In masked polycythemia vera, is the JAK2 V617F mutation more common than exon‑12 mutations?

Masked Polycythemia Vera: JAK2 V617F vs Exon 12 Mutations

Masked polycythemia vera is strongly associated with JAK2 exon 12 mutations, not JAK2 V617F. Exon 12 mutations characteristically present with isolated erythrocytosis and lower platelet/leukocyte counts, creating the "masked" phenotype that can be missed if only V617F testing is performed.

Epidemiology and Mutation Distribution

• JAK2 V617F is found in ≥95% of all PV patients, making it the predominant mutation across the entire PV population 1
• JAK2 exon 12 mutations account for 2-4% of total PV cases but represent a critical diagnostic subset 1, 2
• Among JAK2 V617F-negative PV patients specifically, exon 12 mutations are present in approximately 50% of cases 3
• Geographic variation exists: Taiwanese cohorts show 23% exon 12 prevalence (5 of 22 PV patients), significantly higher than Western populations 4

Clinical Phenotype: The "Masked" Presentation

Exon 12-mutated PV presents with isolated erythrocytosis in two-thirds of patients, lacking the thrombocytosis and leukocytosis typical of V617F disease 5. This creates the masked phenotype:

• Hemoglobin levels are significantly higher at diagnosis in exon 12 patients (p=0.012) 6
• Platelet counts are markedly lower (p<0.001) compared to V617F-positive PV 6, 5
• Leukocyte counts are significantly lower (p<0.001) in exon 12 disease 6, 5
• Bone marrow shows isolated erythroid hyperplasia without the panmyelosis (trilineage proliferation) characteristic of V617F-positive PV 2

Why Exon 12 Creates "Masked" Disease

The isolated erythrocytosis without accompanying thrombocytosis or leukocytosis can lead clinicians to:

• Misclassify the condition as secondary erythrocytosis rather than true PV
• Miss the diagnosis entirely if only JAK2 V617F testing is ordered
• Fail to recognize PV when hemoglobin is lowered by concurrent iron deficiency 2

Purified granulocyte DNA testing is preferred for exon 12 detection because these mutations often have low allele burden that whole-blood testing may miss 1, 2

Diagnostic Algorithm for Suspected Masked PV

When evaluating isolated erythrocytosis:

1. Test for JAK2 V617F first using whole blood or granulocytes 1
2. If V617F-negative but clinical suspicion remains high (elevated hemoglobin/hematocrit, low serum EPO, splenomegaly):
   • Order JAK2 exon 12 mutation analysis on purified granulocytes 1, 2
   • Consider bone marrow biopsy looking for isolated erythroid hyperplasia 2
3. Direct sequencing alone is inadequate; cloning techniques or next-generation sequencing improve detection 3

Clinical Outcomes and Management

Despite the phenotypic differences, exon 12-mutated PV has similar long-term outcomes to V617F disease 5:

• Thrombosis risk is equivalent and predicted by age >60 years and prior thrombosis history 5
• Progression to myelofibrosis and leukemia occurs at similar rates 5
• Overall survival is comparable between mutation types 6, 5
• High allele burden (≥52.5%) confers inferior survival in both exon 12 and V617F patients (p=0.029 and p=0.038 respectively) 6

Management is identical regardless of mutation type: high-risk patients (age >60 or prior thrombosis) receive phlebotomy (target hematocrit <45%), low-dose aspirin, and cytoreductive therapy (hydroxyurea or interferon) 2, 7

Critical Pitfalls to Avoid

• Never assume V617F-negative testing excludes PV in patients with isolated erythrocytosis and low EPO 2, 4
• Laboratories offering only V617F testing may miss 23-50% of V617F-negative PV cases depending on geographic population 4
• Iron deficiency can mask the elevated hemoglobin, leaving only elevated RBC count and microcytosis as clues 2
• Extreme thrombocytosis (>1500×10⁹/L) is uncommon in exon 12 disease, reducing acquired von Willebrand syndrome risk 2