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.