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.

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.

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.

Subtle differences in CTL cytotoxicity determine susceptibility to hemophagocytic lymphohistiocytosis in mice and humans with Chediak-Higashi syndrome.

Perforin-mediated cytotoxicity is important for controlling viral infections, but also for limiting immune reactions. Failure of this cytotoxic pathway leads to hemophagocytic lymphohistiocytosis (HLH), a life-threatening disorder of uncontrolled T-cell and macrophage activation. We studied susceptibility to HLH in 2 mouse strains (souris and beige(J)) and a cohort of patients with partial defects in perforin secretion resulting from different mutations in the LYST gene. Although both strains lacked NK-cell cytotoxicity, only souris mice developed all clinical and histopathologic signs of HLH after infection with lymphocytic choriomeningitis virus. The 2 strains showed subtle differences in CTL cytotoxicity in vitro that had a large impact on virus control in vivo. Whereas beige(J) CTLs eliminated lymphocytic choriomeningitis virus infection, souris CTLs failed to control the virus, which was associated with the development of HLH. In LYST-mutant patients with Chediak-Higashi syndrome, CTL cytotoxicity was reduced in patients with early-onset HLH, whereas it was retained in patients who later or never developed HLH. Thus, the risk of HLH development is set by a threshold that is determined by subtle differences in CTL cytotoxicity. Differences in the cytotoxic capacity of CTLs may be predictive for the risk of Chediak-Higashi syndrome patients to develop HLH.

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.

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.

Typhlitis in acute childhood leukemia.

OBJECTIVE: To review our experience with typhlitis among children treated for acute leukemia. MATERIAL AND METHODS: The medical records of children with acute leukemia and typhlitis between 2006 and 2009 were reviewed for demographics and symptoms, and for microbiological and imaging findings. RESULTS: In the 75 children with acute leukemia--54 with acute lymphoblastic leukemia (ALL) and 21 with acute myeloid leukemia (AML)--there were 10 episodes of typhlitis (4.5%) that developed during 221 periods of severe neutropenia. The cumulative risk of typhlitis was 7.4% in patients with ALL and 28.5% in patients with AML. Frequent symptoms were: abdominal pain and tenderness (100% each); fever and nausea (90% each); emesis (80%); diarrhea (50%), and hypotension, peritonitis and abdominal distension (10% each). The median duration of symptoms was 6 days (range: 2-11 days), and that of neutropenia 14 days (range: 3-25 days). All patients were treated medically and none surgically. Two patients died because of typhlitis and sepsis. CONCLUSIONS: In our study, the rate of typhlitis among leukemic children was 4.5%; however, the mortality rate was 20%. Thus, rapid identification and timely, aggressive medical intervention are necessary to reduce the morbidity and mortality from typhlitis.

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.

The association of oxidant status and antioxidant capacity in children with acute and chronic ITP.

PURPOSE: This study was undertaken to investigate oxidant and antioxidant systems in patients with immune thrombocytopenic purpura (ITP). With this purpose, we measured the levels of serum malondialdehyde (MDA), total antioxidant capacity (TAC), total oxidant status (TOS), and other oxidative stress parameters. PATIENTS AND METHODS: Fifty-two pediatric patients with ITP (25 acute, 27 chronic) and 21 healthy children were included in the study. Patients with acute ITP were studied, before and after, methylprednisolone treatment. RESULTS: Hemoglobin, hematocrit, platelet count, and TAC were statistically significantly lower in patients with acute ITP before treatment than those in the control group (P<0.05). In addition, in this group, MDA, TOS levels, and OSI (oxidative stress index) were found to be higher than those in the control group. In chronic ITP group, although hemoglobin hematocrit, platelet counts, and TAC levels were statistically significantly lower than those in the control groups,the mean platelet volume, MDA, TOS, and OSI were found to be statistically significantly higher (P<0.05). Platelet count and mean platelet volume values were statistically significantly lower in patients with acute ITP before treatment than after treatment (P<0.05). We also found a positive correlation between thrombocyte count and TAC, in patients with acute ITP before treatment (r: 0.601, P<0.001) and acute ITP after treatment (r: 0.601, P<0.001) and chronic ITP (r: 0.601, P<0.001). A negative correlation was found between thrombocyte count and serum MDA levels, in patients with acute ITP before treatment (r: -0.356, P<0.001) and acute ITP after treatment (r: -0.356, P<0.001) and chronic ITP (r: -0.356, P<0.001). We also found a negative correlation between thrombocyte count and serum OSI, in patients with acute ITP before treatment (r: -0.494, P<0.001) and acute ITP after treatment (r: -0.494, P<0.001) and chronic ITP (r: -0.494, P<0.001). A negative correlation was found between thrombocyte count and TOS, in patients with acute ITP before treatment (r: -0.470, P<0.001) and acute ITP after treatment (r: -0.470, P<0.001) and chronic ITP (r: -0.470, P<0.001). In conclusion, increased MDA, TOS and OSI, and decreased TAC levels were found in patients with acute and chronic ITP. CONCLUSIONS: On the basis of these findings, we suggest that free oxygen radicals may have an effect on the structural and functional damage of platelets, and on the mechanism of thrombocytopenia in both, acute and chronic ITP.

A new hemostatic agent--Ankaferd blood stopper: management of gastrointestinal bleeding in an infant and other experiences in children.

Ankaferd blood stopper (ABS) is a standardized medicinal plant extract that stimulates the formation of an encapsulated protein network that provides focal points for erythrocyte aggregation. It has a therapeutic potential to be used for the management of external hemorrhage. Here, the authors report an infant bleeding from peptic ulcer was stopped successfully by gastroscopic application of ABS and other cases that used topical ABS for mucosal bleedings are also presented.

Clinical and laboratory data of primary hemophagocytic lymphohistiocytosis: A retrospective review of the Turkish Histiocyte Study Group.

OBJECTIVE: This study analyzes the clinical and laboratory findings of children with primary hemophagocytic lymphohistiocytosis (HLH) followed in various referral centers of Turkey. METHODS: A simple three-page questionnaire prepared by the Turkish Histiocyte Study Group was used for documentation of patient data. RESULTS: Age at diagnosis varied from 0.6 to 78 months (median±SD, 16.5±26.1). Sex distribution was almost equal (F/M=10/12). The frequencies of parental consanguinity and sibling death in the family history were 100% and 81.1%, respectively. The most common clinical findings were hepatomegaly (100%) and fever (95%). The most common laboratory findings were anemia (100%), hyperferritinemia (100%) and thrombocytopenia (90.9%). Triglyceride and total bilirubin levels in the deceased versus surviving group appear to be high (triglyceride: 394±183 mg/dl, 289±7 mg/dl; total bilirubin: 2.7±6.9 mg/dl, 0.5±1.2 mg/dl, respectively). CONCLUSION: We concluded that fever, hepatosplenomegaly, anemia, thrombocytopenia, and hyperferritinemia are the most common clinical and laboratory findings in primary HLH. Increased triglyceride and total bilirubin level at the time of diagnosis might be an indicator of poor prognosis in HLH.

Avian influenza A (H5N1) infection in eastern Turkey in 2006.

BACKGROUND: An outbreak of highly pathogenic avian influenza A (H5N1) that had previously been detected throughout Asia, with major economic and health repercussions, extended to eastern Turkey in late December 2005 and early January 2006. METHODS: We documented the epidemiologic, clinical, and radiologic features of all cases of confirmed H5N1 virus infection in patients who were admitted to Yuzuncu Yil University Hospital in Van, Turkey, between December 31, 2005, and January 10, 2006. RESULTS: H5N1 virus infection was diagnosed in eight patients. The patients were 5 to 15 years of age, and all eight had a history of close contact with diseased or dead chickens. The mean (+/-SD) time between exposure and the onset of illness was 5.0+/-1.3 days. All the patients had fever, and seven had clinical and radiologic evidence of pneumonia at presentation; four patients died. Results of enzyme-linked immunosorbent assay and rapid influenza tests were negative in all patients, and the diagnosis was made by means of a polymerase-chain-reaction assay. CONCLUSIONS: H5N1, which causes a spectrum of illnesses in humans, including severe and fatal respiratory disease, can be difficult to diagnose.

A novel L218P mutation in NADH-cytochrome b5 reductase associated with type I recessive congenital methemoglobinemia.

The presence of central cyanosis that is unrelated to cardiopulmonary causes alerts clinicians to a possible diagnosis of methemoglobinemia. Congenital methemoglobinemia due to deficiency of nicotinamide-adenine dinucleotide (NADH)-cytochrome b5 reductase (cb(5)r) is an autosomal recessive disorder characterized by life long cyanosis. Here we report a six-year old boy who presented with central cyanosis and upon examination revealed a methemoglobin level of 19.0%. Sequencing the CYB5R3 gene identified a homozygous T-->C transition at base c.653, which changed codon 218 from leucine to proline (L218P) in cb(5)r protein. Treatment with ascorbic acid relieved the cyanosis and returned methemoglobin levels to normal.

Clinical and molecular aspects of Turkish familial hemophagocytic lymphohistiocytosis patients with perforin mutations.

The aim of this study was to elucidate the pathologic sequence changes and associated clinical phenotypes in 9 new patients showing homozygosity for perforin gene among a total of 37 (24%) Turkish FHL families studied by linkage analysis. These 9 unrelated patients (5M/4F) were coming from consanguineous families and their presentation ages of systemic symptoms were ranged from birth to 15 years. Direct sequencing of coding exons of the perforin gene led to the identification of five different homozygous alterations. The nonsense W374X mutation was identified in three patients while four different missense mutations namely G149S, V50M, A91V and novel A523D were detected in the rest six patients.

Acute myeloblastic leukemia-associated Marfan syndrome and Davidoff-Dyke-Masson syndrome: a case report.

We present herein a 23-year-old man with acute myeloblastic leukemia (AML) associated with Davidoff-Dyke-Masson syndrome (DDMS) and Marfan syndrome (MS). The diagnosis of DDMS was based on findings including left facial asymmetry, left hemiparesis, mental retardation, right cerebral hemiatrophy, dilatation of the ipsilateral lateral ventricle and calvarial thickening. The diagnosis of MS was based on clinical findings including tall stature, myopia, retinitis pigmentosa, blue scleras, scoliosis, pectus excavatum, arachnodactyly and low ratio of upper/lower body segment. The patient developed hepatosplenomegaly, gingival hypertrophy and pancytopenia. Peripheral blood film and bone marrow examination showed that most of nucleated cells were blasts; immunophenotype of those cells showed CD11+, CD13+, CD14+, CD33+ and HLA-DR+. These findings confirmed the diagnosis of AML (FAB-M5). After induction chemotherapy, remission was obtained. To the best of our knowledge, our case is the third report of AML in MS syndrome, while AML associated with DDMS and MS has not been previously reported in the literature.

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.