Successful Use of Targeted HIF‐2α Inhibition in EPAS1‐Mutated Congenital Erythrocytosis

We describe the case of an 11‐year‐old female with significant polycythemia and pulmonary hypertension with resultant ischemic stroke. She was identified to have a likely pathogenic germline endothelial PAS‐domain containing protein‐1 (EPAS1) variant, which encodes hypoxia‐inducible factor 2 alpha (HIF‐2α). Following variant identification, she started novel therapy with belzutifan, a small molecule inhibitor of HIF‐2α, to target her underlying disease pathophysiology. This is the first reported usage of belzutifan for EPAS1 ‐associated polycythemia. The therapy has been well tolerated, and her hemoglobin was restored to normal levels without the need for additional phlebotomy. Thus, belzutifan represents a novel strategy for addressing EPAS1 ‐variant driven polycythemia.