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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 3

Meningeal and parenchymal venous malformations in HIF-2α gain-of-function syndrome patients.

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Meningeal and parenchymal venous malformations in HIF-2α gain-of-functio...
(A) Midsagittal T1-weighted MRI of the cervical spine with contrast of patient 1 shows the cavernous malformation of the neck (arrow) and multiple contrast enhancing vessels behind the C4–7 vertebral bodies (arrowheads). Contrast enhancement in abnormal appearing regions of vertebral bodies is also seen (double-lined arrows). Adjacent slice of the same MRI shows contrast enhancement of the meninges connecting to the veins of the malformation (arrowheads) on the left. Abnormal enhancement of the bone and ligaments (double-lined arrows) is found to be continuous with contrast enhancement within the dura posterior to the vertebral bodies (dashed arrows). The neck malformation is again seen (arrow). (B) Posterior coronal view of volumetric reconstruction of the same 3D T1-weighted postcontrast sequence MRI excluding parenchyma and highlighting bone and contrast shows a venous malformation (asterisk) originating from the anterior spinal vein (ASV) corresponding to the intradural contrast enhancing vessels in A; the ASV is connected (arrowheads) to the tentorium (T). BA, basilar artery. (C) Axial T1-weighted postcontrast MRI of the same patient shows the veins in the dural nerve root sleeve (dashed arrow) draining the veins of the spinal cord (arrowheads) with a widened anterior median sulcus; the enlarged external spinal column veins are also seen (arrows). (D) Volumetric reconstruction of T1-weighted postcontrast MRI of the head of patient 2 shows a developmental configuration of the tentorial veins and sinuses on the left (arrow); the left transverse sinus (TS) is smaller than the right.

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