# Hereditary pheochromocytoma and paraganglioma (SDHx, VHL, RET, NF1, MAX and TMEM127)

Source: https://onco.cc/cancers/hereditary-ppgl/  
OnCo record `hereditary-ppgl` (Cancer). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Summary

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.

## Fields

- Kind: Cancer
- Last checked: 2026-09-18
- Also known as: Familial paraganglioma syndromes; SDHB-related paraganglioma; SDHD-related head and neck paraganglioma; VHL-associated pheochromocytoma; MEN2-associated pheochromocytoma; Hereditary PPGL
- Tags: subtype-page; endocrine
- Group: endocrine
- Burden: 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.
- Subtypes: 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)
- Biomarkers: 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

## Sections of this record

The page is a hub with ten sections in reading order; large sections have their own page. The same plan as JSON: https://onco.cc/api/v1/cancers/hereditary-ppgl/sections.json

- Overview (on the hub): The TL;DR, the family this cancer belongs to, the organ, who gets it and what the state of the art is. https://onco.cc/cancers/hereditary-ppgl/#overview [3 state-of-the-art points]
- Types and stages (on the hub): Anatomy, the subtypes and how they differ, how it is staged, and where advanced disease spreads. https://onco.cc/cancers/hereditary-ppgl/#what-it-is [7 subtypes]
- Symptoms and diagnosis (on the hub): How this cancer shows itself, how the diagnosis is confirmed, and the biomarkers clinicians test for. https://onco.cc/cancers/hereditary-ppgl/#finding-it [6 biomarkers]
- Treatment (on the hub): The standard of care by setting, the medicines, surgery and radiotherapy named in it, and the regimens behind them. https://onco.cc/cancers/hereditary-ppgl/#treating-it [6 settings, 4 decisions with options]
- Trials and papers (on the hub): Trials recruiting now, the landmark trials, the trials held by this cancer's subtypes, the key papers and what they mean, the latest literature, and the milestones year by year. https://onco.cc/cancers/hereditary-ppgl/#evidence [1 trial, 3 key papers, 6 milestones]
- Biology and targets (on the hub): The molecular landscape: the targets and how often each appears, the pathways, the mechanics stages and the preclinical models. https://onco.cc/cancers/hereditary-ppgl/#science [3 targets]
- Countries and centres (own page): Cases by country, the UK and NHS pathway and other country lenses, the expert centres with trials on record, and the centres named on this cancer's subtypes. https://onco.cc/cancers/hereditary-ppgl/where-you-are/
- Decisions and support (on the hub): The decisions you may face, the aids that walk through them, the warnings on record, the first sixty days and the questions to ask. https://onco.cc/cancers/hereditary-ppgl/#living-with-it [17 questions, 1 red card]
- Pipeline and open problems (own page): Everything in development, the medicines held by this cancer's subtypes, the open problems and what is being done about them, the roadmaps, and what changed on this record. https://onco.cc/cancers/hereditary-ppgl/coming/ [2 medicines, 1 trial, 4 open problems]
- Data (own page): Every connected record, the notes, the JSON, Markdown and RDF twins, and where the record came from and when it was checked. https://onco.cc/cancers/hereditary-ppgl/data/ [26 connected records]

## Standard of care

- Genetic diagnosis: Germline panel testing offered to every patient; SDHB immunohistochemistry on tumour tissue; cascade testing of relatives with genetic counselling. ([Germline (hereditary) testing](https://onco.cc/technologies/germline-testing/), [Hereditary cancer syndromes](https://onco.cc/terms/hereditary-cancer-syndromes/), [SDH deficiency (SDHB immunohistochemistry loss)](https://onco.cc/terms/sdh-deficiency/))
- Biochemical and imaging work-up: Plasma or urinary metanephrines; CT or MRI; 68Ga-DOTATATE PET as the preferred functional scan for SDHx and other cluster 1 disease. ([Somatostatin receptor PET (68Ga/64Cu-DOTATATE)](https://onco.cc/technologies/sstr-pet/), [MRI](https://onco.cc/technologies/mri/), [CT (computed tomography)](https://onco.cc/technologies/ct/))
- Adrenal tumours in VHL and MEN2: Alpha-blockade then cortical-sparing (partial) adrenalectomy to preserve adrenal function given the risk of bilateral disease. ([Adrenalectomy](https://onco.cc/terms/adrenalectomy/), [Robotic & minimally invasive surgery](https://onco.cc/technologies/robotic-surgery/))
- Head and neck paragangliomas: Observation for small asymptomatic tumours; surgery or fractionated or stereotactic radiotherapy when growing or symptomatic, weighing cranial nerve risk. ([Active surveillance](https://onco.cc/technologies/active-surveillance/), [IMRT / IGRT (modern external beam)](https://onco.cc/technologies/imrt-igrt/), [SBRT / SABR (stereotactic radiotherapy)](https://onco.cc/technologies/sbrt/))
- Surveillance of carriers: 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). ([MRI](https://onco.cc/technologies/mri/), [Germline (hereditary) testing](https://onco.cc/technologies/germline-testing/))
- 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. ([Belzutifan](https://onco.cc/drugs/belzutifan/), [Belzutifan/MK-6482 for the Treatment of Advanced Pheochromocytoma/Paraganglioma (PPGL), Pancreatic Neuroendocrine Tumor (pNET), Von Hippel-Lindau (VHL](https://onco.cc/trials/nct04924075/), [Lutetium-177 dotatate](https://onco.cc/drugs/lutathera/), [Peptide receptor radionuclide therapy (PRRT)](https://onco.cc/technologies/prrt/))

## 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.

## Open problems

- 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.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Paraganglioma
- Endocrine Society PPGL guideline 2014: https://doi.org/10.1210/jc.2014-1498
- Belzutifan in VHL (NEJM 2021): https://doi.org/10.1056/NEJMoa2103425
- Wikipedia: https://en.wikipedia.org/wiki/Paraganglioma

## Connected records

- cancers: [Fumarate hydratase-deficient renal cell carcinoma (HLRCC-associated)](https://onco.cc/cancers/fh-deficient-renal-cell-carcinoma/), [Localised adrenocortical carcinoma (ENSAT stage I to III, resectable)](https://onco.cc/cancers/localised-adrenocortical-carcinoma/), [Medullary thyroid cancer](https://onco.cc/cancers/medullary-thyroid-cancer/), [Metastatic pheochromocytoma and paraganglioma](https://onco.cc/cancers/metastatic-ppgl/), [Multiple endocrine neoplasia type 2 (MEN2A and MEN2B)](https://onco.cc/cancers/men2-syndrome/), [Pheochromocytoma and paraganglioma (PPGL)](https://onco.cc/cancers/pheochromocytoma-paraganglioma/), [Succinate dehydrogenase-deficient renal cell carcinoma](https://onco.cc/cancers/sdh-deficient-renal-cell-carcinoma/)
- technologies: [Active surveillance](https://onco.cc/technologies/active-surveillance/), [CT (computed tomography)](https://onco.cc/technologies/ct/), [Germline (hereditary) testing](https://onco.cc/technologies/germline-testing/), [IMRT / IGRT (modern external beam)](https://onco.cc/technologies/imrt-igrt/), [MRI](https://onco.cc/technologies/mri/), [Peptide receptor radionuclide therapy (PRRT)](https://onco.cc/technologies/prrt/), [Radioligand therapy (beta emitters)](https://onco.cc/technologies/radioligand-therapy/), [Robotic & minimally invasive surgery](https://onco.cc/technologies/robotic-surgery/), [SBRT / SABR (stereotactic radiotherapy)](https://onco.cc/technologies/sbrt/), [Somatostatin receptor PET (68Ga/64Cu-DOTATATE)](https://onco.cc/technologies/sstr-pet/)
- targets: [HIF-2α](https://onco.cc/targets/hif2a/), [RET](https://onco.cc/targets/ret/), [Somatostatin receptor 2](https://onco.cc/targets/sstr2/)
- drugs: [Belzutifan](https://onco.cc/drugs/belzutifan/), [Lutetium-177 dotatate](https://onco.cc/drugs/lutathera/)
- terms: [Adrenalectomy](https://onco.cc/terms/adrenalectomy/), [Hereditary cancer syndromes](https://onco.cc/terms/hereditary-cancer-syndromes/), [Rare cancers](https://onco.cc/terms/rare-cancers/), [SDH deficiency (SDHB immunohistochemistry loss)](https://onco.cc/terms/sdh-deficiency/)
- trials: [Belzutifan/MK-6482 for the Treatment of Advanced Pheochromocytoma/Paraganglioma (PPGL), Pancreatic Neuroendocrine Tumor (pNET), Von Hippel-Lindau (VHL](https://onco.cc/trials/nct04924075/)
- key papers: [Belzutifan for renal cell carcinoma and other tumours in von Hippel-Lindau disease](https://onco.cc/key-papers/paper-belzutifan-vhl-jonasch-nejm-2021/), [Germline mutations in nonsyndromic pheochromocytoma](https://onco.cc/key-papers/paper-neumann-germline-mutations-nonsyndromic-pheochromocytoma-nejm-2002/), [Pheochromocytoma and paraganglioma: an Endocrine Society clinical practice guideline](https://onco.cc/key-papers/paper-endocrine-society-pheochromocytoma-paraganglioma-guideline-jcem-2014/)

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JSON: https://onco.cc/api/v1/entities/hereditary-ppgl.json