Homozygous c.130-131 ins A (pW44X) mutation in the HAX1 gene as the most common cause of congenital neutropenia in Turkey: Report from the Turkish Severe Congenital Neutropenia Registry.

BACKGROUND: Severe congenital neutropenia is a rare disease, and autosomal dominantly inherited ELANE mutation is the most frequently observed genetic defect in the registries from North America and Western Europe. However, in eastern countries where consanguineous marriages are common, autosomal recessive forms might be more frequent. METHOD: Two hundred and sixteen patients with severe congenital neutropenia from 28 different pediatric centers in Turkey were registered. RESULTS: The most frequently observed mutation was HAX1 mutation (n = 78, 36.1%). A heterozygous ELANE mutation was detected in 29 patients (13.4%) in our cohort. Biallelic mutations of G6PC3 (n = 9, 4.3%), CSF3R (n = 6, 2.9%), and JAGN1 (n = 2, 1%) were also observed. Granulocyte colony-stimulating factor treatment was given to 174 patients (80.6%). Two patients died with infectious complications, and five patients developed myelodysplastic syndrome/acute myeloblastic leukemia. The mean (± mean standard error) follow-up period was 129.7 ± 76.3 months, and overall survival was 96.8% (CI, 94.4-99.1%) at the age of 15 years. In Turkey, severe congenital neutropenia mostly resulted from the p W44X mutation in the HAX1 gene. CONCLUSION: In Turkey, mutation analysis should be started with HAX1, and if this is negative, ELANE and G6PC3 should be checked. Because of the very high percentage of consanguineous marriage, rare mutations should be tested in patients with a negative mutation screen.

Kala-Azar and leukemia: A rare association.

Visceral leishmaniasis is an infectious disease that infects and multiplies in macrophages of the liver, spleen, and bone marrow. The most common clinical features are fever, splenomegaly, and anemia. Anemia, leucopenia, and thrombocytopenia are the main hematologic abnormalities commonly seen in visceral leishmaniasis. These findings can be seen in several types of hematologic disorders. The findings are similar to most hematologic disorders and so may make diagnosis problematic. It is difficult to confirm when it is seen except in epidemiologic areas. It can be fatal if it is not treated and appropriate treatment can be lifesaving. In this article a 12 year-old male patient who was followed-up with diagnosis of acute lymphoblastic leukemia and received maintenance therapy while being under remission after BFM-ALL-2000 treatment protocol and diagnosed with hemophagocytic lymphohistiocytosis due to Kala-azar during this period was presented.

A National Registry of Thalassemia in Turkey: Demographic and Disease Characteristics of Patients, Achievements, and Challenges in Prevention.

OBJECTIVE: The Turkish Society of Pediatric Hematology set up a National Hemoglobinopathy Registry to demonstrate the demographic and disease characteristics of patients and assess the efficacy of a hemoglobinopathy control program (HCP) over 10 years in Turkey. MATERIALS AND METHODS: A total of 2046 patients from 27 thalassemia centers were registered, of which 1988 were eligible for analysis. This cohort mainly comprised patients with ß-thalassemia major (n=1658, 83.4%) and intermedia (n=215, 10.8%). RESULTS: The majority of patients were from the coastal areas of Turkey. The high number of patients in Southeastern Anatolia was due to that area having the highest rates of consanguineous marriage and fertility. The most common 11 mutations represented 90% of all ß-thalassemia alleles and 47% of those were IVS1-110(G->A) mutations. The probability of undergoing splenectomy within the first 10 years of life was 20%, a rate unchanged since the 1980s. Iron chelators were administered as monotherapy regimens in 95% of patients and deferasirox was prescribed in 81.3% of those cases. Deferasirox administration was the highest (93.6%) in patients aged <10 years. Of the thalassemia major patients, 5.8% had match-related hemopoietic stem cell transplantation with a success rate of 77%. Cardiac disease was detected as a major cause of death and did not show a decreasing trend in 5-year cohorts since 1999. CONCLUSION: While the HCP has been implemented since 2003, the affected births have shown a consistent decrease only after 2009, being at lowest 34 cases per year. This program failure resulted from a lack of premarital screening in the majority of cases. Additional problems were unawareness of the risk and misinformation of the at-risk couples. In addition, prenatal diagnosis was either not offered to or was not accepted by the at-risk families. This study indicated that a continuous effort is needed for optimizing the management of thalassemia and the development of strategies is essential for further achievements in the HCP in Turkey.

Granulocyte Transfusion Therapy in Childhood.

Despite the use of new broad-spectrum anti-bacterial and anti-fungal agents, infections still represent the major cause of morbidity and mortality in patients with prolonged neutropenia after intensive chemotherapy. The aim of this study is to assess the effect and safety of granulocyte transfusions (GTs) for the treatment of severe life-threatening infections in pediatric patients with febrile neutropenia. In this study, 13 pediatric patients with high-risk febrile neutropenia, who received 24 GTs, were included. GTs were well tolerated in all patients. Upon 24 h post-transfusion, neutrophil and platelet counts increased significantly, when compared to the baseline values. The clinical response and hematologic response rates were 69.2 % respectively. In conclusion, GT is safe and effective in controlling life-threatening infections. Furthermore, randomized controlled studies with long-term follow-up are needed to assess the exact role of GT in the outcome of patients with neutropenia.

Neonatal Outcomes of Pregnancy with Immune Thrombocytopenia.

Neonates born to mothers with immune thrombocytopenia (ITP) have an increased risk for neonatal thrombocytopenia and hemorrhagic complications. The aim of this study was to determine the maternal and neonatal outcomes of pregnancies with ITP and also to identify risk factors that predicts neonatal thrombocytopenia. We performed a retrospective analysis of 40 pregnancies with ITP and their 40 neonates. Among the 40 neonates, thrombocytopenia (platelet count of less than 150 × 109/L) was detected in 15 neonates (37.5 %) whom 8 of them had severe thrombocytopenia (platelet count of less than 50 × 109/L). Ten of the 15 neonates with thrombocytopenia required treatment to increase the platelet counts. There was statistically significant association between neonatal thrombocytopenia and maternal splenectomy history and maternal duration of thrombocytopenia. There was no statistically significant correlation between maternal platelet count and neonatal platelet count. Clinicians should pay special attention in these neonates because of risk for development of neonatal thrombocytopenia. Maternal and neonatal outcomes in patients with idiopathic thrombocytopenic purpura is generally good.

Therapeutic plasma exchange in primary hemophagocytic lymphohistiocytosis: Reports of two cases and a review of the literature.

We report two children who were diagnosed as having primary hemophagocytic syndrome and who successfully underwent therapeutic plasma exchange (TPE). The first patient was a 6-month-old girl diagnosed with HLH who was admitted to the pediatric intensive care unit. The patient's clinical condition worsened on the 9th day of the HLH-2004 treatment protocol. Her ferritin level was found 50.000 ng/mL, and TPE was performed for 9 sessions, after which her clinical condition and laboratory findings improved. The patient is still on the HLH-2004 protocol and waits for a suitable stem cell transplantation donor. Case 2 involved a Syrian girl with HLH under follow-up who was receiving the HLH-2004 treatment protocol for reactivation. She presented to emergency department with fever, where her ferritin level was measured greater than 100.000 ng/mL; she was then transferred to the pediatric intensive care unit where four sessions of TPE were performed, after which her clinical condition and laboratory findings improved. However, the patient was admitted again one month later with gastrointestinal bleeding and died despite all efforts. By describing these two cases, we wish to emphasize that TPE can produce a rapid improvement until the time of stem cell transplantation in patients with hemophagocytic syndrome who do not respond to traditional treatments.

Hemoglobin H Disease in Turkey: Experience from Eight Centers.

The purpose of this study was to research the problem of hemoglobin H (HbH) disease, to reveal the distribution patterns among different health centers, and to emphasize the importance of this disease for Turkey. A total of 273 patients were included from 8 hemoglobinopathy centers. The Antakya Hemoglobinopathy Center reported 232 patients and the remaining 7 centers reported 41 patients. PubMed was also searched for published articles related to Turkish patients with HbH disease, and we found 16 articles involving a total of 198 HbH patients. Most of the patients were reported from Antakya; thus, special attention should be paid to this region. This is a preliminary study to investigate the extent of the problem of HbH disease and it emphasizes the need for hematology associations or the Ministry of Health to record all cases of HbH disease in Turkey.

Conservative management of an acute spinal epidural hemorrhage in a child with hemophilia a with inhibitor.

Hemophilia A is an inherited, X-linked, recessive disorder caused by deficiency of clotting factor VIII. Central nervous system hemorrhage is an uncommon complication in patients with hemophilia. We report the case of a 5-year-old child who had intraspinal hematoma with nonsurgical, conservative management. It should be kept in mind that the optimal management is decided according to patient's condition because of high morbidity and mortality.

A rare combination: congenital factor VII deficiency with Chiari malformation.

Congenital factor (VII) deficiency is a rare bleeding disorder. We present a patient with congenital FVII deficiency and congenital hydrocephalus who underwent a ventriculoperitoneal shunt operation and needed no prophylaxis after the procedure.

Prognostic Factors and Long-Term Outcome in 52 Turkish Children With Hemophagocytic Lymphohistiocytosis.

OBJECTIVES: Hemophagocytic lymphohistiocytosis is a syndrome of pathologic immune activation that shares similar clinical and laboratory phenotypes with severe sepsis. Recent studies led to better recognition of hemophagocytic lymphohistiocytosis by clinicians, but no consensus exists on the criteria for high-risk patients. DESIGN: We retrospectively reviewed the medical records of patients diagnosed with hemophagocytic lymphohistiocytosis to analyze the risk factors associated with poor outcome. SETTING: Pediatric intensive care and hematology units of three tertiary hospitals in Turkey. PARTICIPANTS: Fifty-two children with hemophagocytic lymphohistiocytosis. INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS: There were a total of 52 children meeting the diagnostic criteria of Histiocytic Society. Of them, 28 (54%) had a primary hemophagocytic lymphohistiocytosis. Mutation studies were performed in 18 of 28 patients (65%). Fourteen of them had PRF1, STX11, STXBP2, and UNC13D mutations, and four had Rab27a and LYST mutations. The remaining 24 patients (46%) were defined as having secondary hemophagocytic lymphohistiocytosis. Twenty-one of them had infection-associated hemophagocytic lymphohistiocytosis, and three had lysinuric protein intolerance. The mortality rate was significantly higher in primary hemophagocytic lymphohistiocytosis (64%) than in secondary hemophagocytic lymphohistiocytosis (16%) (p < 0.05). There were no significant differences for survival rate between hemophagocytic lymphohistiocytosis 94 (44%) and hemophagocytic lymphohistiocytosis 2004 (64%) protocols (p > 0.05). Age below 2 years, hyperferritinemia, thrombocytopenia, high disseminated intravascular coagulation score at diagnosis, and no clinical response at 2 weeks of treatment were independent prognostic factors for poor prognosis. CONCLUSIONS: Our data suggest that disseminated intravascular coagulation score greater than or equal to 5 can be used in the definition of high-risk patients. Early recognition of poor risk factors has important prognostic and therapeutic implications.

Novel Βeta (ß)-Thalassemia Mutation in Turkish Children.

Beta (ß)-thalassemia is the most frequently observed hereditary blood disorder in the world. It is characterized by deficiency of hemoglobin ß-globin gene and is also a profoundly heterogeneous both at the molecular and clinical level. In the case of ß-thalassemia, there is reduced (ß(+) type) or absent (ß(o) type) synthesis of the beta chains of hemoglobin. ß-Thalassemia clinically occurs in three main forms: major, intermedia and minor according to requirement of transfusion. The objective of this study was to evaluate ß-thalassemia mutations in 89 patients ranging from 2 months to 16 years of age, who enrolled to Medical School Research and Training Hospital, Gaziantep University. The direct DNA sequence analysis was performed for mutation scanning of ß-globin gene. 89 children with ß-Thalassemia including all types were analyzed, 16 different ß-thalassemia mutations were detected. We have also identified a novel mutation (HBB.c.-80delT, rs397509430) in the promoter region (-30 TATA box) of ß-globin gene, and clinical data of patient having novel mutation was given. The ß-Thalassemia mutations were determined as ß-Thalassemia major type in 42 patients (47.19 %), ß-Thalassemia intermedia in 4 (4.49 %), ß-Thalassemia minor in 43, (48.31 %) patients. The most frequent mutation was IVS I-110 G>A, followed by IVS I-1 G>A, IVS I-6 T>C, IVS II-1 G>A, respectively.

Importance of hyperbilirubinemia in differentiation of primary and secondary hemophagocytic lymphohistiocytosis in pediatric cases.

BACKGROUND AND OBJECTIVE: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyper-inflammatory disease. It is difficult to differentiate between primary and secondary HLH based on clinical findings at the onset of disease. We aimed to find parameters that can help to differentiate primary and secondary HLH at initial diagnosis especially for physicians working in developing countries. PATIENT AND METHOD: We retrospectively analyzed data of 38 HLH patients who were admitted to the Pediatric Hematology Department of Gaziantep University between January 2009 and December 2013. RESULTS: Of 38 patients, 20 were defined as primary, and 18 were secondary HLH. The average age of primary and secondary HLH patients was 31±9 and 81±14 months, respectively (p=0.03). We found consanguinity rates significantly higher in primary HLH patients compared to secondary HLH patients (p=0.03). We found that total and direct bilirubin levels significantly increased in primary HLH patients compared to secondary HLH patients (p=0.006, p=0.044). Also, CRP levels were found markedly increased in secondary HLH patients compared to primary ones (p=0.017). CONCLUSION: We showed that cholestasis and hyperbilirubinemia findings of HLH patients at the initial diagnosis should be considered in favor of primary HLH, and an increased level of CRP should be considered in favor of secondary HLH.

Autoimmune polyglandular syndrome type 3c with ectodermal dysplasia, immune deficiency and hemolytic-uremic syndrome.

Autoimmune polyglandular syndrome (APS) is a disorder which is associated with multiple endocrine gland insufficiency and also with non-endocrine manifestations. The pathophysiology of APS is poorly understood, but the hallmark evidence of APS is development of autoantibodies against multiple endocrine and non-endocrine organs. These autoantibodies are responsible for the dysfunction of the affected organs and sometimes may also cause non-endocrine organ dysfunction. The hemolytic-uremic syndrome (HUS) is a serious and life-threatening disease which develops due to many etiological factors including autoimmune disorders. Here, we present an unusual case of APS. Ectodermal dysplasia with immune deficiency and HUS occurred concomitantly in the same patient with APS type 3c. Once the autoantibody generation was initiated in the human body, development of multiple disorders due to organ dysfunction and also autoantibody-related diseases may have occurred.

Plasma microRNA profiling of pediatric patients with immune thrombocytopenic purpura.

Immune thrombocytopenic purpura (ITP) is a commonly acquired autoimmune bleeding disorder in children. MicroRNAs (miRNAs) are small RNAs which are found in cells and circulation, and play a role in protein synthesis and regulation. In this study, we aimed to determine a biomarker for childhood ITP comparing the plasma miRNA levels of children having ITP with healthy children. A total of 86 patients with ITP and 56 healthy children followed up by the Department of Pediatric Hematology and Oncology in University of Gaziantep since July 2011 were enrolled in the study. The 86 patients with ITP were evaluated in two groups as 43 acute ITP (aITP) and 43 chronic ITP (cITP) patients. Plasma expression levels of 379 miRNAs were investigated by RT-PCR (quantitative RT-PCR) technique and they were compared between aITP, cITP, and control groups. For all miRNAs, the average of raw quantification cycle values of three groups separately in the analysis chip was accepted as the reference gene value, and normalization was done according to this value. Statistically significant differences were detected in seven miRNAs (miR-302c-3p, miR-483-5p, miR-410, miR-544a, miR-302a-3p, miR-223-3p, and miR-597) investigated between the groups with respect to the expression levels. The expression rates were found to be over 95% in miR-302c-3p and miR-483-5p, over 75% in miR-410, and over 40% in miR-544, miR-302a-3p, and miR-223-3p in all three groups. The detection of significant differences between plasma miRNA levels of aITP and cITP patients and healthy children may provide useful information in the prediction of the course of disease, determination of disease etiopathogenesis, and the development of new therapeutic modalities.

Asymmetrical crying face concomitant with Glanzmann's thrombasthenia.

We report a case of a 3-month-old Turkish girl who had clinical and laboratory features of Glanzmann's thrombasthenia associated with asymmetric crying facies (ACF). Although ACF is a minor anomaly, it should not be forgotten that it can be accompanied by major congenital anomalies and if this finding is detected, other anomalies should be investigated.

Evaluation of the plasma micro RNA expression levels in secondary hemophagocytic lymphohistiocytosis.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a life threatening hyper inflammatory disease. Micro RNAs (miRNA) are about 22 nucleotide-long, small RNAs encoded with genes, and they have regulatory functions in immune response. OBJECTIVE: To determine the miRNA expression levels of 11 secondary HLH patients, we evaluated the associations of miRNA levels with pathogenesis, clinical presentation, and prognosis of the disease. PATIENTS AND METHODS: Patients who were diagnosed with secondary HLH from January 2011 to December 2012 were included in this study. We profiled the expressions of 379 miRNAs in plasma of both HLH patients and healthy controls. Patients were evaluated regarding with age, clinical findings, miRNA expresions, laboratory data, treatment, and prognosis, by using descriptive statistics. RESULTS: A total of 11 secondary HLH patients and 11 healthy children were included in this study. miR-205-5p was expressed in all case and controls and expression level of miR-205-5p was found 6.21 fold higher than control group (p=0.01). We detected the second highest expression percent in miR-194-5p with 81% of cases and controls. Expression level of miR-194-5p was found to have 163 fold higher than controls (p= 0.009). miR-30c-5p showed 77% expression percent in cases and controls together. The expression level of this miRNA was detected 9 fold decreased in HLH patients compared to healthy children (p= 0.031). CONCLUSION: We showed that miR-205-5p, miR-194-5p and miR-30c-5p could be useful plasma biomarkers for HLH. Further research is needed in larger and homogenous study groups, especially for these miRNAs as biomarkers for HLH.

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).

The role of prohepcidin in anemia due to Helicobacter pylori infection.

BACKGROUND: Hepcidin, a key regulator of iron homeostasis, increases when inflammation and some infections occur. It plays a critical role in macrophage iron retention, which underlies inflammation/infection caused anemia. It is known that Helicobacter pylori (HP) may lead to iron deficiency (ID) due to occult blood loss or reduced iron absorption. This study investigates the role of prohepcidin, hepcidin's precursor, in ID and ID anemia (IDA) with a concurrent HP infection. METHODS: In this prospectively designed study, 15 patients with IDA and a concurrent HP infection (group 1), 11 patients with an ID and a concurrent HP infection (group 2), and 18 patients with HP infection (group 3) were observed. All groups received only HP eradication therapy. Twenty-five age- and sex-matched children without ID/IDA and HP infection were included in the study as the control group. In all groups and control group, measurements were taken for pre- and posttreatment hemoglobin, serum prohepcidin, serum ferritin, serum iron (SI), transferrin saturation, erythrocyte sedimentation rate, fibrinogen, and C-reactive protein levels. RESULTS: The pretreatment prohepcidin levels were significantly higher only in group 1 compared to the control group (P < .05). In group 1, a significant increase in hemoglobin and SI levels and a significant reduction in prohepcidin levels were additionally observed following HP eradication treatment (P < .05). However, in groups 2 and 3, significant differences in hemoglobin, iron, and prohepcidin levels between pre- and posttreatment were not observed. CONCLUSION: Elevated serum prohepcidin might indicate the role of inflammation in the etiology of anemia concurrent with HP.

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.