Genetic testing in pheochromocytoma: increasing importance for clinical decision making

Hereditary pheochromocytomas and paragangliomas are caused by germline mutations in syndrome-associated genes. This includes multiple endocrine neoplasia Type 2 (MEN 2) caused by mutations in the RET proto-oncogene, von Hippel-Lindau (VHL) syndrome due to mutations of the VHL gene, neurofibromatosis Type I (NF1) caused by mutations of the NF1 gene, and pheochromocytoma/paraganglioma syndromes due to mutations in genes encoding the succinate dehydrogenase subunits D (SDHD) and B (SDHB). At the First International Symposium on Pheochromocytoma (ISP2005) organized by the National Institutes of Health, a panel of specialist clinicians and scientists from around the world addressed the topic of genetic testing in pheochromocytoma patients. This review summarizes the discussions and conclusions of the panel and provides a recommendation for evidence-based management of genetic testing in these patients and their families. A pragmatic algorithm is presented, taking into account patient age, tumor location (extra-adrenal, intra-adrenal, unilateral, and bilateral), biochemical presentation, and financial costs. This was based on cumulative frequencies ranging from 7.5% to 29% for germline mutations in four genes (RET, VHL, SDHB, and SDHD) in patients with apparently sporadic pheochromocytomas. This algorithm will need to be validated by further genetic analysis, multicenter studies, and long-term observations.