Hereditary phaeochromocytomas and paragangliomas: a study of five susceptibility genes

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Abstract
Non-functioning paragangliomas (Pgls), also called chemodectomas, glomus tumours, or non-chromaffin Pgls, are rare, highly vascularised tumours, originating from neural crest derived chief cells of paraganglia in the head and neck region. The main affected sites are the carotid body, a small chemoreceptive organ that senses blood oxygen level, and the jugulotympanic paraganglia. These tumours are typically slow growing and benign but local invasion and distant metastases can occur. Most of the tumours present without causing specific symptoms. Rarely, chemodectomas can secrete catecholamines. Therefore these tumours are diagnosed late on in development when their growth causes symptoms such as dysphagia, bradycardia, or hearing loss. Most chemodectomas occur sporadically whereas 10% to 50% could correspond to familial forms inherited as an autosomal dominant trait with incomplete penetrance. For one susceptibility locus named Pgl1, the tumours are transmitted through the paternal line, a fact suggestive of genomic imprinting.1 Recently, patients with hereditary chemodectomas were shown to harbour a germline mutation in one of the two genes coding the small (SDHD) and large (SDHC) subunits of cytochrome b 2,3 or in the gene encoding the iron sulphur protein subunit of succinate dehydrogenase (SDHB4). Gimm et al 5 also identified germline mutations of SDHD in patients with isolated phaeochromocytomas (Phaeos), thus showing that SDHD was a new Pgl and Phaeo predisposing gene. The three subunits encoded by SDHB, SDHC, and SDHD together with the SDHA flavoprotein subunit are components of the mitochondrial complex II (succinate-coQoxidoreductase) that plays a central part in electron transport and the tricarboxylic acid cycle. Indeed, inherited Phaeos resulting from a germline SDHD mutation show a complete selective loss of complex II enzymatic activity and express higher levels of hypoxia induced factors (HIF1α and EPAS1) and VEGF than their sporadic counterparts.6 ### Key points