocytomas (usually adrenal)
• Associated features: Café-au-lait macules, neurofibromas, axillary freckling, optic gliomas
• Key clues: Clinical NF1 features; PCC incidence ~1–5% in NF1 patients
• Testing: Often clinical diagnosis; genetic testing if uncertain

TMEM127-Related PCC Syndrome

• Gene: TMEM127
• Tumors: Pheochromocytomas (often bilateral or multifocal). Make up less than 2% of all PCCs
• Associated features: Usually isolated PCC; occasional renal tumors
• Key clues: Adrenal PCC, especially bilateral, without classic MEN2 or VHL features
• Testing: Include TMEM127 in multigene panels

MAX-Related PCC/PGL Syndrome

• Gene: MAX
• Tumors: PCCs and PGLs, often bilateral adrenal tumors, accounting for less than 2% of all PCCs
• Associated features: Early onset, high penetrance in males
• Key clues: Bilateral PCC, family history, absence of RET/VHL findings
• Testing: Include MAX in genetic panels

Rare and Emerging Associations

• Genes: FH (hereditary leiomyomatosis and renal cancer), EGLN1/EPAS1 (polycythemia–PGL syndrome)
• Features: Paragangliomas with erythrocytosis, renal or uterine tumors
• Testing: Phenotype-driven or expanded panels in unusual presentations

 

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