Hereditary pheochromocytoma-paraganglioma
Pheochromocytoma and paraganglioma are rare neuroendocrine tumours (incidence <1:100.000 per year). These tumours originate in chromaffin cells of the adrenal medulla or in (para)sympathetic neural ganglia, often along blood vessels and nerves of the head, neck and spine. Tumours that develop in the adrenal gland are called pheochromocytomas (or intra-adrenal paragangliomas), while those that evolve outside are named paragangliomas (or extra-adrenal paraganglioma). Both tumours may produce excessive amounts of hormones, called catecholamines, causing a variety of symptoms such as palpitations, headaches, excessive sweating and nausea. These symptoms might be the first manifestation of the tumours. They are rare for parasympathetic head and neck paragangliomas, whose diagnosis is often related to mass effect. Pheochromocytomas and paragangliomas are typically diagnosed within the third to fifth decade and are most often benign.
A significant proportion of pheochromocytomas and paragangliomas (appr. 30-40%) occur as part of a genetic tumour risk syndrome (also termed hereditary cancer predisposition syndrome). Individuals with hereditary pheochromocytoma-paraganglioma (ORPHA:29072) tend to develop tumours at a younger age (as early as during childhood), and are more likely to develop multifocal, multiple and/or recurrent disease.
Hereditary pheochromocytoma-paraganglioma is caused by pathogenic germline variants in one of multiple genes (such as SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127 and MAX). The most frequently involved genes encode individual subunits of the succinate dehydrogenase (SDHx) enzyme complex, accounting for at least half of the cases. SDHB is one of the major genes predisposing to hereditary pheochromocytoma-paraganglioma, and also the one associated with higher risk of malignant disease. Other tumours occurring in families with pathogenic germline variants in the SDHB, SDHC, and SDHD genes are gastrointestinal stromal tumours, pulmonary chondromas and clear cell renal cell carcinoma. Pheochromocytomas and paragangliomas may also occur in families with other genetic tumour risk syndromes, including Von Hippel-Lindau syndrome (VHL gene), Multiple Endocrine Neoplasia type 2 (RET gene), Neurofibromatosis type 1 (NF1 gene), and Hereditary Leiomyomatosis and Renal Cell Cancer (FH gene).
Hereditary pheochromocytoma-paraganglioma is inherited in an autosomal dominant manner, meaning that each child of an affected individual has a 50% chance to inherit the familial pathogenic variant. Persons with a pathogenic variant are at increased tumour risk, although tumours do not develop in every person (“incomplete penetrance”).
The cancer risk varies dependent on the affected gene. Pathogenic variants in some genes (SDHD, SDHAF2 and possibly MAX) are associated with a parent-of-origin effect, meaning that the tumour risk is increased almost exclusively when they are inherited from the father.
If a pathogenic variant in any of the hereditary pheochromocytoma-paraganglioma associated genes has been detected in an individual, close follow-up is recommended, and healthy relatives should be offered predictive testing. Preimplantation and prenatal genetic testing are possible.
Currently, different guidelines for initial screening after diagnosis, treatment and care of patients with hereditary paraganglioma-pheochromocytoma exist and recommendations can be specific dependent on the affected gene (more information can be found on GeneReviews®).
A lifelong regular screening is advised for individuals with hereditary pheochromocytoma-paraganglioma. This typically includes clinical exams and questionnaires, biochemical examinations (metanephrines) and imaging techniques (including magnetic resonance tomography). The initiation of screening is typically recommended during childhood and the periods of evaluations differ for children and adults. Surveillance should preferably be performed at specialised centres.
More information regarding hereditary pheochromocytoma-paraganglioma can be found on:
GeneReviews® - Hereditary pheochromocytoma-paraganglioma
Orphanet: Hereditary pheochromocytoma-paraganglioma
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ERN GENTURIS webinars - Thematic group 4: Other rare genturis
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A list of healthcare providers with expertise in Thematic Group 4: Other rare - predominantly malignant - genturis can be found here.
A non-exhaustive list of patient associations for genetic tumour risk syndromes in EU member states can be found here.