Santa Casa de São Paulo School of Medical Sciences, São Paulo, SP, Brazil
Fleury Group, São Paulo, SP, Brazil
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, Giminez-Roqueplo et al. 2023 ). Cluster 1 includes genes related to the Krebs cycle. Characteristic genes are SDHA, SDHAF2, SDHB, SDHC, SDHD, FH,MDH2, GOT2, IDH1, SCLC25A11, EPAS1, and VHL . The presence of germline or somatic PVs in these genes
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groups (SDHC and SDHD). It is evident that SDHB is small and sandwiched between the other three subunits, suggesting that its relative fraction of contact surface area is high. This, together with conserved amino acids in SDHB that form Fe-S clusters and
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Background: Approximately 30-40% of paragangliomas (PGL) and pheochromocytomas (PCC) harbor an underlying hereditary cause. Early identification of at-risk individuals is imperative given the early-onset, aggressiveness of tumors, and other tumor/cancer risks associated with hereditary PGLs/PCCs. This study analyzes the clinical presentations and genetic histories of patients with PGL/PCC and/or hereditary risk to contribute to the expanding knowledge in this rare population.
Methods: Retrospective chart review identified two cohorts of patients seen in cancer genetics clinics at an academic medical center and a safety-net hospital between August 2016 and December 2022. Cohort 1 consisted of patients with likely pathogenic/pathogenic variants (LPV/PV) in hereditary PGL/PCC predisposition genes. Cohort 2 consisted of patients with a personal history of a PGL/PCC. Demographics, personal/family history, and genetic testing outcomes were analyzed.
Results: A total of 560 patients met study criteria (Cohort 1, n=364; Cohort 2, n=269). In Cohort 1, 77 (21.1%) patients had an incidental LPV/PV in a PGL/PCC gene. Nearly half (n=36, 46.8%) were in SDHx genes, with a majority in SDHA (n=21). In Cohort 2, 86 patients tested positive for 87 LPV/PV in a hereditary cancer predisposition gene). The SDHx genes were most likely to have a LPV/PV identified (SDHB n=24, SDHD n=23).
Conclusions: Multigene panels identify patients at risk for hereditary PGL/PCC, many of whom are incidentally found. While SDHA LPV/PVs were the most frequent incidental finding, they were less common in patients with PGL/PCC, indicating the need for longitudinal studies to better understand the prevalence and penetrance of these tumors.
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Division of Biomedical Informatics and Personalized Medicine, University of Colorado School of Medicine, Aurora, Colorado, USA
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% NF1 Autosomal dominant 7.7–14% +++ + + ++ ~12% SDHB Autosomal dominant 22–26% by age 60 ++ ++ +++ ++ 25–50% SDHD Autosomal dominant – paternal inheritance 43% by age 60 ++ +++ ++ +++ 3
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Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
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included the most frequently mutated genes in PPGL: RET, VHL, NF1, MAX, SDHA, SDHB, SDHC, SDHD, SDHAF2, and TMEM127 . Depending on phenotypic features and/or year of diagnosis, patients were tested for a variable number of these genes. For patients with
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). This hereditary predisposition falls under the spectrum of hereditary paraganglioma–pheochromocytoma (PPGL) syndromes. Additional genes that cause hereditary PPGL include the other SDHx genes ( SDHB , SDHC , SDHD , and SDHAF2 ), MAX , and TMEM127
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encoding the subunits of SDH ( SDHA, SDHB, SDHC, SDHD, and SDHAF2 ). Patients with pathogenic variants in SDHD are especially prone to developing HNPGLs, which are often multiple. Overall, a germline pathogenic variant can be found in ~37% of all PGL
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oxidase assembly factor heme A:farnesyltransferase COX10 (COX10 ) −1.72 Cytochrome C1 ( CYC1 ) −1.70 Succinate dehydrogenase complex subunit D ( SDHD ) −1.77 Succinate dehydrogenase complex subunit C ( SDHC ) −1.54 ATP
Clinic for Endocrinology, Diabetes and Metabolic Diseases, University Clinical Center Belgrade, Belgrade, Serbia
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Clinic for Endocrinology, Diabetes and Metabolic Diseases, University Clinical Center Belgrade, Belgrade, Serbia
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1 and 4, familial isolated pituitary adenomas, succinate dehydrogenase mutations ( SDHA , SDHB , SDHC , SDHD , MAX , TMEM 127 ) and other conditions (Mc Cune Albright Sy, Carney complex, neurofibromatosis type 1, von Hippel–Lindau syndrome and
