CLINICAL CHARACTERISTICS

Primary familial and congenital erythrocytosis (PFCE), originally described as primary familial and congenital polycythemia, is characterized by isolated erythrocytosis in an individual with a normal to slightly enlarged spleen and absence of disorders causing secondary erythrocytosis. Clinical manifestations relate to the erythrocytosis and include rubor, and may or may not include hyperviscosity syndrome (headache, dizziness, altered mentation, visual disturbances, tinnitus, paresthesia, fatigue, lassitude, and weakness) and arterial and/or venous thromboembolic events. Although the majority of individuals with PFCE have absence of or only mild manifestations of hyperviscosity syndrome such as headache or dizziness, some affected individuals have severe and even fatal complications including arterial hypertension, coronary artery disease, myocardial infarction, intracerebral hemorrhage, and deep vein thrombosis (DVT). Phlebotomy-induced iron deficiency results in lassitude, impaired intellect, and impaired athletic performance, especially in children. Iron deficiency may also increase the risk of thromboses. Leukocyte count and differential are normal and platelet count tends to be low normal or slightly low due to hemodilution from increased red blood cells and increased whole blood volume.

DIAGNOSIS/TESTING: The clinical diagnosis of PFCE can be established in a proband with isolated absolute erythrocytosis, normal serum P, below normal erythropoietin concentration, erythroid progenitors grown in vitro that are hypersensitive to extrinsic erythropoietin, and a family history consistent with autosomal dominant inheritance. The molecular diagnosis is established by identification of a heterozygous pathogenic variant in by molecular genetic testing in an individual with erythrocytosis.

MANAGEMENT

Maintain good hydration; DVT precautions in higher-risk situations (e.g., long-distance airline flights). While the majority of individuals with PFCE are asymptomatic and require no additional treatment, some undergo phlebotomy to decrease symptoms. Hyperviscosity treatment is based on severity of symptoms and includes consideration of aspirin; if phlebotomy is performed, isovolemic replacement by isotonic fluids and correction of iron deficiency. Treatment of hypertension and cardiovascular disease per internist or cardiologist. Treatment of diabetes and hyperlipidemia per internist or diabetes specialist. Thromboemolic events are treated with standard acute therapy, evaluation for additional thombophilic risk factors, and consideration of aspirin therapy and/or life-long anticoagulation. Full blood count as needed; assess and document symptoms and severity of hyperviscosity syndrome at each visit or as needed; cardiology assessment including blood pressure measurement, echocardiography, plasma lipid panel, hemoglobin A1c every few years or as recommended by cardiologist; 24-hour blood pressure in those with increased blood pressure; assess for any clinical manifestations suspicious for a thromboembolic event at each visit or as needed. Dehydration; activities that could increase blood viscosity (e.g., living or prolonged stay at high altitudes, scuba diving, and smoking); additional cardiovascular risks (e.g., hypertension, hyperlipidemia, diabetes, and obesity); erythropoiesis-stimulating agents. It is appropriate to evaluate apparently asymptomatic older and younger at-risk relatives in order to identify as early as possible those with PFCE who would benefit from education regarding treatment for clinical manifestations and agents/circumstances to avoid, namely, exposure to hypoxia and erythropoiesis-stimulating agents.

GENETIC COUNSELING

PFCE is inherited in an autosomal dominant manner. Many individuals diagnosed with PFCE have an affected parent; a significant proportion of individuals (likely exceeding 10%) have the disorder as the result of a pathogenic variant. Each child of an individual with related PFCE has a 50% chance of inheriting the pathogenic variant. Once the pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for PFCE are possible.