Chiari Malformation Type 1 in EPAS1-Associated Syndrome

Abstract

A syndrome of multiple paragangliomas/pheochromocytomas, somatostatinoma, and polycythemia due to somatic mosaic gain-of-function mutation of EPAS1, encoding HIF-2α, was previously described. HIF-2α has been implicated in endochondral and intramembranous ossification. Abnormal bone growth of the skull base may lead to Chiari malformation type I. We report two cases of EPAS1 gain-of-function mutation syndrome with Chiari malformation and developmental skull base anomalies. Patients were referred to the Section on Medical Endocrinology, Eunice Kennedy Shriver NICHD, NIH for evaluation of recurrent and metastatic paragangliomas or pheochromocytoma. The syndrome was confirmed genetically by identification of the functional EPAS1 gain-of-function mutation in the resected tumors and circulating leukocytes. Both patients were confirmed for characteristics of EPAS1 gain-of-function mutation syndrome by complete blood count (CBC), plasma biochemistry, and computed tomography (CT) of the abdomen and pelvis. Chiari malformation type I and abnormal bony development of the posterior fossa was found on MRI and CT of the head. The present study implicates EPAS1 mutations in abnormal posterior fossa development resulting in Chiari malformation type I.

Keywords: Chiari malformation type I; EPAS1; HIF-2α; Pacak-Zhuang syndrome.

Figure 1

Patient 1 Intracranial and Spinal Imaging. Panel (A): Mid-sagittal T1-weighted sequence shows lowest tonsillar position of 7 mm through the foramen magnum. Narrow underdeveloped clivus and occipital bone as well as uncalcified synchondroses of the odontoid are appreciated (arrowheads). Panel (B): Axial CT of the head revealed abnormal ossification of the occipital bone. Panel (C): Axial CT of the head showing uncalcified petroclival synchondrosis (arrowheads). Panel (D): Axial CT of lumbo-sacral spine shows spina bifida occulta of S1 (arrowhead) and segmentation anomaly of the sacral ala (arrow).

Figure 2

Patient 2 Intracranial and Spinal Imaging. Panels (A–E): MRI of the brain. Panel (A): Sagittal post-contrast T1-weighted sequence shows the left cerebellar tonsil at the lowest tonsillar position, 8 mm through the foramen magnum. Narrow, underdeveloped clivus and occipital bone as well as uncalcified synchondroses of the odontoid are also seen (arrowheads). Panel (B): Coronal T1-weighted sequence demonstrating the location of the measurement in A. Panel (C): Axial post-contrast T1-weighted sequence showing crowding of the brainstem by the cerebellar tonsils in the foramen magnum (arrows). Panel (D): Coronal T1-weighted venous phase post-contrast sequence shows a developmental venous anomaly of the Vein of Galen confluens draining the choroid plexus through the velum interpositum (arrowheads). Panel (E): Axial T1-weighted venous phase post-contrast sequence showing the anomalous Vein of Galen confluens. Panel (F): Axial CT of the head showing petroclival dysraphism or uncalcified petroclival synchondrosis (arrowheads). Panel (G): Axial CT of lumbo-sacral spine shows occult dysraphism of S1 (arrowhead) and sacral segmentation anomalies (arrows). Panel (H): Sagittal lumbar CT demonstrating the level of the image shown in G.