ENG Mutations Do Not Cause Polycythemia Vera
No, Endoglin (ENG) mutations do not cause Polycythemia Vera (PV). PV is specifically caused by JAK2 mutations, most commonly JAK2 V617F, which is found in more than 90% of patients with PV, or functionally similar mutations such as JAK2 exon 12 mutations 1.
Genetic Basis of Polycythemia Vera
The 2008 WHO diagnostic criteria for PV explicitly require the presence of JAK2 V617F or other functionally similar mutations such as JAK2 exon 12 mutation as a major diagnostic criterion 1. This is not merely a supportive finding but a mandatory requirement for diagnosis when combined with elevated hemoglobin levels 1.
Key Molecular Features:
- JAK2 V617F mutation is present in >90% of PV cases and serves as proof that the proliferation is clonal 1
- JAK2 exon 12 mutations account for most JAK2 V617F-negative cases 1
- These mutations cause constitutively activated signal transduction pathways leading to erythropoietin-independent erythroid proliferation 1
- PV is a multipotent hematopoietic progenitor cell disorder, not related to endothelial or vascular gene mutations 2
Why ENG is Not Relevant to PV
Endoglin (ENG) is a gene that encodes a vascular endothelial protein involved in angiogenesis and is associated with hereditary hemorrhagic telangiectasia (HHT), not myeloproliferative neoplasms [@General Medicine Knowledge]. The pathophysiology of PV involves:
- Clonal proliferation of hematopoietic stem cells due to JAK2 mutations [@9@, @11@]
- Constitutive activation of JAK-STAT signaling pathways [@11@]
- Erythropoietin-independent erythroid colony formation [@5@, @11@]
None of these mechanisms involve endoglin or vascular endothelial dysfunction.
Diagnostic Algorithm for PV
When evaluating for PV, the diagnostic work-up should focus on:
- Hemoglobin/hematocrit elevation: ≥18.5 g/dL in men or ≥16.5 g/dL in women [@3@, 1]
- JAK2 mutation testing: Screen for JAK2 V617F first, then JAK2 exon 12 if negative [@3@, 1]
- Bone marrow biopsy: Shows hypercellularity with trilineage growth (panmyelosis) [@4@]
- Serum erythropoietin level: Typically below normal range [@4@, 1]
Critical pitfall: Do not pursue alternative genetic testing for vascular or endothelial genes like ENG when evaluating suspected PV, as this will not contribute to diagnosis and may cause unnecessary confusion [@General Medicine Knowledge].
Other Mutations in PV
While JAK2 is the driver mutation, over 50% of PV patients harbor additional DNA sequence variants, most frequently TET2 (18%) and ASXL1 (15%) 3. However, these are secondary mutations that affect prognosis, not causative mutations 3. Prognostically adverse mutations include SRSF2, IDH2, RUNX1, and U2AF1, with a combined incidence of 5-10% 3.
The absence of JAK2 mutations (V617F or exon 12) essentially excludes the diagnosis of PV, making the presence of a normal or increased serum erythropoietin level combined with absent JAK2 mutation highly unlikely to represent PV 1, 3.