Hereditary Paraganglioma-Pheochromocytoma Syndromes

In: GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993.
[updated ].


Clinical characteristics: Hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndromes are characterized by paragangliomas (tumors that arise from neuroendocrine tissues distributed along the paravertebral axis from the base of the skull to the pelvis) and pheochromocytomas (paragangliomas that are confined to the adrenal medulla). Sympathetic paragangliomas cause catecholamine excess; parasympathetic paragangliomas are most often nonsecretory. Extra-adrenal parasympathetic paragangliomas are located predominantly in the skull base and neck (referred to as head and neck PGL [HNPGL]) and sometimes in the upper mediastinum; approximately 95% of such tumors are nonsecretory. In contrast, sympathetic extra-adrenal paragangliomas are generally confined to the lower mediastinum, abdomen, and pelvis, and are typically secretory. Pheochromocytomas, which arise from the adrenal medulla, typically lead to catecholamine excess. Symptoms of PGL/PCC result from either mass effects or catecholamine hypersecretion (e.g., sustained or paroxysmal elevations in blood pressure, headache, episodic profuse sweating, forceful palpitations, pallor, and apprehension or anxiety). The risk for developing metastatic disease is greater for extra-adrenal sympathetic paragangliomas than for pheochromocytomas.

Diagnosis/testing: The diagnosis of a hereditary PGL/PCC syndrome should be suspected in any individual with a diagnosis of paraganglioma or pheochromocytoma. A diagnosis of hereditary PGL/PCC is strongly suspected in an individual with multiple, multifocal, recurrent, or early-onset paraganglioma or pheochromocytoma and/or a family history of paraganglioma or pheochromocytoma. The diagnosis is established in a proband by identification of a germline heterozygous pathogenic variant in MAX, SDHA, SDHAF2, SDHB, SDHC, SDHD, or TMEM127 on molecular genetic testing.

Management: Treatment of manifestations: For secretory PGL/PCC, treatment requires using medications for alpha adrenergic receptor blockade followed by surgery. For nonsecretory HNPGLs, surgical resection should be considered only after a detailed analysis of benefits and risks of a surgical procedure. All individuals with HNPGL should be evaluated for catecholamine excess before surgical resection, which, if present, can suggest an additional primary PGL/PCC. Watchful waiting or radiation therapy are options for HNPGLs. PGL/PCCs identified in individuals known to have SDHB pathogenic variants may benefit from resection over radiation or watchful waiting because of the higher risk for metastatic disease.

Prevention of secondary complications: Early detection through surveillance and removal of tumors may prevent or minimize complications related to mass effects, unregulated catecholamine secretion, and metastatic disease.

Surveillance: Beginning between ages six and eight years, individuals at risk for hereditary PGL/PCC syndromes should have annual biochemical and clinical surveillance for signs and symptoms of PGL/PCC and biennial full-body MRI examination. Consider endoscopic evaluation for gastrointestinal stromal tumors in individuals with unexplained gastrointestinal symptoms.

Agents/circumstances to avoid: Hypoxic conditions (e.g., living at high altitude, cigarette smoking) may increase tumor incidence and promote tumor growth, although data are extremely limited.

Evaluation of relatives at risk: First-degree relatives of an individual with a known MAX, SDHA, SDHAF2, SDHB, SDHC, SDHD, or TMEM127 pathogenic variant should be offered molecular genetic testing to clarify their genetic status to improve diagnostic certainty and reduce the need for costly screening procedures in those who have not inherited the pathogenic variant.

Genetic counseling: The hereditary PGL/PCC syndromes are inherited in an autosomal dominant manner. Pathogenic variants in SDHD demonstrate parent-of-origin effects and generally cause disease only when the pathogenic variant is inherited from the father. Pathogenic variants in SDHAF2 and possibly MAX exhibit parent-of-origin effects similar to those of pathogenic variants in SDHD. A proband with a hereditary PGL/PCC syndrome may have inherited the pathogenic variant from a parent or, rarely, have a de novo pathogenic variant; the proportion of individuals with a de novo pathogenic variant is unknown. Each child of an individual with a hereditary PGL/PCC syndrome-causing pathogenic variant has a 50% chance of inheriting the pathogenic variant. An individual who inherits an SDHD pathogenic variant from the individual's mother is at a very low but not negligible risk of developing disease. An individual who inherits an SDHD pathogenic variant from the individual's father is at high risk of manifesting PGL/PCC. If the pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

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