SDHdeficient

SDH-deficient refers to tumors or cells in which the succinate dehydrogenase (SDH) complex is functionally impaired. The SDH complex, also known as mitochondrial Complex II, participates in both the citric acid (Krebs) cycle and the mitochondrial electron transport chain. It is composed of four core subunits—SDHA, SDHB, SDHC, and SDHD—and assembly factors such as SDHAF2. Deficiency can result from germline or somatic mutations in SDHx genes or from epigenetic silencing, leading to reduced SDH activity and accumulation of the oncometabolite succinate. Succinate can inhibit prolyl hydroxylases, stabilize hypoxia-inducible factors, and drive epigenetic changes that promote tumorigenesis.

SDH-deficient tumors most notably include paragangliomas and pheochromocytomas (PPGL), frequently associated with germline SDHx mutations. They also encompass SDH-deficient gastrointestinal stromal tumors (GISTs), which are often gastric, occur in younger patients, and may lack KIT/PDGFRA mutations; as well as a subset of renal cell carcinomas, pituitary adenomas, and other rare neoplasms. The SDHx gene spectrum includes SDHA, SDHB, SDHC, SDHD, and rarely SDHAF2. Loss of SDH function creates characteristic metabolic and epigenetic profiles that influence tumor behavior and heredity.

Diagnosis commonly relies on immunohistochemistry: loss of SDHB expression in tumor tissue serves as a surrogate marker for SDHx deficiency, while SDHA staining can help identify SDHA-related tumors. Genetic testing for SDHx mutations is recommended for patients with SDH-deficient tumors and for at-risk relatives, given the heritable nature of many SDHx alterations.

Management focuses on tumor-specific treatment and surveillance, with genetic counseling and family screening playing important roles due to the hereditary risk associated with SDH deficiency. Prognosis varies by tumor type and mutation, with SDHB-associated tumors often carrying a higher risk of malignancy.