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Developmental vascular malformations in EPAS1 gain-of-function syndrome
Jared S. Rosenblum, … , Zhengping Zhuang, Karel Pacak
Jared S. Rosenblum, … , Zhengping Zhuang, Karel Pacak
Published January 26, 2021
Citation Information: JCI Insight. 2021;6(5):e144368. https://doi.org/10.1172/jci.insight.144368.
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Research Article Angiogenesis Development

Developmental vascular malformations in EPAS1 gain-of-function syndrome

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Abstract

Mutations in EPAS1, encoding hypoxia-inducible factor-2α (HIF-2α), 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 the NIH 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 2-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 retinas from corresponding developmental time points (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 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 time points. These findings add vascular malformation as a new clinical feature of EPAS1 gain-of-function syndrome.

Authors

Jared S. Rosenblum, Herui Wang, Pauline M. Dmitriev, Anthony J. Cappadona, Panagiotis Mastorakos, Chen Xu, Abhishek Jha, Nancy Edwards, Danielle R. Donahue, Jeeva Munasinghe, Matthew A. Nazari, Russell H. Knutsen, Bruce R. Rosenblum, James G. Smirniotopoulos, Alberto Pappo, Robert F. Spetzler, Alexander Vortmeyer, Mark R. Gilbert, Dorian B. McGavern, Emily Chew, Beth A. Kozel, John D. Heiss, Zhengping Zhuang, Karel Pacak

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Figure 1

Intracranial malformations and rete mirabile in HIF-2α gain-of-function syndrome patients.

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Intracranial malformations and rete mirabile in HIF-2α gain-of-function ...
Representative images are shown. (A) Sagittal T1-weighted postcontrast MRI of the head of patient 1 shows a subarachnoid cavernous angioma (arrow). Prominent interstitial fluid or Virchow-Robins spaces are seen within the corpus callosum (double-lined arrows); these are seen throughout the parenchyma following veins (white circle). Prominent tentorial veins are also seen (arrowhead). (B) Axial T1-FLAIR (left) and T2-weighted (right) sequences of the same patient show the subarachnoid cavernous angioma (arrow) arising from veins. This corresponds to the blue line in A. (C) Reconstruction of TOF MR angiogram of patient 3 shows dysplastic segments of the internal carotid artery bilaterally (arrows). (D) Coronal CT of the neck with contrast of the same patient shows a plexiform jugular vein surrounding a dysplastic carotid, known as a rete mirabile, at the cranio-cervical junction on the right (arrow); volumetric reconstruction of the same CT of the neck demonstrating rete mirabile on the right and left (arrows). ICA, internal carotid artery; IJV, internal jugular vein.

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