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Lee, Hansong, Seongdo Jeong, Yeuni Yu, Junho Kang, Hokeun Sun, Je-Keun Rhee, and Yun Hak Kim. "Risk of metastatic pheochromocytoma and paraganglioma in SDHx mutation carriers: a systematic review and updated meta-analysis." Journal of Medical Genetics 57, no. 4 (October 24, 2019): 217–25. http://dx.doi.org/10.1136/jmedgenet-2019-106324.
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BackgroundPheochromocytoma and paraganglioma (PPGL) are tumours that arise from chromaffin cells. Some genetic mutations influence PPGL, among which, those in genes encoding subunits of succinate dehydrogenase (SDHA, SDHB, SDHC and SDHD) and assembly factor (SDHAF2) are the most relevant. However, the risk of metastasis posed by these mutations is not reported except for SDHB and SDHD mutations. This study aimed to update the metastatic risks, considering prevalence and incidence of each SDHx mutation, which were dealt formerly all together.MethodsWe searched EMBASE and MEDLINE and selected 27 articles. The patients included in the studies were divided into three groups depending on the presence of PPGL. We checked the heterogeneity between studies and performed a meta-analysis using Hartung-Knapp-Sidik-Jonkman method based on a random effect model.ResultsThe highest PPGL prevalence was for SDHB mutation, ranging from 23% to 31%, and for SDHC mutation (23%), followed by that for SDHA mutation (16%). The lowest prevalence was for SDHD mutation, ranging from 6% to 8%. SDHAF2 mutation showed no metastatic events. The PPGL incidence showed a tendency similar to that of its prevalence with the highest risk of metastasis posed by SDHB mutation (12%–41%) and the lowest risk by SDHD mutation (~4%).ConclusionThere was no integrated evidence of how SDHx mutations are related to metastatic PPGL. However, these findings suggest that SDHA, SDHB and SDHC mutations are highly associated and should be tested as indicators of metastasis in patients with PPGL.
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Maher, Megan J., Anuradha S. Herath, Saumya R. Udagedara, David A. Dougan, and Kaye N. Truscott. "Crystal structure of bacterial succinate:quinone oxidoreductase flavoprotein SdhA in complex with its assembly factor SdhE." Proceedings of the National Academy of Sciences 115, no. 12 (March 7, 2018): 2982–87. http://dx.doi.org/10.1073/pnas.1800195115.
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Succinate:quinone oxidoreductase (SQR) functions in energy metabolism, coupling the tricarboxylic acid cycle and electron transport chain in bacteria and mitochondria. The biogenesis of flavinylated SdhA, the catalytic subunit of SQR, is assisted by a highly conserved assembly factor termed SdhE in bacteria via an unknown mechanism. By using X-ray crystallography, we have solved the structure of Escherichia coli SdhE in complex with SdhA to 2.15-Å resolution. Our structure shows that SdhE makes a direct interaction with the flavin adenine dinucleotide-linked residue His45 in SdhA and maintains the capping domain of SdhA in an “open” conformation. This displaces the catalytic residues of the succinate dehydrogenase active site by as much as 9.0 Å compared with SdhA in the assembled SQR complex. These data suggest that bacterial SdhE proteins, and their mitochondrial homologs, are assembly chaperones that constrain the conformation of SdhA to facilitate efficient flavinylation while regulating succinate dehydrogenase activity for productive biogenesis of SQR.
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Guzy, Robert D., Bhumika Sharma, Eric Bell, Navdeep S. Chandel, and Paul T. Schumacker. "Loss of the SdhB, but Not the SdhA, Subunit of Complex II Triggers Reactive Oxygen Species-Dependent Hypoxia-Inducible Factor Activation and Tumorigenesis." Molecular and Cellular Biology 28, no. 2 (October 29, 2007): 718–31. http://dx.doi.org/10.1128/mcb.01338-07.
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ABSTRACT Mitochondrial complex II is a tumor suppressor comprised of four subunits (SdhA, SdhB, SdhC, and SdhD). Mutations in any of these should disrupt complex II enzymatic activity, yet defects in SdhA produce bioenergetic deficiency while defects in SdhB, SdhC, or SdhD induce tumor formation. The mechanisms underlying these differences are not known. We show that the inhibition of distal subunits of complex II, either pharmacologically or via RNA interference of SdhB, increases normoxic reactive oxygen species (ROS) production, increases hypoxia-inducible factor alpha (HIF-α) stabilization in an ROS-dependent manner, and increases growth rates in vitro and in vivo without affecting hypoxia-mediated activation of HIF-α. Proximal pharmacologic inhibition or RNA interference of complex II at SdhA, however, does not increase normoxic ROS production or HIF-α stabilization and results in decreased growth rates in vitro and in vivo. Furthermore, the enhanced growth rates resulting from SdhB suppression are inhibited by the suppression of HIF-1α and/or HIF-2α, indicating that the mechanism of SdhB-induced tumor formation relies upon ROS production and subsequent HIF-α activation. Therefore, differences in ROS production, HIF proliferation, and cell proliferation contribute to the differences in tumor phenotype in cells lacking SdhB as opposed to those lacking SdhA.
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Moog, Sophie, Charlotte Lussey-Lepoutre, and Judith Favier. "Epigenetic and metabolic reprogramming of SDH-deficient paragangliomas." Endocrine-Related Cancer 27, no. 12 (December 2020): R451—R463. http://dx.doi.org/10.1530/erc-20-0346.
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Pheochromocytomas and paragangliomas (PPGL) are rare neuroendocrine tumors arising from the adrenal medulla or extra-adrenal paraganglia. Around 40% of all cases are caused by a germline mutation in a susceptibility gene, half of which being found in an SDHx gene (SDHA, SDHB, SDHC, SDHD or SDHAF2). They encode the four subunits and assembly factor of succinate dehydrogenase (SDH), a mitochondrial enzyme involved both in the tricarboxylic acid cycle and electron transport chain. SDHx mutations lead to the accumulation of succinate, which acts as an oncometabolite by inhibiting iron(II) and alpha-ketoglutarate-dependent dioxygenases thereby regulating the cell’s hypoxic response and epigenetic processes. Moreover, SDHx mutations induce cell metabolic reprogramming and redox imbalance. Major discoveries in PPGL pathophysiology have been made since the initial discovery of SDHD gene mutations in 2000, improving the understanding of their biology and patient management. It indeed provides new opportunities for diagnostic tools and innovative therapeutic targets in order to improve the prognosis of patients affected by these rare tumors, in particular in the context of metastatic diseases associated with SDHB mutations. This review first describes an overview of the pathophysiology and then focuses on clinical implications of the epigenetic and metabolic reprogramming of SDH-deficient PPGL.
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Timmers, Henri J. L. M., Anne-Paule Gimenez-Roqueplo, Massimo Mannelli, and Karel Pacak. "Clinical aspects of SDHx-related pheochromocytoma and paraganglioma." Endocrine-Related Cancer 16, no. 2 (June 2009): 391–400. http://dx.doi.org/10.1677/erc-08-0284.
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Paragangliomas (PGLs) derive from either sympathetic chromaffin tissue in adrenal and extra-adrenal abdominal or thoracic locations, or from parasympathetic tissue of the head and neck. Mutations of nuclear genes encoding subunits B, C, and D of the mitochondrial enzyme succinate dehydrogenase (SDHB 1p35-p36.1, SDHC 1q21, SDHD 11q23) give rise to hereditary PGL syndromes PGL4, PGL3, and PGL1 respectively. The susceptibility gene for PGL2 on 11q13.1 remains unidentified. Mitochondrial dysfunction due to SDHx mutations have been linked to tumorigenesis by upregulation of hypoxic and angiogenesis pathways, apoptosis resistance and developmental culling of neuronal precursor cells. SDHB-, SDHC-, and SDHD-associated PGLs give rise to more or less distinct clinical phenotypes. SDHB mutations mainly predispose to extra-adrenal, and to a lesser extent, adrenal PGLs, with a high malignant potential, but also head and neck paragangliomas (HNPGL). SDHD mutations are typically associated with multifocal HNPGL and usually benign adrenal and extra-adrenal PGLs. SDHC mutations are a rare cause of mainly HNPGL. Most abdominal and thoracic SDHB-PGLs hypersecrete either norepinephrine or norepinephrine and dopamine. However, only some hypersecrete dopamine, are biochemically silent. The biochemical phenotype of SDHD-PGL has not been systematically studied. For the localization of PGL, several positron emission tomography (PET) tracers are available. Metastatic SDHB-PGL is the best localized by [18F]-fluorodeoxyglucose PET. The identification of SDHx mutations in patients with PGL is warranted for a tailor-made approach to the biochemical diagnosis, imaging, treatment, follow-up, and family screening.
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Kim, Se-Hyuk, Tae Hoon Roh, Hyunee Yim, Jin Roh, Kyi Beom Lee, Seon-Yong Jeong, Jang-Hee Kim, and So Hyun Park. "GENE-05. THE LOSS OF SUCCINATE DEHYDROGENASE B EXPRESSION IS FREQUENTLY IDENTIFIED IN HEMANGIOBLASTOMA OF THE CENTRAL NERVOUS SYSTEM." Neuro-Oncology 21, Supplement_6 (November 2019): vi98. http://dx.doi.org/10.1093/neuonc/noz175.407.
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Abstract Succinate dehydrogenase (SDH) is a mitochondrial enzyme that plays an important role in both the Krebs cycle and the electron transport chain. SDH inactivation is associated with tumorigenesis in certain types of tumor. SDH consists of subunits A, B, C and D (SDHA, SDHB, SDHC, and SDHD, respectively). Immunohistochemistry for SDHB is a reliable method for detecting the inactivation of SDH by mutations in SDHA, SDHB, SDHC, SDHD and SDH complex assembly factor 2 (SDHAF2) genes with high sensitivity and specificity. SDHB immunohistochemistry has been used to examine the inactivation of SDH in various types of tumors. However, data on central nervous system (CNS) tumors are very limited. In the present study, we investigated the loss of SDHB immunoexpression in 90 cases of CNS tumors. Among the 90 cases of CNS tumors, only three cases of hemangioblastoma showed loss of SDHB immunoexpression. We further investigated SDHB immunoexpression in 35 cases of hemangioblastoma and found that 28 (80%) showed either negative or weak-diffuse pattern of SDHB immunoexpression, which suggests the inactivation of SDH. Our results suggest that SDH inactivation may represent an alternative pathway in the tumorigenesis of hemangioblastoma.
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Ilanchezhian, Maran, Sarah N. Fuller, Margarita Raygada, Constantine A. Stratakis, Paul S. Meltzer, Markku Miettinen, John Glod, Keith Killian, and Fernanda Irene Arnaldez. "Clinical characterization of patients with SDHC epimutation in gastrointestinal stromal tumors." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): 11033. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.11033.
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11033 Background: Gastrointestinal Stromal Tumors are the most common malignancy in the GI tract. While the vast majority exhibit somatic mutations in KIT and PDGFRA, approximately 15% of GIST patients do not have this feature. This group of KIT and PDGFRA “wildtype” GISTs have in common a negative expression of SDHB when interrogated by immunohistochemistry. Succinate dehydrogenase (SDH) is a conserved enzyme that plays a critical role in cellular metabolism and energy production. A loss in SDH function is a mechanism observed in several types of cancers, and germline SDH mutations are considered a tumor predisposition syndrome. This group has reported that SDH-deficient gastrointestinal stromal tumors often harbor germline mutations in the SDH subunit genes (SDHA, SDHB, SDHC, and SDHD, termed SDHx). There is, however, a defined group that shows lack of SDH expression in the absence of mutation. Methods: We performed targeted exome sequencing on GIST patients’ tumor samples from the NIH GIST clinic and identified 25 SDHx-WT cases. Genome-wide DNA methylation and expression profiling showed SDHC promoter-specific CpG island hypermethylation and gene silencing in these 25 SDHx-WT, SDH deficient GISTs. Results: Clinical characterization of this cohort revealed that 24 of 25 SDHC-epimutant GISTs occurred in female patients, with a median age of 12 upon diagnosis. The median tumor size of this cohort of patients was 4.0 cm. Of the 16 patients from whom we were able to obtain complete pathology data, 15 showed epithelioid or mixed-epithelioid tumor morphology. All of them showed negative immunohistochemical staining for SDHB. 15 of 16 patients had multifocal tumors, which is a common finding in this population. Conclusions: The profiling of this cohort provides further insights into the natural history and pathogenesis of SDHC-epimutant GIST tumors.
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Main, Ailsa Maria, Maria Rossing, Line Borgwardt, Birgitte Grønkær Toft, Åse Krogh Rasmussen, and Ulla Feldt-Rasmussen. "Genotype–phenotype associations in PPGLs in 59 patients with variants in SDHX genes." Endocrine Connections 9, no. 8 (August 2020): 793–803. http://dx.doi.org/10.1530/ec-20-0279.
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Phaeochromocytomas and paragangliomas (PPGLs) are tumours of the adrenal medulla and extra-adrenal sympathetic nervous system which often secrete catecholamines. Variants of the SDHX (SDHA, -AF2, -B, -C, -D) genes are a frequent cause of familial PPGLs. In this study from a single tertiary centre, we aimed to characterise the genotype–phenotype associations in patients diagnosed with germline variants in SDHX genes. We also assessed whether systematic screening of family members resulted in earlier detection of tumours. The study cohort comprised all individuals (n = 59) diagnosed with a rare variant in SDHX during a 13-year period. Patient- and pathology records were checked for clinical characteristics and histopathological findings. We found distinct differences in the clinical and histopathological characteristics between genetic variants in SDHB. We identified two SDHB variants with distinct phenotypical patterns. Family screening for SDHB variants resulted in earlier detection of tumours in two families. Patients with SDHA, SDHC and SDHD variants also had malignant phenotypes, underlining the necessity for a broad genetic screening of the proband. Our study corroborates previous findings of poor prognostic markers and found that the genetic variants and clinical phenotype are linked and, therefore, useful in the decision of clinical follow-up. Regular tumour screening of carriers of pathogenic variants may lead to an earlier diagnosis and expected better prognosis. The development of a combined algorithm with clinical, genetic, morphological, and biochemical factors may be the future for improved clinical risk stratification, forming a basis for larger multi-centre follow up studies.
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Daniel, Eleni, Robert Jones, Matthew Bull, and John Newell-Price. "Rapid-sequence MRI for long-term surveillance for paraganglioma and phaeochromocytoma in patients with succinate dehydrogenase mutations." European Journal of Endocrinology 175, no. 6 (December 2016): 561–70. http://dx.doi.org/10.1530/eje-16-0595.
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Background Patients with SDHx mutations need long-term radiological surveillance for the development of paragangliomas and phaeochromocytomas, but no longitudinal data exist. The aim of the study was to assess the performance of rapid-sequence non-contrast magnetic resonance imaging (MRI) in the long-term monitoring of patients with SDHx mutations. Methods Retrospective study between 2005 and 2015 at a University Hospital and regional endocrine genetics referral centre. Clinical and imaging data of 47 patients with SDHx mutations (SDHB (36), SDHC (6) and SDHD (5)) who had surveillance for detection of paragangliomas by rapid-sequence non-contrast MRI (base of skull to pubic symphysis) were collected. Results Twelve index cases (nine SDHB, one SDHC and two SDHD) and 35 mutation-positive relatives were monitored for a mean of 6.4 years (range 3.1–10.0 years). Mean age at the end of the study: SDHB 46.9 ± 17.6 years; SDHC 42.3 ± 24.4 years; SDHD 54.9 ± 10.6 years. On excluding imaging at initial diagnosis of index cases, 42 patients underwent 116 rapid-sequence MRI scans: 83 scans were negative and 31 scans were positive for sPGL/HNPGL in 13 patients. Most patients had multiple scans (n = number of patients (number of rapid-sequence MRI scans during screening)): n = 9 (2), n = 20 (3), n = 6 (4), n = 1 (6). Nine patients (three index) were diagnosed with new paragangliomas during surveillance and non-operated tumour size was monitored in nine patients. There were two false-positive scans (1.6%). Scans were repeated every 27 ± 9 months. Conclusions Biannual rapid-sequence non-contrast MRI is effective to monitor patients with SDHx mutations for detection of new tumours and monitoring of known tumours.
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Amar, Laurence, Karel Pacak, Olivier Steichen, Scott A. Akker, Simon J. B. Aylwin, Eric Baudin, Alexandre Buffet, et al. "International consensus on initial screening and follow-up of asymptomatic SDHx mutation carriers." Nature Reviews Endocrinology 17, no. 7 (May 21, 2021): 435–44. http://dx.doi.org/10.1038/s41574-021-00492-3.
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AbstractApproximately 20% of patients diagnosed with a phaeochromocytoma or paraganglioma carry a germline mutation in one of the succinate dehydrogenase (SDHx) genes (SDHA, SDHB, SDHC and SDHD), which encode the four subunits of the SDH enzyme. When a pathogenic SDHx mutation is identified in an affected patient, genetic counselling is proposed for first-degree relatives. Optimal initial evaluation and follow-up of people who are asymptomatic but might carry SDHx mutations have not yet been agreed. Thus, we established an international consensus algorithm of clinical, biochemical and imaging screening at diagnosis and during surveillance for both adults and children. An international panel of 29 experts from 12 countries was assembled, and the Delphi method was used to reach a consensus on 41 statements. This Consensus Statement covers a range of topics, including age of first genetic testing, appropriate biochemical and imaging tests for initial tumour screening and follow-up, screening for rare SDHx-related tumours and management of elderly people who have an SDHx mutation. This Consensus Statement focuses on the management of asymptomatic SDHx mutation carriers and provides clinicians with much-needed guidance. The standardization of practice will enable prospective studies in the near future.
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Snezhkina, Anastasiya V., Dmitry V. Kalinin, Vladislav S. Pavlov, Elena N. Lukyanova, Alexander L. Golovyuk, Maria S. Fedorova, Elena A. Pudova, et al. "Immunohistochemistry and Mutation Analysis of SDHx Genes in Carotid Paragangliomas." International Journal of Molecular Sciences 21, no. 18 (September 22, 2020): 6950. http://dx.doi.org/10.3390/ijms21186950.
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Carotid paragangliomas (CPGLs) are rare neuroendocrine tumors often associated with mutations in SDHx genes. The immunohistochemistry of succinate dehydrogenase (SDH) subunits has been considered a useful instrument for the prediction of SDHx mutations in paragangliomas/pheochromocytomas. We compared the mutation status of SDHx genes with the immunohistochemical (IHC) staining of SDH subunits in CPGLs. To identify pathogenic/likely pathogenic variants in SDHx genes, exome sequencing data analysis among 42 CPGL patients was performed. IHC staining of SDH subunits was carried out for all CPGLs studied. We encountered SDHx variants in 38% (16/42) of the cases in SDHx genes. IHC showed negative (5/15) or weak diffuse (10/15) SDHB staining in most tumors with variants in any of SDHx (94%, 15/16). In SDHA-mutated CPGL, SDHA expression was completely absent and weak diffuse SDHB staining was detected. Positive immunoreactivity for all SDH subunits was found in one case with a variant in SDHD. Notably, CPGL samples without variants in SDHx also demonstrated negative (2/11) or weak diffuse (9/11) SDHB staining (42%, 11/26). Obtained results indicate that SDH immunohistochemistry does not fully reflect the presence of mutations in the genes; diagnostic effectiveness of this method was 71%. However, given the high sensitivity of SDHB immunohistochemistry, it could be used for initial identifications of patients potentially carrying SDHx mutations for recommendation of genetic testing.
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Park, Sanghui, So Young Kang, Ghee Young Kwon, Ji Eun Kwon, Sang Kyum Kim, Ji Yeon Kim, Chul Hwan Kim, et al. "Clinicopathologic Characteristics and Mutational Status of Succinate Dehydrogenase Genes in Paraganglioma of the Urinary Bladder: A Multi-Institutional Korean Study." Archives of Pathology & Laboratory Medicine 141, no. 5 (November 7, 2016): 671–77. http://dx.doi.org/10.5858/arpa.2016-0403-oa.
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Context.— Because of the limited number of available primary bladder paraganglioma (PBPG) cases, the rates of succinate dehydrogenase (SDH) mutations and the clinicopathologic characteristics of SDH-deficient tumors have not been fully studied. Objective.— To define the clinicopathologic and molecular characteristics of PBPGs. Design.— A total of 52 PBPGs were collected retrospectively. SDHA and SDHB immunohistochemical stains were performed. In cases of SDHB expression loss, mutation analyses of SDHB, SDHC, and SDHD were performed. Results.— The clinicopathologic features were analyzed for 52 cases (M:F = 27:25), with a mean age of 56 years (range, 22–79 years). Tumor sizes were 0.5 to 8 cm (mean, 2.4 cm). Tumor necrosis was present in 5 of 52 cases (10%), involvement of muscularis propria in 41 (79%), and lymphovascular tumor invasion in 6 (12%). During a mean follow-up period of 41 months (range, 1–161 months), 3 of 52 patients (6%) developed metastases, but no one died from the disease. Immunohistochemistry for SDHA and SDHB showed that all cases were SDHA intact. Among them, 43 cases had intact SDHB, whereas 9 cases were SDHB deficient. Compared with the SDHB-intact cases, the SDHB-deficient cases were characterized by large tumor sizes (4.5 versus 1.9 cm; P < .001), a higher number of mitoses per 10 high-powered fields (2.6 versus 0.1; P = .002), and frequent lymphovascular tumor invasion (33% versus 7%; P = .02) and metastases (22% versus 2%; P = .02). Mutational analyses for SDHB, SDHC, and SDHD were performed in 9 SDHB-deficient cases. Among them, 6 cases were successfully sequenced and revealed SDHB mutations only. Conclusions.— Large tumor size, a higher number of mitoses, and the presence of lymphovascular tumor invasion and SDHB mutations suggest malignant paraganglioma.
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Vega, Byron, and Megan M. Dewdney. "Sensitivity of Alternaria alternata from Citrus to Boscalid and Polymorphism in Iron-Sulfur and in Anchored Membrane Subunits of Succinate Dehydrogenase." Plant Disease 99, no. 2 (February 2015): 231–39. http://dx.doi.org/10.1094/pdis-04-14-0374-re.
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Boscalid, a succinate dehydrogenase inhibitor (SDHI), was registered in 2011 to control Alternaria brown spot (ABS) of citrus, caused by Alternaria alternata. In this study, the effect of boscalid on mycelial growth, conidial germination, and resazurin reduction was established in a subset of 16 sensitive isolates using three different media. Conidial germination and mycelial growth inhibition were not suppressed even at higher concentrations of boscalid, although effective concentration to inhibit 50% growth (EC50) values were established with each method. Resazurin reduction produced the lowest EC50 values and was selected for further sensitivity tests. In total, 419 isolates, never exposed to boscalid and collected from Florida tangerine orchards between 1996 to 2012, were tested for boscalid sensitivity. The sensitivity distribution was a unimodal curve with a mean EC50 value of 0.60 μg/ml and a range of 0.07 to 5.84 μg/ml. The molecular characterization of the succinate dehydrogenase (SDH) genes were also determined in a subset of 15 isolates, exhibiting great variability in boscalid sensitivity, by cloning and sequencing the sdhB, sdhC, and sdhD genes. Sequence comparisons of the SDH complex revealed the presence of mutations in 14 of 15 isolates. In total, 21 mutations were identified. Double and multiple mutations were observed in SDHC and SDHD, respectively. In SDHB, 4 mutations were observed while, in SDHC and SDHD, 5 and 12 mutations were detected, respectively. No mutations were found in the highly conserved histidine residues at positions 277 in SDHB, 134 in SDHC, and 133 in SDHD, typically observed in SDHI-resistant isolates. Our findings suggest that A. alternata populations from Florida are sensitive to boscalid and it could be used in ABS spray programs. Boscalid resistance is currently not a problem, although further monitoring for resistance is advisable.
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Piccini, Valentina, Elena Rapizzi, Alessandra Bacca, Giuseppe Di Trapani, Raffaele Pulli, Valentino Giachè, Benedetta Zampetti, et al. "Head and neck paragangliomas: genetic spectrum and clinical variability in 79 consecutive patients." Endocrine-Related Cancer 19, no. 2 (January 12, 2012): 149–55. http://dx.doi.org/10.1530/erc-11-0369.
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Head and neck paragangliomas (HNPGLs) are neural crest-derived tumors. In comparison with paragangliomas located in the abdomen and the chest, which are generally catecholamine secreting (sPGLs) and sympathetic in origin, HNPGLs are, in fact, parasympathetic in origin and are generally nonsecreting. Overall, 79 consecutive patients with HNPGL were examined for mutations in SDHA, SDHB, SDHC, SDHD, SDHAF2, VHL, MAX, and TMEM127 genes by PCR/sequencing. According to a detailed family history (FH) and clinical, laboratory (including metanephrines), and instrumental examinations, patients were divided into three groups: a) patients with a positive FH for HNPGL (index cases only), b) patients with a negative FH and multiple HNPGLs (synchronous or metachronous) or HNPGL associated with an sPGL, and c) patients with negative FH and single HNPGL. The ten patients in group a) proved to be SDHD mutation carriers. The 16 patients in group b) proved to be SDHD mutation carriers. Among the 53 patients in group c), ten presented with germ-line mutations (three SDHB, three SDHD, two VHL, and two SDHAF2). An sPGL was found at diagnosis or followed up in five patients (6.3%), all were SDHD mutation carriers. No SDHC, SDHA, MAX, and TMEM127 mutations were found. In SDHD mutation carriers, none of the patients affected by HNPGL associated with sPGL presented missense mutations. In conclusion, a positive FH or the presence of multiple HNPGLs is a strong predictor for germ-line mutations, which are also present in 18.8% of patients carefully classified as sporadic. The most frequently mutated gene so far is SDHD but others, including SDHB, SDHAF2, and VHL, may also be affected.
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Bayley, Jean Pierre, Birke Bausch, Johannes Adriaan Rijken, Leonie Theresia van Hulsteijn, Jeroen C. Jansen, David Ascher, Douglas Eduardo Valente Pires, et al. "Variant type is associated with disease characteristics in SDHB, SDHC and SDHD-linked phaeochromocytoma–paraganglioma." Journal of Medical Genetics 57, no. 2 (September 6, 2019): 96–103. http://dx.doi.org/10.1136/jmedgenet-2019-106214.
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BackgroundPathogenic germline variants in subunits of succinate dehydrogenase (SDHB, SDHC and SDHD) are broadly associated with disease subtypes of phaeochromocytoma–paraganglioma (PPGL) syndrome. Our objective was to investigate the role of variant type (ie, missense vs truncating) in determining tumour phenotype.MethodsThree independent datasets comprising 950 PPGL and head and neck paraganglioma (HNPGL) patients were analysed for associations of variant type with tumour type and age-related tumour risk. All patients were carriers of pathogenic germline variants in the SDHB, SDHC or SDHD genes.ResultsTruncating SDH variants were significantly over-represented in clinical cases compared with missense variants, and carriers of SDHD truncating variants had a significantly higher risk for PPGL (p<0.001), an earlier age of diagnosis (p<0.0001) and a greater risk for PPGL/HNPGL comorbidity compared with carriers of missense variants. Carriers of SDHB truncating variants displayed a trend towards increased risk of PPGL, and all three SDH genes showed a trend towards over-representation of missense variants in HNPGL cases. Overall, variant types conferred PPGL risk in the (highest-to-lowest) sequence SDHB truncating, SDHB missense, SDHD truncating and SDHD missense, with the opposite pattern apparent for HNPGL (p<0.001).ConclusionsSDHD truncating variants represent a distinct group, with a clinical phenotype reminiscent of but not identical to SDHB. We propose that surveillance and counselling of carriers of SDHD should be tailored by variant type. The clinical impact of truncating SDHx variants is distinct from missense variants and suggests that residual SDH protein subunit function determines risk and site of disease.
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Bausch, Birke, Ulrich Wellner, Dirk Bausch, Francesca Schiavi, Marta Barontini, Gabriela Sanso, Martin K. Walz, et al. "Long-term prognosis of patients with pediatric pheochromocytoma." Endocrine-Related Cancer 21, no. 1 (October 29, 2013): 17–25. http://dx.doi.org/10.1530/erc-13-0415.
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A third of patients with paraganglial tumors, pheochromocytoma, and paraganglioma, carry germline mutations in one of the susceptibility genes, RET, VHL, NF1, SDHAF2, SDHA, SDHB, SDHC, SDHD, TMEM127, and MAX. Despite increasing importance, data for long-term prognosis are scarce in pediatric presentations. The European-American-Pheochromocytoma–Paraganglioma-Registry, with a total of 2001 patients with confirmed paraganglial tumors, was the platform for this study. Molecular genetic and phenotypic classification and assessment of gene-specific long-term outcome with second and/or malignant paraganglial tumors and life expectancy were performed in patients diagnosed at <18 years. Of 177 eligible registrants, 80% had mutations, 49% VHL, 15% SDHB, 10% SDHD, 4% NF1, and one patient each in RET, SDHA, and SDHC. A second primary paraganglial tumor developed in 38% with increasing frequency over time, reaching 50% at 30 years after initial diagnosis. Their prevalence was associated with hereditary disease (P=0.001), particularly in VHL and SDHD mutation carriers (VHL vs others, P=0.001 and SDHD vs others, P=0.042). A total of 16 (9%) patients with hereditary disease had malignant tumors, ten at initial diagnosis and another six during follow-up. The highest prevalence was associated with SDHB (SDHB vs others, P<0.001). Eight patients died (5%), all of whom had germline mutations. Mean life expectancy was 62 years with hereditary disease. Hereditary disease and the underlying germline mutation define the long-term prognosis of pediatric patients in terms of prevalence and time of second primaries, malignant transformation, and survival. Based on these data, gene-adjusted, specific surveillance guidelines can help effective preventive medicine.
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Wu, Ben-Hong, Shao-Hua Li, Marta Nosarzewski, and Douglas D. Archbold. "Sorbitol Dehydrogenase Gene Expression and Enzyme Activity in Apple: Tissue Specificity during Bud Development and Response to Rootstock Vigor and Growth Manipulation." Journal of the American Society for Horticultural Science 135, no. 4 (July 2010): 379–87. http://dx.doi.org/10.21273/jashs.135.4.379.
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Sorbitol is the primary photosynthate and translocated carbohydrate in apple (Malus ×domestica), and most of it is converted to fructose by sorbitol dehydrogenase (SDH) in sink tissues. We studied the expression of nine SDH genes, SDH activity, and sorbitol content of apple 1) in buds and floral tissues from dormancy to bloom, 2) in leaves and shoot tips of trees on two rootstocks, the moderately vigorous ‘Malling Merton 111’ (MM.111) and the dwarfing ‘Malling 9’ (M.9), and 3) in shoot tips in response to application of prohexadione-Ca to suppress shoot growth and defoliation and girdling (D/G) to deprive the shoot tip of sorbitol. In mature, orchard-grown trees, sorbitol was the main soluble carbohydrate in expressed xylem sap from dormancy to bloom at levels over 3- to 6-fold those of glucose and fructose, the other major sugars present. Sorbitol levels there increased from dormancy to its highest concentration at the half inch green stage and declined by bloom, while those of the other sugars increased. SDH activity per milligram of protein increased over 4-fold from dormancy to flowering. Three of the nine known SDH genes (SDH1, SDH2, and SDH3) were expressed in immature and mature leaves and all buds from dormancy to bloom, as well as in all floral organs, except that only SDH3 transcript was found in stamen tissue. Two genes, SDH6 and SDH9, were floral-tissue specific; SDH6 transcript was detected in all floral organs except stamens at full bloom, and SDH9 was only expressed in anthers with pollen. In buds and leaves of young, container-grown trees, SDH1 and SDH2 generally accounted for the majority of total SDH expression. There were generally no effects of rootstock on SDH expression, SDH activity, or sorbitol concentration in leaves, while apical shoot tips on M.9 rootstock exhibited greater SDH activity than those on MM.111 or lateral shoot tips on either rootstock, though SDH expression of apical and lateral shoot tips on M.9 was lower than on MM.111. Prohexadione-Ca reduced apical but not lateral shoot growth, increased apical but not lateral shoot tip sorbitol content, had no effect on SDH activity, and increased SDH1 expression of all shoot tips. D/G treatment reduced shoot growth, sorbitol content, and SDH activity, but increased SDH1 expression of apical shoot tips only and SDH2 expression of lateral shoot tips only. This work indicates that sorbitol and other sugars are abundantly available from dormancy to bloom, that SDH activity increased during this period, and that SDH expression is at least in part developmentally regulated within the individual floral and leaf tissues. In shoot tips and leaves of young trees, SDH transcript level was not correlated with sorbitol availability or SDH activity, suggesting that other factors have significant regulatory effects after SDH expression on SDH activity.
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Yao, Shirley A., Elizabeth A. Wiley, Lisa R. Susswein, Megan L. Marshall, Natalie J. Carter, Anna K. McGill, Rachel T. Klein, Ying Wang, and Kathleen S. Hruska. "Germline pathogenic variants in patients with pheochromocytoma." Journal of Clinical Oncology 36, no. 6_suppl (February 20, 2018): 668. http://dx.doi.org/10.1200/jco.2018.36.6_suppl.668.
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668 Background: Approximately 25% of pheochromocytomas (PCC) have a hereditary basis, and germline variants in the SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, MAX, VHL, FH, RET, MEN1, and NF1 genes have been associated with a predisposition to PCC and paraganglioma (PGL). Multi-gene hereditary cancer panel testing for PCC has become increasingly more common than single-gene testing algorithms. Identification of a pathogenic or likely pathogenic variant (PV/LPV) in one of these genes has important implications for surveillance in patients and their family members. Here we describe the spectrum of PV/LPV variants identified in individuals with PCC. Methods: We performed a retrospective review of clinical and molecular data for all individuals diagnosed with PCC who underwent panel testing through BioReference Laboratories that included at least SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, MAX, VHL, FH, RET, MEN1, and NF1 between January 2016 and February 2017. Results: Seventy-nine individuals underwent testing due to a personal (n = 76) or family (n = 3) history of PCC. The positive yield was 14% (11/79). The majority of PV/LPV were in SDHB (n = 4; 36%), followed by RET (n = 2, 18%), with the remaining variants being identified in SDHA (1), SDHC (1), VHL (1), TMEM127 (1), and MAX (1). Approximately half (6/11) of those with a PV/LPV had a non-syndromic presentation of a unilateral PCC with no reported family history of PCC or PGL. The average age at tumor diagnosis was lower for probands testing positive than those without PV/LPV (34y±14 vs 44y±16). Conclusions: Our data support previous recommendations that patients with apparently sporadic, non-syndromic PCC be considered for genetic testing. Panel testing is a useful tool for identifying individuals with hereditary PCC.
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Papathomas, Thomas G., Jose Gaal, Eleonora P. M. Corssmit, Lindsey Oudijk, Esther Korpershoek, Ketil Heimdal, Jean-Pierre Bayley, et al. "Non-pheochromocytoma (PCC)/paraganglioma (PGL) tumors in patients with succinate dehydrogenase-related PCC–PGL syndromes: a clinicopathological and molecular analysis." European Journal of Endocrinology 170, no. 1 (January 2014): 1–12. http://dx.doi.org/10.1530/eje-13-0623.
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ObjectiveAlthough the succinate dehydrogenase (SDH)-related tumor spectrum has been recently expanded, there are only rare reports of non-pheochromocytoma/paraganglioma tumors in SDHx-mutated patients. Therefore, questions still remain unresolved concerning the aforementioned tumors with regard to their pathogenesis, clinicopathological phenotype, and even causal relatedness to SDHx mutations. Absence of SDHB expression in tumors derived from tissues susceptible to SDH deficiency is not fully elucidated.Design and methodsThree unrelated SDHD patients, two with pituitary adenoma (PA) and one with papillary thyroid carcinoma (PTC), and three SDHB patients affected by renal cell carcinomas (RCCs) were identified from four European centers. SDHA/SDHB immunohistochemistry (IHC), SDHx mutation analysis, and loss of heterozygosity analysis of the involved SDHx gene were performed on all tumors. A cohort of 348 tumors of unknown SDHx mutational status, including renal tumors, PTCs, PAs, neuroblastic tumors, seminomas, and adenomatoid tumors, was investigated by SDHB IHC.ResultsOf the six index patients, all RCCs and one PA displayed SDHB immunonegativity in contrast to the other PA and PTC. All immunonegative tumors demonstrated loss of the WT allele, indicating bi-allelic inactivation of the germline mutated gene. Of 348 tumors, one clear cell RCC exhibited partial loss of SDHB expression.ConclusionsThese findings strengthen the etiological association of SDHx genes with pituitary neoplasia and provide evidence against a link between PTC and SDHx mutations. Somatic deletions seem to constitute the second hit in SDHB-related renal neoplasia, while SDHx alterations do not appear to be primary drivers in sporadic tumorigenesis from tissues affected by SDH deficiency.
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Testa, Joseph R., David Malkin, and Joshua D. Schiffman. "Connecting Molecular Pathways to Hereditary Cancer Risk Syndromes." American Society of Clinical Oncology Educational Book, no. 33 (May 2013): 81–90. http://dx.doi.org/10.14694/edbook_am.2013.33.81.
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An understanding of the genetic causes and molecular pathways of hereditary cancer syndromes has historically informed our knowledge and treatment of all types of cancers. For this review, we focus on three rare syndromes and their associated genetic mutations including BAP1, TP53, and SDHx (SDHA, SDHB, SDHC, SDHD, SDHAF2). BAP1 encodes an enzyme that catalyzes the removal of ubiquitin from protein substrates, and germline mutations of BAP1 cause a novel cancer syndrome characterized by high incidence of benign atypical melanocytic tumors, uveal melanomas, cutaneous melanomas, malignant mesotheliomas, and potentially other cancers. TP53 mutations cause Li-Fraumeni syndrome (LFS), a highly penetrant cancer syndrome associated with multiple tumors including but not limited to sarcomas, breast cancers, brain tumors, and adrenocortical carcinomas. Genomic modifiers for tumor risk and genotype-phenotype correlations in LFS are beginning to be identified. SDH is a mitochondrial enzyme complex involved in the tricarboxylic acid (TCA) cycle, and germline SDHx mutations lead to increased succinate with subsequent paragangliomas, pheochromocytomas, renal cell carcinomas (RCCs), gastrointestinal stromal tumors (GISTs), and other rarer cancers. In all of these syndromes, the molecular pathways have informed our understanding of tumor risk and successful early tumor surveillance and screening programs.
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Boedeker, Carsten Christof, Hartmut P. H. Neumann, Wolfgang Maier, Birke Bausch, Jörg Schipper, and Gerd Jürgen Ridder. "Malignant Head and Neck Paragangliomas in SDHB Mutation Carriers." Otolaryngology–Head and Neck Surgery 137, no. 1 (July 2007): 126–29. http://dx.doi.org/10.1016/j.otohns.2007.01.015.
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OBJECTIVE: Three of four paraganglioma syndromes (PGLs) have been characterized on a molecular genetic basis. PGL 1 is associated with mutations of the succinate dehydrogenase subunit D ( SDHD) gene, PGL 3 is caused by SDHC gene mutations, and PGL 4 is caused by SDHB gene mutations. The objective of this study was to investigate whether PGLs are associated with malignant head and neck paragangliomas (HNPs). STUDY DESIGN AND SETTING: Through November 2005, we screened 195 HNP patients for mutations of the genes SDHB, SDHC, and SDHD. RESULTS: We detected 5 SDHC, 13 SDHB, and 45 SDHD gene mutations. In seven SDHB mutation carriers, there were distant metastases. No signs of metastases were found in SDHC and SDHD patients. One patient with a sporadic HNP presented with locally metastatic disease. CONCLUSIONS: SDHB mutations are associated with a high rate of malignant HNPs. SIGNIFICANCE: In SDHB patients, a three-body region imaging and scintigraphy or DOPA-PET must be performed to exclude metastases.
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Stanley, Kaitlin, Erika Friehling, Amy Davis, and Sarangarajan Ranganathan. "Succinate Dehydrogenase-Deficient Gastrointestinal Stromal Tumor With SDHC Germline Mutation and Bilateral Renal and Neck Cysts." Pediatric and Developmental Pathology 22, no. 3 (October 9, 2018): 265–68. http://dx.doi.org/10.1177/1093526618805354.
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Gastrointestinal stromal tumors (GISTs) are rare in children. Succinate dehydrogenase (SDH)-deficient GISTs are wild type and lack KIT proto-oncogene receptor tyrosine kinase and platelet-derived growth factor receptor A ( KIT or PDGFRA) mutations. These tumors result from germline SDH mutations, somatic SDH mutations, or SDH epimutants. Germline mutations in SDH genes ( SDHA, SDHB, SDHC, or SDHD) suggest Carney–Stratakis syndrome, a paraganglioma syndrome with predisposition for GIST. Negative immunohistochemistry for SDHB indicates dysfunction of the mitochondrial complex regardless of the subunit affected. We present an adolescent male with an SDH-deficient GIST and SDHC germline mutation who developed bilateral renal cysts and neck cysts, not previously described in children with this mutation. Germline testing is critical when SDH mutations are discovered due to treatment and surveillance implications. Further investigations are necessary to fully define the phenotypic expression of this mutation.
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Cass, Nathan D., Melissa A. Schopper, Jonathan A. Lubin, Lauren Fishbein, and Samuel P. Gubbels. "The Changing Paradigm of Head and Neck Paragangliomas: What Every Otolaryngologist Needs to Know." Annals of Otology, Rhinology & Laryngology 129, no. 11 (June 2, 2020): 1135–43. http://dx.doi.org/10.1177/0003489420931540.
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Background: Recommendations regarding head and neck paragangliomas (HNPGL) have undergone a fundamental reorientation in the last decade as a result of increased understanding of the genetic and pathophysiologic basis of these disorders. Objective: We aim to provide an overview of HNPGL and recent discoveries regarding their molecular genetics, along with updated recommendations on workup, treatment, and surveillance, and their implications for otolaryngologists treating patients with these disorders. Results: SDHx susceptibility gene mutations, encoding subunits of the enzyme succinate dehydrogenase (SDH), give rise to the Hereditary Pheochromocytoma/Paraganglioma Syndromes. SDHA, SDHB, SDHC, SDHD, and SDHAF2 mutations each result in unique phenotypes with distinct penetrance and risk for variable tumor development as well as metastasis. Genetic and biochemical testing is recommended for every patient with HNPGL. Multifocal disease should be managed in multi-disciplinary fashion. Patients with SDHx mutations require frequent biochemical screening and whole-body imaging, as well as lifelong follow-up with an expert in hereditary pheochromocytoma and paraganglioma syndromes. Conclusion: Otolaryngologists are likely to encounter patients with HNPGL. Keeping abreast of the latest recommendations, especially regarding genetic testing, workup for additional tumors, multi-disciplinary approach to care, and need for lifelong surveillance, will help otolaryngologists appropriately care for these patients.
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Benn, Diana E., Ying Zhu, Katrina A. Andrews, Mathilda Wilding, Emma L. Duncan, Trisha Dwight, Richard W. Tothill, et al. "Bayesian approach to determining penetrance of pathogenic SDH variants." Journal of Medical Genetics 55, no. 11 (September 10, 2018): 729–34. http://dx.doi.org/10.1136/jmedgenet-2018-105427.
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BackgroundUntil recently, determining penetrance required large observational cohort studies. Data from the Exome Aggregate Consortium (ExAC) allows a Bayesian approach to calculate penetrance, in that population frequencies of pathogenic germline variants should be inversely proportional to their penetrance for disease. We tested this hypothesis using data from two cohorts for succinate dehydrogenase subunits A, B and C (SDHA–C) genetic variants associated with hereditary pheochromocytoma/paraganglioma (PC/PGL).MethodsTwo cohorts were 575 unrelated Australian subjects and 1240 unrelated UK subjects, respectively, with PC/PGL in whom genetic testing had been performed. Penetrance of pathogenic SDHA–C variants was calculated by comparing allelic frequencies in cases versus controls from ExAC (removing those variants contributed by The Cancer Genome Atlas).ResultsPathogenic SDHA–C variants were identified in 106 subjects (18.4%) in cohort 1 and 317 subjects (25.6%) in cohort 2. Of 94 different pathogenic variants from both cohorts (seven in SDHA, 75 in SDHB and 12 in SDHC), 13 are reported in ExAC (two in SDHA, nine in SDHB and two in SDHC) accounting for 21% of subjects with SDHA–C variants. Combining data from both cohorts, estimated lifetime disease penetrance was 22.0% (95% CI 15.2% to 30.9%) for SDHB variants, 8.3% (95% CI 3.5% to 18.5%) for SDHC variants and 1.7% (95% CI 0.8% to 3.8%) for SDHA variants.ConclusionPathogenic variants in SDHB are more penetrant than those in SDHC and SDHA. Our findings have important implications for counselling and surveillance of subjects carrying these pathogenic variants.
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Kong, Grace, Tess Schenberg, Christopher J. Yates, Alison Trainer, Nirupa Sachithanandan, Amir Iravani, Aravind Ravi Kumar, et al. "The Role of 68Ga-DOTA-Octreotate PET/CT in Follow-Up of SDH-Associated Pheochromocytoma and Paraganglioma." Journal of Clinical Endocrinology & Metabolism 104, no. 11 (April 12, 2019): 5091–99. http://dx.doi.org/10.1210/jc.2019-00018.
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Abstract Purpose Germline succinate dehydrogenase (SDHx) mutation carriers, especially SDHB, are at increased risk for malignancy and require life-long surveillance. Current guidelines recommend periodic whole-body MRI imaging. We assessed the incremental value of 68Ga-DOTA-octreotate (GaTate) positron emission tomography (PET)/CT compared with conventional imaging in such patients. Methods SDHx mutation carriers who had GaTate PET/CT were retrospectively reviewed. Detection of lesions were compared with MRI or CT on a per-patient and per-lesion basis. Proof of lesions were based on histopathology or clinical/imaging follow-up. Results Twenty consecutive patients (median age, 46 years; 10 males) were reviewed. Fourteen patients had SDHB, four, SDHD, one SDHC, and one SDHA mutation. Fifteen had prior surgery and/or radiotherapy. Indications for PET/CT were as follows: 7 patients for surveillance for previously treated disease, 9 residual disease, 2 asymptomatic mutation carriers, and 2 for elevated catecholamines. Median time between modalities was 1.5 months. GaTate PET/CT had higher sensitivity and specificity than conventional imaging. On a per-patient basis: PET/CT sensitivity 100%, specificity 100%; MRI/CT 85% and 50%. Per-lesion basis: PET/CT sensitivity 100%, specificity 75%; MRI/CT 80% and 25%. PET/CT correctly identified additional small nodal and osseous lesions. MRI/CT had more false-positive findings. Change of management resulted in 40% (8/20 patients): 3 received localized treatment instead of observation, 1 changed to observation given extra disease detected, 4 with metastases had radionuclide therapy. Conclusions GaTate PET/CT provided incremental diagnostic information with consequent management impact in SDHx-pheochromocytoma and paraganglioma. Incorporating this modality as part of a surveillance program seems prudent. Further research is needed to define the optimal surveillance strategy including use of MRI.
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Andrews, Katrina A., David B. Ascher, Douglas Eduardo Valente Pires, Daniel R. Barnes, Lindsey Vialard, Ruth T. Casey, Nicola Bradshaw, et al. "Tumour risks and genotype–phenotype correlations associated with germline variants in succinate dehydrogenase subunit genes SDHB, SDHC and SDHD." Journal of Medical Genetics 55, no. 6 (January 31, 2018): 384–94. http://dx.doi.org/10.1136/jmedgenet-2017-105127.
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BackgroundGermline pathogenic variants in SDHB/SDHC/SDHD are the most frequent causes of inherited phaeochromocytomas/paragangliomas. Insufficient information regarding penetrance and phenotypic variability hinders optimum management of mutation carriers. We estimate penetrance for symptomatic tumours and elucidate genotype–phenotype correlations in a large cohort of SDHB/SDHC/SDHD mutation carriers.MethodsA retrospective survey of 1832 individuals referred for genetic testing due to a personal or family history of phaeochromocytoma/paraganglioma. 876 patients (401 previously reported) had a germline mutation in SDHB/SDHC/SDHD (n=673/43/160). Tumour risks were correlated with in silico structural prediction analyses.ResultsTumour risks analysis provided novel penetrance estimates and genotype–phenotype correlations. In addition to tumour type susceptibility differences for individual genes, we confirmed that the SDHD:p.Pro81Leu mutation has a distinct phenotype and identified increased age-related tumour risks with highly destabilising SDHB missense mutations. By Kaplan-Meier analysis, the penetrance (cumulative risk of clinically apparent tumours) in SDHB and (paternally inherited) SDHD mutation-positive non-probands (n=371/67 with detailed clinical information) by age 60 years was 21.8% (95% CI 15.2% to 27.9%) and 43.2% (95% CI 25.4% to 56.7%), respectively. Risk of malignant disease at age 60 years in non-proband SDHB mutation carriers was 4.2%(95% CI 1.1% to 7.2%). With retrospective cohort analysis to adjust for ascertainment, cumulative tumour risks for SDHB mutation carriers at ages 60 years and 80 years were 23.9% (95% CI 20.9% to 27.4%) and 30.6% (95% CI 26.8% to 34.7%).ConclusionsOverall risks of clinically apparent tumours for SDHB mutation carriers are substantially lower than initially estimated and will improve counselling of affected families. Specific genotype–tumour risk associations provides a basis for novel investigative strategies into succinate dehydrogenase-related mechanisms of tumourigenesis and the development of personalised management for SDHB/SDHC/SDHD mutation carriers.
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Bernardo-Castiñeira, Cristóbal, Nuria Valdés, Marta I. Sierra, Inés Sáenz-de-Santa-María, Gustavo F. Bayón, Raúl F. Perez, Agustín F. Fernández, et al. "SDHC Promoter Methylation, a Novel Pathogenic Mechanism in Parasympathetic Paragangliomas." Journal of Clinical Endocrinology & Metabolism 103, no. 1 (November 3, 2017): 295–305. http://dx.doi.org/10.1210/jc.2017-01702.
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Abstract Context Germline mutations in the succinate dehydrogenase A, B, C, and D genes (collectively, SDHx) predispose to the development of paragangliomas (PGLs) arising at the parasympathetic or sympathetic neuroendocrine systems. SDHx mutations cause absence of tumoral immunostaining for SDHB. However, negative SDHB immunostaining has also been found in a subset of PGLs that lack SDHx mutations. Settings Here, we report the comprehensive molecular characterization of one such a tumor of parasympathetic origin compared with healthy paraganglia and other PGLs with or without SDHx mutations. Results Integration of multiplatform data revealed somatic SDHC methylation and loss of the 1q23.3 region containing the SDHC gene. This correlated with decreased SDHC messenger RNA (mRNA) and protein levels. Furthermore, another genetic event found affected the VHL gene, which showed a decreased DNA copy number, associated with low VHL mRNA levels, and an absence of VHL protein detected by immunohistochemistry. In addition, the tumor displayed a pseudohypoxic phenotype consisting in overexpression of the hypoxia-inducible factor (HIF)-1α and miR-210, as well as downregulation of the iron-sulfur cluster assembly enzyme (ISCU) involved in SDHB maturation. This profile resembles that of SDHx- or VHL-mutated PGLs but not of PGLs with decreased VHL copy number, pointing to SDHC rather than VHL as the pathogenic driver. Conclusions Collectively, these findings demonstrate the potential importance of both the SDHC epigenomic event and the activation of the HIF-1α/miR-210/ISCU axis in the pathogenesis of SDHx wild-type/SDHB-negative PGLs. To our knowledge, this is the first case of a sporadic parasympathetic PGL that carries silencing of SDHC, fulfilling the two-hit Knudson’s model for tumorigenesis.
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Aldera, Alessandro Pietro, and Dhirendra Govender. "Gene of the month: SDH." Journal of Clinical Pathology 71, no. 2 (October 25, 2017): 95–97. http://dx.doi.org/10.1136/jclinpath-2017-204677.
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Succinate dehydrogenase (SDH) is a heterotetrameric nuclear encoded mitochondrial protein complex which plays a role in the citric acid cycle and the electron transfer chain. Germline mutations in SDHA are associated with Leigh syndrome. Mutations in SDHB, SDHC and SDHD are found in an increasing number of neoplasms, most notably paragangliomas and wild-type gastrointestinal stromal tumours. SDH deficiency in these tumours has important prognostic implications, and also provides a novel target for molecular therapy. In this article, we outline the structure and function of SDH and provide a summary of its role in various diseases.
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Else, Tobias, Antonio Marcondes Lerario, Jessica Everett, Lori Haymon, Deborah Wham, Michael Mullane, Tremika LeShan Wilson, et al. "Adrenocortical carcinoma and succinate dehydrogenase gene mutations: an observational case series." European Journal of Endocrinology 177, no. 5 (November 2017): 439–44. http://dx.doi.org/10.1530/eje-17-0358.
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Objective Germline loss-of-function mutations in succinate dehydrogenase (SDHx) genes results in rare tumor syndromes that include pheochromocytoma, paraganglioma, and others. Here we report a case series of patients with adrenocortical carcinoma (ACC) that harbor SDHx mutations. Patients and results We report four unrelated patients with ACC and SDHx mutations. All cases presented with Cushing syndrome and large adrenal masses that were confirmed to be ACC on pathology. All four ACC specimens were found to have truncating mutations in either SDHC or SDHA, while cases 1, 2 and 3 also had the mutations confirmed in the germline: Case 1: SDHC c.397C > T, pR133X; Case 2: SDHC c.43C > T, p.R15X; Case 3: SDHA c.91C > T, p.R31X; Case 4: SDHA c.1258C > T, p.Q420X. Notably, Case 1 had a father and daughter who both harbored the same SDHC germline mutation, and the father had a paraganglioma and renal cell carcinoma. A combination of next generation sequencing, and/or immunohistochemistry, and/or mass spectroscopy was used to determine whether there was loss of heterozygosity and/or loss of SDH protein expression or function within the ACC. Potential evidence of loss of heterozygosity was observed only in Case 2. Conclusions We observed truncating mutations in SDHA or SDHC in the ACC and/or germline of four unrelated patients. Given how statistically improbable the concurrence of ACC and pathogenic germline SDHx mutations is expected to be, these observations raise the question whether ACC may be a rare manifestation of SDHx mutation syndromes. Further studies are needed to investigate the possible role of SDH deficiency in ACC pathogenesis.
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Montani, M., A. M. Schmitt, S. Schmid, T. Locher, P. Saremaslani, P. U. Heitz, P. Komminoth, and A. Perren. "No mutations but an increased frequency of SDHx polymorphisms in patients with sporadic and familial medullary thyroid carcinoma." Endocrine-Related Cancer 12, no. 4 (December 2005): 1011–16. http://dx.doi.org/10.1677/erc.1.00996.
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Germline mutations of the three succinate dehydrogenase subunits SDHB, SDHC and SDHD have recently been associated with familial pheochromocytoma and paraganglioma. Several reasons make these genes candidate tumor suppressor genes for medullary thyroid carcinoma (MTC): (1) SDHB lies on chromosome 1p, the region known to be deleted most frequently in MTC, (2) MTCs develop from neural crest-derived cells, as do pheochromocytomas and paragangliomas and (3) patients with germline mutations of the Ret-protooncogene develop MTCs as well as pheochromocytomas, indicating a relationship of these tumors on a genetic level. Therefore, we attempted to determine whether the tumor suppressor genes SDHB, SDHC and SDHD are involved in sporadic and familial MTC. Somatic mutations of the SDH subunits were absent in all 35 investigated MTCs. Loss of heterozygosity was found in 27% (SDHB) and 4% (SDHD) respectively. While the frequency of non-coding, intronic polymorphisms did not differ in MTC patients compared with a control population, an accumulation of amino-acid coding polymorphisms (S163P in SDHB as well as G12S and H50R in SDHD) was found among MTC patients especially patients with familial tumors, suggesting a functional connection of coding SDH polymorphisms to activating Ret mutations.
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Wagner, Andrew J., Stephen P. Remillard, Yixiang Zhang, and Jason L. Hornick. "Immunohistochemical identification of SDHA-mutant gastrointestinal stromal tumors (GISTs)." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 10029. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.10029.
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10029 Background: GISTs are most commonly driven by activating mutations in KIT or PDGFRA. However, 15% of GISTs in adults and >90% in children lack such mutations. A subset of KIT/PDGFRA wild-type GISTs shows distinctive morphologic and clinical features and loss of expression of succinate dehydrogenase (SDH) B. Only a fraction of SDHB-deficient GISTs carry loss-of-function mutations in SDHB or SDHC. Due to the complexity of its locus and the presence of several pseudogenes, SDHA is rarely analyzed. Recently, mutations in SDHA were shown to lead to loss of expression of SDHA and SDHB in paraganglionomas. We sought to determine whether SDHA IHC could identify GISTs with SDHA mutations. Methods: Tumors (n=11) with features of SDH-deficient GIST (gastric origin, epithelioid morphology, multinodular/plexiform architecture) were selected from pathology archives under an IRB-approved protocol. Expression of SDHA and SDHB was determined on tumor sections by IHC. Genomic DNA was isolated from SDHA-negative tumors and amplified using primers specific to introns flanking each of the 15 SDHA exons. Amplicons were bidirectionally sequenced and compared to genomic repository data. Exons with somatic mutations were also examined in DNA from corresponding normal tissue to determine germline status. Results: All tumors (100%) were deficient for SDHB expression by IHC. Four of 11 (36%) SDHB-deficient GISTs also lacked expression of SDHA. SDHA expression was intact in the 7 remaining tumors, including 3 with known SDHB (n=2) or SDHC (n=1) mutations. Nonsense mutations in SDHA were identified in all 4 SDHA-deficient tumors, caused by a single base pair (bp) substitution (n=3) or a single bp deletion (n=1), and heterozygous mutations were also found in DNA from normal tissue of all 4 patients. Somatic loss of the 2nd allele has thus far been found in 3 of 4 tumors; 2 by loss of heterozygosity and 1 by a 13-bp deletion. Further analysis of the 4th specimen is ongoing. Conclusions: SDHA mutations are a common cause of SDH-deficient GISTs and result in combined loss of expression of both SDHA and SDHB. Loss of SDHA expression by IHC reliably predicts SDHA mutations and can be used to select cases for SDHA genetic testing.
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Gruber, Lucinda, and L. James Maher. "Predicted Succinated Dehydrogenase Subunit Variant Pathogenicity: Why Are SDHB Variants “Bad”?" Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A71—A72. http://dx.doi.org/10.1210/jendso/bvab048.144.
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Abstract Variants in the 4 genes encoding subunits A-D of succinate dehydrogenase (SDH) are associated with paraganglioma and pheochromocytoma. Intuitively, loss-of-function variants affecting any of the subunits should equally diminish SDH function leading to succinate accumulation and tumorigenesis after loss of heterozygosity. However, variants in SDHB are associated with a higher prevalence of metastatic disease and a more aggressive clinical course. Evaluation of the SDH protein structure shows the fraction of amino acids in contact with other subunits or essential prosthetic groups to be: 13% (SDHA), 40% (SDHB), 28% (SDHC), and 28% (SDHD). We therefore hypothesized that SDHB missense variants are more penetrant because a larger fraction alter sensitive interfaces with other SDH subunits or essential molecular features (e.g. the three SDHB iron-sulfur clusters). We also wondered if truncating variants are more common for SDHB than other subunits. To test these hypotheses, we combined three databases (Genome Aggregation Database, ClinVar-NCBI-NIH, and Leiden Open Variant Database) and our institution’s data to create a pool of all known SDH variants. We categorized variants as truncating or missense and evaluated missense variants in the context of the SDH protein structure, scoring each variant in relation to important structures/interfaces and the severity of the amino acid change. This provided an ad hoc impact score for each variant, where a higher score predicts a more deleterious effect. We compared these scores to those obtained using the “Sorting Intolerant from Tolerant” (SIFT) tool that predicts impacts of amino acid changes based on evolutionary sequence conservation. SIFT scores of 0 to 0.05 predict deleterious effects. Both mean impact and SIFT scores could be weighted for the prevalence of each variant in the population. Our database included 2333 total SDH variants: SDHA (838, 36%), SDHB (703, 30%), SDHC (381, 16%), and SDHD (412, 18%). The fractions of truncating variants were 38%, 50%, 51%, and 53% for A-D subunits, respectively. When weighted for prevalence, these fractions were 0.39%, 6.8%, 8.2%, and 0.2%. The number of truncating variants per coding region length and the distribution of locations were similar between subunits. Ad hoc impact scores for A-D subunits were 3.08, 14.9, 9.93, and 11.0, respectively and, when weighted for prevalence, were 0.28, 3.25, 6.32, and 1.15. Mean SIFT scores for subunits A-D were: 0.185, 0.162, 0.238, and 0.410 respectively, and, when weighted for prevalence, were 0.58, 0.70, 0.22, and 0.018. Our results do not support the hypothesis SDHB variants predict a worse clinical outcome because average SDHB variants are, by chance, more biochemically severe. This suggests that SDHB loss may uniquely impact SDH biochemical function.
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Choi, Hye-Ryeon, Ja-Seung Koo, Cho-Rok Lee, Jan-Dee Lee, Sang-Wook Kang, Young-Seok Jo, and Woong-Youn Chung. "Efficacy of Immunohistochemistry for SDHB in the Screening of Hereditary Pheochromocytoma–Paraganglioma." Biology 10, no. 7 (July 17, 2021): 677. http://dx.doi.org/10.3390/biology10070677.
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The most common genetic backgrounds of hereditary paraganglioma and pheochromocytoma (PPGL) are SDHx germline mutations. Given the fact that the immunohistochemistry (IHC) result for SDHB is always negative regardless of the type of SDHx mutation, we aimed to evaluate the efficacy of using SDHB IHC for screening SDHx mutations in PPGL cases. In total, 52 patients who underwent surgery for PPGL treatment between 2006 and 2020 and underwent genetic analysis at diagnosis were included. Tissue microarrays (TMAs) were constructed with PPGL tissues and IHC for SDHB was performed on TMA sections. All 10 patients with SDHB-negative IHC contained SDHB or SDHD mutations. The genetic test results of patients with SDHB-weakly positive IHC varied (one SDHB, two RET, one VHL, and three unknown gene mutations). There were no SDHx mutations in the SDHB-positive IHC group. Six patients with weakly positive SDHB IHC with primarily unknown genetic status were re-called and underwent next-generation sequencing. None of them had SDHx mutations. In conclusion, SDHB-negative IHC is a cost-effective and reliable method to predict SDHx mutations. However, in the case of weakly positive SDHB staining, an additional gene study should be considered.
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Zhou, Xiaoting, Yan Gao, Weiwei Wang, Xiaolin Yang, Xiuna Yang, Fengjiang Liu, Yanting Tang, et al. "Architecture of the mycobacterial succinate dehydrogenase with a membrane-embedded Rieske FeS cluster." Proceedings of the National Academy of Sciences 118, no. 15 (April 5, 2021): e2022308118. http://dx.doi.org/10.1073/pnas.2022308118.
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Complex II, also known as succinate dehydrogenase (SQR) or fumarate reductase (QFR), is an enzyme involved in both the Krebs cycle and oxidative phosphorylation. Mycobacterial Sdh1 has recently been identified as a new class of respiratory complex II (type F) but with an unknown electron transfer mechanism. Here, using cryoelectron microscopy, we have determined the structure of Mycobacterium smegmatis Sdh1 in the presence and absence of the substrate, ubiquinone-1, at 2.53-Å and 2.88-Å resolution, respectively. Sdh1 comprises three subunits, two that are water soluble, SdhA and SdhB, and one that is membrane spanning, SdhC. Within these subunits we identified a quinone-binding site and a rarely observed Rieske-type [2Fe-2S] cluster, the latter being embedded in the transmembrane region. A mutant, where two His ligands of the Rieske-type [2Fe-2S] were changed to alanine, abolished the quinone reduction activity of the Sdh1. Our structures allow the proposal of an electron transfer pathway that connects the substrate-binding and quinone-binding sites. Given the unique features of Sdh1 and its essential role in Mycobacteria, these structures will facilitate antituberculosis drug discovery efforts that specifically target this complex.
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White, Gemma, Samantha Anandappa, Michael Masucci, Fahim-Ul Hassan, Louise Breen, Mamta Joshi, Barbara McGowan, et al. "Using Multimodal Functional Imaging in the Management of SDHx-Related Pheochromocytoma and Paraganglioma." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A1034—A1035. http://dx.doi.org/10.1210/jendso/bvab048.2117.
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Abstract Background: Succinate Dehydrogenase (SDH) subunit pathogenic variants predispose to Pheochromocytoma and Paraganglioma (PPGL). Functional imaging harnesses the innate receptor expression and the aberrant cellular pathways in PPGLs to improve diagnostic accuracy & guide treatments, including nuclear medicine therapies. Currently commonly available functional imaging modalities include 18F-FDG PET, 123I-MIBG and 68Ga-DOTATATE. Aims: To analyze the use of 123I-MIBG, 18F-FDG PET and 68Ga-DOTATATE in patients harboring SDHB & SDHD pathogenic variants and determine the detection rates for both primary tumors and metastatic sites of disease. Methods: Retrospective review of patient records and imaging reports allowed tumor characteristics and imaging features of 21 patients with SDH-related PPGL to be recorded. Contrast enhanced CT/MRI were used as control to calculate the sensitivity of each functional imaging modality. Avidity of the primary lesion and metastatic deposits were used to calculate detection rates. 123I-MIBG imaging was available for 22 primary tumors (8 SDHB, 14 SDHD), 18FDG-PET for 24 (9 SDHB, 15 SDHD) and 68Ga-DOTATATE for 6 (2 SDHB, 4 SDHD) respectively. Results: 29 PPGLs (primary and metastases, 13 SDHB, 16 SDHD) were identified in 21 patients. 123I-MIBG detected 14/22 (64%) primary tumors; 5/8 (63%) SDHB and 9/14 (64%) SDHD-related PPGL. According to tumor location, 3/3 PCCs, 6/8 HNPGLs and 4/11 non-HNPGLs demonstrated 123I-MIBG avidity. Both18F-FDG PET and 68Ga-DOTATATE detected all PPGLs imaged; 24 (9 SDHB, 15 SDHD) and 6 (2 SDHB, 4 SDHD) respectively, demonstrating 100% sensitivity in the detection of the primary PPGL in all the above locations. 6 metastatic deposits (located in bone, lungs, liver and local lymph nodes) in 4 patients were imaged using all 3 modalities (3 SDHB, 1 SDHD), all of which were avid on 18F-FDG PET and 68Ga-DOTATATE whereas only 50% demonstrated avidity on 123I-MIBG imaging. Discussion: Recent guidelines promote preferential use of 68Ga-DOTATATE and 18F-FDG PET as initial functional imaging modalities in SDHx-related disease over 123I-MIBG. The results from our patient cohort indicate superior sensitivity (100%) for detection of SDHx-related disease with FDG and Dotatate compared with MIBG. In contrast to the current literature, a high proportion (75%) of HNPGLs in our series demonstrated MIBG avidity. Further prospective studies are needed to further evaluate these and various other novel tracers to inform diagnostic and therapeutic strategy in PPGLs arising from SDHx and various other germline and somatic pathogenic variants.
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Clark, Graeme R., Marco Sciacovelli, Edoardo Gaude, Diana M. Walsh, Gail Kirby, Michael A. Simpson, Richard C. Trembath, et al. "Germline FH Mutations Presenting With Pheochromocytoma." Journal of Clinical Endocrinology & Metabolism 99, no. 10 (October 1, 2014): E2046—E2050. http://dx.doi.org/10.1210/jc.2014-1659.
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Abstract Context: At least a third of the patients with pheochromocytoma (PCC) or paraganglioma (PGL) harbor an underlying germline mutation in a known PCC/PGL gene. Mutations in genes (SDHB, SDHD, SDHC, and SDHA) encoding a component of the tricarboxylic acid cycle, succinate dehydrogenase (SDH), are a major cause of inherited PCC and PGL. SDHB mutations are also, albeit less frequently, associated with inherited renal cell carcinoma. Inactivation of SDH and another tricarboxylic acid cycle component, fumarate hydratase (FH), have both been associated with abnormalities of cellular metabolism, responsible for the activation of hypoxic gene response pathways and epigenetic alterations (eg, DNA methylation). However, the clinical phenotype of germline mutations in SDHx genes and FH is usually distinct, with FH mutations classically associated with hereditary cutaneous and uterine leiomyomatosis and renal cell carcinoma, although recently an association with PCC/PGL has been reported. Objective and Design: To identify potential novel PCC/PGL predisposition genes, we initially undertook exome resequencing studies in a case of childhood PCC, and subsequently FH mutation analysis in a further 71 patients with PCC, PGL, or head and neck PGL. Results: After identifying a candidate FH missense mutation in the exome study, we then detected a further candidate missense mutation (p.Glu53Lys) by candidate gene sequencing. In vitro analyses demonstrated that both missense mutations (p.Cys434Tyr and p.Glu53Lys) were catalytically inactive. Conclusions: These findings 1) confirm that germline FH mutations may present, albeit rarely with PCC or PGL; and 2) extend the clinical phenotype associated with FH mutations to pediatric PCC.
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Korpershoek, Esther, Judith Favier, José Gaal, Nelly Burnichon, Bram van Gessel, Lindsey Oudijk, Cécile Badoual, et al. "SDHA Immunohistochemistry Detects Germline SDHA Gene Mutations in Apparently Sporadic Paragangliomas and Pheochromocytomas." Journal of Clinical Endocrinology & Metabolism 96, no. 9 (September 1, 2011): E1472—E1476. http://dx.doi.org/10.1210/jc.2011-1043.
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Abstract Context: Pheochromocytoma-paraganglioma syndrome is caused by mutations in SDHB, SDHC, and SDHD, encoding subunits of succinate dehydrogenase (SDH), and in SDHAF2, required for flavination of SDHA. A recent report described a patient with an abdominal paraganglioma, immunohistochemically negative for SDHA, and identified a causal germline mutation in SDHA. Objective: In this study, we evaluated the significance of SDHA immunohistochemistry in the identification of new patients with SDHA mutations. Setting: This study was performed in the Erasmus Medical Center in Rotterdam (The Netherlands) and the Université Paris Descartes in Paris (France). Methods: We investigated 316 pheochromocytomas and paragangliomas for SDHA expression. Sequence analysis of SDHA was performed on all tumors that were immunohistochemically negative for SDHA and on a subset of tumors immunohistochemically positive for SDHA. Results: Six tumors were immunohistochemically negative for SDHA. Four tumors from Dutch patients showed a germline c.91C→T SDHA gene mutation (p.Arg31X). Another tumor (from France) carried a germline SDHA missense mutation c.1753C→T (p.Arg585Trp). Loss of the wild-type SDHA allele was confirmed by loss of heterozygosity analysis. Sequence analysis of 35 SDHA immunohistochemically positive tumors did not reveal additional SDHA mutations. Conclusions: Our results demonstrate that SDHA immunohistochemistry on paraffin-embedded tumors can reveal the presence of SDHA germline mutations and allowed the identification of SDHA-related tumors in at least 3% of patients affected by apparently sporadic (para)sympathetic paragangliomas and pheochromocytomas.
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Whitworth, James, Ruth T. Casey, Philip S. Smith, Olivier Giger, Jose Ezequiel Martin, Graeme Clark, Jaqueline Cook, Marlee S. Fernando, Phillipe Taniere, and Eamonn R. Maher. "Familial wild-type gastrointestinal stromal tumour in association with germline truncating variants in both SDHA and PALB2." European Journal of Human Genetics 29, no. 7 (April 15, 2021): 1139–45. http://dx.doi.org/10.1038/s41431-021-00862-5.
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AbstractGastrointestinal stromal tumour (GIST) is a mesenchymal neoplasm arising in the gastrointestinal tract. A rare subset of GISTs are classified as wild-type GIST (wtGIST) and these are frequently associated with germline variants that affect the function of cancer predisposition genes such as the succinate dehydrogenase subunit genes (SDHA, SDHB, SDHC, SDHD) or NF1. However, despite this high heritability, familial clustering of wtGIST is extremely rare. Here, we report a mother–son diad who developed wtGIST at age 66 and 34 years, respectively. Comprehensive genetic testing revealed germline truncating variants in both SDHA (c.1534C>T (p.Arg512*)) and PALB2 (c.3113G>A (p.Trp1038*)) in both affected individuals. The mother also developed breast ductal carcinoma in-situ at age 70 years. Immunohistochemistry and molecular analysis of the wtGISTs revealed loss of SDHB expression and loss of the wild-type SDHA allele in tumour material. No allele loss was detected at PALB2 suggesting that wtGIST tumourigenesis was principally driven by succinate dehydrogenase deficiency. However, we speculate that the presence of multilocus inherited neoplasia alleles syndrome (MINAS) in this family might have contributed to the highly unusual occurrence of familial wtGIST. Systematic reporting of tumour risks and phenotypes in individuals with MINAS will facilitate the clinical interpretation of the significance of this diagnosis, which is becoming more frequent as strategies for genetic testing for hereditary cancer becomes more comprehensive.
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Wang, Gang, and Priya Rao. "Succinate Dehydrogenase–Deficient Renal Cell Carcinoma: A Short Review." Archives of Pathology & Laboratory Medicine 142, no. 10 (October 1, 2018): 1284–88. http://dx.doi.org/10.5858/arpa.2017-0199-rs.
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Succinate dehydrogenase (SDH) is a mitochondrial enzyme complex composed of 4 protein subunits (SDHA, SDHB, SDHC, and SDHD). Germ line mutations of the genes encoding these SDH subunits result in hereditary syndromes harboring pheochromocytomas/paragangliomas, gastrointestinal stromal tumors, renal cell carcinomas, and pituitary adenomas. SDH-deficient renal cell carcinomas are rare, with a mean age of 38 to 40 years. Histologically, these tumors show a characteristic appearance that includes a solid, nested, or tubular architecture with variable cysts. Cells are typically cuboidal, have indistinct cell borders and eosinophilic cytoplasm, and show flocculent intracytoplasmic inclusions. Loss of immunohistochemical staining for SDHB is the hallmark of these tumors. Although most SDH-deficient renal cell carcinomas are clinically indolent, some tumors may behave aggressively, particularly those with a high nuclear grade, tumor necrosis, or sarcomatoid differentiation. Accurate classification of these tumors is important for clinical follow-up, screening, and genetic evaluation of the patients and other family members for this hereditary tumor syndrome.
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Casey, Ruth, Aoife Garrahy, Antoinette Tuthill, Domhnall O'Halloran, Caroline Joyce, Mary B. Casey, Paula O'Shea, and Marcia Bell. "Universal Genetic Screening Uncovers a Novel Presentation of an SDHAF2 Mutation." Journal of Clinical Endocrinology & Metabolism 99, no. 7 (July 1, 2014): E1392—E1396. http://dx.doi.org/10.1210/jc.2013-4536.
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Context: Hereditary pheochromocytoma/paraganglioma (PC/PGL) accounts for up to 60% of previously considered sporadic tumors. Guidelines suggest that phenotype should guide genetic testing. Next-generation sequencing technology can simultaneously sequence 9 of the 18 known susceptibility genes in a timely, cost-efficient manner. Objective: Our aim was to confirm that universal screening is superior to targeted testing in patients with histologically confirmed PC and PGL. Methods: In two tertiary referral hospitals in Ireland, NGS was carried out on all histologically confirmed cases of PC/PGL diagnosed between 2004 and 2013. The following susceptibility genes were sequenced: VHL, RET, SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, and MAX. A multiplex ligation-dependent probe amplification analysis was performed in VHL, SDHB, SDHC, SDHD, and SDHAF2 genes to detect deletions and duplications. Results: A total of 31 patients were tested, 31% (n = 10) of whom were found to have a genetic mutation. Of those patients with a positive genotype, phenotype predicted genotype in only 50% (n = 5). Significant genetic mutations that would have been missed in our cohort by phenotypic evaluation alone include a mutation in TMEM127, two mutations in SDHAF2, and two mutations in RET. Target testing would have identified three of the latter mutations based on age criteria. However, 20% of patients (n = 2) would not have satisfied any criteria for targeted testing including one patient with a novel presentation of an SDHAF2 mutation. Conclusion: This study supports the value of universal genetic screening for all patients with PC/PGL.
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Nannini, Margherita, Milena Urbini, Valentina Indio, Angela Schipani, Bruno Vincenzi, Marianna Silletta, Giovanni Grignani, et al. "Identification of SDHA germline mutations in sporadic SDHA mutant gastrointestinal stromal tumors (GIST): The need of a genetic counselling." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 11537. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.11537.
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11537 Background: SDH- deficient GIST, as defined by the loss of expression of SDHB, account up to about 10% of all gastric GIST and generally affect younger population. Germline mutations in SDHB, SDHC, and SDHD occur in about 20–30% of SDH- deficient, that may be referred to a hereditary condition known as hereditary GIST-paraganglioma syndrome (Carney-Stratakis Syndrome), whereas germline SDHA mutations have been rarely described in apparently sporadic cases. Currently, even germline testing is recommended for SDH- deficient GIST, there are no clear guidelines for genetic counselling and follow-up of SDH x mutation carriers and relatives, especially for SDHA mutant GIST not yet linked to well-defined hereditary syndrome. The aim of this work was to study the SDHA gene in the normal DNA of patients with SDHA mutant GIST. Methods: Thirteen patients carrying SDHA-mutant GIST were studied (8F/5M). Median age of diagnosis was 45,9 years (range 25-74). All GIST were located in the stomach and 3 patients out 13 presented a metastatic disease. In all cases except one, the GIST was the only cancer presentation and no personal or familial history of cancer was revealed. All cases were negative for SDHB immunohistochemistry. Germline mutations were identified through Sanger sequencing of SDHA in the normal counterpart. Results: Germline mutations were identified in all patients for which normal counterpart was available: 4 cases harboured truncating mutations (S384X, R31X and W119X); 5 cases carried pathogenic missense mutations (G233V, R171H, R589Q, G257A and R600Q) and 2 cases had splice site alterations (c.457-3_457-1 delCAG and c.456+9 C > T). In 8 cases the tumor DNA showed the loss of the corresponding wild-type allele, while in the other 3 cases compound heterozygosity for an additional somatic mutation was detected (R589W, R451C,and R171C). In 2 patients, unfortunately, normal DNA was not available, however both tumours carried two mutational hits on SDHA (one with heterozygous G419R and E564K, and one with homozygous R585Q). Of note, 5 patients presented un-usaul SDHA related clinical characteristics as were not young adult ( > 50 years-old) or no multifocal GIST. Conclusions: We demonstrated that germline SDHA mutations are highly frequent in SDHA- deficient GIST. Therefore, although a clear syndrome has not been defined, genetic counselling and follow-up of SDHA mutation carriers and relatives should be clarified.
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De Sousa, Sunita M. C., Mark J. McCabe, Kathy Wu, Tony Roscioli, Velimir Gayevskiy, Katelyn Brook, Lesley Rawlings, et al. "Germline variants in familial pituitary tumour syndrome genes are common in young patients and families with additional endocrine tumours." European Journal of Endocrinology 176, no. 5 (May 2017): 635–44. http://dx.doi.org/10.1530/eje-16-0944.
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Objective Familial pituitary tumour syndromes (FPTS) account for 5% of pituitary adenomas. Multi-gene analysis via next-generation sequencing (NGS) may unveil greater prevalence and inform clinical care. We aimed to identify germline variants in selected patients with pituitary adenomas using a targeted NGS panel. Design We undertook a nationwide cross-sectional study of patients with pituitary adenomas with onset ≤40 years of age and/or other personal/family history of endocrine neoplasia. A custom NGS panel was performed on germline DNA to interrogate eight FPTS genes. Genome data were analysed via a custom bioinformatic pipeline, and validation was performed by Sanger sequencing. Multiplex ligation-dependent probe amplification (MLPA) was performed in cases with heightened suspicion for MEN1, CDKN1B and AIP mutations. The main outcomes were frequency and pathogenicity of rare variants in AIP, CDKN1B, MEN1, PRKAR1A, SDHA, SDHB, SDHC and SDHD. Results Forty-four patients with pituitary tumours, 14 of whom had a personal history of other endocrine tumours and/or a family history of pituitary or other endocrine tumours, were referred from endocrine tertiary-referral centres across Australia. Eleven patients (25%) had a rare variant across the eight FPTS genes tested: AIP (p.A299V, p.R106C, p.F269F, p.R304X, p.K156K, p.R271W), MEN1 (p.R176Q), SDHB (p.A2V, p.S8S), SDHC (p.E110Q) and SDHD (p.G12S), with two patients harbouring dual variants. Variants were classified as pathogenic or of uncertain significance in 9/44 patients (20%). No deletions/duplications were identified in MEN1, CDKN1B or AIP. Conclusions A high yield of rare variants in genes implicated in FPTS can be found in selected patients using an NGS panel. It may also identify individuals harbouring more than one rare variant.
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Abed, Firas M., Melissa A. Brown, Omar A. Al-Mahmood, and Michael J. Dark. "SDHB and SDHA Immunohistochemistry in Canine Pheochromocytomas." Animals 10, no. 9 (September 17, 2020): 1683. http://dx.doi.org/10.3390/ani10091683.
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Pheochromocytomas (PCs) are tumors arising from the chromaffin cells of the adrenal glands and are the most common tumors of the adrenal medulla in animals. In people, these are highly correlated to inherited gene mutations in the succinate dehydrogenase (SDH) pathway; however, to date, little work has been done on the genetic basis of these tumors in animals. In humans, immunohistochemistry has proven valuable as a screening technique for SDH mutations. Human PCs that lack succinate dehydrogenase B (SDHB) immunoreactivity have a high rate of mutation in the SDH family of genes, while human PCs lacking succinate dehydrogenase A (SDHA) immunoreactivity have mutations in the SDHA gene. To determine if these results are similar for dogs, we performed SDHA and SDHB immunohistochemistry on 35 canine formalin-fixed, paraffin-embedded (FFPE) PCs. Interestingly, there was a loss of immunoreactivity for both SDHA and SDHB in four samples (11%), suggesting a mutation in SDHx including SDHA. An additional 25 (71%) lacked immunoreactivity for SDHB, while retaining SDHA immunoreactivity. These data suggest that 29 out of the 35 (82%) may have an SDH family mutation other than SDHA. Further work is needed to determine if canine SDH immunohistochemistry on PCs correlates to genetic mutations that are similar to human PCs.
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Thompson, Michael JW, Venkat Parameswaran, and John R. Burgess. "Clinical utility of chromogranin A for the surveillance of succinate dehydrogenase B- and succinate dehydrogenase D-related paraganglioma." Annals of Clinical Biochemistry: International Journal of Laboratory Medicine 56, no. 1 (November 14, 2018): 163–69. http://dx.doi.org/10.1177/0004563218811865.
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Background Patients with mutations of succinate dehydrogenase B (SDHB) and succinate dehydrogenase D (SDHD) are at high risk of paraganglioma necessitating surveillance. Chromogranin A has been proposed as a biochemical marker of paraganglioma. We sought to determine the diagnostic utility of chromogranin A in a population-based SDHx sample. Methods Tasmania is an island state with one tertiary referral centre for endocrine neoplasia. We performed a cross-sectional analysis of all adult SDHB ( n = 52) and SDHD ( n = 10) patients undergoing paraganglioma surveillance between 2011 and 2017. Chromogranin A was referenced against the outcome of paraganglioma surveillance with a minimum of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) and plasma metanephrines (metanephrine and normetanephrine). Results Chromogranin A correctly predicted the result of paraganglioma surveillance more often in patients with SDHB compared with those with SDHD (77% vs. 22%, P = 0.003). In the SDHB group, chromogranin A demonstrated a sensitivity of 67% and specificity of 79% compared with 22% and 0% in the SDHD group. Chromogranin A identified one of three PET/CT-visualized SDHB-related paragangliomas with normal plasma metanephrines at the expense of nine false-positive results. A normal chromogranin A demonstrated a negative predictive value of 92% for SDHB-related paraganglioma. In patients with SDHB, plasma normetanephrine and metanephrine offered superior specificity (100%, P = 0.01 and 100%, P < 0.01, respectively) with comparable sensitivity (67%, P = 1.0 and 11%, P = 0.06, respectively) to chromogranin A. Conclusion Chromogranin A does not provide additive benefit to standard surveillance for predicting the presence of SDHB- or SDHD-related paraganglioma, but has a useful negative predictive value when normal in patients with SDHB mutation.
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Pankratova, Iu V., E. G. Przhiyalkovskaya, E. A. Pigarova, and L. K. Dzeranova. "The enzyme succinate dehydrogenase (SDH) and its role in hereditary pituitary adenomas." Obesity and metabolism 10, no. 4 (December 15, 2013): 10–15. http://dx.doi.org/10.14341/omet2013410-15.
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Despite active research involving familial pituitary adenomas and characterization of five hereditary syndromes, the genetic defects in more than 80 - 95% of patients remain not found. Besides, there is more than 25 cases of coexistence of pheochromocytomas and pituitary adenomas described in literature that up to date is not integrated in any syndrome; genetic defects of such coexistence also aren't defined. However it is supposed that in pituitary tumorigenesis, germline mutations of SDH can take part that is obviously important aspect of further investigation. Germline mutations of SDH were found in patients with different phenotypes of pituitary adenomas. Studying of mutations in genes SDHD, SDHB, SDHC, SDHA and their prevalence in patients with familial pituitary adenomas or with phenotypes of multiple endocrine neoplasia without mutations in MEN1, CDKN1B, PRKAR1A, AIP genes can provide clarity in a role of mutations in SDH in endocrine and in particular pituitary tumorigenesis.
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Malinoc, Angelica, Maren Sullivan, Thorsten Wiech, Kurt Werner Schmid, Cordula Jilg, Joern Straeter, Serdar Deger, et al. "Biallelic inactivation of the SDHC gene in renal carcinoma associated with paraganglioma syndrome type 3." Endocrine-Related Cancer 19, no. 3 (February 20, 2012): 283–90. http://dx.doi.org/10.1530/erc-11-0324.
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The etiology and pathogenesis of renal cell carcinoma (RCC) are only partially understood. Key findings in hereditary RCC, which may be site specific or a component of a syndrome, have contributed to our current understanding. Important heritable syndromes of RCC are those associated with pheochromocytoma, especially von Hippel–Lindau disease (VHL) associated with germline VHL mutations, and pheochromocytoma and paraganglioma syndrome (PGL) associated with mutations in one of the four genes (SDHA–D) encoding succinate dehydrogenase. A subset of individuals with SDHB and SDHD germline DNA mutations and variants develop RCC. RCC has never been described as a component of SDHC-associated PGL3. The European–American Pheochromocytoma and Paraganglioma Registry comprises 35 registrants with germline SDHC mutations. A new registrant had carotid body tumor (CBT) and his mother had CBT and bilateral RCC. Blood DNA, paragangliomas, and RCCs were analyzed for mutations and loss-of-heterozygosity (LOH) in/flanking SDHC and VHL. The proband with unilateral CBT had a germline SDHC c.3G>A (p.M1I) mutation. His mutation-positive mother had CBT at age 42, clear cell RCC (ccRCC) at age 68, and papillary RCC (pRCC) at age 69. Both paraganglial tumors showed somatic LOH of the SDHC locus. Both ccRCC and pRCC did not have a somatic SDHC mutation but showed LOH for intragenic and flanking markers of the SDHC locus. LOH was also present for the VHL locus. Our findings suggest that RCC is a component of PGL3. Biallelic inactivation of the SDHC gene may represent a new pathway of pathogenesis of syndromic and nonsyndromic RCC, perhaps of both clear cell and papillary histologies.
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Bayley, Jean-Pierre, Marjan M. Weiss, Anneliese Grimbergen, Bernadette T. J. van Brussel, Frederik J. Hes, Jeroen C. Jansen, Senno Verhoef, Peter Devilee, Eleonora P. Corssmit, and Annette H. J. T. Vriends. "Molecular characterization of novel germline deletions affecting SDHD and SDHC in pheochromocytoma and paraganglioma patients." Endocrine-Related Cancer 16, no. 3 (September 2009): 929–37. http://dx.doi.org/10.1677/erc-09-0084.
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A major cause of paraganglioma and pheochromocytoma is germline mutation of the tumor suppressor genes SDHB, SDHC, and SDHD, encoding subunits of succinate dehydrogenase (SDH). While many SDH missense/nonsense mutations have been identified, few large deletions have been described. We performed multiplex ligation-dependent probe amplification deletion analysis in 126 point mutation-negative patients, and here we describe four novel deletions of SDHD and SDHC. Long-range PCR was used for the fine mapping of deletions. One patient had a 10 kb AluSg–AluSx-mediated deletion including SDHD exons 1 and 2, the entire TIMM8B gene, and deletion of exons of C11orf57. A second patient had a deletion of SDHD exons 1 and 2 and exon 1 of the TIMM8B gene. A third patient showed a deletion of exon 2 of SDHD, together with a 235 bp MIRb–Tensin gene insertion. In a fourth patient, a deletion of exons 5 and 6 of the SDHC gene was found, only the second SDHC deletion currently known. The deletions of the TIMM8B and C11orf57 genes are the first to be described, but do not appear to result in an additional phenotype in these patients. Four of the eight breakpoints occurred in Alu sequences and all three SDHD deletions showed an intron 2 breakpoint. This study underlines the fact that clinically relevant deletions may encompass neighboring genes, with the potential to modify phenotype. Gene deletions of SDHD and SDHC represent a substantial proportion of all mutations, and must be considered in paraganglioma patients shown to be negative for mutations by sequencing.
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Benn, Diana E., Bruce G. Robinson, and Roderick J. Clifton-Bligh. "15 YEARS OF PARAGANGLIOMA: Clinical manifestations of paraganglioma syndromes types 1–5." Endocrine-Related Cancer 22, no. 4 (June 11, 2015): T91—T103. http://dx.doi.org/10.1530/erc-15-0268.
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The paraganglioma (PGL) syndromes types 1–5 are autosomal dominant disorders characterized by familial predisposition to PGLs, phaeochromocytomas (PCs), renal cell cancers, gastrointestinal stromal tumours and, rarely, pituitary adenomas. Each syndrome is associated with mutation in a gene encoding a particular subunit (or assembly factor) of succinate dehydrogenase (SDHx). The clinical manifestations of these syndromes are protean: patients may present with features of catecholamine excess (including the classic triad of headache, sweating and palpitations), or with symptoms from local tumour mass, or increasingly as an incidental finding on imaging performed for some other purpose. As genetic testing for these syndromes becomes more widespread, presymptomatic diagnosis is also possible, although penetrance of disease in these syndromes is highly variable and tumour development does not clearly follow a predetermined pattern. PGL1 syndrome (SDHD) and PGL2 syndrome (SDHAF2) are notable for high frequency of multifocal tumour development and for parent-of-origin inheritance: disease is almost only ever manifest in subjects inheriting the defective allele from their father. PGL4 syndrome (SDHB) is notable for an increased risk of malignant PGL or PC. PGL3 syndrome (SDHC) and PGL5 syndrome (SDHA) are less common and appear to be associated with lower penetrance of tumour development. Although these syndromes are all associated with SDH deficiency, few genotype–phenotype relationships have yet been established, and indeed it is remarkable that such divergent phenotypes can arise from disruption of a common molecular pathway. This article reviews the clinical presentations of these syndromes, including their component tumours and underlying genetic basis.
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Filonenko, Daria A., Andrey A. Meshcheryakov, Petr P. Arkhiri, Maxim P. Nikulin, and Evgeniia S. Kolobanova. "SDH-deficient gastrointestinal stromal tumors: paradoxical effect of imatinib." Journal of Modern Oncology 22, no. 2 (July 15, 2020): 133–36. http://dx.doi.org/10.26442/18151434.2020.2.200053.
Full textAbstract:
Succinate dehydrogenase deficient gastrointestinal stromal tumors (dSDH GIST) is a unique group of GISTs with an energy metabolism defect as the key oncogenic mechanism without mutations in the proto-oncogene receptor tyrosine kinase (KIT) and platelet-derived growth factor receptor a (PDGFRA). SDH-deficiency is a result of mutations in SDHA, SDHB, SDHC, SDHD. There are three variants of dSDH GIST: sporadic dSDH GIST, Carney triad or Carney-Stratakis syndrome. dSDH GISTs are characterized by young age, female prevalence, gastric location, multiple tumors, lymph node metastases, indolent behavior and poorly response to imatinib. Despite the literature data, we report the response to imatinib in patient with dSDH GIST. 21 year old female patient presented with incomplete Carney triad (multiply gastric GIST with liver and peritoneal metastases, left lung chondroma). The patient received imatinib with clinical response in a month and radiological response in three months-cystic transformation of primary gastric tumor and liver metastases. The duration of response was 8 months.
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Jafri, Mariam, and Eamonn R. Maher. "GENETICS IN ENDOCRINOLOGY: The genetics of phaeochromocytoma: using clinical features to guide genetic testing." European Journal of Endocrinology 166, no. 2 (February 2012): 151–58. http://dx.doi.org/10.1530/eje-11-0497.
Full textAbstract:
Phaeochromocytoma is a rare, usually benign, tumour predominantly managed by endocrinologists. Over the last decade, major advances have been made in understanding the molecular genetic basis of adrenal and extra-adrenal phaeochromocytoma (also referred to as adrenal phaeochromocytoma (aPCA) and extra-adrenal functional paraganglioma (eFPGL)). In contrast to the previously held belief that only 10% of cases had a genetic component, currently about one-third of all aPCA/eFPGL cases are thought to be attributable to germline mutations in at least nine genes (NF1, RET, SDHA, SDHB, SDHC, SDHD, TMEM127, MAX and VHL). Recognition of inherited cases of aPCA/eFPGL is critical for optimal patient management. Thus, the identification of a germline mutation can predict risks of malignancy, recurrent disease, associated non-chromaffin tumours and risks to other family members. Mutation carriers should be offered specific surveillance programmes (according to the relevant gene). In this review, we will describe the genetics of aPCA/eFPGL and strategies for genetic testing.