GENETICS IN ENDOCRINOLOGY: The genetics of phaeochromocytoma: using clinical features to guide genetic testing

Abstract

Phaeochromocytoma is a rare, usually benign, tumour predominantly managed by endocrinologists. Over the last decade, major advances have been made in understanding the molecular genetic basis of adrenal and extra-adrenal phaeochromocytoma (also referred to as adrenal phaeochromocytoma (aPCA) and extra-adrenal functional paraganglioma (eFPGL)). In contrast to the previously held belief that only 10% of cases had a genetic component, currently about one-third of all aPCA/eFPGL cases are thought to be attributable to germline mutations in at least nine genes (NF1, RET, SDHA, SDHB, SDHC, SDHD, TMEM127, MAX and VHL). Recognition of inherited cases of aPCA/eFPGL is critical for optimal patient management. Thus, the identification of a germline mutation can predict risks of malignancy, recurrent disease, associated non-chromaffin tumours and risks to other family members. Mutation carriers should be offered specific surveillance programmes (according to the relevant gene). In this review, we will describe the genetics of aPCA/eFPGL and strategies for genetic testing. European Journal of Endocrinology 166 151-158

SDHB/SDHA immunohistochemistry in pheochromocytomas and paragangliomas: a multicenter interobserver variation analysis using virtual microscopy: a Multinational Study of the European Network for the Study of Adrenal Tumors (ENS@T)

“…In addition to a comprehensive next-generation sequencing-based strategy for the analysis of multiple pheochromocytoma/paraganglioma susceptibility genes, [43][44][45] several algorithms have been proposed as a targeted approach to genetic testing in clinical practice. 8,[71][72][73][74] In this rapidly expanding field, the importance of assessing the pathogenicity of a 'variant of unknown significance' has become a major and complex problem facing diagnostic laboratories. Our data further strengthen the role of SDHB/SDHA immunohistochemistry in determining the functionality of such variants, alone or in an integrated approach with in silico analysis 75,76 and/or western blot analysis, succinate dehydrogenase enzymatic assay, and mass spectrometric-based measurements of ratios of succinate/fumarate and other metabolites.…”

Prevalence, birth incidence, and penetrance of von Hippel–Lindau disease (vHL) in Denmark

“…16 The majority of the assumed cases were nonfamilial based on their families' medical histories alone. This is not surprising, as the possibility of vHL is easier to recognize when several family members are affected.…”

Mainstreaming genetic testing of cancer predisposition genes

“…For some cancers, the overall contribution of CPGs is sizeable, with approximately 15% of ovarian cancer, approximately 20% of medullary thyroid cancer and >30% of phaeochromocytoma resulting from CPG mutations. [5][6][7] …”