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Hereditary Erythrocytosis: Primary and Secondary Forms Explained

Jan 22, 2026

Key takeaways

  • Hereditary erythrocytosis is an umbrella term that includes familial and de novo germline conditions.
  • Disorders are classified as primary (EPOR-related) or secondary (oxygen-sensing pathway–related) based on mechanism.
  • Family history may be absent despite a hereditary cause. Correct classification guides testing, counseling, and long-term management.


Overview

Hereditary erythrocytosis encompasses a group of genetically defined disorders characterized by persistent elevation of hemoglobin and hematocrit due to increased red blood cell production. Unlike acquired causes such as polycythemia vera, hereditary erythrocytosis arises from germline variants affecting erythropoietin signaling or oxygen-sensing pathways. These conditions are typically lifelong and may be identified in childhood or adulthood, with variable clinical impact depending on the underlying gene and mechanism. [1][2][3]

Primary hereditary erythrocytosis (EPOR-related)

Primary hereditary erythrocytosis is caused by variants in the erythropoietin receptor (EPOR) gene. [1][3]


Mechanism: Increased receptor signaling leads to red cell production even at low erythropoietin levels. [1]

Laboratory pattern: Erythrocytosis with low serum erythropoietin (EPO). [1][3]

Inheritance: Usually autosomal dominant, with variable penetrance. [1]


Patients often have lifelong elevations in hemoglobin and hematocrit but may remain asymptomatic or experience mild hyperviscosity-related symptoms. [1][3]

Secondary hereditary erythrocytosis (oxygen-sensing pathway)

Secondary hereditary erythrocytosis arises from variants affecting how the body senses oxygen availability, most commonly involving the following genes: [2][3]

  • VHL
  • EGLN1 (PHD2)
  • EPAS1 (HIF-2α)


Mechanism: Impaired oxygen sensing leads to inappropriate signaling of hypoxia and increased erythropoietin production. [2][3]


Laboratory pattern: Erythrocytosis with normal or elevated serum EPO. [2]


Inheritance: Often autosomal dominant; VHL-related Chuvash polycythemia is classically autosomal recessive. [3]


Some oxygen-sensing pathway variants are associated with genotype-specific thrombotic risks, underscoring the importance of precise molecular diagnosis.[2]

Why family history may be absent

Not all hereditary erythrocytosis is familial. De novo variants, incomplete penetrance, and small family size can obscure inheritance patterns. Consequently, the absence of an affected relative does not rule out a hereditary cause and should not delay appropriate genetic evaluation. [1][2][3]

How does this differ from polycythemia vera?

Unlike hereditary erythrocytosis, polycythemia vera (PV) is an acquired clonal disorder driven by somatic JAK2 mutations. PV often involves additional blood cell abnormalities and carries a higher risk of thrombosis and disease progression. Genetic context and erythropoietin patterns reliably distinguish hereditary erythrocytosis from PV in clinical practice. [2][3]

Final thoughts

Hereditary erythrocytosis encompasses distinct genetic disorders with different mechanisms and risks. Dividing cases into primary and secondary forms clarifies diagnosis, avoids confusion with acquired conditions such as PV, and supports appropriate monitoring, counseling, and individualized management. [1][2][3]

References

  1. Bento, C., Percy, M. J., Gardie, B., et al. Genetic basis of congenital erythrocytosis: Mutation update and online databases. Human Mutation 2014;35(1):15–26.
  2. Gangat, N., Hanson, C. A., & Tefferi, A. Erythrocytosis associated with EPAS1, EGLN1, and VHL variants. Haematologica 2022;107(6):1351–61.
  3. McMullin, M. F., Mead, A. J., Ali, S., et al. Diagnosis and management of congenital and idiopathic erythrocytosis. British Journal of Haematology 2019;184(2):161–175.