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Hereditary pheochromocytoma and paraganglioma is the inherited form of these adrenaline-producing tumours, caused by a fault in one of more than a dozen genes, most often SDHB, SDHD, VHL and RET. Knowing the gene changes care: SDHB carriers have the highest risk of spread, VHL and MEN2 patients get adrenal-sparing surgery because tumours arise on both sides, and relatives are screened.
Pheochromocytomas (adrenal) and paragangliomas (sympathetic chain, head and neck) have the strongest hereditary basis of any tumour type: germline mutations are found in 30 to 40 percent of patients, in the succinate dehydrogenase genes (SDHB, SDHD, SDHC, SDHA and SDHAF2), VHL, RET (MEN2), NF1, MAX, TMEM127, FH and others, and the Endocrine Society guideline recommends that all patients be offered testing. The genes fall into two clusters that shape the tumour: cluster 1 (SDHx, VHL, FH, EPAS1) tumours are pseudohypoxic, noradrenergic or non-secreting, often extra-adrenal and multiple, and express somatostatin receptors strongly; cluster 2 (RET, NF1, MAX, TMEM127) tumours are kinase-driven, adrenergic and usually adrenal. SDHB mutations carry the highest risk of metastasis, SDHD (paternally inherited) causes multiple head and neck paragangliomas, VHL and MEN2 cause bilateral pheochromocytomas alongside their other tumours, and SDHx carriers are also at risk of gastrointestinal stromal tumours, renal cell carcinoma and pituitary adenomas.
Management differs from sporadic disease at every step. Diagnosis rests on plasma or urinary metanephrines and, for non-secreting head and neck tumours, imaging; SDHB immunohistochemistry on the tumour flags an SDHx mutation, and 68Ga-DOTATATE PET is the preferred whole-body scan for cluster 1 disease because of its somatostatin receptor expression. Surgery follows alpha-blockade, and in VHL and MEN2 a cortical-sparing adrenalectomy is preferred to avoid lifelong steroid dependence after bilateral tumours; head and neck paragangliomas, which rarely secrete and grow slowly, are often watched or irradiated rather than resected because surgery risks the cranial nerves. Carriers enter lifelong surveillance with annual metanephrines and periodic whole-body MRI from childhood in SDHB and SDHD families, and cascade testing is offered to relatives. For carriers who develop advanced disease, the HIF-2 alpha inhibitor belzutifan, approved for VHL-associated tumours in 2021 and for advanced pheochromocytoma and paraganglioma in 2025, exploits the pseudohypoxia pathway directly, and radioligand therapy with lutetium-177 dotatate suits the somatostatin-receptor-rich cluster 1 tumours. The genetics also guide prognosis: metastatic risk, multiplicity and the chance of a second primary all follow the gene.
Up to four in ten pheochromocytomas and paragangliomas are caused by a germline mutation, the highest proportion of any cancer, so every patient is offered genetic testing; carriers face lifelong surveillance for new tumours.
Renal cell carcinoma comes from the kidney's filtering cortex, urothelial cancer from the lining of the collecting system and bladder, and the adrenal on top hosts cortical and medullary (neuroblastoma) tumours.
Same organ: Collecting duct carcinoma of the kidney, Renal medullary carcinoma (SMARCB1-deficient), TFE3-rearranged (translocation) renal cell carcinoma, Fumarate hydratase-deficient renal cell carcinoma (HLRCC-associated), Succinate dehydrogenase-deficient renal cell carcinoma, Mucinous tubular and spindle cell carcinoma of the kidney, Eosinophilic solid and cystic renal cell carcinoma, Clear cell papillary renal cell tumour, Urothelial carcinoma of the urethra, Squamous cell carcinoma of the urethra, Adenocarcinoma of the urethra (including clear cell adenocarcinoma), Melanoma of the urethra, Non-muscle-invasive bladder cancer, Muscle-invasive and advanced bladder cancer, Bladder & urothelial cancer, Clear cell renal cell carcinoma, Papillary renal cell carcinoma, Chromophobe renal cell carcinoma, Renal cell carcinoma, Wilms tumour (nephroblastoma), Neuroblastoma (paediatric), Low-risk neuroblastoma (INRG very low and low risk, including stage MS), Intermediate-risk neuroblastoma, High-risk neuroblastoma, Adrenocortical carcinoma, Pheochromocytoma and paraganglioma (PPGL), Urethral cancer, Penile cancer, Localised penile cancer (organ-confined, node-negative), Node-positive and metastatic penile cancer, Localised adrenocortical carcinoma (ENSAT stage I to III, resectable), Advanced and metastatic adrenocortical carcinoma (ENSAT stage IV or unresectable), Metastatic pheochromocytoma and paraganglioma
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Also on OnCo: Symptoms and red flags · Early detection roadmap.
Germline panel testing offered to every patient; SDHB immunohistochemistry on tumour tissue; cascade testing of relatives with genetic counselling.
Plasma or urinary metanephrines; CT or MRI; 68Ga-DOTATATE PET as the preferred functional scan for SDHx and other cluster 1 disease.
Alpha-blockade then cortical-sparing (partial) adrenalectomy to preserve adrenal function given the risk of bilateral disease.
Observation for small asymptomatic tumours; surgery or fractionated or stereotactic radiotherapy when growing or symptomatic, weighing cranial nerve risk.
Annual metanephrines and clinical review from childhood, with whole-body MRI every two to three years in SDHB and SDHD carriers; screening for associated tumours (GIST, renal cell carcinoma, pituitary).
Belzutifan (approved for VHL-associated tumours 2021 and for advanced pheochromocytoma and paraganglioma 2025); lutetium-177 dotatate for somatostatin-receptor-positive disease; see the metastatic record.
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Belzutifan is the first systemic therapy for von Hippel-Lindau disease, approved for renal, central nervous system and pancreatic tumours not needing immediate surgery, changing a lifetime of surveillance and surgery for many patients.
The diagnostic, surgical and follow-up rows on both pheochromocytoma and paraganglioma pages follow this guideline.
Every patient with a pheochromocytoma or paraganglioma is now offered germline testing, which directs surveillance of the patient and relatives and, with SDHB, warns of metastatic risk.
Query for this cancer: (TITLE:"Hereditary pheochromocytoma and paraganglioma" OR ABSTRACT:"Hereditary pheochromocytoma and paraganglioma" OR TITLE:"SDHx, VHL, RET, NF1, MAX and TMEM127" OR ABSTRACT:"SDHx, VHL, RET, NF1, MAX and TMEM127" OR TITLE:"Familial paraganglioma syndromes" OR ABSTRACT:"Familial paraganglioma syndromes" OR TITLE:"SDHB-related paraganglioma" OR ABSTRACT:"SDHB-related paraganglioma" OR TITLE:"SDHD-related head and neck paraganglioma" OR ABSTRACT:"SDHD-related head and neck paraganglioma" OR TITLE:"VHL-associated pheochromocytoma" OR ABSTRACT:"VHL-associated pheochromocytoma") AND (treatment OR therapy OR trial OR survival OR diagnosis). Results are unfiltered search hits about Hereditary pheochromocytoma and paraganglioma (SDHx, VHL, RET, NF1, MAX and TMEM127), not a curated reading list.
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Sudden severe bone pain, or back pain with weakness or numbness in the legs (possible spinal cord compression).
See all on the product pages:Lutetium-177 dotatate·Printable cards in the navigator
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