Expanding the clinical tumor phenotype of the EPAS1-asssociated tumor syndrome

Context: Since the original discovery of the Pacak-Zhuang syndrome (PZS) in 2012, defined by the clinical triad of pheochromocytoma/paraganglioma (PPGL) and/or duodenal ampullar somatostatinoma with erythrocytosis, multiple multisystemic phenotypes have been identified in patients with somatic mosaic pathogenic variants in EPAS1/HIF2A. Deep phenotyping of patients along with evaluation of a transgenic murine model has led to the understanding of the role of HIF-2α in developmental processes, including tumor development. Interestingly, pancreatic NETs occur in von Hippel-Lindau disease and the VHL gene product regulates HIF-2α expression. Objective and results: Herein, we describe a novel series from two institutions of patients with EPAS1 associated pancreatic neuroendocrine tumors including a case of a nonfunctioning pancreatic neuroendocrine tumor (NET) in association with an EPAS1 somatic mosaic variant. This case study extends our current understanding of the phenotypic spectrum in PZS and links pancreatic NETs to an additional hypoxia-associated gene, namely EPAS1