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Pheochromocytomas, Paragangliomas and Disorders of the Sympathoadrenal System pp 63–87Cite as

Heritable and Syndromic Pheochromocytoma and Paraganglioma

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Part of the book series: Contemporary Endocrinology ((COE))

Abstract

Pheochromocytomas (PCC) and paragangliomas (PGL) are rare neuroendocrine neoplasias that develop in the adrenal medulla or in the paravertebral extra-adrenal ganglia. Although they are more commonly benign (~75%) than malignant (~25%), they can be associated with a high degree of morbidity and a substantial mortality due to the hypersecretion of catecholamines or mass effects. Although PCC/PGL occur more commonly as sporadic tumors, about 30–40% are inherited and associated with predisposing germline mutations in more than 15 susceptibility genes. Several classic autosomal dominant tumor syndromes (von Hippel-Lindau, neurofibromatosis type 1, multiple endocrine neoplasia type 2) are associated with an increased risk for the development of PCC/PGL. Mutations in the TMEM127, MAX, MDH2, FH, and EPAS1/HIF2A genes, among others, can be associated with PCC/PGL, and mutations in the genes encoding the succinate dehydrogenase (SDH) subunits A, B, C, and D or its cofactor SDHAF2 lead to a predisposition to developing paragangliomas (paraganglioma syndrome types 1–5).

Mutational analysis of these susceptibility genes is of increasing clinical importance for the early identification and treatment of carriers, as well as genetic counseling. Important insights into the oncogenic events have been obtained through the recently completed comprehensive molecular characterization of 173 PCC/PGL in The Cancer Genome Atlas (TCGA) project. It has revealed a broad spectrum of somatic mutations (CSDE1, HRAS, RET, EPAS1, NF1) or rearrangements (MAML3, BRAF, NGFR, NF1) affecting several genes and pathways. A thorough understanding of the genetic susceptibility factors and the oncogenic mechanisms underlying PCC/PGL is essential for clinical management, genetic counseling, the identification of tumors with an aggressive behavior, and the development of novel targeted therapeutic modalities for metastatic tumors.

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  1. Division of Endocrinology, Metabolism and Molecular Medicine and Center for Genetic Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

    Peter Kopp

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    Lewis Landsberg

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Kopp, P. (2018). Heritable and Syndromic Pheochromocytoma and Paraganglioma. In: Landsberg, L. (eds) Pheochromocytomas, Paragangliomas and Disorders of the Sympathoadrenal System. Contemporary Endocrinology. Humana Press, Cham. https://doi.org/10.1007/978-3-319-77048-2_4

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