EGLN1-positive familial erythrocytosis: a rare variant with an unusually aggressive clinical course.

Abstract

Familial erythrocytosis type 3 (ECYT3) is a rare condition caused by loss of function germline mutations in the prolyl hydroxylase domain-2 (PHD2), a regulator in the hypoxia-sensing pathway. Although mutations in PHD2 have been previously described, this particular variant lacks clinical characterization and presents with an aggressive course. We report the case of a patient with vasomotor symptoms and elevations in hematocrit (HCT) and hemoglobin (Hgb) despite frequent therapeutic phlebotomy. He had a family history of erythrocytosis spanning four generations. Germline genetic testing revealed a rare pathogenic variant of PHD2, confirming a diagnosis of ECYT3. Therapeutic phlebotomy yielded only transient Hgb and HCT reductions and only partial symptomatic control. This case highlights the diagnostic challenges and limitations of current treatments for hereditary erythrocytosis and underscores the need for symptom-centered management strategies. Furthermore, we highlight a gap in the literature around the pathophysiology and management of ECYT3.