Abstract
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 neuroendocrine tumors (NETs) occur in von Hippel-Lindau disease and the VHL gene product regulates HIF-2α expression.
Objective:
Characterize pancreatic NETs in PZS.
Methods:
We have reviewed the clinical records in the index patient at Addenbrooke’s Hospital (UK) and a cohort of patients with PZS from the NIH were assessed for pancreatic NETs.
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 NET in association with an EPAS1 somatic mosaic variant.
Conclusion:
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.
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 neuroendocrine tumors (NETs) occur in von Hippel-Lindau disease and the VHL gene product regulates HIF-2α expression.
Objective:
Characterize pancreatic NETs in PZS.
Methods:
We have reviewed the clinical records in the index patient at Addenbrooke’s Hospital (UK) and a cohort of patients with PZS from the NIH were assessed for pancreatic NETs.
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 NET in association with an EPAS1 somatic mosaic variant.
Conclusion:
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.
| Original language | English |
|---|---|
| Number of pages | 10 |
| Journal | Journal of Clinical Endocrinology and Metabolism |
| Early online date | 10 Jan 2026 |
| DOIs | |
| Publication status | E-pub ahead of print - 10 Jan 2026 |
Bibliographical note
Copyright © The Author(s) 2026. Published by Oxford University Press on behalf of the Endocrine Society. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. See the journal About page for additional terms.Data Access Statement
All clinical data were obtained from electronic medical records at Cambridge University Hospitals and the National Institutes of Health. The authors confirm that the data supporting the findings are available within the article. Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.Keywords
- EPAS1
- pancreatic neuroendocrine tumor
- paraganglioma/pheochromocytoma
- genotype-phenotype
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