Is polycythemia vera (a myeloproliferative neoplasm) hereditary?

Is Polycythemia Vera Hereditary?

Polycythemia vera (PV) is not inherited in a classic Mendelian pattern, but familial clustering occurs in approximately 7.6% of cases, suggesting a genetic predisposition to acquiring the causative JAK2 mutations rather than direct inheritance of the disease itself. 1, 2

Understanding the Genetic Nature of PV

The JAK2 Mutation is Acquired, Not Inherited

• The JAK2V617F mutation (present in >95% of PV cases) is an acquired somatic mutation, not a germline mutation passed from parent to child. 1, 2, 3
• PV is fundamentally a clonal stem cell disease where the disease-causing mutation occurs during a person's lifetime in their bone marrow cells. 1
• The molecular lesion responsible for PV remains acquired at the cellular level, distinguishing it from truly hereditary conditions with Mendelian inheritance patterns. 1

Familial Predisposition Does Exist

• Familial PV occurs when at least two relatives in the same family develop chronic myeloproliferative disorders, with a prevalence of at least 7.6% among all PV cases. 2
• A higher disease incidence has been documented in persons of Jewish ancestry and among parent-offspring pairs. 1
• The inheritance pattern in familial cases is consistent with an autosomal dominant trait with decreased penetrance, meaning a genetic susceptibility to acquiring JAK2 mutations may be inherited. 2, 4

Critical Distinction: Familial PV vs. Hereditary Erythrocytosis

Familial PV Characteristics

• In familial PV, the JAK2 mutations occur as secondary genetic events—the predisposition to acquire these mutations appears inherited, but the mutations themselves are not. 2
• Both JAK2V617F and JAK2 exon 12 mutations have been reported in the same pedigree, supporting the concept of inherited susceptibility rather than direct mutation inheritance. 2
• Clinical presentation, complications (thrombosis, hemorrhage), and disease evolution in familial PV are identical to sporadic cases. 2

True Hereditary Erythrocytosis (Different Entity)

• Familial PV must be distinguished from hereditary erythrocytosis, which involves Mendelian transmission with single hematopoietic lineage proliferation. 2
• Hereditary erythrocytosis includes conditions like high oxygen-affinity hemoglobinopathy (autosomal dominant) and 2,3-diphosphoglycerate mutase deficiency (autosomal recessive). 1
• Some autosomal-dominant congenital polycythemia cases carry activating EPOR gene mutations, resulting in truncated receptors with enhanced signal transduction. 1
• Chuvash polycythemia represents another hereditary form with mutations in the von Hippel-Lindau gene. 1

Clinical Implications for Family Members

When to Consider Familial Risk

• If a patient has PV and a family history of myeloproliferative disorders, family members have an increased risk but do not require routine screening unless symptomatic. 2
• The 10-year survival for familial PV is 83%, identical to sporadic cases, indicating similar disease behavior. 2
• Children are rarely diagnosed with PV, with only approximately 7% of patients diagnosed before age 40 years. 1

Genetic Counseling Considerations

• Genetic counseling should emphasize that PV itself is not directly inherited, but a predisposition to develop it may run in families. 2, 4
• Family members should be educated about symptoms (plethora, pruritus, thrombotic events) rather than subjected to routine JAK2 mutation screening. 2
• The mode of inheritance remains unclear, but genetic factors appear involved in pathogenesis. 4

Common Pitfalls to Avoid

• Do not confuse familial PV (acquired JAK2 mutations with inherited predisposition) with truly hereditary erythrocytosis (germline mutations in EPOR, VHL, or hemoglobin genes). 1, 2
• Do not order JAK2 mutation testing in asymptomatic family members as a screening tool—the mutation is acquired, not inherited. 2
• Do not assume that because PV runs in families, it follows classic Mendelian inheritance—the pattern shows decreased penetrance and variable expression. 2, 4
• When evaluating young patients with erythrocytosis and family history, measure serum EPO levels and consider hemoglobin electrophoresis to distinguish hereditary erythrocytosis from early-onset familial PV. 1, 5