Succinate dehydrogenase (SDH), also known as mitochondrial complex II, is an enzyme complex located on the inner mitochondrial membrane and formed by four subunits SDHA, SDHB, SDHC, SDHD, and an assembly factor SDHAF2 required for flavination of SDHA. Subunits are encoded by corresponding autosomal genes (SDHA, SDHB, SDHC, SDHD, and SDHAF2). The complex functions as an enzyme of aerobic respiration in both the Krebs cycle and the electron transport chain1.

Biallelic inactivation of genes encoding any of the components, almost always in the presence of a germline mutation, causes loss of function of the entire complex and degradation of the SDHB subunit, loss of which can be detected by immunohistochemistry. The most common manifestations of SDH-deficient neoplasms are SDH-deficient pheochromocytoma(PCC)/paraganglioma(PGL), followed by SDH-deficient gastrointestinal stromal tumor (GIST) and SDH-deficient renal cell carcinoma (RCC), and rarely SDH-deficient pituitary neuroendocrine tumors (PitNETs)/pituitary adenoma (PA) and pulmonary chondroma1, 2, 3, 4, 5, 6, 7, 8.

These tumors may exhibit morphologic features distinct from their non-SDH-deficient counterparts9. Moreover, a great majority of SDH-deficient neoplasms occur in syndromic settings due to germline mutations in one of the SDH genes or epigenetic events (promoter hypermethylation) of the SDHC gene2,9,10. As sporadic SDH-deficient tumors are very rare, identification of SDH-deficient neoplasms should be considered as strong evidence of syndromic disease. In this context, SDHB immunohistochemistry serves as a reliable surrogate marker for mutations in SDH genes and therefore a strong predictor of syndromic disease.

Awareness of genotype-phenotype correlations and low threshold for applying SDHB immunohistochemistry help proper identification of patients with hereditary SDH-deficient tumor syndromes, guidance for the management of patients, and genetic counseling for their families.

In this review we summarize recent developments on the clinical and genetic features, diagnostic approach, and pitfalls of SDH-deficient syndrome, focusing on SDH-deficient renal cell carcinomas.

SDH-deficient tumor syndrome is a group of syndromes characterized by SDH-deficient neoplasia1,2,9. Historically, they are known as hereditary paraganglioma-pheochromocytoma syndromes type 1(PGL1), type 2(PGL2), type 3 (PGL3), type 4 (PGL4), and type 5 (PGL5) associated with germline mutations in SDHD, SDHAF2, SDHC, SDHB, and SDHA, respectively11. It also included Carney-Stratakis dyad/syndrome defined by the coexistence of paragangliomas and GISTs12 and associated with germline mutations in SDHB, SDHC, and SDHD; however that terminology is no longer recommended9,13. Carney triad is a syndromic but non-hereditary disease associated with SDHC epimutation and includes SDH-deficient GIST, SDH-deficient paraganglioma, and pulmonary chondroma9,13.

Clinical presentation is related to tumor localization, mass-related symptoms, and biochemical status (active/silent) in the case of PCC/PGL and PitNETs/PA. Strong genotype-phenotype correlations are noted as certain mutations occur much more frequently in certain tumors or constellations of tumours or are related to tumors of certain locations9. The clinical and genetic features of SDH-deficient syndrome are summarized in Table 1.

Although the pattern of inheritance is autosomal dominant, a few factors complicate the recognition of SDH-deficient tumor syndrome. First, in the case of SDHD and SDHAF2 mutations, the disease is inherited from the father due to maternal imprinting. It results in the frequent absence of a family history suggestive of a syndromic disease. Another factor is the highly variable penetrance, the highest for SDHD and SDHB mutations, followed by SDHC, and extremely low penetrance for SDHA14,15. Moreover, different tumour components of these syndromes tend to occur in a highly asynchronous manner with intervals ranging from years to decades16. Lastly, it is known that SDH mutation carriers may develop tumors other than PCC/PGL, GIST, RCC, and PitNET/PA such as papillary thyroid cancers, carcinoid, ependymoma, neuroblastoma, melanoma, bone and soft tissue sarcoma, B cell lymphoma and colon cancer17. It seems that those tumours are incidental due to the close follow-up of these patients and unrelated to the SDH deficiency2. Neoplasms outside the SDH-deficient spectrum may, however, mislead to incorrect interpretation and exclusion of the possibility of SDH-deficient tumor syndromes during the initial workup.