Reevaluating the Evolution of Vertebrobasilar Dolichoectasia (VBD) Through Pacak-Zhuang Syndrome

Introduction: Vertebrobasilar dolichoectasia (VBD) is a lengthening (dolicho) and widening (ectasia) of vertebrobasilar arteries. The basilar artery is often tortuous in VBD. Collagen vascular disorders, tumors, and glycogen storage disorders are associated with VBD. Genetic mechanistic studies of VBD are lacking. Furthermore, the diagnostic criteria, phenotypes, pathophysiology, and evolution vary according to VBD etiology.

We previously described that venous regression during fetal development leads to systemic vascular malformations and aberrant skull base development in Pacak-Zhuang syndrome (PZS). PZS is a congenital disorder characterized by multiple paragangliomas, somatostatinoma, and polycythemia due to gain-of-function mutations in EPAS1, which encodes hypoxia-inducible factor-2α, a significant regulator of VEGF and mediator of epithelial to mesenchymal transition in embryonic development. Because vascular and skull base malformations occur in PZS, we hypothesized aberrant development of the vertebral and basilar arteries and susceptibility to VBD in patients with the EPAS1 mutation. This study aimed to characterize the effects of the EPAS1 mutation on vertebrobasilar morphology in patients with Pacak-Zhuang syndrome and a corresponding transgenic mouse model.

Methods: We compared the morphology of the vertebrobasilar system in Pacak-Zhuang syndrome patients (n = 10, ages 16–63, F = 8) to normal controls. All PZS patients had hotspot gain-of-function mutations in the oxygen degradation domain of EPAS1 tumors or tissues. We also evaluated the vertebrobasilar system in a corresponding transgenic mouse model (Epas1A529V). In patients, we measured the total basilar artery length and the diameter of the basilar artery at the origin of AICA, SCA, and PCA on MRI with contrast sequences using ImageJ. In EPAS1-transgenic and control wild-type mice, we measured these vessels on high-resolution micro-computed tomography (micro-CT) images acquired following their terminal vascular casting with Microfil silicate polymer using Neurosimplicity Imaging Suite software.

Results: In EPAS1-mutant mice, B2 and B3 diameters were significantly narrower than in control wild-type mice (p < 0.05; [Table 1]). However, the basilar artery total length and B1 segment diameter were not significantly different between these groups. In EPAS1-syndrome patients, the basilar artery was significantly longer (p = 0.0104), and the B3 diameter significantly narrower than control cadaveric specimens (p = 0.0178; [Table 2]). Imaging in the EPAS1-human disease and murine models consistently showed a tortuous, elongated basilar artery morphology with significant stenosis at the basilar apex (B3 segment) ([Figs. 1] and [2]).

Conclusion: The basilar artery in EPAS1-related VBD was elongated (dolicho) and took a tortuous, extended intracranial course. However, the basilar artery was stenotic in EPAS1-related VBD, unlike non-syndromic VBD in which the basilar artery is dilated (ectasia) from vessel stress from hypertension or other condition. Pacak-Zhuang syndrome is a rare disease caused by genetic mosaicism, with some cells containing the EPAS1 disease-causing mutation. Current VBD diagnosis depends on the mean vessel diameter along the entire basilar artery course. The basilar artery diameter was narrowed segmentally in our EPAS1-mutated patients and mouse model. Studies of the vertebrobasilar system that measure segmental basilar artery narrowing and non-aneurysmal expansion may identify new VBD phenotypes and VBD genotypes, like those seen in the Pacak-Zhuang syndrome.

No conflict of interest has been declared by the author(s).

Publication History

Article published online:
01 February 2023