Hereditary pheochromocytoma and paraganglioma (SDHx, VHL, RET, NF1, MAX and TMEM127)
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.
Overview
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.
State of the art
- Universal germline testing and gene-based surveillance find tumours before they cause harm.
- The cluster 1 and cluster 2 framework links gene, biochemistry, imaging and therapy.
- Belzutifan is the first drug aimed at the pseudohypoxia pathway that drives cluster 1 tumours.
Red cards
From the labels and guidelines behind the standard of care. Your team's thresholds win.- Emergency services nowBone pain flare or fracture (radium-223)
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
Anatomy and lymph node drainage
- Renal cortex (RCC)
- Renal pelvis and ureter (upper tract urothelial)
- Bladder lining (non-muscle-invasive)
- Bladder muscle wall (muscle-invasive)
- Adrenal cortex
- Adrenal medulla and sympathetic chain (neuroblastoma)
- Developing kidney (Wilms tumour)
- Nodes: renal hilar
- Nodes: para-aortic and paracaval
- Nodes: obturator and iliac (bladder)
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.
- Renal cortex (RCC)VHL-associated pheochromocytoma (bilateral, noradrenergic; belzutifan eligible) · MEN2 (RET)-associated pheochromocytoma (bilateral, adrenergic; with medullary thyroid cancer)
- Renal pelvis and ureter (upper tract urothelial)
- Bladder lining (non-muscle-invasive)
- Bladder muscle wall (muscle-invasive)
- Adrenal cortexSDHB-related paraganglioma (highest metastatic risk; extra-adrenal, abdominal and thoracic) · NF1, MAX and TMEM127-associated pheochromocytoma (adrenal, later onset)
- Adrenal medulla and sympathetic chain (neuroblastoma)SDHB-related paraganglioma (highest metastatic risk; extra-adrenal, abdominal and thoracic) · SDHD-related head and neck paraganglioma (multiple, paternal inheritance, rarely secreting) · SDHC, SDHA and SDHAF2-related paraganglioma (rarer, lower penetrance) · VHL-associated pheochromocytoma (bilateral, noradrenergic; belzutifan eligible) · MEN2 (RET)-associated pheochromocytoma (bilateral, adrenergic; with medullary thyroid cancer) · NF1, MAX and TMEM127-associated pheochromocytoma (adrenal, later onset) · Carney triad and Carney-Stratakis dyad (paraganglioma with gastrointestinal stromal tumour)
- Developing kidney (Wilms tumour)VHL-associated pheochromocytoma (bilateral, noradrenergic; belzutifan eligible) · MEN2 (RET)-associated pheochromocytoma (bilateral, adrenergic; with medullary thyroid cancer)
- renal hilar
- para-aortic and paracaval
- obturator and iliac (bladder)
Same organ: 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
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.
- MRIStandard of care
Nothing recorded yet.
Nothing recorded yet.
Also on OnCo: Symptoms and red flags · Early detection roadmap.
Cases by country
No country-level case numbers. This cancer is not mapped to a GLOBOCAN site.
One section per setting: the options named, what each is for, the trials behind them, the recorded trade-offs and the questions to ask.
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.
Subtypes & biomarkers
top- SDHB-related paraganglioma (highest metastatic risk; extra-adrenal, abdominal and thoracic)
- SDHD-related head and neck paraganglioma (multiple, paternal inheritance, rarely secreting)
- SDHC, SDHA and SDHAF2-related paraganglioma (rarer, lower penetrance)
- VHL-associated pheochromocytoma (bilateral, noradrenergic; belzutifan eligible)
- MEN2 (RET)-associated pheochromocytoma (bilateral, adrenergic; with medullary thyroid cancer)
- NF1, MAX and TMEM127-associated pheochromocytoma (adrenal, later onset)
- Carney triad and Carney-Stratakis dyad (paraganglioma with gastrointestinal stromal tumour)
- Germline panel testing (SDHA, SDHB, SDHC, SDHD, SDHAF2, VHL, RET, NF1, MAX, TMEM127, FH, EPAS1)
- Plasma free or urinary fractionated metanephrines (noradrenergic pattern in cluster 1)
- SDHB immunohistochemistry (loss indicates any SDHx mutation)
- 68Ga-DOTATATE PET (somatostatin receptor expression, staging and radioligand eligibility)
- Tumour size, extra-adrenal site and SDHB status as metastatic risk factors
- Surveillance whole-body MRI in carriers
How often this target appears
- 1993RET mutations identified in MEN2; VHL gene cloned
- 2000SDHD mutations found in familial head and neck paraganglioma; SDHB follows in 2001
- 2014Endocrine Society guideline recommends germline testing for all patients
- 2017TCGA analysis defines the pseudohypoxia and kinase clusters
- 2021Belzutifan approved for VHL-associated tumours
- 2025Belzutifan approved for advanced pheochromocytoma and paraganglioma
Dated changes read from the records linked to this cancer: approvals, regulatory steps, reported trials, guideline versions and milestones. Newest first; no date is inferred.
All 13 changes by month →- 2026-09-18This recordHereditary pheochromocytoma and paraganglioma (SDHx, VHL, RET, NF1, MAX and TMEM127)Facts on this page last checked
When this page itself was last checked or edited.
- 2025MilestoneBelzutifanBelzutifan approved for advanced pheochromocytoma and paraganglioma
A milestone in how this cancer is treated.
- 2021MilestoneBelzutifanBelzutifan approved for VHL-associated tumours
A milestone in how this cancer is treated.
- 2017MilestoneHereditary pheochromocytoma and paraganglioma (SDHx, VHL, RET, NF1, MAX and TMEM127)TCGA analysis defines the pseudohypoxia and kinase clusters
A milestone in how this cancer is treated.
- 2014GuidelineHereditary pheochromocytoma and paraganglioma (SDHx, VHL, RET, NF1, MAX and TMEM127)Guideline Endocrine Society clinical practice guideline 2014; NCCN Neuroendocrine and Adrenal Tumors: Adrenal tumours in VHL and MEN2
Alpha-blockade then cortical-sparing (partial) adrenalectomy to preserve adrenal function given the risk of bilateral disease.
- 2014GuidelineHereditary pheochromocytoma and paraganglioma (SDHx, VHL, RET, NF1, MAX and TMEM127)Guideline Endocrine Society clinical practice guideline 2014; NCCN Neuroendocrine and Adrenal Tumors: Advanced disease in carriers
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.
What is in development for Hereditary pheochromocytoma and paraganglioma (SDHx, VHL, RET, NF1, MAX and TMEM127), drawn from the whole corpus: 1 items. Drugs are grouped by the most advanced trial phase they have reached anywhere; approved treatments sit under standard of care. Technologies are the methods being tested for this cancer, trials are the studies recorded here, and ideas are proposals not yet in a trial.
Trials under way · 1
Open problems and what is being done
Penetrance of SDHx mutations is incomplete and variable, so how intensively to screen carriers is debated.
No treatment prevents new tumours in carriers.
Whether belzutifan works in SDHx-related as well as VHL-related disease needs more data.
Head and neck paragangliomas have no effective medical therapy.
Trials
topTrials recruiting now
Country and place are remembered in this browser only. A postcode is sent to OpenStreetMap's Nominatim service to find coordinates when you press the button; nothing else leaves your device.
Landmark trials
Expert centres
topExpert centres
Seoul · hospital | South Korea | none recorded | 0 | 464 | 3,248 | #22 | |
Stanford · university | United States | 0 | 3,000 | 50,162 | #30 | ||
Shanghai · hospital | China | none recorded | 0 | 2,872 | 31,534 | - | |
Sydney · cancer center | Australia | none recorded | 0 | 2,222 | 33,278 | - | |
Beijing · hospital | China | none recorded | 0 | 1,784 | 18,230 | - | |
Dallas, TX · cancer center | United States | 0 | 1,744 | 19,757 | - | ||
Utrecht · cancer center | Netherlands | none recorded | 0 | 1,422 | 20,323 | - | |
Guangzhou · hospital | China | none recorded | 0 | 1,245 | 12,931 | - | |
Tianjin · cancer center | China | none recorded | 0 | 1,219 | 11,455 | - | |
Hangzhou · cancer center | China | none recorded | 0 | 1,219 | 17,635 | - | |
Beijing · hospital | China | none recorded | 0 | 1,154 | 11,808 | - | |
Rozzano (Milan) · hospital | Italy | none recorded | 0 | 1,031 | 10,720 | - | |
L'Hospitalet de Llobregat · cancer center | Spain | 0 | 988 | 14,310 | - | ||
Changsha · cancer center | China | none recorded | 0 | 930 | 14,477 | - | |
Jinan · cancer center | China | none recorded | 0 | 920 | 7,804 | - |
These are the things we can measure; they are not a ranking of quality. Each column is a field on the institution record or a count over what OnCo has linked; a centre that treats many patients with Hereditary pheochromocytoma and paraganglioma but is thinly recorded here will look small.
Not known: OnCo holds no case-volume or outcome figures for centres, so none are shown. Where a national audit or registry publishes them, the centre's page links to it. Default order: Newsweek rank, then trials for this cancer, then research output.
Questions to ask
topQuestions to ask your oncologist about Hereditary pheochromocytoma and paraganglioma
Newly diagnosed
- What is my exact diagnosis, stage, and grade, and which tests established them?Why: Everything else follows from an accurate stage and subtype.
- Which biomarkers have been tested on my tumour (for example Germline panel testing, Plasma free or urinary fractionated metanephrines, SDHB immunohistochemistry, 68Ga-DOTATATE PET, Tumour size, extra-adrenal site and SDHB status as metastatic risk factors), and what were the results?Why: These results decide eligibility for targeted therapy, immunotherapy, and trials.
- Which subtype is my cancer, and does that change the recommended treatment?Why: Recognised subtypes for this cancer include SDHB-related paraganglioma, SDHD-related head and neck paraganglioma, SDHC, SDHA and SDHAF2-related paraganglioma.
- Is germline (inherited) genetic testing recommended for me or my family?Why: Inherited variants can change treatment and matter for relatives.
Genetic diagnosis
- For my situation (genetic diagnosis), which of the standard options do you recommend and why?Why: Guideline options include: Germline panel testing offered to every patient; SDHB immunohistochemistry on tumour tissue; cascade testing of relatives with genetic counselling.
Biochemical and imaging work-up
- For my situation (biochemical and imaging work-up), which of the standard options do you recommend and why?Why: Guideline options include: Plasma or urinary metanephrines; CT or MRI; 68Ga-DOTATATE PET as the preferred functional scan for SDHx and other cluster 1 disease.
Adrenal tumours in VHL and MEN2
- For my situation (adrenal tumours in vhl and men2), which of the standard options do you recommend and why?Why: Guideline options include: Alpha-blockade then cortical-sparing (partial) adrenalectomy to preserve adrenal function given the risk of bilateral disease.
Head and neck paragangliomas
- For my situation (head and neck paragangliomas), which of the standard options do you recommend and why?Why: Guideline options include: Observation for small asymptomatic tumours; surgery or fractionated or stereotactic radiotherapy when growing or symptomatic, weighing cranial nerve risk.
Surveillance of carriers
- For my situation (surveillance of carriers), which of the standard options do you recommend and why?Why: Guideline options include: 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).
Advanced disease in carriers
- For my situation (advanced disease in carriers), which of the standard options do you recommend and why?Why: Guideline options include: 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.
- Am I a candidate for Belzutifan, Lutetium-177 dotatate, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
- How do the results of Belzutifan/MK-6482 for the Treatment of Advanced Pheochromocytoma/Paraganglioma (PPGL), Pancreatic Neuroendocrine Tumor (pNET), Von Hippel-Lindau (VHL apply to someone like me?Why: Trial populations differ from individual patients; ask how closely you match.
Any stage
- Are there clinical trials I could join, for example of Belzutifan, Belzutifan/MK-6482 for the Treatment of Advanced Pheochromocytoma/Paraganglioma (PPGL), Pancreatic Neuroendocrine Tumor (pNET), Von Hippel-Lindau (VHL, Lutetium-177 dotatate, Peptide receptor radionuclide therapy (PRRT)?Why: Trials are how the next standard of care is set; asking early keeps options open.
- Would a second opinion at a high-volume centre change anything, and can you help arrange it?Why: Rare or high-stakes decisions benefit from a centre that treats many similar patients.
- What supportive care (symptom control, nutrition, exercise, mental health, financial help) is available from the start?Why: Supportive care improves quality of life and helps patients complete treatment.
- I read that “Penetrance of SDHx mutations is incomplete and variable, so how intensively to screen carriers is debated”. How does that affect my plan?Why: Open problems are where trials and second opinions matter most.
- I read that “No treatment prevents new tumours in carriers”. How does that affect my plan?Why: Open problems are where trials and second opinions matter most.
Newly diagnosed? Read the first 60 days with Hereditary pheochromocytoma and paraganglioma, then print the one-page appointment sheet with room for the answers.
Print this page for your appointment (your browser's print command). These prompts are for discussion; your clinical team knows your case.
Direct links plus the targets, companies, and technologies of this cancer's products.
technologies
11targets
3drugs
2companies
2terms
4trials
1key papers
3Belzutifan 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.
Latest papers
topQuery 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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