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Tobias Else

The last decades have elucidated the genetic basis of pheochromocytoma (PC) and paraganglioma (PGL) (PCPGL)-associated hereditary syndromes. However, the history of these syndromes dates back at least another 150 years. Detailed descriptions by clinicians and pathologists in the 19th and 20th centuries led to the recognition of the PCPGL-associated syndromes von Hippel-Lindau disease, neurofibromatosis type 1, and multiple endocrine neoplasia type 2. In the beginning of the current millennium the molecular basis of the hereditary PGL syndrome was elucidated by the discovery of mutations in genes encoding enzymes of the Krebs cycle, such as succinate dehydrogenase genes (SDHx) and other mutations, causing ‘pseudo-hypoxia’ signaling. These recent developments also marked a paradigm shift. It reversed the traditional order of genetic research that historically aimed to define the genetic basis of a known hereditary syndrome but now is challenged with defining the full clinical phenotype associated with a newly defined genetic basis. This challenge underscores the importance to learn from medical history, continue providing support for clinical research, and train physicians with regards to their skills to identify patients with PCPGL-associated syndromes to extend our knowledge of the associated phenotype. This historical overview provides details on the history of the paraganglial system and PCPGL-associated syndromes. As such, it hopefully will not only be an interesting reading for the physician with a historical interest but also emphasize the necessity of ongoing astute individual clinical observations and clinical registries to increase our knowledge regarding the full phenotypic spectrum of these conditions.

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Isobel C Mouat, Kei Omata, Andrew S McDaniel, Namita G Hattangady, Debnita Talapatra, Andi K Cani, Daniel H Hovelson, Scott A Tomlins, William E Rainey, Gary D Hammer, Thomas J Giordano and Tobias Else

Several somatic mutations specific to aldosterone-producing adenomas (APAs) have been described. A small proportion of adrenocortical carcinomas (ACCs) are associated with hyperaldosteronism, either primary aldosteronism or hyperreninemic hyperaldosteronism. However, it is unknown whether they harbor mutations of the same spectrum as APAs. The objective of this study is to describe the clinical phenotype and molecular genotype of ACCs with hyperaldosteronism, particularly the analysis for common APA-associated genetic changes. Patients were identified by retrospective chart review at a specialized referral center and by positive staining for CYP11B2 of tissue microarrays. Twenty-five patients with ACC and hyperaldosteronism were initially identified by retrospective chart review, and tissue for further analysis was available on 13 tumors. Seven patients were identified by positive staining for CYP11B2 in a tissue microarray, of which two were already identified in the initial chart review. Therefore, a total number of 18 patients with a diagnosis of ACC and features of either primary aldosteronism or hyperreninemic hyperaldosteronism were therefore included in the final study. Mutational status for a select list of oncogenes, tumor suppressor genes and genes known to carry mutations in APAs were analyzed by next-generation sequencing. Review of clinical data suggested autonomous aldosterone production in the majority of cases, while for some cases, hyperreninemic hyperaldosteronism was the more likely mechanism. The mutational landscape of ACCs associated with hyperaldosteronism was not different from ACCs with a different hormonal phenotype. None of the ACCs harbored mutations of known APA-associated genes, suggesting an alternative mechanism conferring aldosterone production.