Pathological mechanisms and parent-of-origin effects in hereditary paraganglioma/pheochromocytoma (PGL/PCC).

Paragangliomas/pheochromocytomas (PGL/PCC) are tumors of the paraganglia. They can occur sporadically, as one sign in a hereditary (tumor) syndrome or as the only manifestation in hereditary PGL/PCC. To date, five forms of hereditary PGL/PCC have been described. They are inherited as autosomal dominant traits and are caused by mutations in genes required for structure and function of complex II of the respiratory chain (succinate-ubiquinone oxidoreductase, succinate dehydrogenase, SDH). Mutations in genes encoding the small subunits of SDH, i.e., SDHD and SDHC, cause PGL1 and PGL3. Mutations in the large subunit genes SDHB, SDHA (currently only one case), and in SDHAF2 cause PGL4, 5, and 2, respectively. This article gives an overview of PGL/PCC in the context of the anatomy and function of paraganglia. It describes SDH, the genes encoding SDH, and provides information on genetic mechanisms in hereditary PGL/PCC. A model is proposed to explain exclusive paternal inheritance and loss of the maternal (putatively imprinted) allele as a prerequisite for tumor formation in PGLs 1 and 2.