SDHDrelated

SDHDrelated refers to the spectrum of disorders and phenotypes associated with pathogenic variants in the SDHD gene, which encodes the succinate dehydrogenase complex subunit D. SDHD is located on chromosome 11q23.3 and encodes a mitochondrial inner membrane protein that is part of complex II of the electron transport chain and also participates in the citric acid cycle.

Most SDHD-related disease is inherited in an autosomal dominant manner with imprinting; disease tends to manifest when the variant is inherited from the father, while maternal transmission shows reduced penetrance. This parent-of-origin effect influences risk assessment and family counseling.

Clinical features are dominated by head and neck paragangliomas, typically arising along the carotid body, jugular bulb, and other parasympathetic ganglia. Pheochromocytoma is less common but reported. Tumors are often benign but can cause local symptoms and require intervention. Malignant transformation and metastasis are possible, though uncommon.

Pathogenic SDHD variants lead to loss of complex II function, causing accumulation of the metabolite succinate, stabilization of hypoxia-inducible factors, and activation of pseudohypoxic signaling that promotes tumorigenesis. This mechanistic link underpins the tumor predisposition seen in SDHDrelated conditions.

Genetic testing identifies pathogenic, likely pathogenic, or variants of uncertain significance in SDHD, and testing of at-risk relatives is common. Management focuses on tumor surveillance and surgical treatment when tumors develop; imaging and biochemical monitoring guide care.

Overall penetrance is incomplete and age-related, with many carriers remaining asymptomatic. The condition is primarily associated with benign head and neck tumors, though malignant transformation and metastasis, while uncommon, can occur.