15 YEARS OF PARAGANGLIOMA: Pheochromocytoma, paraganglioma and genetic syndromes: a historical perspective

Abstract

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.