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Hereditary Pheochromocytoma and Paraganglioma Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
The SDHA (succinate dehydrogenase complex flavoprotein subunit A) gene encodes a major catalytic subunit of succinate-ubiquinone oxidoreductase, which participates in the transfer of electrons from succinate to ubiquinone in the mitochondrial electron transport chain. Heterozygous SDHA mutations are occasionally associated with pheochromocytoma (PCC), thoracoabdominal paraganglioma (TAPGL), head and neck paraganglioma (HNPGL), gastrointestinal stromal tumor (GIST) and pituitary adenoma (PA). In contrast, homozygous germline SDHA mutations are implicated in Leigh syndrome (an inherited mitochondrial respiratory chain deficiency). Homozygous germline mutations in SDHA cause neurological disorder (Leigh syndrome), as well as a syndrome of optic atrophy, ataxia, and myopathy [12].
Endocrine hypertension
Published in Philip E. Harris, Pierre-Marc G. Bouloux, Endocrinology in Clinical Practice, 2014
Frances McManus, John M. Connell, Marie Freel
The genetics of pheochromocytoma and paraganglioma is a rapidly changing and evolving field. For example, in 2010, loss-of-function mutations in the FP/TMEM127 gene were identified in 2% of patients with familial and sporadic pheochromocytoma, but not paraganglioma. TMEM127 is a negative regulator of mammalian target of rapamycin (mTOR) effector proteins.65 In addition, mutations within the SDH5 (SDHA2) gene have recently been identified as causing familial paraganglioma syndromes in one kindred first identified in the 1980s.66 SDH5 is important for the flavination and function of SDHA. However, this genetic syndrome remains extremely rare, and only one further kindred has been identified so far.
Endocrine and neuroendocrine tumours
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2014
Ashley B. Grossman, Márta Korbonitis, P. Nicholas Plowman
Phaeochromocytomas are rare, with a prevalence of about 1:6,500 to 1:10,000, and are reported in less than 1% of hypertensive patients. Sporadic phaeochromocytomas are often single and unilateral, whereas familial phaeochromocytomas (about 10%) are often multi-centric and bilateral, have an earlier onset and have a lower risk of being malignant. About 10% of phaeochromocytomas are malignant, metastasizing to bone, lung, brain or liver, this proportion being more significant in families with mutations of SDHB (see later). Hereditary phaeochromocytomas (autosomal dominant inheritance) can be part of MEN2 or MEN3, syndromes associated with mutations in the RET proto-oncogene. About 10%–20% of patients with von Hippel–Lindau disease develop phaeochromocytoma, with an early age of onset. In neurofibromatosis type 1, the risk of phaeochromocytomas is about 1% and it occurs in the fifth decade, but because this is a common genetic disease it represents an important proportion of hereditary tumours. Mutations in the SDH gene have been extensively identified in familial paraganglioma syndromes.210 These include SDHA, SDHB, SDHC, SDHD and SDH-AF2, each syndrome having specific phenotypes. Allele-specific LOH has been detected at the chromosome 2 locus in phaeochromocytomas.211 Other more recently identified genes include TMEM-127 and MAX. However, as phaeochromocytomas are identified in families with as yet unidentified genetic mutations it is likely that still other genes are involved in the aetiology of the disease.212,213 At present, some 30% of all patients presenting with phaeochromocytomas have some identifiable genetic cause, more with paragangliomas.
Genotype-phenotype associations in paragangliomas of the temporal bone in a multi-ethnic cohort
Published in Acta Oto-Laryngologica, 2023
Simon I. Angeli, Juan A. Chiossone K, Stefania Goncalves, Fred F. Telischi
Mutation analyses were conducted as part of the patient’s clinical care in a CLIA-certified laboratory (Invitae, San Francisco, California, USA). After obtaining informed consent from the patients, genomic DNA was isolated from blood leukocytes or cheek swabs and enriched for targeted regions using a hybridization-based protocol and sequenced using Illumina technology. The targeted regions that were sequenced and evaluated for sequence changes and exonic deletion/duplications involved the following genes: SDHB (8 exons), SDHC (6 exons), SDHD (4 exons), SDHAF2, RET, NF1, VHL, TMEM127, and MAX. The SDHA gene was evaluated for sequence changes only. The reference sequence was GRCh37. When a TBPGL patient is found to have a pathologic germline mutation, clinical and genetic screening was offered to first degree relatives.
Upregulation of SDHA inhibited proliferation, migration, and invasion of clear cell renal cell carcinoma cells via inactivation of the Wnt/β-catenin pathway
Published in Journal of Receptors and Signal Transduction, 2022
Xiaolong Xu, Naiwei Zhang, Ruxu Gao, Jianfeng Wang, Zhihong Dai, Jianbin Bi
SDHA is a major catalytic submit of SDH, a complex of the mitochondrial respiratory chain [16]. Increasing evidence has confirmed that the gene defect and abnormal expression of SDHA have been found in wild-type gastrointestinal stromal tumors [17], breast cancer [18], renal carcinoma, pituitary adenomas [19], paraganglioma and pheochromocytoma [20]. At present, the existed research showed that the adjustment disorders of the protein stability of SDHA have been closely related to neurological diseases and many kinds of tumors, but the regulatory mechanisms of protein stability of SDHA have not been reported so far. Intriguingly, our data showed that the expression of SDHA in ccRCC tissues and cell lines was lower than that in adjacent tissues and the human renal proximal tubule epithelial cell line. Moreover, overexpression of SDHA suppressed the proliferation and metastasis abilities of ccRCC cells. Importantly, recent studies have confirmed that the dysregulation of SDHA acetylation [21] or desuccinylation [22] contributed to accelerating the carcinogenesis process. Another study showed that elevated SDHA contributed to pathological metabolism in highly metastatic uveal melanoma [23].
Head and neck paragangliomas in Norway, importance of genetics, updated diagnostic workup and treatment
Published in Acta Oto-Laryngologica, 2021
Mohammad Usman Rana, Arild André Østhus, Ketil Heimdal, Peter Jebsen, Mona-Elisabeth R. Revheim, Terje Andreas Osnes
PGs may occur sporadically or in hereditary forms. Hereditary forms count for approximately 1/3 (40%) of HNPGs and between 35 and 40% of all paraganglioma-pheocromocytomas [2,3]. This may depend on the population. In the head and neck area particularly, the hereditary PGs are frequently linked to mutations in the succinate dehydrogenase (SDHx) genes. The commonest mutations causing hereditary HNPGs are found in SDHD and SDHB, the SDHD mutation being the single most frequent [4]. The SDHx mutations are part of five hereditary PG syndromes which have different features; PGL1 (SDHD mutation, most frequent mutation, rarely malignant but often multifocal), PGL4 (SDHB mutation, second most frequent hereditary HNPG, with higher risk of malignant disease and functional PGs), PGL3 (SDHC mutation, rare), PGL2 (SDHAF2 mutation, rare and associated with multifocality) and PGL5 (SDHA mutation, rare) [5]. Additionally, there are other established familial syndromes that commonly include PGs; Neurofibromatosis 1 (NF1), Multiple endocrine neoplasia type 2 (MEN2, caused by RET mutation), Von-Hippel Lindau (VHL) and Carney-Stratakis dyad [6].