Clinical Characterization of the Pheochromocytoma and Paraganglioma Susceptibility Genes SDHA, TMEM127, MAX, and SDHAF2 for Gene-Informed Prevention

Bausch, Birke; Schiavi, Francesca; Ni, Ying; Welander, Jenny; Patócs, Attila; Ngeow, Joanne; Wellner, Ulrich; Malinoc, Angelica; Taschin, Elisa; Barbon, Giovanni; Lanza, Virginia; Söderkvist, Peter; Stenman, Adam; Larsson, Catharina; Svahn, Fredrika; Chen, Jinlian; Marquard, Jessica; Fraenkel, Merav; Walter, Martin A.; Pęczkowska, Mariola; Prejbisz, Aleksander; Jarząb, Barbara; Hasse-Lazar, Kornelia; Petersenn, Stephan; Moeller, Lars C.; Meyer, Axel; Reisch, Nicole; Trupka, A.; Brase, Christoph; Galiano, Matthias; Preuss, Simon F.; Kwok, Pingling; Lendvai, Nikoletta; Berisha, Gani; Makay, Özer; Boedeker, Carsten C.; Weryha, G.; Rácz, Kàroly; Januszewicz, Andrzej; Walz, Martin K.; Gimm, Oliver; Opocher, Giuseppe; Eng, Charis; Neumann, Hartmut P. H.

doi:10.1001/jamaoncol.2017.0223

Cited by 160 publications

(197 citation statements)

References 41 publications

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“…Mutations in the SDHA gene remain a rare cause of PGL and account for 1% to 7% of all PGL cases . About half of SDHA mutation carriers present with HNPGL, although sympathetic PGL and PCC are also reported . Recently, van der Tuin et al calculated the penetrance of SDHA mutation in a cohort comprising 86 patients (30 index and 56 non‐index patients).…”

Section: Phenotype Of Sdhx Mutation Carriersmentioning

confidence: 99%

Clinical implications of the oncometabolite succinate in SDHx‐mutation carriers

et al. 2019

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Succinate dehydrogenase (SDH) mutations lead to the accumulation of succinate, which acts as an oncometabolite. Germline SDHx mutations predispose to paraganglioma (PGL) and pheochromocytoma (PCC), as well as to renal cell carcinoma and gastro-intestinal stromal tumors. The SDHx genes were the first tumor suppressor genes discovered which encode for a mitochondrial enzyme, thereby supporting Otto Warburg's hypothesis in 1926 that a direct link existed between mitochondrial dysfunction and cancer. Accumulation of succinate is the hallmark of tumorigenesis in PGL and PCC. Succinate accumulation inhibits several α-ketoglutarate dioxygenases, thereby inducing the pseudohypoxia pathway and causing epigenetic changes. Moreover, SDH loss as a consequence of SDHx mutations can lead to reprogramming of cell metabolism. Metabolomics can be used as a diagnostic tool, as succinate and other metabolites can be measured in tumor tissue, plasma and urine with different techniques. Furthermore, these pathophysiological characteristics provide insight into therapeutic targets for metastatic disease. This review provides an overview of the pathophysiology and clinical implications of oncometabolite succinate in SDHx mutations. K E Y W O R D S oncometabolites, paraganglioma, pheochromocytoma, SDH mutation, succinate 1 | INTRODUCTION Mutations of genes encoding for the succinate dehydrogenase (SDH) complex, associated with familial paraganglioma (PGL) and pheochromocytoma (PCC), lead to accumulation of succinate, which disturbs the metabolic regulation of the cell. Nowadays metabolic dysregulation is recognized as one of the eight hallmarks of cancer. 1 Although germline mutations in SDHx genes are predominantly linked to PGL and PCC, these mutations also predispose to renal cell carcinoma (RCC), gastrointestinal stromal tumors (GISTs) and, possibly, pituitary adenomas. PCC, PGL and head and neck PGL (HNPGL) are rare neuroendocrine tumors arising from chromaffin cells that can synthesize and release catecholamines. Sympathetic PGLs are derived from sympathetic paraganglia in the chest, abdomen or pelvis. PCC are PGLs located in the adrenal medulla. 2 HNPGLs are derived from parasympathetic paraganglia. Common locations for HNPGLs include the carotid body and the middle ear, as well as the vagus nerve and internal jugular vein. While parasympathetic PGLs are most often non-functional tumors, PCC and sympathetic PGL release catecholamines into the circulation and can

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Section: Phenotype Of Sdhx Mutation Carriersmentioning

confidence: 99%

Clinical implications of the oncometabolite succinate in SDHx‐mutation carriers

et al. 2019

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“…Amongst unselected cases of PPGL, 0.6–2% have pathogenic variants in TMEM127 . The average age of onset amongst index patients seems to be just above 40 years ; the median age of 29 cases was 47 years (range 18–76 years) ; and in one summary, 10% of 28 patients had an onset before 36 years of age . The penetrance of TMEM127 mutation in one large family with six affected generations was calculated to be 3% by age 30 years, 24% by age 50 years and 32% by age 65 years, and screening was recommended thus from the age of 22 years .…”

Section: Clinical Characteristics (See Table For a Summary)mentioning

confidence: 99%

“…No reliable penetrance estimations are available for MAX carriers, but healthy obligate carriers have been reported and only 7/19 reported index patients had a known family history suggesting reduced penetrance . One very small study found a high penetrance (73% by age 40 years), but this was based on 8 index patients and three relatives and therefore highly biased . 21/28 patients had multiple PCC; four developed thoracic or abdominal PGL, and four had metastatic disease .…”

Section: Clinical Characteristics (See Table For a Summary)mentioning

confidence: 99%

Genetic testing and surveillance guidelines in hereditary pheochromocytoma and paraganglioma

et al. 2019

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Pheochromocytoma and paraganglioma (PPGL) are rare tumours and at least 30% are part of hereditary syndromes. Approximately 20% of hereditary PPGL are caused by pathogenic germ line variants in genes of the succinate dehydrogenase complex (SDHx), TMEM127 or MAX. Herein we present guidelines regarding genetic testing of family members and their surveillance based on a thorough literature review. All cases of PPGL are recommended genetic testing for germ line variants regardless of patient and family characteristics. At minimum, FH, NF1, RET, SDHB, SDHD and VHL should be tested. In addition, testing of MEN1, SDHA, SDHAF2, SDHC, TMEM127 and MAX is recommended. Healthy first‐degree relatives (and second‐degree relatives in the case of SDHD and SDHAF2 which are maternally imprinted) should be offered carrier testing. Carriers of pathogenic variants should be offered surveillance with annual biochemical measurements of methoxy‐catecholamines and bi‐annual rapid whole‐body magnetic resonance imaging and clinical examination. Surveillance should start 5 years before the earliest age of onset in the family and thus only children eligible for surveillance should be offered pre‐symptomatic genetic testing. The surveillance of children younger than 15 years needs to be individually designed. Our guidelines will provide a framework for patient management with the possibility to follow outcome via national registries and/or follow‐up studies. Together with improved insights into the disease, this may enable optimisation of the surveillance scheme in order to minimise both anxiety and medical complications while ensuring early disease detection.

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“…Only head and neck tumors, predominantly carotid body tumors (70%), have been reported in SDHAF2 variant carriers, with an average age of onset of 33 years (range, . However, all descriptions of the SDHAF2 phenotype are based on a single family (53,60). Germline SDHA variants have been observed in association with both PHEOs and paragangliomas (sympathetic and parasympathetic; ref.…”

Section: Molecular Genetics Of Hpp Syndromesmentioning

confidence: 99%

Von Hippel–Lindau and Hereditary Pheochromocytoma/Paraganglioma Syndromes: Clinical Features, Genetics, and Surveillance Recommendations in Childhood

Rednam

Erez

Druker

et al. 2017

Clinical Cancer Research

208

157

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Von Hippel-Lindau disease (vHL) is a hereditary tumor predisposition syndrome that places affected individuals at risk for multiple tumors, which are predominantly benign and generally occur in the central nervous system or abdomen. Although the majority of tumors occur in adults, children and adolescents with the condition develop a significant proportion of vHL manifestations and are vulnerable to delayed tumor detection and their sequelae. Although multiple tumor screening paradigms are currently being utilized for patients with vHL, surveillance should be reassessed as the available relevant clinical information continues to expand. We propose a new vHL screening paradigm similar to existing approaches, with important modifications for some tumor types, placing an emphasis on risks in childhood. This includes advancement in the timing of surveillance initiation and increased frequency of screening evaluations. Another neuroendocrine-related familial condition is the rapidly expanding hereditary paraganglioma and pheochromocytoma syndrome (HPP). The tumor spectrum for patients with HPP syndrome includes paragangliomas, pheochromocytomas, renal cancer, and gastrointestinal stromal tumors. The majority of patients with HPP syndrome harbor an underlying variant in one of the SHDx genes (SDHA, SDHB, SDHC, SDHD, SDHA, and SDHAF2), although other genes also have been described (MAX and TMEM127). Annual screening for elevated plasma or urine markers along with complete blood count and biennial whole-body MRI accompanied by focal neck MRI is recommended for older children and adults with HPP syndrome to detect tumors early and to decrease morbidity and mortality from HPP-related tumors.

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Clinical Characterization of the Pheochromocytoma and Paraganglioma Susceptibility Genes SDHA, TMEM127, MAX, and SDHAF2 for Gene-Informed Prevention

Cited by 160 publications

References 41 publications

Clinical implications of the oncometabolite succinate in SDHx‐mutation carriers

Clinical implications of the oncometabolite succinate in SDHx‐mutation carriers

Genetic testing and surveillance guidelines in hereditary pheochromocytoma and paraganglioma

Von Hippel–Lindau and Hereditary Pheochromocytoma/Paraganglioma Syndromes: Clinical Features, Genetics, and Surveillance Recommendations in Childhood

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