4.3 Article

Neuraxial dysraphism in EPAS1-associated syndrome due to improper mesenchymal transition

Journal

NEUROLOGY-GENETICS
Volume 6, Issue 3, Pages -

Publisher

LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1212/NXG.0000000000000414

Keywords

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Funding

  1. Eunice Kennedy Shriver National Institute of Child Health and Human Development
  2. National Cancer Institute
  3. National Institute of Neurologic Disorders and Stroke, NIH
  4. NATIONAL CANCER INSTITUTE [ZIABC011773] Funding Source: NIH RePORTER
  5. NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [ZIAHL006247] Funding Source: NIH RePORTER
  6. NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [ZIANS003050] Funding Source: NIH RePORTER

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ObjectiveTo investigate the effect of somatic, postzygotic, gain-of-function mutation of Endothelial Per-Arnt-Sim (PAS) domain protein 1 (EPAS1) encoding hypoxia-inducible factor-2 alpha (HIF-2 alpha) on posterior fossa development and spinal dysraphism in EPAS1 gain-of-function syndrome, which consists of multiple paragangliomas, somatostatinoma, and polycythemia.MethodsPatients 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.ResultsAll 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.ConclusionsThis study characterized posterior fossa and spinal malformations seen in EPAS1 gain-of-function syndrome and suggests that gain-of-function mutation in HIF-2 alpha results in improper mesenchymal transition.

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