Search

Objective To investigate the value of presepsin and proadrenomedullin (proADM) as new markers for febrile neutropenia, by comparing them with conventional markers. Methods Plasma specimens for presepsin, proADM, C-reactive protein (CRP), and procalcitonin (PCT) were collected every 3 days during each episode of febrile neutropenia. Results A total of 39 patients experiencing a collective 47 episodes of febrile neutropenia with hematological malignant neoplasms, as well as 40 healthy control patients without infectious disease, were enrolled in this study. Levels of the studied analytes in the presepsin 1 group (with baseline values taken at admission), presepsin 2 group (values recorded on the 3rd day of febrile neutropenia), and presepsin 3 group (values recorded on the 6th day of hospitalization) were all higher in the subgroups with bacteremia. C-reactive protein 1 (baseline value taken at admission), procalcitonin 1 (as recorded at admission), and procalcitonin 2 (recorded on the 3rd day of febrile neutropenia) were higher in the subroups with bacteremia (P =.03, P = .04, and P = .04, respectively). In multivariate logistic regression analysis, presepsin 1 and/or PCT 1/CRP 1 combined analysis was superior in predicting bacteremia. Conclusion Presepsin could be used in combination with other biomarkers to detect bacteremia.

Children with acute leukemia (ALL) often suffer from several disease and treatment related side-effects during treatment. The aim of the present study was to determine the gross and fine motor functioning and basic cognitive performance of children (n = 25) with ALL who were undergoing induction or consolidation chemotherapy and to compare these characteristics to a normative group (n = 21) of age-matched typically developing children. We assessed the children’s motor functions with the Bruininks-Oseretsky Test of Motor Proficiency Second Edition-Short Form and the Nine-hole Peg Test, and we used the Modified Mini-Mental State Exam (MMSE) to evaluate their cognitive performance. Compared to the normative group, children with ALL had lower scores on total motor proficiency and sub-tests scores of motor functions ( p < .05), and on the Nine-hole Peg Test performance ( p < .05); but their cognitive performance on the MMSE was not significantly different. Children with ALL would likely benefit from structured exercise and rehabilitative interventions during chemotherapy to prevent and/or ameliorate ALL-related motor dysfunction. We also suggest that their cognitive functioning should be further investigated with more extensive well-validated neurocognitive tests for children (e.g., the Wechsler intelligence scales).

Background Invasive fungal infections (IFIs) are a leading cause of morbidity and death in immunocompromised patients. Data on efficacy and pharmacokinetics of posaconazole in pediatric patients are rare (1 to 5). Herein, we retrospectively analyzed adolescent patients who had received posaconazole as antifungal prophylaxis. Methods We retrospectively analyzed patients who received posaconazole as primary or secondary antifungal prophylaxis. Results A total of 34 adolescent patients, 19 men (55.9%) and 15 women (44.1%) with a mean age of 15.8±2.1 years were included. Twenty-five of 34 (73.5%) patients were on primary and nine of 34 (26.5%) patients were on secondary antifungal prophylaxis. Diagnosis of the patients receiving posaconazole as primary antifungal prophylaxis were acute myeloid leukemia (n=12, 48%), hematopoietic stem cell transplantation (n=7, 28%), acute lymphoblastic leukemia (n=5, 20%), and Fanconi aplastic anemia (n=1, 4%). Five patients (55.6%) with hematopoietic stem cell transplantation, 1 patient with acute myeloid leukemia (11.1%), 1 patient with Fanconi aplastic anemia (11.1%), and 2 (22.2%) patients with chronic granulomatous disease received posaconazole as secondary antifungal prophylaxis. Twelve of 25 (48%) patients receiving posaconazole as primary antifungal prophylaxis were complicated by IFI; 4 of them were proven, 6 probable, and 2 with possible IFI. Three of 9 patients (33.3%) receiving posaconazole as secondary antifungal prophylaxis was complicated by IFI (P=0.29), 2 of them were probable and 1 was possible IFI. Five of 25 patients (20%) receiving posaconazole as primary prophylaxis died because of IFI. Conclusion Improvement of antifungal prophylaxis in patients with high risk of invasive infections seems clearly necessary, and analyzing serum posaconazole levels and individualizing dosing may be 1 approach to improve outcomes.

In this case report; a 12-year-old male with ALL who developed transient left hemiparesis associated with dysphasia and central facial paralysis 14 days after high dose methotrexate (5g/m2) and intrathecal MTX (12 mg, according to age) treatment has been reported. Cranial magnetic resonance imaging (MRI) revealed restricted diffusion in bilateral centrum semiovale compatible with MTX-induced acute encephalopathy. All clinical symptoms resolved completely without any treatment. Clinical findings including headache, nausea, emesis, lethargy, altered mental status, blurred vision, aphasia, dysphasia, hemiparesis and cranial MRI findings of restricted diffusion that does not comply with the territory of ​​any artery seizure should alert the physician for MTX-induced acute encephalopathy.

Objective.Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive autoinflammatory disorder associated with ADA2 mutations. We aimed to investigate the characteristics and ADA2 enzyme activities of patients with DADA2 compared to non-DADA2 patients.Methods.This is a descriptive study of 24 patients with DADA2 who were admitted to the Adult and Pediatric Rheumatology, Pediatric Haematology, and Pediatric Immunology Departments of Hacettepe University. All ADA2 exons were screened by Sanger sequencing. Serum ADA2 enzyme activity was measured by modified spectrophotometric method.Results.Twenty-four patients with DADA2 were included: 14 with polyarteritis nodosa (PAN)-like phenotype (Group 1); 9 with Diamond-Blackfan anemia (DBA)-like features, and 1 with immunodeficiency (Group 2). Fourteen PAN-like DADA2 patients did not have the typical thrombocytosis seen in classic PAN. Inflammatory attacks were evident only in Group 1 patients. Serum ADA2 activity was low in all patients with DADA2 except one, who was tested after hematopoietic stem cell transplantation. There was no significant difference in ADA2 activities between PAN-like and DBA-like patients. In DADA2 patients with one ADA2 mutation, serum ADA2 activities were as low as those of patients with homozygote DADA2. ADA2 activities were normal in non-DADA2 patients. ADA2 mutations were affecting the dimerization domain in Group 1 patients and the catalytic domain in Group 2 patients.Conclusion.We suggest assessing ADA2 activity along with genetic analysis because there are patients with one ADA2 mutation and absent enzyme activity. Our data suggest a possible genotype–phenotype correlation in which dimerization domain mutations are associated with PAN-like phenotype, and catalytic domain mutations are associated with hematological manifestations.

Familial hemophagocytic lymphohistiocytosis is an autosomal recessive, life-threatening condition characterized by defective immune response. A retrospective analysis was performed on 57 patients diagnosed with familial hemophagocytic lymphohistiocytosis at Hacettepe University Pediatric Hematology Department, Ankara, Turkey. Mutation analysis was performed on 37 patients, and of these: 11 had UNC13D, 10 had PRF1 and 3 had STX11 gene mutation. Of these patients, 44% were found to have central nervous system involvement on admission and spinal cord involvement was also seen in 5 patients. Remission was achieved in 24 patients with the treatment, in a median time of 76 days (min-max: 15–705 days). Time to remission was prolonged 3.1 times in patients with a ferritin level 1500 mg/dL or more. When patients were grouped according to age [Group 1 (≤ 2 years), Group 2 (>2 years)]; patients in Group 1 had higher ferritin and aspartate aminotransferase levels but lower fibrinogen levels. The 5-year survival rate was also lower in Group 1. When patients in Group 1 were divided into two sub-groups according to hepatic involvement, the 5-year survival rate of patients who had hepatic involvement was significantly lower than those patients without hepatic involvement (0.7%, 27%, respectively) (P=0.002). The 5-year survival rate of patients who underwent hematopoietic stem cell transplantation was significantly higher than the patients who didn’t (44%, 16%, respectively) (P=0.02). In conclusion, age two years and under, ferritin level above 1500 mg/dL, spinal cord or hepatic involvement should be considered as poor prognostic factors in familial hemophagocytic lymphohistiocytosis.

The purpose of this study was to compare the effectiveness of different oral iron preparations in children with iron deficiency anemia (IDA).Sixty children with IDA, aged between 6 months and 180 months, were randomly assigned into three treatment groups. Group I included children with IDA who received ferrous sulfate (Fe-S); Group II included children receiving iron polymaltose complexes (Fe-OH-PM), and Group III included children receiving a single preparation of combined iron and zinc (Fe-Zn). The effect of different iron preparations were evaluated and compared. The duration of treatment was 8 weeks. Hemoglobin (Hgb) levels, as well as other hematological parameters were determined at admission and the first, fourth, and eighth weeks of the treatment.The Hgb levels of patients in all three groups were statistically higher in the fourth (P=0.001) and eighth (P0.001) weeks compared to baseline; although there was no difference between the groups at the end of the treatment period (P0.05).Our results indicate that, Fe-OH-PM and Fe-Zn preparations may also be preferred as a choice like Fe-S for treatment of children with IDA.

Background Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive autoinflammatory disorder caused by ADA2 mutations. Objectives We aimed to investigate the characteristics of DADA2 patients along with the ADA2 enzyme levels. Methods 24 DADA2 patients who admitted to the Adult and Pediatric Rheumatology, Pediatric Haematology, and Pediatric Immunology Departments were included. All exons of the ADA2 gene were screened by Sanger sequencing in all DADA2 patients. Serum ADA2 enzyme activity was measured by modified spectrophotometric method. Results 24 DADA2 patients were included; Group 1, 14 DADA2 patients with polyarteritis nodosa (PAN)-like phenotype; Group 2, 9 patients with Diamond-Blackfan anemia (DBA)-like features and one with immune deficiency. 14 PAN-like DADA2 patients did not have the typical thrombocytosis seen in classical PAN. Inflammatory attacks were evident in only Group 1 patients. Serum ADA2 was low in all DADA2 patients except one who was tested after hematopoietic stem cell transplantation. There was no significant difference in ADA2 levels between PAN-like and DBA-like DADA2 patients (Figure 1). ADA2 activities of heterozygote family members were about half the level of the control subjects. However, in heterozygote DADA2 patients, serum ADA2 levels were as low as the ones of homozygote DADA2 patients. ADA2 mutations were affecting the dimerization domain in Group 1 patients and in the catalytic domain in Group 2 patients (Table 1). Conclusion We suggest that enzyme activity of ADA2 should be assessed along with genetic analysis since there are heterozygote patients with absent enzyme activity. Our data confirms a possible genotype phenotype correlation where dimerization domain mutations are associated with a PAN-like phenotype whereas catalytic domain mutations are associated with hematological manifestations. References [1] Navon Elkan P, et al. Mutant ADA2 in a PAN vasculopathy. N Engl J Med 2014;370(10):921-931 [2] Zhou Q, et al. Early-onset stroke and vasculopathy associated with mutations in ADA2. N Engl J Med 2014;370(10):911-920 Acknowledgement This study was supported by Scientific and Technological Research Council of Turkey (TUBITAK) with grant numbers of 315S192. Prof. Nurten Akarsu performed the molecular studies of DBA patients and special thanks to her for great support. Disclosure of Interests Ezgi Deniz Batu: None declared, Ekim Z. Taskiran: None declared, Hatice Asuman Ozkara: None declared, Sule Unal: None declared, Naz Guleray: None declared, Abdulsamet Erden: None declared, Omer Karadag: None declared, Fatma Gumruk: None declared, Mualla Cetin: None declared, Yelda Bilginer: None declared, Hafize Emine Sonmez: None declared, Deniz Cagdas Ayvaz: None declared, Ilhan Tezcan: None declared, Seza Ozen Consultant for: Seza Ozen is receiving consultancy fees from Novartis, Speakers bureau: Roche

Glucose-6-phosphate isomerase (GPI, EC 5.3.1.9) is a dimeric enzyme that catalyzes the reversible isomerization of glucose-6-phosphate to fructose-6-phosphate, the second reaction step of glycolysis. GPI deficiency, transmitted as an autosomal recessive trait, is considered the second most common erythro-enzymopathy of anaerobic glycolysis, after pyruvate kinase deficiency. Despite this, this defect may sometimes be misdiagnosed and only about 60 cases of GPI deficiency have been reported. GPI deficient patients are affected by chronic non-spherocytic hemolytic anemia of variable severity; in rare cases, intellectual disability or neuromuscular symptoms have also been reported. The gene locus encoding GPI is located on chromosome 19q13.1 and contains 18 exons. So far, about 40 causative mutations have been identified. We report the clinical, hematological and molecular characteristics of 12 GPI deficient cases (eight males, four females) from 11 families, with a median age at admission of 13 years (ranging from 1 to 51); eight of them were of Italian origin. Patients displayed moderate to severe anemia, that improves with aging. Splenectomy does not always result in the amelioration of anemia but may be considered in transfusion-dependent patients to reduce transfusion intervals. None of the patients described here displayed neurological impairment attributable to the enzyme defect. We identified 13 different mutations in the GPI gene, six of them have never been described before; the new mutations affect highly conserved residues and were not detected in 1000 Genomes and HGMD databases and were considered pathogenic by several mutation algorithms. This is the largest series of GPI deficient patients so far reported in a single study. The study confirms the great heterogeneity of the molecular defect and provides new insights on clinical and molecular aspects of this disease.

Yaman-Bajin İ, Aytaç S, Kuşkonmaz B, Uçkan-Çetinkaya D, Ünal Ş, Gümrük F, Çetin M. Infant lymphoblastic leukemia: a single centers 10 year experience. Turk J Pediatr 2019; 61: 325-329. Infant acute lymphoblastic leukemia (ALL) is a rare disease and consists of 4-5% of all childhood ALL. Despite improved survival rates in childhood ALL, infants with ALL have a worse prognosis. We aimed to evaluate the clinical features and treatment outcomes of our patients diagnosed with infant ALL at Hacettepe University, Pediatric Hematology Department between 1 January 2008 and 1 January 2018 retrospectively. There were 13 patients with a median age of 7 months. Three of the patients were triplets born from a spontaneous monozygotic triplet pregnancy. Relapse were observed in 4 patients. Hematopoietic stem cell transplantation (HSCT) was performed for five patients. Relapse after HSCT was observed in 3 patients. After a median follow-up period of 18 months, 6 patients (45%) (3 after HSCT and 3 who only received chemotherapy) were alive and in remission. Prognosis of infant ALL is poor in that only half of the patients survive. Our results suggest that bone marrow transplantation seems to be a good and efficient choice of treatment for selected patients. However, there is still a big issue to decide which patient should undergo transplantation and more studies are needed to reevaluate the eligibility criteria for HSCT in this group of patients.

Computed tomography (CT) is commonly used to detect pulmonary infection in immunocompromised children. To compare MRI and multidetector CT findings of pulmonary abnormalities in immunocompromised children. Seventeen neutropaenic children (6 girls; ages 2-18 years) were included. Non-contrast-enhanced CT was performed with a 64-detector CT scanner. Axial and coronal non-enhanced thoracic MRI was performed using a 1.5-T scanner within 24 h of the CT examination (true fast imaging with steady-state free precession, fat-saturated T2-weighted turbo spin echo with motion correction, T2-weighted half-Fourier single-shot turbo spin echo [HASTE], fat-saturated T1-weighted spoiled gradient echo). Pulmonary abnormalities (nodules, consolidations, ground glass opacities, atelectasis, pleural effusion and lymph nodes) were evaluated and compared among MRI sequences and between MRI and CT. The relationship between MRI sequences and nodule sizes was examined by chi- square test. Of 256 CT lesions, 207 (81%, 95% confidence interval [CI] 76–85%) were detected at MRI. Of 202 CT-detected nodules, 157 (78%, 95% CI 71–83%) were seen at motion-corrected MRI. Of the 1–5-mm nodules, 69% were detected by motion-corrected T2-weighted MRI and 38% by HASTE MRI. Sensitivity of MRI (both axial fat-saturated T2-weighted turbo spin echo with variable phase encoding directions (BLADE) images and HASTE sequences) to detect pulmonary abnormalities is promising.

The aim was to evaluate baseline demographic, clinical, and laboratory characteristics, treatment modalities, and outcome of children with idiopathic hypereosinophilic syndrome (HES) followed up in our center. Children who fulfilled the criteria of idiopathic HES followed up at Hacettepe University Faculty of Medicine, Pediatric Hematology Department between June 2004 and October 2013 were included in this study. Medical records of all children with idiopathic HES were reviewed to obtain regarding data. The mean age of 6 children with idiopathic HES was 52.8± 44.3 months (13 to 132 mo) at diagnosis. Among 6 children with idiopathic HES; 2 had pulmonary involvement; 1 had cardiac and pulmonary involvement and splenomegaly; 1 had cardiac involvement and hepatosplenomegaly; 1 had cardiac and central nervous system involvement; and 1 had skin involvement. The mean follow-up duration was 36.5± 31.4 months. Methyl prednisolone (MP) was used for the first-line therapy. Complete response was achieved with MP in 3 children. All steroid responsive children are alive; whereas 3 children who did not respond to MP had expired. In conclusion, cardiac and pulmonary involvement is the major causes of mortality in HES. Resistance to steroid therapy indicates poor prognosis

In this study, we aimed to evaluate the incidence, risk factors, causes and clinical management of intracranial haemorrhage (ICH) diagnosed during foetal life or in the first month of life in term neonates with a discussion of the role of haematological risk factors. This study included term neonates (gestational age 37-42 weeks) with ICH diagnosed, treated and followed up in the Neonatal Intensive Care Unit of Hacettepe University, Ankara, Turkey, between January 1994 and January 2014. Medical follow-up was obtained retrospectively from hospital files and prospectively from telephonic interviews and/or clinical visits. During the study period, 16 term neonates were identified as having ICH in our hospital. In six (37.5%) neonates, ICH was diagnosed during foetal life by obstetric ultrasonography, and in 10 (62.5%) neonates, it has been diagnosed after birth. Haemorrhage types included intraventricular haemorrhage (IVH) in eight (50.0%), intraparenchymal haemorrhage in six (37.5%), subarachnoid haemorrhage in one (6.2%) and subdural haemorrhage in one (6.2%) neonate. IVH was the most common (n = 5/6, 83.3%) haemorrhage type among neonates diagnosed during foetal life. Overall, haemorrhage severity was determined as mild in three (18.7%) neonates, moderate in three (18.75%) neonates and severe in 10 (62.5%) neonates. During follow-up, one infant was diagnosed as afibrinogenemia, one diagnosed as infantile spasm, one cystic fibrosis, one orofaciodigital syndrome and the other diagnosed as Friedrich ataxia. Detailed haematological investigation and search for other underlying diseases are very important to identify the reason of ICH in term neonates. Furthermore, early diagnosis, close monitoring and prompt surgical interventions are significant factors to reduce disabilities.

Background Fanconi anemia (FA) is a heterogeneous autosomal recessive (and rarely X linked) disorder, which is characterized by congenital malformations, progressive bone marrow failure, and predisposition to malignancies. Hematopoietic stem cell transplantation (HSCT) is the only definitive treatment for the hematological manifestations in FA. Procedure Twenty-seven patients with FA underwent HSCT using fludarabine (Flu) based regimen at our center between April 2004 and May 2014. One patient who developed acute leukemia before HSCT was excluded from the study. The remaining 26 patients were included. The median age of the patients at the time of transplantation was 9.6 years (range 5.6–17.0 years) and male/female ratio was 19/7. Donors were Human leukocyte antigen (HLA)-identical sibling in 18 patients, HLA-identical other relatives in six patients, and HLA 1-antigen mismatched sibling in two patients. Conditioning regimen consisted of Flu, cyclophosphamide, and antithymocyte globulin. Results All patients engrafted but one developed poor graft function and underwent second HSCT. Acute graft versus host disease (GVHD) (≥grade 2) occurred in two patients (7.6%) and chronic GVHD in one patient (3.9%). Three patients developed venoocclusive disease (11.5%). Survival rate was 96.2% (25/26) at a median follow-up of 54 months (10–131 months) and all patients who survived were in good clinical condition. None of the patients developed secondary malignancy during the follow-up period. Conclusions The present study from Turkey, a middle-income country, shows successful transplant outcome with low toxicity using Flu-based conditioning in patients with FA who underwent HSCT from HLA-related donors.

Transcobalamin II deficiency is one of the rare causes of inherited vitamin B12 disorders in which the patients have characteristically normal or high vitamin B12 levels related to the transport defect of vitamin B12 into the cell, ending up with intracellular cobalamin depletion and high homocysteine and methylmalonic acid levels.Herein, we describe the findings at presentation of four patients who were diagnosed to have transcobalamin II deficiency with novel mutations.These patients with transcobalamin II deficiency were found to have novel mutations, of whom 2 had the same large deletion (homozygous c.1106+1516-1222+1231del).Transcobalamin II deficiency should be considered in differential diagnosis of any infant with pancytopenia, failure to thrive, diarrhea, and vomiting.Amaç: Transkobalamin II eksikliği nadir bir kalıtsal B12 vitamini bozukluğudur. Defektin B12 vitamininin transportu ile ilgili olması nedeniyle hastalar normal ya da yüksek B12 vitamini düzeylerine eşlik eden yüksek homosistein ve metilmalonik asit düzeylerine sahiptir. Gereç ve Yöntemler: Bu çalışmada transkobalamin II eksikliği tanısı alan dört hasta sunulmuştur. Bu hastalarda daha önce bildirilmemiş yeni mutasyonlar saptanmıştır. Bulgular: Hastaların ikisinde aynı büyük delesyon olduğu görülmüştür (homozigot c.1106+1516-1222+1231del). Sonuç: Pansitopeni, büyüme geriliği, ishal ya da kusması olan tüm bebeklerde transcobalamin II eksikliği ayırıcı tanıda düşünülmelidir.

Introduction: Paroxysmal nocturnal hemoglobinuria(PNH) in the classical hemolytic form is rare among childhood and children may present with aplastic anemia (AA) phenotype or with an overlapping phenotype of both aplastic and hemolytic components. In the recent years the introduction of FLAER methods prompted a more accurate determination of PNH clones in the suspected patients. Among the patients with aplastic anemia, PNH clone positivity has been detected in 18-59% of these patients with more sensitive FLAER methods. There is limited data related to the effect of PNH clone positivity on treatment outcomes in pediatric AA. Methods: A total of 142 patients, who were diagnosed with acquired AA, from 12 centers were included. All of the patients were tested for PNH clone positivity with either CD55/CD59, FLAER. None of the patients were DEB positive. Results: PNH clone was tested initially at diagnosis with CD55/CD59 flow cytometric analyses in 64 (45%) of the ppatients 66 received IST.atients and with FLAER method in 78 (55%) of the patients. Thirthy three (23.2%) were found to be PNH clone positive, two of them were negative with CD55/CD59 at diagnosis, but were found positive with FLAER during follow-up.Of the PNH clone positive patients 71% were male, compared to 43% in PNH clone nnegative group (p=0.001). The mean ages of patients in PNH clone positive and negative groups were 146±50 vs 121±53 months, respectively(p=0.016). There was no statistically significant difference between clone postive and negative patients in terms of mean Hb, WBC, platelet, AST, ALT, indirect bilirubin and haptoglobin levels measured at diagnosis of AA. However serum creatinin level was significantly higher at diagnosis in PNH clone postive patients compared to negative patients (0.57±0.18 vs 0.49±0.15 mg/dl); whereas MCV levels were significantly higher in clone postive group (93.2±9.7 vs 87±11.5 fl). Of 33 patients with PNH clone positivity, 19 (57.6%) were treated with immunosuppressive treatment (IST), as first line treatment, whereas of the clone negative 109 patients, 66 received IST (60.6%) (p=0.76). Of the 19 clone postive patients 11 (57.9%) had treatment response; whereas 36/65 (55.4%) of clone negative patients responded to IST. There was no statistically significant difference between PNH clone positive and negative groups in terms of IST response. IST response was not affected according to gender, age, ALT, AST, WBC, Hb, thrombocyte count, size of the erythrocyte and granulocyte clone at diagnosis. Thrombosis developed in 2 of clone positive (6.1%) and 2 of clone gative patients (1.8%) (p=0.23). Three year survival was 97.6±2.4% and 37.2±8.7% among IST responders and IST non-responders, respectively (p=0.0). Of the 142 patients, 59 underwent HSCT, five received eculizimab and 1 received eltrombopag treatments. Three patients developed clonality during follow-up. Thirty-seven (26%) of the patients deceased among the all study group and the causes of mortality were fungal infection, sepsis, pneumonia, leukemia progression, HSCT related complications, thrombosis and bleeding. Conclusions: PNH clone positivity was found in 23.2% of our patients with pediatric acquired AA. We found no impact of clone positivity on outcome in terms of IST response. This is one of the largest cohort of pediatric patients which investigated the impact of PNH clone positivity on AA outcome. Disclosures No relevant conflicts of interest to declare.

Klinefelter syndrome is characterized by gynecomastia, hypogonadism, small testes, elevated levels of follicle-stimulating hormone and an extra X chromosome (ie, 47,XXY).1 These patients tend to have an increased risk of developing male breast cancer and mediastinal germ cell tumors.2,3 Hematologic malignancies including acute or chronic leukemia are also observed in these patients,4 but only a few case reports with Klinefelter syndrome who developed myelodysplastic syndrome (MDS) were published.4–7

Basal cell carcinoma (BCC) is a rare secondary malignancy which may occur more often in children with acute lymphoblastic leukemia (ALL) who have previously received radiation therapy compared to to those who received no radiation.

The use of cardiac and hepatic T2* MRI measurements to predict the amount of iron accumulation in these organs has been studied extensively and was suggested to be used reliably. However, it may not be practical to screen other organs with MRI related to economical issues and also the prolonged imaging durations. Herein, we aimed to test the use of fasting glucose, fasting, and postprandial insulin, homeostasis model assessment-insulin resistance (HOMA-IR) (calculated as insulin (μIU/ml) × glucose (mg/dl)/22.5), and homeostasis model assessment B score (HOMA-B) (calculated as insulin (μIU/ml) × 20/glucose (mg/dl) - 3.5) to estimate the tissue iron measured with MRI. A total of 37 patients with β-thalassemia major (BTM), age 20.8 ± 6.3 years (7.1-36.8), were enrolled. MRI measurements were done concomitantly to the biochemical tests for glucose metabolism. A positive correlation between HOMA-IR and hepatic iron loading and a negative correlation between pancreatic T2* and fasting blood glucose were found. A positive correlation was found between fasting insulin levels and pancreatic R2* measures. Additionally, a correlation was detected between cardiac and pancreatic iron accumulations. In centers where T2*/R2* MRI facilities are unavailable, fasting insulin, fasting glucose, and HOMA-IR measurements may be used to predict iron overload and may urge the physician for MRI assessment in case of a deterioration in these biochemical tests. Since hepatic iron loading correlated with insulin resistance development, the insulin resistance among patients with BTM may partially be explained with decreased hepatic insulin clearance from heavily iron-loaded liver.

Hypercalcemia is a rare complication of hematological malignancy in children. An 8-year-old girl with CALLA (+) Pre-B-cell ALL developed hypercalcemia during bone marrow relapse. She had nausea, vomiting, leg pain, polyuria, polydipsia, and muscle weakness. At the time of relapse, the ionized calcium level was 1.99 mmol/L. Rehydration with 0.9% saline and furosemide and methylprednisolone (MP) treatment were used for the treatment of hypercalcemia. The serum ionized calcium level increased to 2.2 mmol/L despite hydration, furosemide, and MP treatment. Then, a single-dose pamidronate (1 mg/kg/dose) was administered. Despite pamidronate treatment, the calcium level continued to rise. Next, calcitonin at a dose of 8 IU/kg/dose, 4 doses per day, was added to the treatment. After commencement of calcitonin treatment, her ionized calcium level decreased to normal reference ranges. In conclusion, because of the postponed effect of bisphosphonate treatment, pamidronate and calcitonin combination is an effective treatment option in the early resolution of malignancy-related hypercalcemia.

WOS: 000400127500011, PubMed ID: 28192253, Preimplantation genetic diagnosis involves the diagnosis of a genetic disorder in embryos obtained through in vitro fertilization, selection of healthy embryos, and transfer of the embryos to the mother's uterus. Preimplantation genetic diagnosis has been used not only to avoid the risk of having an affected child, but it also offers, using HLA matching, preselection of potential HLA-genoidentical healthy donor progeny for an affected sibling who requires bone marrow transplantation. Here, we share the hematopoietic stem cell transplantation results of 52 patients with different benign and malign hematological or metabolic diseases or immunodeficiencies whose donors were siblings born with this technique in Turkey since 2008. The median age of the patients' at the time of the transplantation was 8 years (range, 3 to 16 years) and the median age of the donors was 2 years (range,.5 to 6 years). The most common indication for HSCT was thalassemia major (42 of all patients, 80%). The stem cell source in all of the transplantations was bone marrow. In 37 of the transplantations, umbiliCal cord blood of the same donor was also used. In 50 of the 52 patients, full engraftment was achieved with a mean of 4.6 x 10(6) CD 34(+) cells per kg of recipient weight. Ninety-six percent of the patients have been cured through hematopoietic stem cell transplantation without any complication. Primary engraftment failure was seen in only 2 patients with thalassemia major. All of the donors and the patients are alive with good health status. Preimplantation genetic diagnosis with HLA matching offers a life-saving chance for patients who need transplantation but lack an HLA genoidentical donor. (C) 2017 American Society for Blood and Marrow Transplantation.

Background Transfusions with packed erythrocytes is a common practice in pediatric patients with acute lymphoblastic leukemia (ALL) who are on chemotherapy. Since there is no physiological excretion mechanism for iron, the iron related to erythrocyte transfusions accumulates and may contribute to late cardiac, hepatic and endocrine complications in these patients. Procedure In order to evaluate the iron burden among pediatric patients with ALL and define the risk factors associated with higher iron loading, we evaluated 79 pediatric patients with ALL (36 were off-therapy). Cardiac and hepatic T2* were ordered to a total of 22 (28%) patients who were either transfused with erythrocytes ≥10 times (n = 11; 50%), had serum ferritin (SF) ≥1000 ng/ml (n = 2; 9.1%) or both (n = 9; 40.9%). Results Half of the patients who were screened by T2* MRI had hepatic T2* < 7 ms and six (27%) of the patients had cardiac T2* < 20 ms, indicating iron loading. Patients who had serum ferritin

The aim of this study was to describe the incidence and contributory risk factors for thromboembolic complications in children with nephrotic syndrome (NS) and thrombosis. Among 188 children with the diagnosis of NS (80 girls; mean age: 12.6 ± 5.4 years) followed up in our hospital for the last 5 years, 17 (9.0 %) children (16 boys) identified as having thromboembolic complications. All 17 children with NS and thrombosis were screened for laboratory risk factors for thrombosis. The diagnosis was confirmed by cranial magnetic resonance imaging, doppler ultrasonography, and echocardiography. Among 17 children with thrombosis, 14 (82.3 %) were found to have focal segmental glomerulosclerosis (FSGS) as underlying pathology by renal biopsy. The mean age of the thrombotic children was 4.5 ± 3.2 years at the diagnosis of NS and that was 7.1 ± 4.9 years at the time of thrombosis. The mean time from NS diagnosis to the first thrombosis development was 2.6 ± 2.3 years. Thrombosis occurred during the first year of NS in 9/17 (52.9 %) children. Most of the children (88.2 %) had venous thrombosis. Among the screened risk factors, high factor VIII level (64.7 %) was the leading factor followed by decreased antithrombin III level (29.4 %). Furthermore, 4 children had central venous catheters and 2 had infection as clinical risk factors for thrombosis. In this case series, subtype of FSGS, active disease state of NS, central venous catheters, and some inherited and acquired thrombotic risk factors have been identified as contributory factors for the development of thrombosis in children with NS.

Infantacute lymphoblastic leukemia (ALL) is a rare disease and consist of 4-5% of all childhood ALL. Despite improved survival rates of childhood ALL, infants with ALL have a worse prognosis . There were 206 patients diagnosed with ALL at Hacettepe University, Pediatric Hematology Department between 1 January 2008 and 31 December 2016, 11 out of 206 (5.3%) were diagnosed as infant ALL. We aimed to evaluate clinical findings, laboratory results and treatment outcome of our infant ALL patients retrospectively. There were 9 boys and two girls with a median age of 8 months (range 1-12 months) and nine out of 11 (82%) were older than 6 months of age at the initial diagnosis. Interestingly 2 of 3 siblings born from spontaneous triplet pregnancy diagnosed at the same time when they were 7 months old while the other sibling diagnosed 4 months later when he was 11 months old. Physical examination revealed hepatosplenomegaly in 10 out of 11 patients and 1 patient had extramedullary involvement with subcutaneous nodules on the forehead. On admission median WBC count was found 202x10-9/L (range 37.4-739x10-9/L) with a median hemoglobin level 9 g/dL (range 2.6-12.9 g/dL) and median platelet count 81x10-9/L (range10- 314x10-9/L). Immunophenotyping revealed CALLA+ B cell leukemia in 3 patients, CALLA- B cell in 6 patients and T cell leukemia in 2 patients. Cytogenetic analysis showed t(4;11) positivity in 4 patients and 3 of them were spontaneous triplets. Initial CNS involvement were positive in 2 of the patients. Eight patients (73%) were treated with Interfant protocols (Interfant 99 (n=4), Interfant 06 (n=4)) and 3 patients received Modified St. Jude Total XV protocol. Relapse were observed in 2 patients (one had both CNS and bone marrow relapse one year after the completion of chemotherapy and the other experienced an early bone marrow relapse at the 7thmonth of the treatment). Hematopoetic stem cell transplantation (HSCT) was performed in five patients from matched related donor (n=2), unmatched related donor(n=1), and matched unrelated donor(n=2). Moreover, relapse after HSCT was observed in 2 patients 3 and 4 months later; one received second transplantation and survived while the other died because of progressive disease. Four of the five patients who had HSCT survived 74 months, 45, 18 and 13 months after the initial diagnosis, respectively. After a median of 18 months (range 4- 74 months ) follow-up period 6 patients are alive (45 %) and on remission 4 after HSCT and 2 with only chemotherapy. Infant leukemia usually presents with high hyperleucocytosis and extramedullary involvement. The prognosis is poor and international colloborative studies reprorted that 4 year -event free survival rates were between 28-54%. Our results suggest that bone marrow transplantation seems to be a good and efficient choice of treatment. However there is still a big issue to decide which patient should go under transplantation and more studies are needed to reevaluate the eligibility criteria for HSCT in this group of patients. Moreover to the best of our knowledge infant leukemia in triplets without monozygocity were first time reported. Disclosures No relevant conflicts of interest to declare.

Introduction: Childhood acute lymphoblastic leukemia (ALL) treatment with St. Jude Total therapies showed superior outcome with event-free and overall survival rates 85.6 ± 2.9% and 93.5 ± 1.9%, respectively. Here, we studied prognostic features and the outcome of Turkish children with newly diagnosed ALL treated with modified St. Jude Total Therapy XV Protocol. Patients and methods: There were 182 newly diagnosed ALL patients aged 1-18 years old and treated with modified Total Therapy XV between 1 January 2008 and 30 January 2016. According to our previous successful results with high dose methylprednisolone (HDMP), each patient received 7 days of HDMP as an initial treatment and randomized at doses of 20 mg/kg/d or 10mg/kg/d HDMP, not exceeding at maximum 1000 mg MP. After the first 7-day steroid treatment, concomitant chemotherapy was given and the steroid doses were tapered to 10mg/kg/d and 5mg/kg/d during the next week in each group, respectively. Afterwards, the whole group received 2 mg/kg/d MP for the following two weeks. Also, there were a third group received lower doses ( Results: Out of 182 patients, 174 completed the treatment and 1 patient experienced induction failure, 4 patients died during remission induction, 3 patients abandoned treatment during maintenance. 97.2% of the children entered complete remission after remission induction. 16 patients (8.9%) had relapses during follow-up, 9 isolated bone marrow, 7 isolated CNS and 3 of 7 patients who had CNS relapse experienced a second relapse (bone marrow) afterwards. The five-year event-free survival (EFS) and overall survival (OS) were 85.6±2.6 % and 89.2±2.3%, respectively. There was no significant difference according to the survival rates between different MP doses (10 and 20mg/kg/d) which were given before induction. Moreover, difference in frequency of infection between patient groups treated with different steroid doses during induction period was not found statistically significant. Univarite analysis showed that age ≥ 10 years at the time of diagnosis, initial leukocyte count ≥50x109/L, low MP doses (20%) at diagnosis [HR=2.49, 95% CI: 1.08-5.73, p=0.031]. Response to MP measured as Conclusion: Our encouraging EFS result with modified St. Jude Total XV in childhood ALL patients is comparable with the one in original protocol. Favorable effect of higher doses of MP (20 mg/kg/d) on survival could not be demonstrated when compared with 10mg/kg/d. Disclosures No relevant conflicts of interest to declare.

Kesici S, Unal S, Kuskonmaz B, Aytac S, Cetin M, Gumruk F. Fanconi anemia: a single center experience of a large cohort. Turk J Pediatr 2019; 61: 477-484. Fanconi anemia (FA) is an inherited disease, characterized by congenital malformations, short stature, progressive bone marrow failure and predisposition to leukemia and solid tumors. The aim of this study was to evaluate the clinical and prognostic features of FA patients followed in a single center. The charts of FA patients were reviewed 35 years retrospectively and a total of 175 patients were included in the study in which 51.4% of patients were male. The mean age at diagnosis was 6.3±4.1 years. The incidence of microcephaly was 92.6%, skin findings were 88.0%, eye abnormality was 74.3%, thumb and radius abnormality was 53.1%, urinary system abnormality was 30.9%, skeletal system abnormality other than thumb and radius was 18.9%, genital system abnormality was 11.4%, cardiovascular system abnormality was 11.4%, ear and hearing abnormalities were 9.7% and gastrointestinal system abnormality was 5.7%. Short stature was present in 75.4% of the patients. Of the 175 patients 167 (95.4%) developed bone marrow failure during follow-up and the mean age of bone marrow failure was 7.1 ±3.7 years (1 month-old-19.8 years). The first clinical symptom was thrombocytopenia in 83.4% of patients. Malignancy developed in a total of 23 (13.1 %) patients (20 leukemia, 3 solid tumors) during follow-up. Of 175 patients, 35 (20%) underwent hematopoietic stem cell transplantation. Fatality rate among patients who underwent hematopoietic stem cell transplantation was 31.4% (11/35) and fatality rate among other patients was 63.4% (83/131; p < 0.05). Of 94 patients who deceased, death was due to bleeding in 44.7%, infection in 34%, leukemia progression in 16.0% and graft versus host disease in 5.3%. In terms of the number of patients included, this study is one of the largest cohorts with a remarkable duration of follow-up time. Hematopoietic stem cell transplantation was found to have a good impact on sur vival of patients.

Background Microcephalic osteodysplastic primordial dwarfism type II (MOPD II) is a rare primordial dwarfism that is similar to Seckel syndrome. Seckel syndrome is known to be associated with various hematological abnormalities; however, hematological findings in MOPD II patients have not been previously reported. The present study aimed to describe the hematological findings in a series of eight patients with MOPD II from a single center. Materials and Methods The study included eight patients with MOPD II that were analyzed via molecular testing, and physical and laboratory examinations. Results Molecular testing showed that seven of the eight patients had pericentrin (PCNT) gene mutations. Hematological evaluation showed that 7 (87.5%) patients had thrombocytosis, 6 (75%) had leukocytosis, 5 (62.5%) had both leukocytosis and thrombocytosis, and 2 (25%) had anemia. Conclusions We report leukocytosis and thrombocytosis as a common hematologic abnormality in patients with MOPD II. The present findings may improve our understanding of the potential function of the PCNT gene in hematopoietic cell proliferation and differentiation. Pediatr Blood Cancer 2014;61:302–305. © 2013 Wiley Periodicals, Inc.

Background Recurrent macrophage activation syndrome (MAS) is rarely reported. Aim To describe recurrent MAS in a 2.5-year-old girl with systemic juvenile idiopathic arthritis and heterozygous perforin mutation, which may have a role in the patient's first recurrence despite use of the HLH-2004 treatment protocol. Observations In the presented case, MAS was initially controlled after the addition of etoposide to the treatment regimen. However, recurrence occurred 6.5 months after cessation of the HLH-2004 protocol. Subsequent recurrences may have occurred because of the family's noncompliance with treatment. Conclusions The patient's extremely high serum ferritin level (267,054 ng/mL) and the recurrent course of MAS may have been because of the coexistence of juvenile idiopathic arthritis and heterozygous perforin W374X mutation. We suggest to search for mutations in HLH genes in recurrent MAS cases.

CDA are a group of inherited, rare diseases that are characterized by dyserythropoiesis and ineffective erythropoiesis associated with transfusion dependency in approximately 10% of cases. For these latter patients, the only curative treatment is HSCT. There are very limited data on HSCT experience in this rare disease. Herein, we report a five-yr six-month-old girl with compound heterozygous mutations in SEC23B gene, who was diagnosed to have CDA type II and underwent successful HSCT from her matched sibling donor.

Macrophage activation syndrome (MAS) is a hyper-inflammatory disorder secondary to a rheumatic disease such as systemic juvenile idiopathic arthritis (SJIA) and systemic lupus erythematosus (SLE). We aimed to present the characteristics of our pediatric MAS patients. Clinical features, laboratory parameters, treatment, and outcome of 34 patients (28 SJIA; six SLE; 37 MAS episodes) followed at a tertiary health center between 2009 and 2015 were retrospectively reviewed. The median age at MAS onset was 11 years. More SJIA patients had MAS at disease onset than SLE patients (53.6 vs. 16.7 %). Fever, high C-reactive protein and hyperferritinemia were present in all MAS episodes. Rash was less (p = 0.03), and fatigue was more frequent (p = 0.042) in SLE than SJIA patients. All received corticosteroids. Cyclosporine was given in 74.2 % of SJIA-MAS; 66.7 % of SLE-MAS episodes. Intravenous immunoglobulin, anakinra, or etoposide was administered during 67.7; 41.9; 32.3 % of SJIA-MAS and 33.3; 33.3; 50 % of SLE-MAS episodes, respectively. Plasmapheresis was performed during 41.9 % of SJIA-MAS and 33.3 % of SLE-MAS episodes. The mortality rate was 11.8 % (n = 4;3 SJIA, 1 SLE). Hepatosplenomegaly was more frequent (p = 0.005), and plasmapheresis was performed more frequently (p = 0.021) in the patients who died compared to the cured patients. The median duration between symptom onset and admission to our hospital was longer among the patients who died (16.5 vs. 7 days; p = 0.049). Our patients' characteristics were similar to the reported cases, but our mortality rate is slightly higher probably due to late referral to our center. Early diagnosis and effective treatment are crucial to prevent mortality.

The aim of this study was to investigate the reliability and validity of the Turkish version of the Pediatric Quality of Life Inventory (PedsQL) 3.0 Cancer Module for 2- to 7-year-old and the PedsQL 4.0 Generic Core Scales for 5- to 7-year-old in childhood cancer.The PedsQL 3.0 Cancer Module and PedsQL 4.0 Generic Core Scales were administered to children with cancer and their parents at Hacettepe University. Internal consistency was determined by using Cronbach's alpha and test-retest reliability was determined by using the intraclass correlation coefficient (ICC). Construct validity was assessed by comparing the results of the PedsQL 3.0 Cancer Module with those of the PedsQL 4.0 Generic Core Scales.Cronbach's alpha of the PedsQL 3.0 Cancer Module varied from 0.803 to 0.873 and that of the PedsQL 4.0 Generic Core Scales from 0.665 to 0.841. Test-retest ICC values of the PedsQL 3.0 Cancer Module varied from 0.877 to 0.949 and those of the PedsQL 4.0 Generic Core Scales from 0.681 to 0.824. The correlation of the PedsQL 3.0 Cancer Module with subscale scores of the PedsQL 4.0 Generic Core Scales showed that there were excellent to fair correlations between the two scales. The relationship between parent proxy-report and child self-report of the PedsQL 3.0 Cancer Module had very good correlation (r=0.694, p0.001), as did the PedsQL 4.0 Generic Core Scales (r=0.540, p=0.002).This study demonstrated the reliability, validity, and feasibility of the Turkish version of the PedsQL 3.0 Cancer Module in 2- to 4-year-old and 5- to 7-year-old and the PedsQL 4.0 Generic Core Scales in 5- to 7-year-old in childhood cancer.Amaç: Çalışmamızın amacı, çocukluk çağı kanserlerinde Çocuklar için Yaşam Kalitesi Ölçeği (ÇİYKÖ) 3.0 Kanser Modülü Türkçe versiyonunun 2-7 yaşları arasındakiler için ve ÇİYKÖ 4.0 Genel Skalası’nın 5-7 yaşları arasındakiler için geçerliliğini ve güvenilirliğini araştırmaktır. Gereç ve Yöntemler: ÇİYKÖ 3.0 Kanser Modülü ve ÇİYKÖ 4.0 Genel Skalası Hacettepe Üniversitesi’ndeki kanserli çocuklara ve ebeveynlerine uygulanmıştır. Cronbach’s alpha kullanılarak iç tutarlılık, sınıf içi korelasyon katsayısı (SKK) kullanılarak test-retest güvenirliği belirlenmiştir. Yapı geçerliliği ÇİYKÖ 3.0 Kanser Modülü ile ÇİYKÖ 4.0 Genel Skalası sonuçlarının karşılaştırılmasıyla değerlendirilmiştir. Bulgular: ÇİYKÖ 3.0 Kanser Modülü’nün Cronbach’s alpha değerleri 0,803-0,873 arasında, ÇİYKÖ 4.0 Genel Skalası’nın ise 0,665-0,841 arasında değişiklik göstermektedir. Test-retest SKK değerleri ise ÇİYKÖ 3.0 Kanser Modülü’nde 0,877-0,949 arasında, ÇİYKÖ 4.0 Genel Skalası’nda ise 0,681-0,824 arasında değişiklik göstermektedir. ÇİYKÖ Kanser Modülü ile Genel Skalası’nın alt başlık skorlarının korelasyonlarının mükemmel-orta düzeyde olduğu gösterilmiştir. ÇİYKÖ Kanser Modülü Çocuk Formu ile Ebeveyn Formu arasındaki ilişki çok iyi düzeyde korele (r=0,694, p0,001), ÇİYKÖ Genel Skalası’nda ise iyi düzeyde koreledir (r=0,540, p=0,002). Sonuç: Bu çalışma ÇİYKÖ 3.0 Kanser Modülü’nün Türkçe versiyonunun 2-4 yaş ile 5-7 yaşları arasındaki ve ÇİYKÖ 4.0 Genel Skalası Türkçe versiyonunun 5-7 yaşları arasındaki kanserli çocuklarda geçerli, güvenilir ve uygulanabilir olduğunu göstermiştir.

Background Posterior reversible encephalopathy syndrome (PRES) is a clinical and radiologic condition characterized by headache, seizures, impaired vision, acute hypertension, and typical cranial MRI findings. Observation A 10-year-old boy with FLT3-ITD-positive acute myelogenous leukemia who developed PRES during sorafenib treatment has been presented here. In English literature, there are 2 adult patients with metastatic cholangiocarcinoma or hepatocellular carcinoma who developed PRES under sorafenib treatment. Our patient is the first pediatric case with the diagnosis of acute myelogenous leukemia who developed PRES that might be attributed to sorafenib use. Conclusions Thus, PRES might be a rare, potentially serious, but manageable, side effect of sorafenib that should be kept in mind by pediatric hematologists and oncologists.

We report an infant diagnosed with Majewski osteodysplastic primordial dwarfism type II at age 8 months, who experienced cerebrovascular morbidities related to this entity. Molecular analysis identified c.2609+1 G>A, intron 14, homozygous splice site mutation in the pericentrin gene. At age 18 months, she developed recurrent strokes and hemiparesis. Brain magnetic resonance imaging and magnetic resonance angiography showed abnormal gyral pattern, cortical acute infarcts, bilateral stenosis of the internal carotid arteries and reduced flow on the cerebral arteries, consistent with moyamoya disease. In Majewski osteodysplastic primordial dwarfism type II, life expectancy is reduced because of high risk of stroke secondary to cerebral vascular anomalies (aneurysms, moyamoya disease). Periodic screening for vascular events is recommended in individuals with Majewski osteodysplastic primordial dwarfism type II every 12–18 months following diagnosis. Our patient was medically managed with low molecular weight heparin followed with aspirin prophylaxis, in addition to carbamazepine and physical rehabilitation. Conclusion: We report an infant with moyamoya disease and recurrent stroke presenting 10 months after diagnosis (at age 18 months), and discuss the outcome of nonsurgical medical management. The presented case is the second youngest case developing stroke and moyamoya disease.

Aim: The aim of this study was to analyze the hematological features in children with systemic lupus erythematosus (SLE) and to review our current treatment protocols. Methods: We evaluated hematological findings of 43 children with SLE diagnosed and followed at the Pediatric Rheumatology Division of Hacettepe University, Turkey. Thirty-seven patients with hematological abnormalities were analyzed in detail. Results: Median age at presentation was 13 years. Hematological involvement was seen in 86% of patients. The most common hematological finding was anemia ( n = 30). Anemia was either a Coombs (+) hemolytic one, or was due to other causes. Hemolytic anemia was treated with steroids and intravenous gamma globulin (IVIG). Leucopenia and thrombocytopenia were detected in 35.1 % and 37.8 %, respectively. Bone marrow aspiration was performed in 15, mainly for cytopenia. Secondary dysplastic changes were common. Acute lymphoblastic leukemia (ALL) was diagnosed in one patient. Six patients were diagnosed as having macrophage activation syndrome (MAS). One patient died due to secondary infections and multiorgan failure despite aggressive treatment. In patients diagnosed early, treatment with steroids and cyclosporine resulted in an excellent response. Thrombotic microangiopathy was detected in two patients. Both were treated successfully with steroids and plasma exchange. Antiphospholipid and anticardiolipin antibodies were positive in 12 and 15 of the patients, respectively. Five developed deep vein thrombosis (DVT), one cerebral sinus thrombosis and one presented with purpura fulminans. They were effectively treated with anticoagulation protocol. Conclusion: Hematological findings should be carefully assessed and treated vigorously to prevent the morbidity and possible mortality.

The 'RASopathies' are a group of disorders sharing many clinical features and a common pathophysiology. In this study, we aimed to clinically evaluate a group of Turkish patients and elucidate the underlying genetic etiology. Thirty-one patients with a clinical diagnosis of one of the RASopathy syndromes were included in the study. Of these, 26 (83.8%) had a clinical diagnosis of Noonan syndrome, whereas 5 had a clinical diagnosis of either Costello, LEOPARD or cardio-facio-cutaneous syndromes. Twenty of 31 (64.5%) patients were found to be mutation positive. Mutations in PTPN11, SOS1 and SHOC2 genes were detected in patients with Noonan syndrome (57.6%). Mutations in MEK1, PTPN11, BRAF and HRAS genes were detected in the remaining. Pulmonary stenosis was the most common (61.5%) cardiac anomaly. Among Noonan syndrome patients with a confirmed mutation, mild intellectual disability tended to be more common in patients with PTPN11 mutation than in those with SOS1 mutation. Hematologic evaluation revealed coagulation defects in three Noonan syndrome patients with a mutation. This is currently the largest clinical and molecular study in Turkish RASopathy patients. Our findings indicate that molecular epidemiology and genotype-phenotype correlations in RASopathies are relatively independent from the ethnic population background.

Hemophagocytic lymphohistiocytosis (HLH) may develop secondary to infections, malignancies, immune deficiency syndromes, and rheumatologic and metabolic disorders. Associations between HLH and inborn errors of metabolism, including lysinuric protein intolerance, multiple sulfatase deficiency, galactosemia, Gaucher disease, Pearson syndrome, and galactosialidosis, have previously been reported in the literature. In this report the authors present 3 children with disorders of propionate metabolism--1 with methylmalonic acidemia and 2 with propionic acidemia--who developed secondary HLH during their metabolic attacks. All patients fulfilled the 5 HLH criteria of the Histiocyte Society. Familial HLH was ruled out by molecular analysis. Plasma exchange was performed for 2 of them. Unfortunately 1 died of multiorgan failure despite intensive therapy. This is the first report of such an association.

Numerous acquired etiological factors, such as infections, malignancies, and collagen tissue disorders, are involved in the development of acquired hemophagocytic lymphohistiocytosis (AHLH). Not everyone with the same etiological factors developments AHLH, which suggests the role of additional genetic or environmental predisposing factors that remain to be identified.Perforin gene A91V missense transition (CT change at position 272 in exon 2 of the perforin gene) and TNF-α gene promoter-1031 TC nucleotide substitution are 2 candidate genetic predisposing factors due to their potential to alter inflammatory responses. In the present study these changes were investigated in healthy controls and AHLH patients.A91V transition was observed in 7 of the 159 (4.4%) controls. Among the 44 AHLH patients, 5 (11.3%) were heterozygous and the difference in the frequency of A91V transition, although striking (odds ratio: 2.8), was not statistically significant (p=0.09). All A91V-positive patients had infection. TNF-α-1031 TC polymorphism was examined in 164 healthy controls and 40 AHLH patients, and the CC risk-elevating genotype was noted in 7 (4.3%) of the controls and 1 (2.5%) of the AHLH patients. The frequency of C and T alleles was 22.5% (n=18) and 77.5% (n=62) among the AHLH patients, and 22% (n=72) and 78% (n=259) among the controls, respectively. There wasn't a statistically significant difference between the groups in terms of allele frequencies (p0.05).The present results indicate that compared to controls, A91V mutation was 2.8-fold more prevalent (according to the odds ratio) in the AHLH patients. A91V mutation is not uncommon in the general population and increases the risk of AHLH in patients with an underlying condition, especially those with an underlying infection.AMAÇ: Edinsel hemofagositik lenfohistiositozun (EHL) gelişmesinde enfeksiyonlar, habis hastalıklar, kollajen doku hastalıkları gibi çok çeşitli etmen rol oynamaktadır. Aynı tetikleyici faktörü bulunan hastaların tümünde EHL’un gelişmemesi EHL’ye yatkınlık yapan ek genetik ve çevresel faktörlerin varlığına işaret etmektedir. YÖNTEMLER: Perforin geninde A91V yanlış anlam değişikliği (perforin geninde ekzon 2, pozisyon 272’de CT değişikliği) ve tumor nekrozis faktör (TNF)-α geninin promoter bölgesinde –1031TC nükleotid değişikliği inflamatuvar yanıtı değiştirebilen ve bu nedenle EHL’ye yatkınlığa neden olabilen iki potansiyel adaydır. Çalışmamızda EHL’li hastalar ve kontrollerde bu değişiklikler incelenmiştir.159 sağlıklı Türk popülasyonunda A91V değişikliği 7 (%4.4) kişide saptanmıştır. 44 EHL olgusunun beşinde (%11.3) bu değişiklik saptanmış olup, fark dikkat çekici olmakla birlikte istatistiksel anlamlılık göstermemiştir (p=0.09); odds oranı 2.8 olarak hesaplanmıştır. A91V pozitif olan hastaların tümünde enfeksiyon altta yatan etiolojik nedendi. TNF-α -1031TC polimorfizmi 164 sağlıklı birey ve 40 EHL’li hastada çalışıldı. Kontrollerin 7’sinde (%4.3) ve EHL bulunan hastaların 1’inde (%2.5) riski artıran CC genotipi saptandı. C ve T allel frekansları sırasıyla EHL’de 18 (%22.5) ve 62 (%77.5), kontrollerde 72 (%22) ve 259 (%78) olarak bulundu. Allel frekansları açısından gruplar arasında fark saptanmadı (p0.05). SONUÇ: Çalışmamızın sonuçları edinsel HLH’li hastalarda sağlıklı kontrollara göre A91V sıklığının 2.8 kat odds oranına göre daha sık olduğunu, A91V’nin sağlıklı Türk populasyonunda nadir olmadığını ve özellikle enfeksiyonu olanlarda EHL’ye yatkınlık yapabileceğini göstermektedir.

SUMMARYWe evaluated the incidence of varicella-zoster virus (VZV) infections, including herpes zoster (HZ), and investigated the associated risk factors for HZ and compared lymphocyte subsets of these patients at 1, 3 and 6 months following haematopoietic stem cell transplantation (HSCT) in a case-control study in children and adolescents. The incidence of HZ infection at the first year after HSCT was 17/125 (13·6%). The cumulative incidence of HZ infection was 22/125 (17·6%). Sixteen (73%) cases with HZ and 11 (32%) cases in the control group had a diagnosis of malignant disorder. No significant difference was noted between the HZ group and the control group in absolute lymphocyte number and subsets (except WBC) at the pre-transplant evaluation. Pre-transplant WBC count was statistically lower in the HZ group (P

Introduction Juvenile myelomonocytic leukemia (JMML) is a unique, aggressive hematopoietic disorder of childhood caused by excessive proliferation of cells of monocytic and granulocytic lineages. Childhood JMML is classified as a bridging disorder between myelodysplastic syndrome (MDS) and myeloproliferative diseases.More than 95% of JMML patients are diagnosed under the age of six years. Children with JMML mostly present with hepatosplenomegaly, lymphadenopathy, bleeding, anemia, fever, recurrent infections, rash, failure to thrive and pulmonary disease. Approximately 90% of patients carry either somatic or germline mutations of PTPN-11,K-RAS,N-RAS,CBL or NF-1 in their leukemic cells. Aim We want to describe the clinical and laboratory features in 55 cases of JMML seen at the Hacettepe University Pediatric Hematology Department during a 18 year period (January 2000-June 2018). Patients & Methods There were 38 males and 17 females aged between 1 months and 168 months (median 36 months). On admission mean Hb, WBC and platelet was found to be 9.1±1.9 g/dl (range 5.7-14.6g/dl), 38.7±4.3 x10 3 µ/L (range 1.4 - 214 x10 3 µ/L) and 156 ± 7.8x 109 range (8-1598x109/L) , respectively.Results of cytogenetic analysis showed monosomy 7/7qdel in 16 cases.Somatic PTPN11 mutation was found in 23 children whereas somatic KRAS mutation in 7 and germline mutation in one case, somatic NRAS mutation in 3 cases and c-CBL mutation in 5 cases. On admission 49% of patients had no blast cells on the peripheral blood smear.But 3 of 55 patients had 100% blast cells in peripheral blood smear.Monosomy 7 mutation was positive in all of these 3 patients and one of these case had an history of familial MDS and a positive GATA mutation, one other had NF-1 mutation.All three patients were died despite hematopoietic stem cell transplantation(HSCT). On admission, 7 out of 55 patients had >30% blast cells in bone marrow aspiration and 3 of them had %100 blast cells on the peripheral smear. The rest of this group except one who had a positive KRAS mutation and diagnosed as AML-M4 were treated with HSCT and 4/6 were stil alive.On the other hand, 7 out of 55 patients had 20-30% blast cells in bone marrow aspiration on admission and none of these patients had neither monosomy 7/7qdel nor trisomy 8 mutation. c-CBL mutation was found to be positive in 5 case and all were still alive (two siblings with c-CBL and one other patient had a diagnosis of juvenile xanthogranulamatosis), and one patient with c-CBL mutation had a diagnosis of portal hypertension.On the other hand two siblings with monosomy 7 have a diagnosis of GATA mutation and both were died after HSCT.Almost 40% of this pediatric group (20/55) were died after a median follow up time 16 months (1-211 months). Discussion JMML is a clonal hematopoietic disorder of infancy and early childhood which results from oncogenic mutations in genes involved in the Ras pathway and allogeneic HSCT remains the only curative treatment more than 50% of patients.However, the timing of diagnosis and treatment is critical to outcome.Prompt HSCT is recommended for all children with NF1, somatic PTPN11 and KRAS mutations, and for most children with somatic NRAS mutations.'Watch and wait' strategy is usually for the group of patients with germline CBL mutations, specific somatic NRAS mutation, and in Noonan syndrome patients, cause spontaneous resolution has been reported in this group. Our results were compatible with the literature , however it seems that in our group despite allogeneic HSCT, relapse is the main treatment failure. Disclosures Niemeyer: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Gray platelet syndrome (GPS) is an inherited bleeding disorder characterized by macrothrombocytopenia and absence of platelet α-granules resulting in typical gray platelets on peripheral smears. GPS is associated with a bleeding tendency, myelofibrosis, and splenomegaly. Reports on GPS are limited to case presentations. The causative gene and underlying pathophysiology are largely unknown. We present the results of molecular genetic analysis of 116 individuals including 25 GPS patients from 14 independent families as well as novel clinical data on the natural history of the disease. The mode of inheritance was autosomal recessive (AR) in 11 and indeterminate in 3 families. Using genome-wide linkage analysis, we mapped the AR-GPS gene to a 9.4-Mb interval on 3p21.1-3p22.1, containing 197 protein-coding genes. Sequencing of 1423 (69%) of the 2075 exons in the interval did not identify the GPS gene. Long-term follow-up data demonstrated the progressive nature of the thrombocytopenia and myelofibrosis of GPS resulting in fatal hemorrhages in some patients. We identified high serum vitamin B12 as a consistent, novel finding in GPS. Chromosome 3p21.1-3p22.1 has not been previously linked to a platelet disorder; identification of the GPS gene will likely lead to the discovery of novel components of platelet organelle biogenesis. This study is registered at www.clinicaltrials.gov as NCT00069680 and NCT00369421.