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 paragangliomas [HNPGLs]) and sometimes in the upper mediastinum; approximately 95% of such tumors are nonsecretory. In contrast, extra-adrenal sympathetic 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/PCCs 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. Additional tumors reported in individuals with hereditary PGL/PCC syndromes include gastrointestinal stromal tumors (GISTs), pulmonary chondromas, and clear cell renal cell carcinoma.
Diagnosis/testing: A diagnosis of a hereditary PGL/PCC syndrome 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 with a personal or family history of paraganglioma or pheochromocytoma and a germline heterozygous pathogenic variant in MAX, SDHA, SDHAF2, SDHB, SDHC, SDHD, or TMEM127 identified by molecular genetic testing.
Management: Treatment of manifestations: SDHB-related PGL/PCCs are typically treated with surgical resection because of the higher risk for metastatic disease. In general, most HNPGLs (carotid body, glomus jugulotympanicum, vagal, and jugular paragangliomas) are nonsecretory and may be treated with active observation, surgical resection, or radiation therapy. For secretory PGL/PCCs, alpha-adrenergic receptor blockade followed by surgical resection. All individuals with HNPGLs should be evaluated for catecholamine excess before surgical resection, which, if present, can suggest an additional primary PGL/PCC. Metastatic PGL/PCCs are treated with blood pressure control, surgical debulking, radiation therapy especially for bony lesions, liver-directed therapy, systemic chemotherapy, or radionuclide therapy. GIST treatment includes surgical resection and/or tyrosine kinase inhibitor. Clear cell renal cell carcinoma treatment is early surgical resection and standard treatments for metastatic disease.
Surveillance: Individuals at risk for hereditary PGL/PCC syndromes should have annual clinical assessment for manifestations of PGL/PCCs and GISTs, plasma-free fractionated metanephrines or 24-hour urine fractionated metanephrines every two years in childhood and then annually in adults, and whole-body MRI every two to three years. Age of initiation for screening varies by gene. Consider endoscopic evaluation for GISTs in individuals with unexplained anemia and gastrointestinal symptoms.
Agents/circumstances to avoid: As for all cancer predisposition syndromes, activities such as cigarette smoking that predispose to chronic lung disease should be discouraged. Hypoxic conditions (e.g., cyanotic heart disease, 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 hereditary PGL/PCC syndrome and 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: Hereditary PGL/PCC syndromes are inherited in an autosomal dominant manner. Most individuals diagnosed with a hereditary PGL/PCC syndrome inherited a PGL/PCC-related pathogenic variant from a parent; rarely, a proband with a hereditary PGL/PCC syndrome has the disorder as the result of a de novo pathogenic variant. Each child of an individual with a hereditary PGL/PCC syndrome-causing pathogenic variant has a 50% chance of inheriting the pathogenic variant. Pathogenic variants in SDHD, SDHAF2, and possibly MAX demonstrate parent-of-origin effects and cause disease almost exclusively when they are paternally inherited: an individual who inherits an SDHD or SDHAF2 pathogenic variant from the individual's father is at high risk of manifesting PGLs and PCCs; an individual who inherits an SDHD or SDHAF2 pathogenic variant from the individual's mother is usually not at risk of developing disease – however, exceptions occur. Once the PGL/PCC syndrome-related pathogenic variant has been identified in an affected family member, predictive molecular genetic testing for at-risk family members and prenatal and preimplantation genetic testing are possible.
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