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.
Highlights
Chiari malformation type I is characterized by caudal displacement of the cerebellar tonsils through the foramen magnum of at least 5 mm in adults [1]
While Chiari malformation type I has been found to co-occur with genetic syndromes such as achondroplasia, to date, no causative gene mutation has been identified for most patients diagnosed with Chiari I malformation [4,5]
Chiari malformation type I has not been reported to be associated with systemic cancer, posterior fossa tumors may produce cerebellar tonsillar herniation similar to seen in Chiari I malformation
Summary
Chiari malformation type I is characterized by caudal displacement of the cerebellar tonsils through the foramen magnum of at least 5 mm in adults [1]. Several studies have implicated shortened posterior fossa bones and reduced posterior fossa volume in the development of Chiari malformation type I [2]. While Chiari malformation type I has been found to co-occur with genetic syndromes such as achondroplasia, to date, no causative gene mutation has been identified for most patients diagnosed with Chiari I malformation [4,5]. Chiari malformation type I has not been reported to be associated with systemic cancer, posterior fossa tumors may produce cerebellar tonsillar herniation similar to seen in Chiari I malformation. Posterior fossa bones are formed by endochondral ossification [8]. We report two patients with EPAS1 gain-of-function mutation syndrome, Chiari malformation type I and other developmental anomalies of the posterior fossa and spine
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