VHL and the genetics of phaeochromocytoma
Inherited cancer syndromes with phaeochromocytoma as a component feature include von Hippel-Lindau syndrome (VHL, MIM 193300) and multiple endocrine neoplasia type 2 (MEN 2, MIM 171400), and less frequently, neurofibromatosis type 1. In addition germline mutations in the SDHB and SDHD (succinate dehydrogenase subunits B and D) genes cause susceptibility to phaeochromocytoma and/or head and neck paragangliomas (Reviewed in Maher ER Eng C. The pressure rises: update on the genetics of phaeochromocytoma. Hum Molec Genetics 2002;11:2347-54).Genotype-phenotype correlations in VHL disease are complex, but phaeochromocytoma susceptibility is usually associated with missense mutations. Approximately 40% of patients with apparently non-syndromic familial phaeochromocytoma have germline VHL mutations and a furyther 30% may have SDHD or SDHB mutations. SDHB and SDHD muttaions are more frequently associated with extra-adrenal phaeochromocytoomas than VHL mutations. Germline VHL and SDH subunit mutations may occur is significant subset of patients with apparently sporadic phaeochromocytoma, although further data is required to define this risk in different populations. Molecular genetic investigation of phaeochromocytoma sucseptibility allows a
precise diagnosis to be made, screening for other relevant tumours (e.g. renal cel carcinoma in VHL disease) to be instigated and at risk relatives to be tested. In addition the correlating the genotype-phenotype associations seen in VHL disease with the effects of specific VHL mutations on pVHL functions (e.g. ability to regulate HIF, Clifford et al Hum Mol Genet. 2001;10:1029-38)
can provide insights into the molecular pathogenesis of phaeochromocytoma susceptibility. The mechanism by which SDH subunit mutations predispose to phaeochromocytomas has not been defined in detail, but dysregulation of hypoxia-responsive genes and impairment of mitochondria-mediated apoptosis have both been suggested.