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Neuraxial dysraphism in EPAS1-associated syndrome due to improper mesenchymal transition
To investigate the effect of somatic, postzygotic, gain-of-function mutation of Endothelial Per-Arnt-Sim (PAS) domain protein 1 ( ) encoding hypoxia-inducible factor-2α (HIF-2α) on posterior fossa development and spinal dysraphism in gain-of-function syndrome, which consists of multiple paragangliom...
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Published in: | Neurology. Genetics 2020-06, Vol.6 (3), p.e414-e414 |
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Main Authors: | , , , , , , , , , , , , , , , |
Format: | Article |
Language: | English |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | To investigate the effect of somatic, postzygotic, gain-of-function mutation of Endothelial Per-Arnt-Sim (PAS) domain protein 1 (
) encoding hypoxia-inducible factor-2α (HIF-2α) on posterior fossa development and spinal dysraphism in
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
gain-of-function syndrome by identification of the
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
in identified malformations.
All 8 patients with
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
gain-of-function syndrome and suggests that gain-of-function mutation in HIF-2α results in improper mesenchymal transition. |
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ISSN: | 2376-7839 2376-7839 |
DOI: | 10.1212/NXG.0000000000000414 |