New advances in the genetics of pheochromocytoma and paraganglioma syndromes

The discovery of the SDH genes in 2000/2001 dramatically changed the genetics of pheochromocytoma (PHEO) and paraganglioma (PGL). Five years on, it is widely accepted that all patients with PHEO/PGL, whatever their age, should undergo genetic testing, because 25-30% of PHEOs are caused by a germline mutation in one of the five PHEO susceptibility genes. However, genetic testing should be targeted according to family and clinical history. The identification of a causal mutation modifies the management and follow-up of the patient and provides an opportunity for presymptomatic genetic testing for other family members. Moreover, the demonstration that the SDH genes, are tumor suppressor genes and that their inactivation is involved in the hypoxia-angiogenic pathway activating the transcription factor hypoxia-inducible factor (HIF) by inhibiting prolyl hydroxylases (PHDs) may lead to the identification of new therapeutic targets for these rare diseases. We discuss here these recent findings and their clinical consequences for the management of PHEO/PGL families and the future of research in this field.