Genetics and clinical characteristics of hereditary pheochromocytomas and paragangliomas

Abstract

Pheochromocytomas (PCCs) and paragangliomas (PGLs) are rare neuroendocrine tumors of the adrenal glands and the sympathetic and parasympathetic paraganglia. They can occur sporadically or as a part of different hereditary tumor syndromes. About 30% of PCCs and PGLs are currently believed to be caused by germline mutations and several novel susceptibility genes have recently been discovered. The clinical presentation, including localization, malignant potential, and age of onset, varies depending on the genetic background of the tumors. By reviewing more than 1700 reported cases of hereditary PCC and PGL, a thorough summary of the genetics and clinical features of these tumors is given, both as part of the classical syndromes such as multiple endocrine neoplasia type 2 (MEN2), von Hippel-Lindau disease, neurofibromatosis type 1, and succinate dehydrogenase-related PCC-PGL and within syndromes associated with a smaller fraction of PCCs/PGLs, such as Carney triad, Carney-Stratakis syndrome, and MEN1. The review also covers the most recently discovered susceptibility genes including KIF1Bb, EGLN1/PHD2, SDHAF2, TMEM127, SDHA, and MAX, as well as a comparison with the sporadic form. Further, the latest advances in elucidating the cellular pathways involved in PCC and PGL development are discussed in detail. Finally, an algorithm for genetic testing in patients with PCC and PGL is proposed.

A MEN1 syndrome with a paraganglioma

“…4,7 Conversely, MEN1 gene mutation has never been identified while investigating familial or sporadic PGL etiology. In the literature, o10 cases (o1%) of PHEO have been reported in the course of MEN1.…”

“…In the literature, o10 cases (o1%) of PHEO have been reported in the course of MEN1. 4 However, the LOH on chromosome 11q might be critical for the development of PGL or PHEO. 13 As PGL is more likely to occur in SDHs gene-related syndromes, we investigated SDHA, SDHB, SDHC, SDHD, and SDHAF2 gene sequences and found no mutation.…”

“…Several other genes have been demonstrated to be predisposing for PHEO/PGL (ie TMEM127, MAX, SDHAF2, and HIF2A). 4,5 Also, the Carney-Stratakis syndrome associates PGL and gastrointestinal stromal tumors and is linked with SDHs gene mutations. 6 Another new syndrome, which associates pituitary adenoma and PHEO or PGL, has been speculated by Xekouki et al 7 and could be linked with germline mutations of SDHs genes.…”

Consensus Statement on next-generation-sequencing-based diagnostic testing of hereditary phaeochromocytomas and paragangliomas

“…Some of these driver genes are only mutated at the germ line level, while others can be mutated either at the germ line or somatic level. A third group of driver genes are only mutated somatically 1,2,48 . The relative frequency of overall mutations and specific germ line and/ or somatic events for each of these genes varies (TABLE 1).…”

Role of SDHAF2 and SDHD in von Hippel–Lindau Associated Pheochromocytomas

“…They frequently cause hypertension due to excessive catecholamine production and secretion. With the current data related to discoveries of new genes in the pathogenesis of PCCs and PGLs, the proportion of hereditary tumors is estimated to be around 30-35% [2][3][4]. The vast majority of these patients belong to one of the following syndromes: von Hippel-Lindau (VHL) [5], multiple endocrine neoplasia type 2 (MEN 2) [6], von Recklinghausen (NF1) [7] or pheochromocytomaparaganglioma syndrome (PGL types 1-4) [8][9][10][11], which are caused by germline mutations in VHL, RET, NF1 and SDHx (SDHA, SDHB, SDHC, SDHD, and SDHAF2/SDH5), respectively.…”