Succinate dehydrogenase (SDH) mutations are inherited genetic changes that disrupt a critical enzyme complex involved in the body’s energy production. These mutations are among the most important known causes of hereditary phaeochromocytoma and paraganglioma (PPGLs), and are also associated with other tumours including gastrointestinal stromal tumours (GISTs) and a distinctive form of kidney cancer.
SDH mutations affect a group of genes collectively known as SDHx. These include SDHA, SDHB, SDHC, SDHD, and the assembly factor SDHAF2. Each of these genes produces a different component of the SDH enzyme, and mutations in any of them can lead to tumour development, though the specific tumour type, risk level, and age of onset vary depending on which gene is affected.
Because SDH mutations are inherited and can increase the risk of developing certain neuroendocrine and other rare tumours, , they have important implications not only for the person diagnosed but also for their close family members. Lifelong surveillance and genetic counselling are central to managing these conditions.
At NeuroEndocrine Cancer Australia (NECA), we support people living with SDH-related syndromes and their families through education, resources, advocacy, and access to the NET Nurse, Counsellor and Dietitian services.
Succinate dehydrogenase is a mitochondrial enzyme complex, also known as Complex II, that plays a dual role in the cell. It is a component of both the Krebs cycle (also called the citric acid cycle), which generates cellular energy, and the mitochondrial electron transport chain, which powers this process.
When an SDH gene is mutated and the enzyme loses function, a compound called succinate accumulates inside the cell. Succinate is normally a temporary part of the cell’s energy making process and is quickly broken down, but in SDH-deficient cells it builds up to abnormal levels and behaves as an oncometabolite, a substance that promotes cancer development.
Accumulated succinate disrupts the activity of enzymes that regulate how DNA is packaged and read, leading to widespread changes in gene regulation that can lock affected cells in an immature, rapidly proliferating state. Succinate also mimics a low-oxygen environment within the cell, activating hypoxic signalling pathways that further promote tumour growth and spread.
These mechanisms explain why SDH mutations are powerful drivers of tumour development in specific tissues, particularly those derived from neural crest cells. Neural crest cells are specialised cells formed during early development that can develop into a variety of cell types including the cells that give rise to phaeochromocytomas and paragangliomas.
SDH mutations cause a group of inherited conditions collectively referred to as hereditary paraganglioma-phaeochromocytoma syndrome, though the clinical picture varies considerably depending on which SDH gene is affected.
All SDHx mutations follow an autosomal dominant inheritance pattern, meaning that only one altered copy of the gene is sufficient to increase the risk of developing tumours. A person with an SDHx mutation has a 50 per cent chance of passing the mutation to each of their children.
There is an important exception. SDHD mutations follow a distinct pattern known as a parent-of-origin effect. Because the copy of SDHD inherited from the mother is normally silenced through a process called genomic imprinting, tumours typically only develop in people who inherited the SDHD mutation from their father. A person who inherits the SDHD mutation from their mother generally have a much lower risk of developing associated tumours themselves, but can still pass the SDHD mutation on to their children.
Not everyone who carries an SDHx mutation will develop a tumour. The likelihood of developing disease (called penetrance) varies between the different SDH gene subtypes, and SDHB mutations carry the highest malignancy risk of all SDHx variants.
De novo (new, spontaneous) SDH mutations can also occur, and in these cases there may be no family history of the condition.
While all SDHx mutations share common biochemical features, each gene subunit is associated with a distinct clinical picture.
SDHB mutations carry the highest risk of malignancy and metastatic disease of all the SDH subunits. They are strongly associated with extra-adrenal abdominal paragangliomas and with a distinctive form of renal cell carcinoma (kidney cancer). SDHB-related tumours have a significantly higher risk of spreading to distant sites compared with tumours caused by other SDH gene mutations, and require intensive monitoring and prompt treatment.
SDHD mutations are most strongly associated with multifocal head and neck paragangliomas, which often occur at multiple sites simultaneously. These tumours tend to behave less aggressively than SDHB-related tumours but can still cause significant symptoms related to their location. As described above, tumours in SDHD mutation carriers most commonly develop when the mutation is inherited from the biological father due to a parent-of-origin effect.
SDHC mutations primarily cause head and neck paragangliomas and are generally associated with a lower risk of tumour development and metastatic disease than SDHB or SDHD mutations. SDHC is also linked to SDH-deficient gastrointestinal stromal tumours (GIST), sometimes through a mechanism called epigenetic silencing (promoter hypermethylation) rather than an inherited germline mutation.
SDHA mutations have the lowest likelihood of SDHx-related tumour development compared with other SDHx genes. When they do cause tumours, these are most commonly SDH-deficient gastrointestinal stromal tumours, particularly arising in the stomach. In rare cases where both copies of the SDHA gene are affected (biallelic mutations), the result is a severe metabolic disorder called Leigh syndrome, a form of mitochondrial encephalopathy that presents in infancy or early childhood.
SDHAF2 is a gene that helps the succinate dehydrogenase (SDH) complex work properly inside cells. Mutations in SDHAF2 are rare and are primarily associated with hereditary head and neck paraganglioma syndromes.
SDH mutations are associated with a defined range of tumour types, each linked to specific gene subunits.
Paragangliomas are neuroendocrine tumours arising from paraganglia, small clusters of specialised cells found along nerve pathways in the head, neck, chest, abdomen, and pelvis. They are the most common tumour type associated with SDHx mutations.
Parasympathetic paragangliomas, which most commonly arise in the head and neck, typically do not produce hormones but instead cause symptoms through their physical location rather than hormonal excess. Sympathetic paragangliomas, found in the chest, abdomen, and pelvis, are more likely to produce catecholamines and cause symptoms similar to phaeochromocytoma.
SDHB-related paragangliomas carry the highest metastatic risk.
Phaeochromocytomas are neuroendocrine tumours arising from the chromaffin cells inside the adrenal medulla. They frequently produce excess catecholamines including adrenaline and noradrenaline, causing episodes of high blood pressure, headache, sweating, and palpitations.
SDH mutations, particularly those in SDHB and SDHD, are among the most common genetic causes of hereditary phaeochromocytoma.
SDH-deficient GISTs, most commonly linked to SDHA and SDHC, have distinct features that set them apart from the more GISTs driven by changes in genes such as KIT. They typically arise in the stomach, are often multifocal, predominantly affect younger patients, and are naturally resistant to standard imatinib therapy. The behaviour of these tumours is often indolent, though metastatic spread to lymph nodes and liver can occur.
SDHB mutations are specifically associated with a distinctive subtype of renal cell carcinoma (kidney cancer) characterised by a unique cellular appearance under the microscope. These tumours are classified as SDH-deficient renal cell carcinoma, a recognised entity in the WHO Classification of Tumours. They tend to present in younger individuals and can behave aggressively in some cases.
Pituitary neuroendocrine tumours (PitNETs), previously called pituitary adenomas, have been reported in a small number of SDHx mutation carriers, most commonly in association with SDHD and SDHB mutations. These are less common manifestations within the overall SDH tumour spectrum. Some produce excess growth hormone, which can lead to a condition called acromegaly, while others do not produce hormones.
The effects of SDH mutations on the body depend primarily on which SDH gene subunit is affected, the type and location of any tumours that develop, and whether those tumours produce hormones.
For people with hormone-secreting paragangliomas or phaeochromocytomas, the main systemic effects are driven by excess catecholamines. These include episodes of severe high blood pressure, rapid or irregular heartbeat, severe headaches, sweating, and anxiety-like symptoms. These episodes can be triggered by exercise, stress, surgery, anaesthesia, or pressure on the tumour, and can pose a serious safety risk if unrecognised.
For people with non-secreting head and neck paragangliomas, effects tend to be localised. Depending on tumour location, these may include hearing changes, tinnitus, a lump in the neck, hoarseness, or difficulty swallowing.
For people with SDH-deficient renal cell carcinoma, effects depend on tumour size and extent of spread. Early renal tumours may cause no symptoms, while advanced disease can cause blood in the urine, flank pain, or systemic symptoms including fatigue and weight loss.
Symptoms vary considerably depending on which tumour type develops and where it is located.
Symptoms that may suggest a hormone-secreting paraganglioma or phaeochromocytoma include:
Symptoms that may suggest a head or neck paraganglioma include:
Symptoms that may suggest renal cell carcinoma include:
Many SDH-related tumours cause no symptoms in their early stages and are found through surveillance imaging in people known to carry a mutation.
Diagnosis involves genetic testing to identify the SDH gene mutation, biochemical testing to detect hormone-secreting tumours, and imaging to locate and monitor tumours. In people with an existing tumour, pathological testing of the tissue can also confirm SDH deficiency. If SDH deficiency is found, genetic testing may be recommended to determine whether an inherited SDHx mutation is present.
Genetic testing is the cornerstone of SDH syndrome diagnosis. It may be initiated because of a personal or family history of paraganglioma, phaeochromocytoma, GIST, pituitary neuroendocrine tumours or SDH-deficient renal cell carcinoma, or because a pathologist identifies loss of SDHB expression in a tumour tissue specimen.
Testing involves analysis of the SDHx genes in a blood sample to identify the specific causative mutation. A clinical geneticist or genetic counsellor is involved to explain the implications of the results, discuss inheritance patterns, and advise on family screening.
Genetic counselling should be offered before and after testing to ensure the person fully understands what a positive result means for them and their family.
For people known to carry an SDHx mutation, regular biochemical screening is recommended to detect hormone-secreting tumours at an early and treatable stage.
Testing typically involves plasma free metanephrines (normetanephrine and metanephrine) or 24-hour urine fractionated metanephrines. These are breakdown products of catecholamines and are elevated when a phaeochromocytoma or secreting paraganglioma is present. The frequency of biochemical testing is guided by the specific gene subunit, individual risk profile, and specialist advice.
Whole-body MRI from the head to the pelvis is the preferred imaging modality for surveillance in SDHx mutation carriers, as it avoids repeated radiation exposure from CT scanning.
International guidelines recommend that surveillance imaging begins between the ages of 6 and 10 for SDHB mutation carriers, given their higher malignancy risk, and between the ages of 10 and 15 for carriers of other SDH subunit mutations.
If a phaeochromocytoma or paraganglioma is identified or suspected, additional functional imaging, such as Gallium-68 DOTATATE PET/CT, may be used to better characterise the tumour, assess the extent of disease, and determine whether it has spread to other parts of the body.
For SDHB mutation carriers, regular renal imaging is also recommended given the specific risk of SDH-deficient renal cell carcinoma.
In tumour tissue obtained by biopsy or surgery, pathologists use a test called immunohistochemistry (IHC) to assess for loss of SDHB protein expression. Loss of SDHB staining in a tumour is a reliable marker of SDH deficiency regardless of which specific SDHx subunit is mutated, and is now a standard part of the pathological workup for paraganglioma, phaeochromocytoma, GIST, and renal cell carcinoma.
Treatment depends on the tumour type, location, size, grade, whether it is hormone-secreting, and whether it has spread. People with SDH-related syndromes should be managed by a specialist multidisciplinary team with expertise in hereditary tumour syndromes, ideally at a centre experienced in neuroendocrine cancers.
Before any surgery for a phaeochromocytoma or hormone-secreting paraganglioma, blood pressure must be carefully controlled with medications to prevent a dangerous catecholamine surge during anaesthesia. This typically involves alpha-blockers, with beta-blockers added in selected cases only after adequate alpha-blockade is established. This step is critical and must not be omitted before surgery proceeds.
Surgery is the primary treatment for localised paragangliomas and phaeochromocytomas and is potentially curative in many cases. For head and neck paragangliomas, the approach depends on tumour size, location, and the risks of surgery relative to observation. For SDH-deficient renal cell carcinoma and GISTs, surgery is also the primary treatment when the tumour is localised and resectable.
Somatostatin analogues such as octreotide or lanreotide may be used to control symptoms and slow tumour growth in advanced or metastatic SDH-related paragangliomas and phaeochromocytomas that express somatostatin receptors.
PRRT delivers targeted radiation to neuroendocrine tumour cells using a radioactive molecule bound to a somatostatin analogue. It may be considered for advanced, inoperable, or metastatic paragangliomas or phaeochromocytomas that show somatostatin receptor expression on functional imaging.
SDH-deficient GISTs are resistant to imatinib, which is the standard treatment for KIT-driven GISTs. Management of advanced SDH-deficient GIST requires specialist guidance and may involve alternative systemic agents.
For advanced phaeochromocytomas and paragangliomas, belzutifan is a targeted therapy that works by inhibiting the HIF-2alpha (hypoxia-inducible factor 2 alpha) pathway, a key pathway activated by SDH deficiency and other pseudohypoxia-related mutations. Access to emerging targeted therapies should be discussed with the treating specialist team, including whether clinical trial participation is available.
For SDH-deficient renal cell carcinoma, systemic therapies including targeted agents and immunotherapy may be considered for advanced disease, guided by a specialist.
External beam radiotherapy or stereotactic radiosurgery may be considered for head and neck paragangliomas where surgery carries significant risk, or for residual, recurrent, or inoperable tumours in other locations.
Living with an SDH mutation means living with the knowledge of an ongoing, lifelong cancer risk that affects not only the individual but potentially their children, siblings, and parents. This can carry significant psychological weight, even in the absence of a current tumour diagnosis.
For many people, the first encounter with SDH mutations comes either through an incidental tumour diagnosis or through cascade testing following a relative’s diagnosis. Both pathways can be confronting, and access to clear information, specialist care, and peer support is essential. NeuroEndocrine Cancer Australia provides access to a specialist NET counsellor as part of its support services.
People with SDH mutations who have been treated for a tumour may face the reality of ongoing surveillance, the possibility of new tumour development at other sites, and the complexity of managing a hereditary condition within the family. This is a lifelong commitment that requires regular engagement with specialist healthcare.
There are no specific dietary restrictions associated with SDH mutations in general. However, people with hormone-secreting tumours may be advised by their specialist to avoid certain substances that can trigger catecholamine release, including high-tyramine foods, caffeine, and specific medications. Advice should be individualised and discussed with the treating team.
People undergoing treatment for an SDH-related tumour may benefit from nutritional support depending on the type of treatment received. NeuroEndocrine Cancer Australia provides access to a specialist NET dietitian as part of its support services.
People living with SDH mutations should be aware of the symptoms that may indicate tumour development or progression, particularly symptoms of catecholamine excess such as episodes of headache, sweating, palpitations, and high blood pressure occurring together. Any new or changing symptoms should be reported to the treating team promptly.
Adherence to the recommended surveillance schedule is the most important step a person with an SDH mutation can take to protect their health, as many tumours are detectable and treatable before they cause significant symptoms.
Living with hereditary cancer syndrome involves ongoing uncertainty and the complexity of implications for family members. Psychological support, access to genetic counsellors, peer connection with others in similar situations, and clear reliable information all contribute meaningfully to quality of life.
NeuroEndocrine Cancer Australia provides education, resources, advocacy, and access to specialist services for people affected by SDH mutations and their families, including the NET Nurse service and specialist NET counsellor and dietitian.
Research into SDH mutations is advancing rapidly, driven by improved understanding of the underlying biology and the development of targeted therapies that exploit the specific molecular vulnerabilities of SDH-deficient cells.
Clinical trials are investigating novel targeted agents for SDH-deficient tumours, including HIF-2alpha inhibitors for advanced phaeochromocytoma and paraganglioma and alternative systemic agents for SDH-deficient GIST. Research is also underway into the biology of the SDH-related immune microenvironment and the potential role of immunotherapy in these tumours.
Australia participates in international clinical trial networks for hereditary tumour syndromes and neuroendocrine cancers. People with advanced or treatment-resistant SDH-related tumours should ask their treating team about relevant clinical trials.
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