What are the causes of polycythemia in pediatric patients?

Causes of Polycythemia in Children

Primary Classification Framework

Polycythemia in children results from three major mechanisms: apparent (relative) polycythemia due to plasma volume depletion, primary clonal disorders, or secondary causes driven by either hypoxia-dependent or hypoxia-independent mechanisms. 1

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Apparent (Relative) Polycythemia

Relative polycythemia occurs when plasma volume decreases without true increase in red cell mass: 1

• Severe dehydration from diarrhea, vomiting, or inadequate fluid intake 1
• Diuretic use causing plasma volume contraction 1
• Severe burns with capillary leak and fluid shifts 1
• Capillary leak syndrome 1

These conditions are clinically obvious and do not require specialized hematologic testing. 1

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Primary Polycythemia

Polycythemia Vera (Rare in Children)

• JAK2-mutated myeloproliferative neoplasm with clonal erythrocytosis 1
• Characterized by low or inappropriately normal serum erythropoietin (EPO) levels 1, 2
• JAK2 V617F mutation present in up to 97% of cases 1, 3
• Often presents with thrombocytosis, leukocytosis, and panmyeloid hyperplasia 1

Primary Familial and Congenital Polycythemia (PFCP)

• Autosomal dominant condition caused by gain-of-function mutations in the erythropoietin receptor (EPOR) gene 4, 5
• Characterized by low EPO levels and increased erythroid precursor responsiveness to EPO 4
• Erythroid compartment expands independently of extrinsic influences 5

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Secondary Polycythemia: Hypoxia-Driven Causes

Cyanotic Congenital Heart Disease

The most clinically important cause of polycythemia in children is cyanotic congenital heart disease with right-to-left shunting. 6

• Right-to-left shunting causes systemic arterial oxygen desaturation and tissue hypoxia 6
• Kidneys release erythropoietin to stimulate red cell production (erythrocytosis) in response to hypoxia 6
• Aortic oxygen saturations <75% represent the critical threshold below which decompensated erythrocytosis occurs 6
• EPO levels remain elevated as the body attempts to achieve normal tissue oxygenation by increasing red cell mass and hemoglobin concentration (decompensated erythrocytosis) 6

Critical pitfall: Iron deficiency commonly develops as red cell mass increases, creating microcytic hypochromic red cells that are rigid, less deformable in capillaries, and have decreased oxygen-carrying capacity—paradoxically worsening tissue oxygenation. 6

Chronic Lung Disease

• Chronic obstructive pulmonary disease (COPD) triggers compensatory erythropoiesis through tissue hypoxia 1, 3
• Pulmonary fibrosis causes chronic hypoxemia 1
• Hypoventilation syndromes including obstructive sleep apnea cause chronic intermittent hypoxia 1, 3

High-Altitude Exposure

• High-altitude habitation leads to physiologic polycythemia as adaptive response to reduced atmospheric oxygen 1, 3
• Symptomatic high-altitude pulmonary hypertension (SHAPH) most commonly afflicts infants and children, primarily offspring of Chinese Han ancestry who moved from low altitude to Qinghai-Tibet Plateau above 3000 m 6
• Unlike Monge disease, patients with SHAPH do not present with polycythemia 6

Congenital Hemoglobin Disorders

• High oxygen-affinity hemoglobinopathies (autosomal dominant) cause low tissue oxygen tension despite normal arterial oxygen saturation 4, 5, 7
• Methemoglobinemia reduces oxygen delivery to tissues 4
• 2,3-bisphosphoglycerate (2,3-BPG) deficiency or 2,3-bisphosphoglycerate mutase deficiency increases hemoglobin-oxygen affinity, reducing oxygen release to tissues 4, 5, 7

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Secondary Polycythemia: Hypoxia-Independent Causes

Defective Hypoxia Sensing

• Von Hippel-Lindau (VHL) gene mutations (homozygous or compound heterozygous) cause inappropriately normal or elevated EPO despite normoxia and erythrocytosis 4, 5
• Chuvash polycythemia represents abnormal oxygen homeostasis with elevated EPO set point 3
• Affected children have high risk of arterial thrombosis and early mortality 4

Tumor-Associated Erythrocytosis (Rare in Children)

• Renal cell carcinoma produces EPO independently of hypoxia 1, 3
• Hepatocellular carcinoma produces EPO autonomously 1, 3
• Cerebellar hemangioblastoma (associated with VHL disease) produces EPO 1
• Wilms tumor and other pediatric renal tumors may produce EPO 1

Exogenous Causes

• Exogenous erythropoietin administration or androgen preparations 3

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Diagnostic Algorithm for Pediatric Polycythemia

Step 1: Confirm True Polycythemia

• Verify hemoglobin/hematocrit values are truly elevated beyond age-, sex-, and race-adjusted normal values 1, 2
• Assess for clinically obvious plasma volume depletion (dehydration, vomiting, diarrhea) 1, 2

Step 2: Measure Serum EPO Level (Key Discriminator)

• Low or inappropriately normal EPO → suggests polycythemia vera or PFCP 1, 3, 2
• Elevated EPO → suggests secondary polycythemia 1, 3, 2

Critical nuance: In chronic hypoxic states, EPO may normalize after hemoglobin stabilizes at a compensatory higher level, potentially mimicking primary polycythemia. 3

Step 3: If EPO Low/Normal → Test for Primary Polycythemia

• JAK2 V617F mutation testing (present in up to 97% of polycythemia vera) 1, 3, 2
• Bone marrow examination showing hypercellularity, abnormal megakaryocytes, and decreased iron stores confirms polycythemia vera 1, 2
• Consider EPOR gene mutation testing for familial cases with low EPO 4, 5

Step 4: If EPO Elevated → Evaluate for Hypoxia

• Arterial blood gas analysis or pulse oximetry to assess oxygenation 1, 3, 2
• Chest X-ray to evaluate for chronic lung disease 1, 3, 2
• Echocardiography to assess for cyanotic congenital heart disease with right-to-left shunting 6
• Sleep study if hypoventilation syndrome or obstructive sleep apnea suspected 3

Step 5: If EPO Elevated Without Hypoxia → Screen for Tumors

• Abdominal ultrasound or CT to screen for renal cell carcinoma, hepatocellular carcinoma, or other EPO-producing tumors 1, 3, 2

Step 6: Consider Congenital Causes in Young Patients

• Hemoglobin electrophoresis for high oxygen-affinity hemoglobinopathy 1, 2
• Genetic testing for VHL gene mutations, EPOR mutations, or 2,3-BPG mutase deficiency 1, 4, 5

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Common Pitfalls to Avoid

• Failing to distinguish relative from true polycythemia leads to unnecessary hematologic workup 3
• Overlooking iron deficiency in cyanotic heart disease: Iron-deficient microcytic red cells worsen tissue oxygenation despite elevated hematocrit, creating a vicious cycle 6
• Misinterpreting normal EPO in chronic hypoxic states: EPO may normalize after hemoglobin stabilizes, mimicking primary polycythemia 3
• Assuming polycythemia vera without checking EPO levels: Always measure EPO before pursuing JAK2 testing or bone marrow examination 3, 2
• Aggressive phlebotomy in secondary polycythemia: Risks iron depletion, decreased oxygen-carrying capacity, and paradoxically increased stroke risk 3