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Hereditary paraganglioma-phaeochromocytoma (SDHB)
People with SDHB variants face elevated risks of developing paragangliomas and phaeochromocytomas - typically benign tumours arising from chromaffin cells in the adrenal glands or nerve tissue elsewhere. Some tumours may become malignant, and early detection through surveillance is important for optimal outcomes.
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Overview
Hereditary paraganglioma-phaeochromocytoma syndrome associated with SDHB is a rare inherited condition characterising increased susceptibility to developing specific types of neuroendocrine tumours. These tumours arise from chromaffin cells - specialised nerve cells that produce hormones such as adrenaline and noradrenaline. When these tumours occur in the adrenal glands (small hormone-producing organs sitting atop the kidneys), they are called phaeochromocytomas. When they develop outside the adrenal glands - in the head, neck, chest, abdomen or pelvis - they are termed paragangliomas.
Research suggests that SDHB-related tumours carry a higher risk of malignancy compared to paragangliomas and phaeochromocytomas arising from other genetic causes. Whilst many affected individuals develop tumours during adulthood, onset can occur from childhood through to later life. The condition follows an autosomal dominant inheritance pattern, meaning a pathogenic variant in one copy of the SDHB gene is sufficient to increase cancer risk. Because penetrance is incomplete, not everyone who inherits a pathogenic SDHB variant will develop tumours during their lifetime, though regular surveillance is recommended for all carriers.
The condition is rare, with exact prevalence not well established in the general population. However, pathogenic SDHB variants account for a meaningful proportion of hereditary paraganglioma and phaeochromocytoma cases, making genetic testing an important consideration for individuals with relevant personal or family histories of these tumours.
Symptoms & clinical features
Clinical features of SDHB-related hereditary paraganglioma-phaeochromocytoma depend largely on tumour location and whether the tumour is hormonally active. Phaeochromocytomas and some paragangliomas produce excess catecholamines (adrenaline and noradrenaline), leading to episodic or sustained high blood pressure, severe headaches, excessive sweating, rapid or irregular heartbeat, and pale skin. Some people experience panic-like episodes with tremor, anxiety and palpitations. These symptoms may occur in sudden attacks or persist more continuously.
Paragangliomas in the head and neck region may be non-functional (not producing hormones) and instead cause symptoms through local mass effect. These can include a palpable neck mass, difficulty swallowing, changes in voice, hearing loss or tinnitus (ringing in the ears) depending on precise location. Abdominal or thoracic paragangliomas might produce vague symptoms such as abdominal pain or be discovered incidentally during imaging for other reasons. Evidence suggests that SDHB-associated tumours more frequently involve extra-adrenal sites compared to other genetic causes of these conditions.
Malignant paragangliomas or phaeochromocytomas may spread to distant sites including bones, lymph nodes, liver or lungs. Symptoms of metastatic disease vary with location but can include bone pain, breathing difficulties or organ-specific dysfunction. Some individuals remain asymptomatic until tumours are detected through surveillance imaging, highlighting the importance of proactive monitoring in known SDHB variant carriers.
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Affected organs
The primary organs and tissues affected in SDHB-related hereditary paraganglioma-phaeochromocytoma are those containing chromaffin cells or paraganglia - clusters of specialised neuroendocrine cells distributed throughout the body. The adrenal glands represent a common site, with phaeochromocytomas developing in the adrenal medulla (the inner part of these glands). However, SDHB-associated tumours show particular predilection for extra-adrenal locations.
Paragangliomas can arise along the paravertebral sympathetic chain (running alongside the spine), in the organ of Zuckerkandl (near the aorta in the abdomen), within the chest cavity, or in the head and neck region including the carotid body, jugular bulb and vagal paraganglia. The cardiovascular system may be secondarily affected through catecholamine excess, leading to hypertensive complications, cardiac arrhythmias or cardiomyopathy in some cases. When malignant transformation occurs, metastatic spread most commonly involves bones, lungs, liver and lymph nodes. Research indicates that SDHB variants confer higher rates of malignancy and metastatic potential compared to variants in other succinate dehydrogenase subunit genes, making comprehensive surveillance across multiple anatomical sites particularly important in this population.
Risks & severity
The lifetime risk of developing paragangliomas or phaeochromocytomas in SDHB variant carriers is substantial, with penetrance estimates varying across different study populations. Age of onset is variable, with tumours reported from childhood through to the seventh decade of life, though most present between the second and fifth decades. Individual clinical course varies considerably - some develop single, benign tumours amenable to curative resection, whilst others experience multiple tumours or disease requiring ongoing management.
A distinguishing feature of SDHB-related disease is the elevated risk of malignancy. Evidence suggests that SDHB-associated paragangliomas and phaeochromocytomas show increased rates of malignant behaviour with capacity for metastatic spread, representing higher malignancy potential than seen with other genetic causes of these tumours. This elevated malignancy risk necessitates careful long-term surveillance even after successful treatment of an initial tumour, as metastases may appear years or decades later. Factors influencing individual prognosis include tumour location, size at detection, presence of metastases, and completeness of surgical resection where feasible. Early detection through surveillance generally offers better treatment options and outcomes.
Genetic causes
Hereditary paraganglioma-phaeochromocytoma syndrome in this context arises from pathogenic variants in SDHB, located on chromosome 1p36. This gene encodes one protein component within the four-subunit succinate dehydrogenase enzyme assembly, which performs critical cellular functions. Within mitochondria (the structures generating cellular energy), succinate dehydrogenase participates in both the citric acid cycle and the electron transport chain, making it essential for energy metabolism and respiration.
Beyond its metabolic function, SDHB acts as a tumour suppressor. Under normal circumstances, the encoded protein helps coordinate cellular responses to oxygen availability and maintains appropriate constraints on cell proliferation. When SDHB function is disrupted by pathogenic variants, succinate accumulates within cells, acting as an oncometabolite that interferes with multiple cellular processes. This accumulation promotes abnormal activation of hypoxia-inducible factors (proteins normally activated under low-oxygen conditions), even when oxygen is plentiful. The resulting cellular changes favour tumour development, particularly in chromaffin cells and paraganglia which appear especially vulnerable to this mechanism.
Most SDHB pathogenic variants result in loss of function through mechanisms including frameshift, nonsense or splice-site changes that prevent production of functional protein. The condition follows autosomal dominant inheritance with a parent-of-origin effect - research suggests that maternally inherited SDHB variants may show reduced penetrance compared to paternally inherited variants, though the mechanisms underlying this observation remain under investigation. Despite inheriting one pathogenic variant, affected individuals typically require a second somatic event (loss of the remaining functional copy) within specific cells for tumour formation to occur, consistent with Knudsen's two-hit hypothesis for tumour suppressor genes.
- SDHB succinate dehydrogenase complex iron sulfur subunit BSDHB encodes an iron-sulphur subunit of succinate dehydrogenase, a mitochondrial enzyme that bridges the citric acid cycle and oxidative phosphorylation while preventing uncontrolled cell growth.
Inheritance pattern
SDHB-related hereditary paraganglioma-phaeochromocytoma follows an autosomal dominant pattern of inheritance. This means that inheriting one pathogenic variant in the SDHB gene from either parent is sufficient to substantially increase an individual's risk of developing tumours, even though they possess one normal working copy of the gene. Each child of an affected parent has a 50% chance of inheriting the pathogenic variant.
However, not everyone who carries a pathogenic SDHB variant will develop tumours - a concept called incomplete penetrance. Family members who inherit the same variant may have different outcomes, with some developing multiple tumours whilst others remain unaffected throughout life. The reasons for this variability are not fully understood but may involve additional genetic factors, environmental influences and chance somatic events. Because of incomplete penetrance, families may observe the condition appearing to 'skip generations' when variant carriers remain unaffected but pass the variant to children who do develop tumours. All individuals carrying a pathogenic SDHB variant are advised to undergo regular surveillance regardless of whether they have symptoms, as early tumour detection improves treatment outcomes. Genetic counselling helps families understand inheritance patterns, recurrence risks and options for predictive testing in at-risk relatives.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
Diagnosis & testing
Diagnosis of SDHB-related hereditary paraganglioma-phaeochromocytoma typically begins with clinical suspicion based on personal or family history of paragangliomas, phaeochromocytomas or related features. Individuals presenting with these tumours, particularly those with extra-adrenal, multifocal or malignant disease, or those diagnosed at younger ages, should be considered for genetic evaluation. Family history of similar tumours in multiple relatives also raises suspicion for an inherited syndrome.
Confirmation requires genetic testing through DNA sequencing of SDHB to identify pathogenic variants. In the UK, referral to clinical genetics services occurs through various routes including endocrinology, oncology or general practice. The NHS Genomic Medicine Service includes paraganglioma and phaeochromocytoma on PanelApp testing panels (such as R207 for phaeochromocytoma and paraganglioma), facilitating access to comprehensive genetic testing for eligible patients. Biochemical testing measuring catecholamines and their metabolites (such as plasma or urinary metanephrines) helps identify hormonally active tumours and guides monitoring. Imaging studies including CT, MRI or functional imaging with specific radiotracer scans help localise tumours and assess for metastatic disease. Immunohistochemistry testing of tumour tissue for SDHB protein expression may support genetic findings, as SDHB-deficient tumours typically show absent protein staining. Genetic counselling forms an integral part of the diagnostic pathway, ensuring individuals understand test implications, inheritance patterns and cascade testing opportunities for at-risk family members.
Management & lifestyle
Management of SDHB-related hereditary paraganglioma-phaeochromocytoma centres on surveillance for early tumour detection, treatment of identified tumours, and long-term monitoring for recurrence or new primary tumours. In the UK, care typically involves multidisciplinary teams including endocrinologists, surgeons, oncologists, radiologists and clinical geneticists. Surveillance protocols generally recommend regular biochemical testing (measuring catecholamines and metanephrines) combined with whole-body imaging at intervals determined by individual risk factors and clinical findings. Some centres use MRI-based protocols whilst others incorporate functional imaging techniques.
When tumours are identified, surgical resection represents the primary treatment approach where feasible. Phaeochromocytomas and paragangliomas require careful perioperative management including alpha-blockade before surgery to control blood pressure and prevent hypertensive crises. For malignant or metastatic disease not amenable to complete resection, treatment options may include targeted radiotherapy, chemotherapy, radionuclide therapy or newer targeted therapies, with selection guided by tumour characteristics and distribution. Some individuals benefit from medications to control symptoms related to catecholamine excess when curative treatment is not possible.
Lifestyle considerations include avoiding medications or substances that might precipitate hypertensive episodes in those with functional tumours. Evidence does not support specific dietary modifications for tumour prevention in variant carriers, though maintaining overall cardiovascular health remains sensible given potential blood pressure complications. Regular follow-up continues lifelong, as new tumours can develop decades after initial diagnosis. The NHS care pathway provides access to specialist centres with expertise in managing these rare tumours, and genetic counselling services remain available to address family planning questions and facilitate predictive testing for relatives. Patients are encouraged to inform healthcare providers about their genetic diagnosis before any surgical procedures or when new symptoms develop.
UK care pathway
In the UK, individuals with suspected or confirmed SDHB-related hereditary paraganglioma-phaeochromocytoma access care through the NHS Genomic Medicine Service and specialist multidisciplinary teams. Referral to clinical genetics services can occur from various specialties including endocrinology, general practice or oncology. Genetic testing is available through the NHS for eligible patients meeting criteria defined in the National Genomic Test Directory, with paraganglioma and phaeochromocytoma included under specific testing indications such as R207. PanelApp panels ensure comprehensive gene testing appropriate to clinical presentation.
Following genetic diagnosis, patients typically receive coordinated care involving endocrinology for surveillance and hormone management, surgery for tumour resection where appropriate, and oncology input for malignant disease. Genetic counselling provides essential support, explaining inheritance patterns, facilitating cascade testing for family members, and discussing reproductive options including prenatal or preimplantation genetic diagnosis where desired. Specialist centres with expertise in rare endocrine tumours often coordinate long-term surveillance protocols. Access to genetic counsellors remains available throughout the care journey to address evolving questions about the condition, family implications and surveillance strategies. Patient support organisations can provide additional resources and connections with others managing similar conditions.
Frequently asked questions
If I carry an SDHB variant but have no tumours, do I still need regular monitoring?
Yes, surveillance is recommended for all SDHB variant carriers regardless of symptoms, as tumours can develop at various ages throughout life. Regular biochemical testing and imaging allow early detection when treatment is typically most effective. Your clinical genetics team will recommend an appropriate surveillance schedule based on current evidence and your individual circumstances.
Are SDHB-related tumours always cancerous?
No, many SDHB-related paragangliomas and phaeochromocytomas are benign. However, SDHB variants do carry higher malignancy risk compared to other genetic causes of these tumours. Regular surveillance helps detect tumours early and monitor for any concerning changes over time.
Can my children be tested for the SDHB variant I carry?
Yes, predictive genetic testing is available for at-risk family members, though timing and approach depend on age and individual circumstances. Testing in children is generally considered when results would influence medical management, such as initiating surveillance protocols. Genetic counselling helps families make informed decisions about testing timing and understand the implications for each family member.
Will I definitely pass this condition to my children?
Each of your children has a 50% chance of inheriting the SDHB variant, as the condition follows autosomal dominant inheritance. However, inheriting the variant doesn't guarantee tumour development due to incomplete penetrance - some variant carriers never develop tumours. Genetic counselling can discuss reproductive options including prenatal testing if desired.
What should I do if I develop symptoms between surveillance appointments?
Contact your healthcare team promptly if you experience new symptoms such as persistent headaches, rapid heartbeat, excessive sweating, unexplained high blood pressure, or notice any new lumps. Whilst these symptoms have various potential causes, early evaluation is important in SDHB variant carriers. Your GP or specialist team can arrange appropriate investigations if needed between scheduled surveillance visits.