Succinate dehydrogenase gene (SDHx) germline mutations increase the risk of sympathetic paragangliomas, head and neck paragangliomas, pheochromocytomas, renal cell carcinoma (RCC), and gastric gastrointestinal stromal tumors (GIST) 1,2,6,7.
Pathology
There are four SDH genes - SDHA, SDHB, SDHC, SDHD (collectively called SDHx) - which encode the four protein subunits of the SDH mitochondrial enzyme 6,7. In addition, SDHAF2 is needed for SDHA protein flavination 7.
In the citric acid cycle, SDH converts succinate to fumarate. Mutations in any one of the SDHx genes can result in mitochondrial dysfunction (SDH-deficiency) leading to neoplasia 6,7:
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SDHA mutation
limited data
associated with SDH-deficient GIST
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SDHB mutation
primarily retroperitoneal paraganglioma (more common) and pheochromocytoma
common in SDH-deficient RCC
highest risk of metastases
tumor risk in patients is probably <50% 5
-
SDHC mutation
limited data
primarily head and neck paragangliomas
common in SDH-deficient RCC
lower penetrance than SDHD mutation
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SDHC epimutation (promotor hypermethylation)
associated with SDH-deficient GIST
-
SDHD mutation
primarily head and neck paragangliomas
highest penetrance
Associations
PitNET/pituitary adenoma: SDH-deficiency in <0.3% 7
pulmonary chondroma: very rare outside Carney triad 7
Treatment and prognosis
Asymptomatic SDHx carriers should undergo clinical and biochemical screening from childhood 6. MRI is recommended for childhood screening, and MRI and PET-CT recommended for adulthood screening 6.