DISCUSSION
Full blood counts are a frequently ordered laboratory assay for pediatric patients, in which physicians evaluating Hgb generally focus on the presence of anemia. The normal level of Hgb varies with age and sex in childhood, however, and physicians are not always aware of normal Hgb levels in children. Beyond that, symptoms of CE are non-specific, and in some asymptomatic patients, erythrocytosis is an incidental laboratory finding.5 In our study, erythrocytosis was indeed incidentally detected in six asymptomatic patients, and headache was the most common symptom. In the literature, gastrointestinal symptoms such as nausea, vomiting, abdominal pain, and rectal bleeding are not emphasized among symptoms of hyperviscosity. In the present study, some patients with gastrointestinal symptoms had been followed up in a pediatric gastroenterology outpatient clinic where Hgb levels had been overlooked. Patients with minor transient rectal bleeding had been referred to the hematology unit for the evaluation of bleeding disorders. Previously, in a sample of adults with idiopathic erythrocytosis, 4.8% suffered from bleeding: one from gastrointestinal bleeding and six with minor hemorrhaging. In the same sample, the incidence of bleeding was lower than among patients with PV, and bleeding did not increase with the use of low-dose aspirin.14 Minor, self-limited mucosal bleeding (e.g., epistaxis and gingival bleeding) also ranked among the symptoms of three patients at presentation, although coagulation assays and platelet counts revealed normal results.
Most patients (87.5%) in our study were males, and research suggests that testosterone stimulates EPO production.15 Some female adolescents in our study had reported a drop in the frequency of symptoms of hyperviscosity and requirement of phlebotomy after menarche, likely due to menstrual blood loss. None of the patients’ mothers had erythrocytosis, although their histories included thrombotic episodes in both female and male maternal and paternal relatives. Most (70%) patients had been at least 15 years old at diagnosis, whereas the youngest patient had been only eight years of age. The Hgb levels of adolescents generally range from 16.50 to 18.00 g/dL, and only three patients had shown values ranging from 20.0 to 23.0 g/dL.
Among other results, 43.58% of patients had a family history of erythrocytosis.5,15 In one family, a 10-year-old girl presented with a 2-year history of headache, abdominal ache, nausea, recurrent rectal bleeding, and epistaxis, coupled with an Hgb level of 16.3 g/dL. Her mother, a physician, had visited multiple specialists but never received a diagnosis. Her mother had a normal Hgb level (12.0 g/dL) but experienced an unprovoked stroke at the age of 40 years. No risk factor of thrombophilia or acquired risk factor (e.g., smoking, obesity, or diabetes mellitus) could be detected. The maternal grandfather also had erythrocytosis that required regular phlebotomies, but genetic analysis revealed no EPOR mutation. It is suggested that the mother experienced the incomplete penetrance of a dominant mutation not already identified. In earlier work, a pathogenic EPOR variant was identified with sequence analysis in only 12%–15% of patients with CE.16–18 In our series, family history of erythrocytosis was present in 43.58% of patients, and more than half of the patients may have had de novo mutations.5,6 The frequency of consanguineous marriage in our series was not higher than in Turkey’s general population, although recessive mutations are possible.
A normal or low serum EPO level excludes secondary causes of polycythemia associated with hypoxia, but not PV.2Serum EPO levels below 2.9 mU/mL are specific and moderately sensitive (92% and 64%, respectively) to PV, while levels exceeding 15.1 mU/mL, albeit also specific, are largely insensitive (98% and 47%, respectively) to secondary erythrocytosis.19 In our study, serum EPO levels ranged between 2.65 and 16.9 mU/mL, and 31 patients’ EPO levels were within the normal range of laboratory reference values. Before 20 years of age, PV is quite rare compared with CE.20 During the 20-year period of our retrospective study, only one adolescent with PV was diagnosed in pediatric hematology. All 40 patients were referred from a population of roughly 2 million in that period.
The medical histories and physical examinations of the patients did not reveal any other disease. Tissue oxygenation shown by capillary pulse oximetry and venous blood gas analysis excluded hypoxia due to cardiopulmonary disease. All patients had capillary oxygen saturation exceeding 95%. Although invasive, arterial oxygen saturation is a more sensitive indicator of tissue hypoxia; it is less than 92% in hypoxia except in cases of chronic carbon monoxide poisoning, smoking, Hgb with high oxygen affinity, and obstructive sleep apnea.1,21,22 Arterial oxygen saturation must be performed in patients with elevated EPO levels.
The management of CE in childhood is not evidence-based. Phlebotomy and low-dose acetylsalicylic acid are recommended in symptomatic patients and patients with any past thrombotic episode or with relatives who have experienced such episodes.23 Our series did not contain any thrombotic events, and no patient was older than 27 years at data collection. Diagnosis and treatment, along with heeding recommendations about lifestyle, can prevent thrombosis. The risk of thrombosis seems to increase with age, although family histories in our series indicated myocardial infarction in 20-year-old relative and sudden deaths in 15- and 18-year-old relatives. Thrombotic events in adults with CE are widely documented and known to be less common than in patients with secondary erythrocytosis.24 Meanwhile, the risk of thrombosis during childhood and adolescence remains unclear.25 Phlebotomy is recommended to maintain Hct levels less than 45% depending on experience in PV.26In our study, all patients had undergone phlebotomy with intervals depending on their needs and the development of symptoms of hyperviscosity. Although some had refused phlebotomy because they claimed to be well and believed that the procedure makes no difference, with age they confessed that they indeed had symptoms but had refused phlebotomy for fear of pain caused by the needle. Family histories included stroke, myocardial infarction, and sudden death but without any diagnosis of CE in most relatives aged 15–48 years.
Limitation of the study: We consider that our patients had EPOR mutations, and erythroid progenitors are hypersensitive to EPO. Although the means to analyze EPOR mutations are unavailable in the country where we conducted the study and could not be performed in most patients, we know that many mutations have remained unidentified.