EPAS1 and Chiari malformation: The appearance of incidental Chiari malformation and reduced bony development of the spine and skull base in our patients with gain-of-function EPAS1 mutation suggests that persistent hypoxic signaling resulted in incomplete mesenchymal development that manifested as 1) reduced ossification of posterior fossa bones and, secondarily, Chiari I malformation, 2) impaired development of the sacrum leading to spina bifida occulta of S1 and segmentation anomalies of the sacral ala, and 3) impaired development of other brain structures resulting in asymptomatic brain vascular anomalies [16].