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Hereditary paraganglioma (SDHD)
This condition occurs due to changes in genes like SDHD, affecting how cells produce energy. It primarily affects adults and may lead to tumours that can sometimes produce hormones, potentially impacting various body systems.
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Overview
Hereditary paraganglioma is a rare inherited condition that makes individuals more likely to develop specific types of tumours called paragangliomas and phaeochromocytomas [PMID:33221976]. These tumours develop from specialised nerve cells found throughout the body. Paragangliomas typically occur in the head, neck, and chest, while phaeochromocytomas are paragangliomas that develop in the adrenal glands, located above the kidneys.
While many paragangliomas are benign (non-cancerous), they can still cause symptoms due to their size or location, or by producing certain hormones. In some cases, they can be malignant (cancerous) and spread to other parts of the body. The condition is often diagnosed in adulthood, though the age of onset can vary significantly between individuals.
Symptoms & clinical features
The symptoms of hereditary paraganglioma can vary widely depending on the location of the tumour and whether it produces hormones. Paragangliomas in the head and neck, often occurring near major blood vessels or nerves, may present with symptoms such as a palpable mass, hearing loss, ringing in the ears (tinnitus), or hoarseness [PMID:24177263].
Phaeochromocytomas, and some paragangliomas, can produce excessive amounts of hormones called catecholamines, such as adrenaline and noradrenaline. High levels of these hormones can lead to symptoms like high blood pressure, headaches, palpitations (a sensation of a racing heart), excessive sweating, and anxiety or panic attacks. These symptoms can be intermittent or persistent. Tumours that do not produce hormones may only cause symptoms due to their physical presence, for example, by pressing on nearby structures.
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Affected organs
Hereditary paraganglioma primarily affects specific endocrine glands and nerve tissues. The most commonly affected organs are the adrenal glands, where tumours are called phaeochromocytomas. Paragangliomas can also develop in other areas, including the head and neck region, along the sympathetic and parasympathetic nervous systems [PMID:33221976].
Less commonly, these tumours can occur in the chest, abdomen, or pelvis. The presence of tumours in these various locations can impact the function of nearby blood vessels, nerves, and other organs, leading to the diverse range of symptoms observed in this condition.
Risks & severity
The severity of hereditary paraganglioma can vary greatly, even within the same family. Individuals with a pathogenic variant in SDHD have a significantly increased lifetime risk of developing paragangliomas and phaeochromocytomas. Research suggests that around 50% to 70% of individuals with an SDHD pathogenic variant will develop a tumour by the age of 50, though the risk continues throughout life [PMID:24177263].
While most paragangliomas are benign, approximately 10-20% can be malignant, meaning they can spread to other parts of the body. The risk of malignancy is thought to be slightly higher for phaeochromocytomas and paragangliomas in the abdomen or pelvis compared to those in the head and neck. Early detection and regular surveillance are important to manage these risks effectively.
Genetic causes
Hereditary paraganglioma is most commonly associated with pathogenic variants in the SDHD gene. The SDHD gene provides instructions for making one part of a larger protein complex called succinate dehydrogenase (SDH) [PMID:33221976]. The SDH complex plays a critical role in the mitochondria, the 'powerhouses' of the cell, where it is involved in two essential cellular processes: the citric acid cycle (also known as the Krebs cycle) and the electron transport chain (oxidative phosphorylation). These processes are crucial for converting food into energy.
Pathogenic variants in SDHD disrupt the normal function of the SDH complex. When this complex doesn't work correctly, it can lead to a build-up of certain molecules within the cell. This build-up is thought to trigger a pathway that promotes cell growth and division, ultimately increasing the risk of tumour formation, particularly paragangliomas and phaeochromocytomas.
- SDHD succinate dehydrogenase complex subunit DThe SDHD gene provides instructions for a key component of the succinate dehydrogenase enzyme complex, essential for cellular energy conversion within mitochondria.
Inheritance pattern
Hereditary paraganglioma associated with SDHD is inherited in an autosomal dominant pattern. This means that a person only needs to inherit one copy of a changed SDHD gene from one parent to have an increased risk of developing the condition. However, a unique feature of SDHD-related paraganglioma is its strong parental origin effect.
Typically, symptoms and tumours only develop if the changed SDHD gene is inherited from the father. If the changed gene is inherited from the mother, the individual often does not develop symptoms, although they can still pass the changed gene on to their children [PMID:24177263]. This phenomenon is called genomic imprinting. Each child of an affected parent has a 50% chance of inheriting the altered gene. If inherited from the father, the child is at risk of developing the condition; if inherited from the mother, they are typically a carrier without symptoms.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
Diagnosis & testing
The diagnosis of hereditary paraganglioma is often suspected based on clinical symptoms, a family history of paragangliomas or phaeochromocytomas, or the presence of multiple or recurrent tumours. Initial investigations may include imaging studies such as MRI or CT scans to locate tumours, and biochemical tests to measure levels of catecholamines and their metabolites in blood or urine, which can indicate hormone-producing tumours.
A definitive diagnosis is confirmed through genetic testing. If hereditary paraganglioma is suspected, a referral to a clinical genetics service is typically made. Genetic testing for the SDHD gene, and other related genes (such as SDHB, SDHC, and SDHAF2), can identify a pathogenic variant. This testing falls under the NHS Genomic Medicine Service, and relevant tests can be found using specific R-codes, such as R253 Phaeochromocytoma and Paraganglioma, when referred by a specialist clinician.
Management & lifestyle
Management of hereditary paraganglioma focuses on regular surveillance, treatment of existing tumours, and managing associated symptoms. Individuals with a pathogenic SDHD variant are typically advised to undergo lifelong screening to detect tumours early. This often includes regular imaging (such as MRI of the head, neck, chest, and abdomen) and biochemical testing for hormone levels [PMID:33221976].
Treatment for paragangliomas and phaeochromocytomas depends on their size, location, and whether they produce hormones. Options may include surgical removal, radiation therapy, or medical management to control blood pressure and other hormone-related symptoms. A multidisciplinary team, including endocrinologists, surgeons, oncologists, and clinical geneticists, is generally involved in providing comprehensive care. Genetic counselling is also a key component, offering support and information to individuals and their families regarding inheritance patterns and testing options for relatives.
UK care pathway
In the UK, individuals suspected of having hereditary paraganglioma, or those with a family history, will typically be referred to an NHS Clinical Genetics service. Genetic counselling is an integral part of this pathway, providing detailed information about the condition, inheritance patterns, and testing options for both the affected individual and their wider family. The NHS Genomic Medicine Service provides genetic testing, which can be accessed via specific R-codes like R253 (Phaeochromocytoma and Paraganglioma) if clinically indicated by a specialist. Management is then coordinated by multidisciplinary teams, often involving specialists in endocrinology, oncology, and surgery.
Frequently asked questions
What is the difference between a paraganglioma and a phaeochromocytoma?
Both are tumours that arise from specialised nerve cells. Phaeochromocytomas are specifically paragangliomas that develop in the adrenal glands, located above the kidneys. Other paragangliomas can occur elsewhere in the body, such as the head, neck, chest, or abdomen.
If my mother has an SDHD pathogenic variant, am I at risk?
With SDHD-related hereditary paraganglioma, if the pathogenic variant is inherited from your mother, you typically will not develop the condition yourself. However, you would still be a carrier and could pass the variant on to your children, who would be at risk if they inherited it from you (if you are male) or if their father also had the variant.
How often do I need to be screened if I have an SDHD pathogenic variant?
The frequency of screening varies, but it typically involves regular imaging scans (like MRI) and biochemical tests (blood or urine tests for hormones). Your specialist healthcare team will develop a personalised surveillance plan based on your specific risk factors and clinical history.
Are all paragangliomas cancerous?
No, most paragangliomas are benign (non-cancerous). However, they can still cause symptoms due to their size or if they produce hormones. A smaller proportion, around 10-20%, can be malignant (cancerous) and may spread to other parts of the body.
Can hereditary paraganglioma be prevented?
As hereditary paraganglioma is a genetic condition, it cannot be prevented. However, regular surveillance and early detection of tumours can significantly improve management and outcomes. Genetic counselling can help families understand their risks and make informed decisions.