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Hereditary Pheochromocytoma and Paraganglioma Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
The SDHAF2 (succinate dehydrogenase complex assembly factor 2) gene encodes a mitochondrial protein involved in the flavination of SDHA. Mutations in SDHAF2 are implicated in the development of HNPGL (Table 58.2).
Rare Mendelian cancer syndromes and other cancers
Published in Angus Clarke, Alex Murray, Julian Sampson, Harper's Practical Genetic Counselling, 2019
Characterised by the development of mainly non-malignant tumours in paraganglia, this condition is caused by mutations in the succinate dehydrogenase subunit genes SDHA, SDHAF2, SDHB, SDHC and SDHD. The paragangliomas are mostly found in the head and neck, especially around the carotid bifurcation, or in the adrenal glands, when they are known as phaeochromocytomas. The inheritance is autosomal dominant, but the SDHD gene is maternally imprinted, which means that only those individuals who inherit the mutation from their father will manifest the condition.
Genetics in Otology and Neurotology
Published in John C Watkinson, Raymond W Clarke, Louise Jayne Clark, Adam J Donne, R James A England, Hisham M Mehanna, Gerald William McGarry, Sean Carrie, Basic Sciences Endocrine Surgery Rhinology, 2018
PGL2 has a very interesting history, as it was the first PGL to be described.84 In 1982 Van Baars et al. 85 reported on a large Dutch family (295 living family members) with familial HNPGs. It was not until the year 2009 though, that Hao et al. 86 identified a mutation of the SDHAF2 gene, situated on 11q13, as the underlying cause of PGL2.86, 87 SDHAF2, also known as SDH5, plays an important role in flavination of SDHA.86
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
In this series, mutations were identified in four of thirteen GJ (31%) unrelated index cases, despite absence of a positive family history. All mutations occurred in patients of Hispanic ethnicity, two of mixed race and two Caucasians. No mutations were found in the four African American patients in this series. The mutations only occurred in the SDH-gene complex: two of the mutations were associated with SDHC, one mutation was associated with SDHB, and one mutation was associated with SDHD. All these mutations have been previously reported as pathogenic. [3,5–10] It has been reported that germline mutations can be present in up to 40% of cases of HNPGL. [3,5,8] HNPGL are usually associated with germline mutations in the genes encoding the four subunits of complex II and its accessory proteins (SDHD, SDHB, SDHC, SDHA, SDHAF2), which are tumour suppressor genes. Also, mutations in these genes have been associated with non-paraganglioma tumours such as renal cell carcinoma, pituitary adenoma, and gastrointestinal stromal tumour.
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].
Prevalence of succinate dehydrogenase deficiency in paragangliomas and phaeochromocytomas at a tertiary hospital in Cape Town: a retrospective review
Published in Journal of Endocrinology, Metabolism and Diabetes of South Africa, 2021
Cassandra Bruce-Brand, Abraham C van Wyk
The SDH enzyme complex (mitochondrial complex II) catalyses the conversion of succinate to fumarate in the Krebs cycle.16 Loss of heterozygosity with inactivating germline mutations results in destabilisation of the SDH protein complex and abolishes its enzymatic activity leading to an accumulation of succinate.16,18–20 This results in reactive oxygen species causing free radical damage and activation of a pseudohypoxia pathway by increasing hypoxia-inducible factors.16,18–21 A third mechanism that has been proposed to explain how Krebs cycle dysfunction can lead to neoplasia is through a decrease in apoptosis.21 The SDH complex consists of four subunits, SDHA, SDHB, SDHC and SDHD. Hereditary PC/PGL syndrome can be caused by germline mutations in any of the SDH subunits as well as in SDHAF2, a mitochondrial protein that flavinates SDHA and promotes maturation of SDHB.16,21–24