Clinicoradiological manifestations of paraganglioma syndromes associated with succinyl dehydrogenase enzyme mutation

BACKGROUND: Paragangliomas are rare tumours derived from the autonomic nervous system that have increasingly been recognised to have a genetic predisposition. Mutations of the enzyme succinyl dehydrogenase (SDH) have proven to result in paraganglioma formation. There are four subunits (A through D) that form the enzyme complex and are associated with different genophenotypic expressions of disease. SDHB and SDHD mutations are more common, whereas SDHA and SDHC mutations are rare. Patients with SDHB mutations are prone to extra-adrenal pheochromocytomas, malignant disease and extra-paraganglial neoplasia, whereas SDHD mutations have a greater propensity for multiple, benign head and neck paragangliomas. METHODS: Diagnosis of a sporadic paraganglioma or pheochromocytoma should lead to a full genetic workup of the patient and family if SDH mutations are found. RESULTS: Further annual screening will be required depending on the mutation, which can have a significant impact on radiologists and the resources of the radiology department. CONCLUSION: We present our imaging experience with a series of patients with proven SDH mutations resulting in paragangliomas with a review of the literature

Mutation analysis of SDHB and SDHC: novel germline mutations in sporadic head and neck paraganglioma and familial paraganglioma and/or pheochromocytoma

BACKGROUND: Germline mutations of the SDHD, SDHB and SDHC genes, encoding three of the four subunits of succinate dehydrogenase, are a major cause of hereditary paraganglioma and pheochromocytoma, and demonstrate that these genes are classic tumor suppressors. Succinate dehydrogenase is a heterotetrameric protein complex and a component of both the Krebs cycle and the mitochondrial respiratory chain (succinate:ubiquinone oxidoreductase or complex II). METHODS: Using conformation sensitive gel electrophoresis (CSGE) and direct DNA sequencing to analyse genomic DNA from peripheral blood lymphocytes, here we describe the mutation analysis of the SDHB and SDHC genes in 37 patients with sporadic (i.e. no known family history) head and neck paraganglioma and five pheochromocytoma and/or paraganglioma families. RESULTS: Two sporadic patients were found to have a SDHB splice site mutation in intron 4, c.423+1G>A, which produces a mis-spliced transcript with a 54 nucleotide deletion, resulting in an 18 amino acid in-frame deletion. A third patient was found to carry the c.214C>T (p.Arg72Cys) missense mutation in exon 4 of SDHC, which is situated in a highly conserved protein motif that constitutes the quinone-binding site of the succinate: ubiquinone oxidoreductase (SQR) complex in E. coli. Together with our previous results, we found 27 germline mutations of SDH genes in 95 cases (28%) of sporadic head and neck paraganglioma. In addition all index patients of five families showing hereditary pheochromocytoma-paraganglioma were found to carry germline mutations of SDHB: four of which were novel, c.343C>T (p.Arg115X), c.141G>A (p.Trp47X), c.281G>A (p.Arg94Lys), and c.653G>C (p.Trp218Ser), and one reported previously, c.136C>T, p.Arg46X. CONCLUSION: In conclusion, these data indicate that germline mutations of SDHB and SDHC play a minor role in sporadic head and neck paraganglioma and further underline the importance of germline SDHB mutations in cases of familial pheochromocytoma-paraganglioma

Mitochondrial tumour suppressors: A genetic and biochemical update

Since the discovery 5 years ago that the D-subunit of succinate dehydrogenase ( SDHD) can behave as a classic tumour suppressor, other nuclear-encoded mitochondrial proteins (SDHB, SDHC and fumarate hydratase) have been implicated in tumour susceptibility. Mutations in these proteins are principally involved in familial predisposition to benign tumours, but the spectrum of inherited lesions is increasingly recognized to include malignant tumours, such as malignant phaeochromocytomas and renal cell carcinomas. Here we review recent advances in the field of mitochondrial tumour suppressors, the biochemical pathway that links mitochondrial dysfunction with tumorigenesis, and potential therapeutic approaches to these malignancies