To investigate the effect of somatic, postzygotic, gain-of-function mutation of Endothelial Per-Arnt-Sim (PAS) domain protein 1 (EPAS1) encoding hypoxia-inducible factor-2α (HIF-2α) on posterior fossa development and spinal dysraphism in EPAS1 gain-of-function syndrome, which consists of multiple paragangliomas, somatostatinoma, and polycythemia.

Patients referred to our institution for evaluation of new, recurrent, and/or metastatic paragangliomas/pheochromocytoma were confirmed for EPAS1 gain-of-function syndrome by identification of the EPAS1 gain-of-function mutation in resected tumors and/or circulating leukocytes. The posterior fossa, its contents, and the spine were evaluated retrospectively on available MRI and CT images of the head and neck performed for tumor staging and restaging. The transgenic mouse model underwent Microfil vascular perfusion and subsequent intact ex vivo 14T MRI and micro-CT as well as gross dissection, histology, and immunohistochemistry to assess the role of EPAS1 in identified malformations.

All 8 patients with EPAS1 gain-of-function syndrome demonstrated incidental posterior fossa malformations—one Dandy-Walker variant and 7 Chiari malformations without syringomyelia. These findings were not associated with a small posterior fossa; rather, the posterior fossa volume exceeded that of its neural contents. Seven of 8 patients demonstrated spinal dysraphism; 4 of 8 demonstrated abnormal vertebral segmentation. The mouse model similarly demonstrated features of neuraxial dysraphism, including cervical myelomeningocele and spinal dysraphism, and cerebellar tonsil displacement through the foramen magnum. Histology and immunohistochemistry demonstrated incomplete mesenchymal transition in the mutant but not the control mouse.

This study characterized posterior fossa and spinal malformations seen in EPAS1 gain-of-function syndrome and suggests that gain-of-function mutation in HIF-2α results in improper mesenchymal transition.

研究编码缺氧诱导因子 2α (HIF-2α)的内皮 Per-Arnt-Sim (PAS) 结构域蛋白 1 ( EPAS1 ) 的体细胞、合子后功能获得性突变对后颅窝发育和脊柱裂隙的影响在EPAS1功能获得综合征中，该综合征由多个副神经节瘤、生长抑素瘤和红细胞增多症组成。

通过鉴定切除肿瘤和/或循环白细胞中的 EPAS1 功能获得性突变，转诊到我们机构评估新的、复发性和/或转移性副神经节瘤/嗜铬细胞瘤的患者被确认为EPAS1功能获得性综合征。后颅窝、其内容物和脊柱在可用的头颈部 MRI 和 CT 图像上进行回顾性评估，用于肿瘤分期和再分期。转基因小鼠模型接受了 Microfil 血管灌注和随后完整的离体 14T MRI 和 micro-CT 以及大体解剖、组织学和免疫组织化学，以评估EPAS1在确定的畸形中的作用。

所有 8名EPAS1功能获得综合征患者均表现出偶然的后颅窝畸形——1 名 Dandy-Walker 变异型和 7 名 Chiari 畸形无脊髓空洞症。这些发现与小后颅窝无关；相反，后颅窝的体积超过了其神经内容物的体积。8 名患者中有 7 名表现出脊柱畸形；8 个中有 4 个显示异常的椎体分割。小鼠模型同样显示了椎管内拉脱症的特征，包括颈脊髓脊膜膨出和脊柱拉脱症，以及小脑扁桃体通过枕骨大孔移位。组织学和免疫组织化学显示突变体中的间充质转化不完全，而对照小鼠则没有。

该研究描述了EPAS1功能获得综合征中的后颅窝和脊柱畸形，并表明 HIF-2α 中的功能获得突变导致间充质转化不当。