EGLN1-Positive Familial Erythrocytosis: A Rare Variant with an Unusually Aggressive Clinical Course

Introduction

EGLN1, also known as PHD2, plays a role in the oxygen-sensing pathway, inhibiting VHL under normoxic conditions. Pathogenic variants of EGLN1 lead to increased transcription of EPO and subsequent erythropoiesis, known as familial erythrocytosis type 3. Familial erythrocytosis is a rare disease which presents similarly to polycythemia vera with erythrocytosis, thrombosis and vasomotor symptoms. While polycythemia vera has been extensively studied, there is limited information on the associated manifestations, clinical course and management of other rare forms of primary erythrocytosis.

Case Description

This case study details the diagnosis, sequelae and clinical management of a patient with a rare, autosomal dominant mutation in EGLN1, associated with familial erythrocytosis type 3. Notably, despite achieving optimal hemoglobin (Hgb) and hematocrit (HCT) control, the patient continues to experience refractory symptoms, highlighting a challenge in the management of EGLN1 positive hereditary erythrocytosis.

The patient originally presented at age 48 in 2011 with complaints of fatigue for two years associated with itching, frequent headaches and abdominal discomfort. He had high-normal Hgb (up to 18 g/dL), HCT (47.7%) and red blood cell count (5.52 million/mcL). Serum Epo level was normal at 7.3 mIU/mL. Two bone marrow biopsies confirmed normal cellularity with trilineage hematopoiesis, with no evidence of fibrosis, and negative molecular studies including JAK2 (V617F, exon 12, exon 13), CALR, MPL, and BCR/ABL. The findings were not felt to be consistent with polycythemia vera. Additional workup returned negative for a distinct etiology for secondary erythrocytosis. The patient was a lifelong non-smoker and had a past medical history of hypercholesterolemia and venous stasis but was otherwise non-contributory. Notably, his family history was remarkable for erythrocytosis in his maternal grandfather, mother and brother. After his son was diagnosed with erythrocytosis in 2021, our patient underwent comprehensive genetic familial erythrocytosis testing which revealed a rare autosomal dominant pathogenic mutation in EGLN1, c.494del p(Pro165Glnfs*9), frameshift, exon 1, consistent with familial erythrocytosis type 3. To the best of our knowledge, this particular pathogenic variant has only been reported twice as isolated cases, though it is absent from large population genome databases and lacks clinical characterization.

Although a presentation with erythrocytosis and associated vasomotor symptoms would be expected, several key features set this case apart from other rare variants. He requires therapeutic phlebotomy every 2-4 weeks indefinitely to maintain HCT control. This aggressive phlebotomy requirement is out of proportion to the usually milder phenotype in most congenital erythrocytosis conditions. Additionally, he had disproportionately severe and refractory vasomotor symptoms, namely diffuse pruritus and headache, limiting his quality of life. These symptoms do not respond to cimetidine or hydroxyzine but are partially controlled to HCT targets well below 45%, with the best symptom relief at 38-40%.

Furthermore, he has subsequently developed idiopathic inflammatory polyarthritis and interstitial pulmonary disease with exhaustive work up by rheumatology and pulmonology, respectively, returning negative for specific cause.

Conclusions

This case is the first clinical characterization of EGLN1 c.494del p(Pro165Glnfs*9) positive familial erythrocytosis. It underscores the challenge of diagnosing and managing symptoms of EGLN1 positive hereditary erythrocytosis. Our case stands out based on severity and potential (though certainly not proven) disease associations. This raises the question of whether our rarely described variant of EGLN1 may be associated with a distinct clinical presentation. His refractory symptoms despite optimal hematologic control suggest that HCT level may be an inadequate indicator of disease control in familial erythrocytosis. As recognition, awareness, and testing of congenital JAK2 negative erythrocytosis increases, further research is needed to characterize the genotype and phenotype correlation for variants of this rare condition.

No relevant conflicts of interest to declare.