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A syndrome of multiple paragangliomas/pheochromocytomas, somatostatinoma, and polycythemia due to somatic mosaic gain-of-function mutation of <i>EPAS1</i>, encoding HIF-2&#945;, was previously described. HIF-2&#945; 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 <i>EPAS1</i> gain-of-function mutation syndrome with Chiari malformation and developmental skull base anomalies. Patients were referred to the Section on Medical Endocrinology, <i>Eunice Kennedy Shriver</i> NICHD, NIH for evaluation of recurrent and metastatic paragangliomas or pheochromocytoma. The syndrome was confirmed genetically by identification of the functional <i>EPAS1</i> gain-of-function mutation in the resected tumors and circulating leukocytes. Both patients were confirmed for characteristics of <i>EPAS1</i> 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 <i>EPAS1</i> mutations in abnormal posterior fossa development resulting in Chiari malformation type I.