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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biochemical impact of the particular inherited variant on SDH activity. A related hypothetical model has also recently been proposed ( Bayley & Devilee 2022 ). Clinicians have long appreciated that PPGL in carriers of SDHB variants tend to present with a
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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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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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Division of Biomedical Informatics and Personalized Medicine, University of Colorado School of Medicine, Aurora, Colorado, USA
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hereditary paraganglioma-heochromocytoma syndrome SDHA, B, C, D : Paraganglioma, pheochromocytoma at any location, renal cell carcinoma, GI stromal tumors SDHAF2 : Head/neck paraganglioma SDHB: 6–10 years old plasma-free metanephrines or 24-h urine
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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
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
