Developmental vascular malformations in EPAS1-gain-of-function syndrome.

EPAS1, encoding HIF-2α, mutations were previously identified in a syndrome of multiple paragangliomas, somatostatinoma, and polycythemia. HIF-2α, when dimerized with HIF-1β, acts as an angiogenic transcription factor. Patients referred to our institution for new, recurrent, and/or metastatic paraganglioma or pheochromocytoma were confirmed for EPAS1-gain-of-function mutation; imaging was evaluated for vascular malformations. We evaluated the Epas1A529V transgenic syndrome mouse model, corresponding to the mutation initially detected in the patients (EPAS1A530V), for vascular malformations via intravital two photon microscopy of meningeal vessels, terminal vascular perfusion with Microfil silicate polymer and subsequent intact ex vivo 14T MRI and Micro-CT, and histologic sectioning and staining of the brain and identified pathologies. Further, we evaluated retina from corresponding developmental timepoints (P7, P14, and P21) and the adult dura via immunofluorescent labeling of vessels and confocal imaging. We identified a spectrum of vascular malformations in all 9 syndromic patients and in all of our tested mutant mice. Patient vessels had higher variant allele frequency than adjacent normal tissue. Veins of the murine retina and intracranial dura failed to regress normally at the expected developmental timepoints. These findings add vascular malformation as a new clinical feature of EPAS1-gain-of-function syndrome.