PT  - JOURNAL ARTICLE
AU  - Rosenblum, Jared S.
AU  - Cappadona, Anthony J.
AU  - Argersinger, Davis P.
AU  - Pang, Ying
AU  - Wang, Herui
AU  - Nazari, Matthew A.
AU  - Munasinghe, Jeeva P.
AU  - Donahue, Danielle R.
AU  - Jha, Abhishek
AU  - Smirniotopoulos, James G.
AU  - Miettinen, Markku M.
AU  - Knutsen, Russell H.
AU  - Kozel, Beth A.
AU  - Zhuang, Zhengping
AU  - Pacak, Karel
AU  - Heiss, John D.
TI  - Neuraxial dysraphism in <em>EPAS1-</em>associated syndrome due to improper mesenchymal transition
AID  - 10.1212/NXG.0000000000000414
DP  - 2020 Jun 01
TA  - Neurology Genetics
PG  - e414
VI  - 6
IP  - 3
4099  - http://ng.neurology.org/content/6/3/e414.short
4100  - http://ng.neurology.org/content/6/3/e414.full
SO  - Neurol Genet2020 Jun 01; 6
AB  - Objective 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.Methods 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.Results 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.Conclusions 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.CMI=Chiari malformation; NICHD=National Institute of Child Health and Development