Hereditary
paraganglioma (PGL) is characterized by the development of slow-growing, highly vascularized
tumors that can present either as hormonally silent head and neck
tumors or as abdominal
pheochromocytomas. PGL
tumors are caused by germline inactivating heterozygous mutations in the SDHB, SDHC and SDHD genes, which encode three of the four subunits of
succinate dehydrogenase (SDH;
succinate:ubiquinone oxidoreductase; mitochondrial complex II). Here, potential mechanisms by which SDH mutations could lead to
tumor development are discussed. Mechanisms that lead to variations in the prevalence, penetrance and expressivity of SDH subunit mutations remain to be clarified to improve the clinical management of PGL patients. Recently, germline mutations in the FH gene, the product of which (
fumarate hydratase) catalyzes the conversion of
fumarate to
malate in the Krebs cycle, have been detected in a distinct hereditary
tumor syndrome, which is characterized by uterine and skin
leiomyomatosis and papillary
renal cancer. Although the exact mechanisms of
tumorigenesis in both disorders are unknown, SDH and FH could be involved in the control of cell proliferation under normal physiological conditions in the affected tissue types. Whereas SDH might be involved in hypoxic proliferation of paraganglia, FH might play an important role in the regulation of
ammonium metabolism in smooth muscle cells.