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.