Extra-adrenal and adrenal pheochromocytomas associated with a germline SDHC mutation
A 46-year-old man presented with headaches, paroxysmal palpitations, anxiety and hypertension. The patient had undergone surgery for a retroperitoneal tumor at the age of 31 years, when histological examination revealed an extra-adrenal pheochromocytoma. The patient's 68-year-old mother had a history of a carotid body tumor, which had been resected when she was 34 years old. She was diagnosed with a meningioma at 54 years of age and a jugular paraganglioma at 68 years of age.
A 24h urine catecholamine assay was performed. CT imaging of the abdomen and (123)I-labeled metaiodobenzylguanidine scintigraphy revealed a right pheochromocytoma and left adrenal incidentaloma. An inherited neoplasia syndrome was suspected and molecular genetic analyses were performed.
Right adrenal pheochromocytoma and left adrenal nonfunctioning incidentaloma, as part of a familial pheochromocytoma-paraganglioma syndrome associated with a germline mutation in SDHC (gene encoding succinate dehydrogenase complex, subunit C, integral membrane protein, 15 kDa).
Predictive testing, with genetic counseling. Management included surgical resection of the existing pheochromocytoma. The patient continues to be monitored with MRI scans of the neck, thorax, abdomen and pelvis every 1-2 years and an annual 24h urine collection for the measurement of metanephrines and catecholamines.
Available from: PubMed Central
- "Linkage analyses of large families revealed this third locus for hereditary PGL, termed PGL3 (Niemann & Muller 2000, Niemann et al. 2003, Muller et al. 2005). Overall, germline SDHC mutations are found in around 4% of HNPGL (Schiavi et al. 2005) but very few functioning PPGLs (Mannelli et al. 2007, Peczkowska et al. 2008). Patients with SDHC mutations are more likely to develop carotid body tumours, less likely to have multiple tumours than in SDHD mutated PGL, and have low malignant potential compared to SDHB-mutated PGL (Schiavi et al. 2005). "
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ABSTRACT: 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.
© 2015 The authors.
Endocrine Related Cancer 08/2015; 22(4):T91-T103. DOI:10.1530/ERC-15-0268 · 4.81 Impact Factor
Available from: Dennis Winge
- "E-mail: email@example.com commonly associated with mutations in SDHB, SDHC and SDHD, however SDHA mutations have recently been implicated in rare cases (Astuti et al., 2001; Baysal, 2000; Burnichon et al., 2010; Peczkowska et al., 2008). Mutations in SDHA, SDHB and SDHC have also been associated with WT-GIST, a mesenchymal tumor of the digestive tract (Janeway et al., 2011; Pantaleo et al., 2011, 2014). "
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ABSTRACT: Succinate dehydrogenase (or complex II; SDH) is a heterotetrameric protein complex that links the tribarboxylic acid cycle with the electron transport chain. SDH is composed of four nuclear-encoded subunits that must translocate independently to the mitochondria and assemble into a mature protein complex embedded in the inner mitochondrial membrane. Recently, it has become clear that failure to assemble functional SDH complexes can result in cancer and neurodegenerative syndromes. The effort to thoroughly elucidate the SDH assembly pathway has resulted in the discovery of four subunit-specific assembly factors that aid in the maturation of individual subunits and support the assembly of the intact complex. This review will focus on these assembly factors and assess the contribution of each factor to the assembly of SDH. Finally, we propose a model of the SDH assembly pathway that incorporates all extant data.
Critical Reviews in Biochemistry and Molecular Biology 12/2014; 50(2). DOI:10.3109/10409238.2014.990556 · 7.71 Impact Factor
Available from: Attje S Hoekstra
- "Although the number of SDHC-related patients is still insufficient to allow firm conclusions to be drawn, the penetrance of SDHC mutations appears to be low, more closely reflecting that of SDHB than SDHD. The clinical expression of SDHC mutations appears to be comparable to that of SDHD however, with most patients showing primarily head and neck paragangliomas, although some sympathetic paragangliomas have been reported  . "
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ABSTRACT: Genetically-defined mitochondrial deficiencies that result in the loss of complex II function lead to a range of clinical conditions. An array of tumor syndromes caused by complex II-associated gene mutations, in both succinate dehydrogenase and associated accessory factor genes (SDHA, SDHB, SDHC, SDHD, SDHAF1, SDHAF2), have been identified over the last twelve years and include hereditary paraganglioma-pheochromocytomas, a diverse group of renal cell carcinomas, and a specific subtype of gastrointestinal stromal tumors (GIST). In addition, congenital complex II deficiencies due to inherited homozygous mutations of the catalytic components of complex II (SDHA and SDHB) and the SDHAF1 assembly factor lead to childhood disease including Leigh syndrome, cardiomyopathy and infantile leukodystrophies. The role of complex II subunit gene mutations in tumorigenesis has been the subject of intensive research and these data have led to a variety of compelling hypotheses. Among the most widely researched are the stabilization of hypoxia inducible factor 1 under normoxia, and the generation of reactive oxygen species due to defective succinate:ubiquinone oxidoreductase function. Further progress in understanding the role of complex II in disease, and in the development of new therapeutic approaches, is now being hampered by the lack of relevant cell and animal models. This article is part of a Special Issue entitled: Respiratory complex II: Role in cellular physiology and disease.
Biochimica et Biophysica Acta 11/2012; 1827(5). DOI:10.1016/j.bbabio.2012.11.005 · 4.66 Impact Factor
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