Pyruvate kinase deficiency in 29 Turkish patients with two novel intronic variants.

Pyruvate kinase (PK) is a key enzyme of anaerobic glycolysis. The genetic heterogeneity of PK deficiency (PKD) is high, and over 400 unique variants have been identified. Twenty-nine patients who had been diagnosed as PKD genetically in seven distinct paediatric haematology departments were evaluated. Fifteen of 23 patients (65.2%) had low PK levels. The PK:hexokinase ratio had 100% sensitivity for PKD diagnosis, superior to PK enzyme assay. Two novel intronic variants (c.695-1G>A and c.694+43C>T) have been described. PKD should be suspected in patients with chronic non-spherocytic haemolytic anaemia, even if enzyme levels are falsely normal. Total PKLR gene sequencing is necessary for the characterization of patients with PKD and for genetic counselling.

A randomized, placebo-controlled, double-blind trial of canakinumab in children and young adults with sickle cell anemia.

Excessive intravascular release of lysed cellular contents from damaged red blood cells (RBCs) in patients with sickle cell anemia (SCA) can activate the inflammasome, a multiprotein oligomer promoting maturation and secretion of proinflammatory cytokines, including interleukin-1ß (IL-1ß). We hypothesized that IL-1ß blockade by canakinumab in patients with SCA would reduce markers of inflammation and clinical disease activity. In this randomized, double-blind, multicenter phase 2a study, patients aged 8 to 20 years with SCA (HbSS or HbSß0-thalassemia), history of acute pain episodes, and elevated high-sensitivity C-reactive protein >1.0 mg/L at screening were randomized 1:1 to received 6 monthly treatments with 300 mg subcutaneous canakinumab or placebo. Measured outcomes at baseline and weeks 4, 8, 12, 16, 20, and 24 included electronic patient-reported outcomes, hospitalization rate, and adverse events (AEs) and serious AEs (SAEs). All but 1 of the 49 enrolled patients were receiving stable background hydroxyurea therapy. Although the primary objective (prespecified reduction of pain) was not met, compared with patients in the placebo arm, patients treated with canakinumab had reductions in markers of inflammation, occurrence of SCA-related AEs and SAEs, and number and duration of hospitalizations as well as trends for improvement in pain intensity, fatigue, and absences from school or work. Post hoc analysis revealed treatment effects on weight, restricted to pediatric patients. Canakinumab was well tolerated with no treatment-related SAEs and no new safety signal. These findings demonstrate that the inflammation associated with SCA can be reduced by selective IL-1ß blockade by canakinumab with potential for therapeutic benefits. This trial was registered at www.clinicaltrials.gov as #NCT02961218.

Pediatric posterior reversible encephalopathy syndrome: Age related clinico-radiological profile and neurologic outcomes.

BACKGROUND: The aim of this study was to analyze the characteristics of pediatric posterior reversible encephalopathy syndrome (PRES) to determine clinical and radiologic differences between younger and older age groups, and to identify risk factors for development of any neurologic sequelae. METHODS: The study cohort consisted of confirmed pediatric PRES patients in a tertiary care university hospital from January, 2015, to December, 2020. Demographic and clinical properties, radiological manifestations, and neurologic outcomes were noted. Children aged ≤6 years were compared with those older than 6 years and factors affecting neurologic outcomes were evaluated. RESULTS: The most common underlying diseases were oncological (37%) and kidney diseases (29%). Epileptic seizures were the most frequent symptoms at initial clinical presentation. The regions in the brain that were most commonly involved were the occipital region (n = 65, 96%), the parietal region (n = 52, 77%), and the frontal lobe (n = 35, 54%). Magnetic resonance imaging (MRI) findings were consistent with atypical patterns in most of the study cohort (71%). Patients with unfavorable clinical outcomes (n = 13, 19.1%) had longer initial seizure times and longer encephalopathy times, lower leucocyte and absolute neutrophil counts, and lower neutrophil to lymphocyte ratios. No relationship was found between MRI findings, involvement patterns, and neurologic outcomes. CONCLUSIONS: No clinically specific differences between two different age groups were found. Atypical imaging manifestations of pediatric PRES in our study had an incidence that was as high as those found in earlier adult studies. Multivariate logistic regression analysis showed that the initial neutrophil to lymphocyte ratio, absolute neutrophil counts, and white cell counts could not predict poor neurologic outcomes.

Deep Vein Thrombosis After a Wild Bee Sting.

Allergic reactions from insect bites are mostly observed with bee stings. Bee sting reactions can be classified into 3 main headings: local, systemic, and rare reactions. Vascular thrombosis is considered both in rare and systemic reactions. The wild bee venom induces the secretion of many inflammatory mediators, including histamine, phospholipase A1, and thromboxane, leading to vasoconstriction and thrombosis. Inflammatory cytokines also cause endothelial injury and deterioration of the microcirculation. In the literature, rare reactions have been reported including various central and arterial vascular pathologies such as aortic thrombosis, cerebral infarction, and myocardial infarction; however, there is rare publication concerning peripheral deep vein thrombosis (DVT). Although DVT produces good results with effective and rapid treatment, it can be fatal because of causes such as pulmonary embolism in the absence of timely intervention. Herein, for the first time in the literature, we present a pediatric case of peripheral DVT after a wild bee sting.

Comparison of the clinical course of COVID-19 infection in sickle cell disease patients with healthcare professionals.

It is highly expected that COVID-19 infection will have devastating consequences in sickle cell disease (SCD) patients due to endothelial activation and decreased tissue and organ reserve as a result of microvascular ischemia and continuous inflammation. In this study, we aimed to compare the clinical course of COVID-19 in adult SCD patients under the organ injury mitigation and clinical care improvement program (BASCARE) with healthcare professionals without significant comorbid conditions. The study was planned as a retrospective, multicenter and cross-sectional study. Thirty-nine SCD patients, ages 18 to 64 years, and 121 healthcare professionals, ages 21 to 53, were included in the study. The data were collected from the Electronic Health Recording System of PRANA, where SCD patients under the BASCARE program had been registered. The data of other patients were collected from the Electronic Hospital Data Recording System and patient files. In the SCD group, the crude incidence of COVID-19 was 9%, while in healthcare professionals at the same period was 23%. Among the symptoms, besides fever, loss of smell and taste were more prominent in the SCD group than in healthcare professionals. There was a significant difference between the two groups in terms of development of pneumonia, hospitalization, and need for intubation (43 vs 5%, P < 0.00001; 26 vs 7%, P = 0.002; and 10 vs 1%, P = 0.002, respectively). Prophylactic low molecular weight heparin and salicylate were used more in the SCD group than in healthcare professionals group (41 vs 9% and 28 vs 1%; P < 0.0001 for both). The 3-month mortality rate was demonstrated as 5% in the SCD group, while 0 in the healthcare professionals group. One patient in the SCD group became continously dependent on respiratory support. The cause of death was acute chest syndrome in the first case, hepatic necrosis and multi-organ failure in the second case. In conclusion, these observations supported the expectation that the course of COVID-19 in SCD patients will get worse. The BASCARE program applied in SCD patients could not change the poor outcome.

A Case With Wiskott-Aldrich Syndrome and Ascending Aorta Aneurysm.

Wiskott-Aldrich syndrome (WAS) is a rare X-linked primary immunodeficiency disorder that is characterized by a triad of microthrombocytopenia, severe immunodeficiency, and eczema. We report the case of a 7-year-old male patient with chronic thrombocytopenia that was diagnosed as WAS after dilatation of the ascending aorta was noticed. WAS is rare, and it is a disease that requires high suspicion for diagnosis. We recommend periodic echocardiography and magnetic resonance imaging examinations to evaluate aortic aneurysms in children with WAS and that surgical intervention should not be delayed when aneurysm is detected.

Silent cerebral infarct in sickle cell anemia patients of southern Turkey

Background/aim: Silent cerebral infarct (SCI) is an ischemic lesion seen before clinical signs of brain infarct and ischemic changes in brain tissue. This study aimed to detect SCI with noninvasive methods and to determine related risk factors in patients with sickle cell anemia (SCA). Materials and methods: Fifty-four SCA patients who had no history of cerebral infarct and whose neurological examinations were normal were included in this study. Brain magnetic resonance imaging (MRI) and diffusion MRI were taken and the acquired data was compared statistically. Results: SCI was detected in 11.1% (6/54) of the patients. No statistical differences in age, sex, physical examination findings, or treatments were detected between the 2 groups (with and without SCI). When examined in terms of HbS, the median (min­max) value in SCI-positive patients was 85.4 (80.5­92.1); the median value was 77.2 (49.0­96.7) in SCI-negative patients. The HbS values of the SCI group were statistically significantly higher than those of the group without SCI (P = 0.014). Patients with the HbSS or HbSß0 genotypes had a significantly higher prevalence of SCI when compared with other sickle cell syndromes (P = 0.038). Conclusion: SCI is not uncommon among SCA patients in Turkey. The presence of homozygote HbSS/Sß0 genotype, high MCV, and HbS are risk factors for SCI.

A homozygote novel L451W mutation in CECR1 gene causes deficiency of adenosine deaminase 2 in a pediatric patient representing with chronic lymphoproliferation and cytopenia.

Deficiency of Adenosine Deaminase 2 (DADA2) is a monogenic autoinflammatory disorder characterized by livedo reticularis, skin ulcers, subcutaneous rash, aphthous ulcers, and leukocytoclastic vasculitis, neurological signs such as early onset stroke and polyneuropathy. A minority of DADA2 patients suffer from severe cytopenia and lymphoproliferation. Herein, we report an adolescent patient, followed up as having a hematological disorder for many years, eventually diagnosed as having DADA2. In view of the presence of elevated acute phase reactants, hepatosplenomegaly, low IgM level, lymphopenia, anemia, and neutropenia, and a subtle neurological involvement we considered DADA2 diagnosis. The diagnosis was confirmed by identification of a novel L451W mutation in CECR1 gene. The patient has been successfully treated with etanercept, monthly intravenous immunoglobulin replacement, and low-dose methylprednisolone. In conclusion, although the absence of skin and neurological findings, low IgM levels, and persistent lymphopenia should lead the physicians to consider DADA2 in patients with particularly complicated hematological abnormalities.

Successful Management of a Rare Cause of Hemolytic Uremic Syndrome With Eculizumab in a Child.

BACKGROUND: Hemolytic uremic syndrome (HUS) is characterized by microangiopathic hemolytic anemia, acute renal failure, and thrombocytopenia. It very rarely coexists with acute lymphoblastic leukemia (ALL) emerging before, simultaneously, or after the diagnosis has been made, and management of the patient may be difficult. CASE: We present the case of a 7-year-old boy who was diagnosed with HUS and initially managed by hemodialysis (HD). Thereafter, HUS progressed, and neurological findings developed. The patient was treated with eculizumab, agressive blood pressure control, and antiepileptic drugs. At the fifth month of follow-up, the patient was diagnosed with acute B-cell lymphoblastic leukemia with fever, bone pain, hepatosplenomegaly, and pancytopenia. After initiation of ALL treatment, he had no episodes of HUS, despite cessation of eculizumab. CONCLUSION: In conclusion, eculizumab may be a treatment of choice to prevent further systemic damage in recurrent HUS episodes of patients with borderline changes in the bone marrow until ALL is constantly diagnosed.

Spontaneous acute cerebral hematoma in a child with factor XIII deficiency.

Factor XIII deficiency is a very rare bleeding disorder. We report here on the clinical outcome of a young child with intracranial bleeding due to factor XIII deficiency. Clinicians should bear in mind that severe factor XIII deficiency is associated with a significant risk of unexpected intracranial hemorrhage (ICH).

Prevalence and clinical significance of antithyroid antibodies in children with immune thrombocytopenic purpura.

BACKGROUND AND OBJECTIVE: To determine the prevalence and the clinical significance of thyroid autoantibodies and their influence on treatment response in children with idiopathic thrombocytopenic purpura (ITP). PATIENT AND METHOD: We retrospectively analyzed the antithyroglobulin (anti-TG) and antithyroid peroxidase (anti-TPO) antibodies from the records of 151 ITP patients who were admitted to the Pediatric Hematology Department of Gaziantep University between 2009 and 2012. RESULTS: Anti-TPO and/or anti-TG was found positive in 38 (36.8%) of 103 patients whose thyroid autoantibody levels were measured. The comparison of positivity ratios of autoantibodies between acute and chronic ITP patients showed no significant difference. However, the separate comparison of each group of ITP patients with control group showed significantly high positivity ratios of autoantibodies in ITP patients. The initial mean platelet count of anti-TPO positive patients at diagnosis was significantly less than that of the negative patients (P = .008). One month after treatment, platelet count of anti-TPO positive patients was significantly less than that of the negative patients (P = .01). Moreover, the mean platelet counts of anti-TPO positive patients were significantly less than those of the negative patients after intravenous immunoglobulin treatment (P < .001). CONCLUSION: We demonstrated that the thyroid-autoimmune-diseases-related autoantibodies are frequently found in childhood ITP. Although no recommendation is found in international guidelines regarding screening for thyroid autoantibodies in patients with ITP, in view of the high incidence of antithyroid antibodies and their potential negative effect on treatment response, screening these patients for such antibodies would be recommended.

Detection of Left Ventricular Regional Function in Asymptomatic Children with beta-Thalassemia Major by Longitudinal Strain and Strain Rate Imaging.

OBJECTIVE: Cardiac failure due to iron overload remains the most common cause of death in patients with beta-thalassemia major. This study aimed to evaluate myocardial function in children with beta-thalassemia major using standard echocardiography technique and strain rate imaging. MATERIALS AND METHODS: Conventional echocardiographic analysis, tissue velocity imaging, and strain/strain rate imaging of the left ventricle were evaluated in 48 children with beta-thalassemia major (19 girls, 29 boys; 8.39±4.05 years) and 22 healthy children (11 girls, 11 boys; 8±3.72 years). RESULTS: Conventional echocardiographic examinations revealed that beta-thalassemia patients had larger left ventricular end-systolic diameter, end-diastolic and end-systolic volume, left ventricular mass index, and mitral early/late diastolic flow velocity ratio (p<0.05). Strain and strain rate imaging study of the basal lateral wall of the left ventricle was higher in patients than in controls, at p=0.035 and p=0.008, respectively. CONCLUSION: We found that superior systolic strain and strain rate imaging of the left ventricle indicated the presence of regional systolic function in the left ventricular wall. We suggest that left ventricle volume and mass index parameters might be more sensitive than the other conventional and strain/strain rate imaging parameters during childhood. However, the adulthood strain and strain rate imaging values may be lower than controls, exceeding the critical level of iron overload. CONFLICT OF INTEREST: None declared.

Hemophagocytic lymphohistiocytosis in 2 pediatric patients secondary to hepatitis A virus infection.

Hemophagocytic lymphohistiocytosis (HLH) is a rare clinical syndrome characterized by uncontrolled activation of cytotoxic T cells and antigen-presenting cells. Common clinical manifestations include high fever, maculopapular rash, neurological symptoms, coagulopathy, and abnormal liver function tests [1]. HLH can be either primary, that is, due to an underlying genetic defect, or secondary, associated with malignancies, autoimmune diseases, or infections. The true incidence of secondary HLH is difficult to define. Infection associated HLH are most commonly associated with viral infections mainly of the herpes group, with Epstein-Barr virus (EBV) that is proposed to be the most common cause [2]. Despite the high incidence of hepatitis A virus (HAV) infection in the pediatric population in general, there are few pediatric case reports in the literature about HAV-associated hemophagocytic syndrome [3]. We encountered 2 patients with HAV-associated hemophagocytic syndrome.

Wiskott-Aldrich syndrome mutation in two Turkish siblings with X-linked thrombocytopenia.

Wiskott-Aldrich syndrome (WAS) is a clinical condition characterized by thrombocytopenia, eczema, and life-threatening infections. In some cases autoimmunity-related problems and even malignancy might be seen; however, some patients have milder clinical manifestations due to mutations in the same gene family, such as in X-linked thrombocytopenia (XLT), which is generally not associated with serious symptoms of disease, except for thrombocytopenia. Herein we report 2 siblings with chronic thrombocytopenia that were diagnosed with XLT based on a missense mutation in the WASP gene (223G>A, Val75Met). To the best of our knowledge this mutation has not been previously reported in a Turkish patient with XLT.

Neurologic findings of nutritional vitamin B12 deficiency in children.

We report herein our interesting case series of 15 infants admitting with neurological symptoms who were found to have vitamin B12 deficiency. Infants who were admitted to our hospital between 2004 and 2007 with neurological symptoms and were found to have vitamin B12 deficiency were included in this study. Data regarding clinical and laboratory features were obtained. Of 15 infants, 9 were boys (60%) and 6 were girls (40%). The mean age was 11.7 months. Anorexia, pallor, hypotonia, and neurodevelopmental retardation were present in all infants. Seizures and tremor were observed in 46.6% (7/15) and 33% (5/15) of patients, respectively. Seizures were generalized tonic-clonic in 4 patients, generalized tonic in 1 patient and focal in 2 patients. Four patients had tremor on admission and 1 patient had occurrence after vitamin B12 treatment. Vitamin B12 deficiency may lead to serious neurological deficits in addition to megaloblastic anemia. Persistent neurological damage can be prevented with early diagnosis and treatment. We believe that a thorough clinical and neurological assessment might prevent failure to notice rare but possible vitamin B12 deficiency in infants with neurological deficits and neurodevelopmental retardation.

Outcomes of Eltrombopag Treatment and Development of Iron Deficiency in Children with Immune Thrombocytopenia in Turkey

Objective: Immune thrombocytopenia (ITP) is a rare autoimmune disease and hematologic disorder characterized by reduced platelet counts that can result in significant symptoms, such as bleeding, bruising, epistaxis, or petechiae. The thrombopoietin receptor agonist eltrombopag (EPAG) is a second-line agent used to treat chronic ITP purpura in adults and children. Materials and Methods: The present retrospective study evaluated the efficacy, safety, and side effects of EPAG treatment in pediatric patients with acute refractory and chronic immune thrombocytopenia, particularly focusing on iron-deficiency anemia. Results: The diagnosis was chronic ITP in 89 patients and acute refractory ITP in 16 patients. The mean age of patients was 9.5±4.5 years (minimum-maximum: 1.2-18 years) at the beginning of EPAG treatment. The overall response rate was 74.3% (n=78). The mean time for platelet count of ≥50x109/L was 11.6±8 weeks (range: 1-34 weeks). The treatment was stopped for 27 patients (25.7%) at an average of 6.8±9 months (range: 1-38 months). The reason for discontinuation was lack of response in 18 patients, nonadherence in 4 patients, and hepatotoxicity in 2 patients. Response to treatment continued for an average of 4 months after cessation of EPAG in 3 patients. Conclusion: Results of the current study imply that EPAG is an effective therapeutic option in pediatric patients with acute refractory and chronic ITP. However, patients must be closely monitored for response and side effects during treatment, and especially for iron deficiency.

Evaluation of nine children with reversible posterior encephalopathy syndrome.

BACKGROUND: Reversible posterior leukoencephalopathy syndrome (PRES) is a neurological disorder characterized by signs of posterior cerebral edema upon radiographic examination. MATERIALS AND METHODS: We retrospectively analyzed the records of nine children with the diagnosis of PRES. RESULTS: Of the nine patients, seven were receiving immunosuppressive therapy and two were acute hypertensive crisis associated with renal disease. Immunosupressive drugs were intrathecal methotrexate in two patients, cyclosporine in two patients, intrathecal cytarabine in one patient, cyclophasphamide in one patient, and intravenous immunoglobulin (IVIg) in another one patient. The most presenting symptoms were seizure, headache, and altered consciousness. Six patients had seizures. Altered consciousness was present in four patients. Headache and nausea or vomiting was present also in six patients. Visual abnormalities were noted in two patients. Magnetic resonance imaging (MRI) studies showed white-matter abnormalities suggestive of edema in the posterior regions of the cerebral hemispheres, but the changes often involved other cerebral areas, the brain stem, basal ganglia or the cerebellum. The patients were treated with antihypertensive medications, and immunosuppressive therapy was withdrawn. In all the patients, the clinical and radiological findings resolved more completely. CONCLUSION: Reversible posterior leukoencephalopathy may develop in patients who have renal insufficiency or hypertension or who are immunosuppressed. This syndrome should be recognized immediately and trigger agents can be discontinued to prevent long-term sequelae.

Transfusion-Associated Acute Lung Injury following Donor Granulocyte Transfusion in Two Pediatric Patients.

Transfusion-associated acute lung injury (TRALI) is one of the complications seen due to transfusion. Hypoxemia and bilateral pulmonary infiltration in posteroanterior chest roentgenogram is seen in all cases during transfusion or within the first 6 hours; fever, hypotension, and pink frothy bleeding from endotracheal tube may also be seen. It can be seen following the administration of any blood product. The management strategies for TRALI include withholding the transfusion, positive pressure breathing support, and diuretics. There are few reported cases of TRALI occurring following donor granulocyte transfusion (DGT). In this article, we discuss two cases of TRALI following DGT transfusion.

Eltrombopag For Immune Thrombocytopenic Children in a Single Region.

Objective Child patients of chronic thrombocytopenic purpura with severe and resistant thrombocytopenia were evaluated to observe whether their clinical or laboratory states improve by one of the thrombomimetic therapeutic agent called Eltrombopag as in adults in a single center of different country from previous studies. Materials and Methods Nineteen patients with chronic immune thrombocytopenia were treated with Eltrombopag to dose in international guidelines. Results Approximately half (11/19:58%) of the patients benefitted from the treatment with Eltrombopag either by an increase of platelet levels at safe levels with a decrease in the frequency of bleedings which needed rescue treatment. Conclusion Thrombomimetic treatment options have strengthened the clinician's hand where the regular treatment options became insufficient.