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The increased longevity of patients with thalassemia and sickle cell disease (SCD) introduces new clinical challenges due to the accumulation of disease-related morbidity, psychosocial issues and health care adjustments. Patients with thalassemia major now live into adulthood without suffering heart failure but must confront delayed puberty, impaired fertility and progressive bone disease. The increased survival in SCD brings to the front previously unrecognized complications including pulmonary hypertension, silent cerebral infarcts and also reproductive dysfunction. Adolescents and young adults (AYAs) have age-related psychosocial needs in their transition from the pediatric health care environment to the adult system. In this review we present the uniquely age-related medical issues facing the AYA thalassemia and SCD cohort in their transition into adulthood.

Background: Essential thrombocythemia (ET) is a chronic myeloproliferative neoplasm. As it is extremely rare in children, data regarding its clinical course are scarce and pediatric treatment guidelines are lacking. Aim: To evaluate diagnosis, treatment and clinical outcome in a group of pediatric ET patients. Methods: Medical files of all pediatric patients (age 0-18 years) diagnosed with ET between January 2010 and February 2019 in three tertiary hospitals were reviewed. Study was approved by all institutional ethics committees. Diagnosis was established according to the WHO criteria of ET. All patients had undergone bone marrow biopsy (BMB) and molecular evaluation for JAK2V617F. Patients with wild type JAK2V617F were also tested for JAK2 exon 12 mutation, calreticulin (CALR) mutations and thrombopoietin receptor (MPL) mutation. Complete blood count parameters at first evaluation and follow up were collected. Lag in diagnosis, defined as the period between the time at which thrombocytosis was first noticed until diagnosis of ET was documented. Patients were evaluated for acquired von Willebrand syndrome (AVWS) by testing for von Willebrand antigen level and activity. Clinical data included any adverse events particularly those related to thrombosis or bleeding. Initial treatment strategies and any need for therapy modifications were recorded. Results: Twelve children (5 males and 7 females) followed for a median time of 27.5 months (range 4-108 months) were included. Table 1 displays their demographic and clinical data. Family history of thrombocytosis was negative in all patients. Median age at which thrombocytosis was first noted was 8 years (range 1-14.5 years). In 5/12 patients thrombocytosis was detected as an incidental finding. In 7/12 patients CBC was performed due to symptoms including headache, visual disturbances, seizure and acroparesthesia (table 1). Patients who suffered from neurological symptoms had undergone cranial MRI; all were interpreted as normal. The mean lag period between the time in which thrombocytosis was first noted until diagnosis of ET was 36 months (range: 0.1-120 months). Molecular diagnosis yielded 5/12 patients who were positive for JAK2V617F, one patient with a JAK2 exon 12 mutation and 2/12 patients with mutations involving CALR (one with type 1 and one with type 2 mutation). No subjects with CMPL mutation were detected. Four children tested negative for all mutations. Bone marrow biopsies were compatible with ET and no chromosomal aberrations were identified in our cohort. Evaluation for AVWS was performed in nine of the panties. It was diagnosed in 67% of assessed patients. Median VWF:Rco/VWF:Ag 0.18 (range: 0.01-0.76). At diagnosis treatment with Aspirin was initiated in 4/12 patients. Cytoreductive therapy with Hydroxyurea was added at diagnosis in 2/4 patients, both symptomatic at presentation. One Patient underwent plateletpheresis at presentation due to severe headache and extreme thrombocytosis. In 3/8 untreated patients, therapy was added during follow up, with either Aspirin (n=1, due to increased severity of headaches and raising platelet count) or Hydroxyurea (n=2, following TIA). During follow up period neither leukemia nor myelofibrosis evolved in our cohort. One patient developed a provoked DVT, secondary to a femoral CVL. Three patients experienced TIA during study period. Two females experienced excessive bleeding (heavy menstrual bleedings and bleeding due to a raptured corpus luteum), both diagnosed with AVWS. Conclusions: Our study suggests that pediatric hematologists should increase awareness to ET as delayed diagnosis is common. Among children with ET, AVWS may be more prevalent as compared to adults and may increase the risk of bleeding. Further collaborative multicenter studies are required for robust data collection and may facilitate future ET treatment in children. Table 1 Disclosures Kenet: Alnylam: Consultancy, Honoraria, Research Funding; CSL: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Shire: Consultancy, Honoraria, Research Funding; Opko Biologics: Consultancy, Honoraria, Research Funding; BPL: Research Funding. Steinberg Shemer:Emendo bio: Consultancy. Revel-Vilk:Prevail therapeutics: Honoraria, Other: Travel, Research Funding; Sanofi: Honoraria, Other: Travel, Research Funding; Pfizer: Honoraria, Other: Travel, Research Funding; Takeda: Honoraria, Other: Travel, Research Funding.

Although the majority of children with immune thrombocytopenia (ITP) have a short duration of the disease, the very rare but significant complications of the disease often cause fear and anxiety among families of children with ITP. Added to the reduced quality of life (QoL) of those children are restrictions imposed on daily activities to avoid trauma. Treatment decisions in chronic ITP and especially regarding splenectomy are hampered by the inability to predict when recovery will take place. Identification of predictors of recovery would be beneficial for improving treatment decisions and QoL of both children and families. This literature review focuses on clinical parameters and emerging genetic biomarkers for prediction of duration of childhood ITP. Higher recovery rates were found among infants with newly diagnosed ITP. In contrast onset of the disease at adolescence was associated with worse recovery rates. Six clinical features were found to be associated with short duration of disease; the most prominent ones were abrupt onset of bleeding symptoms (2 weeks) and age at onset ≤ 10 years. Two genetic biomarkers have been suggested as predictors of chronic disease: overexpression of vanin-1 (VNN-1), an oxidative stress sensor, and the Q63R missense variant of the gene encoding the cannabinoid receptor type 2. To be clinically useful each of those predictors requires further validation in larger studies. Genetic biomarkers will potentially offer direct and early prognosis estimation.

Background Inherited platelet deficiency and/or dysfunction may be more common in the general population than has previously been appreciated. In 2013 the Israeli Inherited Platelet Disorder (IPD) Registry was established. Methods Clinical and laboratory data were collected to pre-specified registration forms. The study protocol was approved by the local hospital ethics committees. Results To date we have included in the registry 89 patients (male 52%) from 79 families. Most patients (74%) have a not-yet specified inherited thrombocytopenia (n = 39) or non-specific platelet function disorder (n = 27). Full clinical data were available for 81 (91%) patients. The median (range) age at presentation and time of follow-up were 1.8 years (1 day–17.8 years) and 4.7 (0–26) years, respectively. The Pediatric Bleeding Questionnaire was available for 78 patients; abnormal bleeding score (≥ 2) was recorded in 47 (52.8%, 95% CI 42%–63.5%) patients and was less frequent in patients followed for isolated thrombocytopenia. Abnormal score was associated with a longer time of follow-up, OR 1.19 (95% CI 1.04–1.36). Conclusion Long term follow-up of patients with IPDs is important as bleeding risks may increase with time. We expect that clinical and laboratory information of patients/families with IPDs gathered in a systemic format will allow for better diagnosis and treatment of these patients.

Objective α-Thalassemia, one of the most common genetic diseases, is caused by deletions or point mutations affecting one to four α-globin genes. Molecular diagnosis is important to prevent the most severe forms of the disease. However, the diagnosis of α-thalassemia is complex due to a high variability of the genetic defects involved, with over 250 described mutations. We summarize herein the findings of genetic analyses of DNA samples referred to our laboratory for the molecular diagnosis of α-thalassemia, along with a detailed clinical description. Methods We utilized a diagnostic algorithm including Gap-PCR, to detect known deletions, followed by sequencing of the α-globin gene, to identify known and novel point mutations, and multiplex ligation-dependent probe amplification (MLPA) for the diagnosis of rare or novel deletions. Results α-Thalassemia was diagnosed in 662 of 975 samples referred to our laboratory. Most commonly found were deletions (75.3%, including two novel deletions previously described by us); point mutations comprised 25.4% of the cases, including five novel mutations. Our population included mostly Jews (of Ashkenazi and Sephardic origin) and Muslim Arabs, who presented with a higher rate of point mutations and hemoglobin H disease. Overall, we detected 53 different genotype combinations causing a spectrum of clinical phenotypes, from asymptomatic to severe anemia. Conclusion Our work constitutes the largest group of patients with α-thalassemia originating in the Mediterranean whose clinical characteristics and molecular basis have been determined. We suggest a diagnostic algorithm that leads to an accurate molecular diagnosis in multiethnic populations.

Diamond Blackfan anemia (DBA) is an inherited syndrome usually presenting with severe macrocytic anemia in infancy, paucity of erythroid precursors in the bone marrow, and congenital anomalies. We describe a child with mild, transfusion independent normocytic anemia whose diagnosis of DBA was established by identification of a novel de novo mutation disrupting normal splicing of the ribosomal protein RPL5. The diagnosis of DBA was confirmed by elevated erythrocyte adenosine deaminase levels and an abnormal ribosomal RNA profile. This case demonstrates the usefulness of genomic analysis in establishing the diagnosis of DBA in patients with a nonclassical presentation of the disease.

A recent Intercontinental Cooperative ITP Study Group (ICIS) meeting in September 2015 focused on immunomodulation across the spectrum of autoimmune conditions. It became clear to the attendees that in this wide range of conditions, there is a subset of patients that remain highly refractory to first line therapy. Therapeutic approaches to these patients vary greatly and while many different immunomodulatory agents have been investigated, few have seen universal success. We outline here the landscape of immunomodulation therapy for refractory patients across a variety of autoimmune conditions in order to highlight the variety of agents that have been studied, the lack of overall consensus about management, and the need for ongoing research in this area.

The congenital dyserythropoietic anemias (CDAs) are a group of rare genetic disorders characterized by ineffective erythropoiesis and the development of secondary hemochromatosis. Distal limb anomalies are a well-documented though rare feature of congenital dyserythropoietic anemia type I, that have not been reported so far in other types. We describe a patient with congenital dyserythropoietic anemia type II and four members of a family with clinical features of congenital dyserythropoietic anemia type III with distal limb anomalies. The patient with congenital dyserythropoietic anemia type II presented with bilateral complete osseous syndactyly of the hands, and bilateral complete cutaneous syndactyly of feet. Three of the four affected family members with congenital dyserythropoietic anemia type III had partial absence of fingers, small or absent nails, overlapping toes, and short metatarsals. We suggest that similar to congenital dyserythropoietic anemia type I, distal anomalies may appear in some patients with congenital dyserythropoietic anemia types II and III. Patients presenting with anemia and distal limb anomalies should be further investigated for the presence of congenital dyserythropoietic anemia. © 2016 Wiley Periodicals, Inc.

Neonatal cyanosis is relatively common. It is usually a consequence of cyanotic heart disease or a pulmonary disorder, and warrants a thorough and quick investigation. Mutations causing decreased affinity of hemoglobin to oxygen may change α1 to β2 binding. We describe a new mutation (asp 102 serine), in the γ chain of hemoglobin, causing neonatal cyanosis which resolves as the baby matures. In this case we would like to emphasize the importance of early diagnosis in order to avoid unnecessary disease workup.

The diagnosis, treatment, and prognosis of immune trombocytopenic purpura (ITP) have been extensively studied, but data on its effect on health-related quality of life in children remain sparse. To shed more light on this issue, we administered the Kids' ITP Tools (KIT) questionnaire to 17 children with ITP attending a tertiary pediatric medical center and their parents (n=34). The mean KIT score was significantly lower in the parents' group than in the children's group (P=0.000). The main domains of concern for the parents were disease side effects and their child's future; the children were mostly concerned about the need to restrict physical activities. The presence of acute versus chronic disease had no impact on the KIT score in either group. These findings stress the need to develop different interventional programs for children with ITP and their parents to provide appropriate support to each.

Background: Autoimmune neutropenia of infancy (AIN), the most frequent type of severe neutropenia in young children, occurs due to recognition of membrane antigens by anti-neutrophil antibodies, resulting in peripheral neutrophil destruction. Despite the often severe and prolonged neutropenia, serious infectious complications are less frequent in AIN compared with other etiologies of severe neutropenia. Objectives and methods: The purpose of this historical prospective study was to describe the demographics and clinical course of AIN with a focus on the incidence of infectious events, the pathogens involved and assessment of contributing factors. Data was extracted from the medical records of AIN patients treated at the pediatric hematology clinic in Schneider Children's Medical Center of Israel between 2001-2016. Results: One hundred and one patients diagnosed with AIN were included in the study, representing a total of 175 patient-years of follow-up, with a mean of 1.9 years per patient. Mean age at presentation was 0.8 years and at resolution 2.8 years; 90% were healthy by the age 3.8 years. The reason for performing a blood count was febrile infection in 56.3% while nearly 20% were diagnosed by the routine blood count performed between ages 9-12 months in the well-baby clinic. Prophylactic antibiotic use did not correlate with the number of infectious events or days of fever. At least one microbiologically proven bacterial infection was identified in 26% of the patients including acute otitis, urinary tract infections, skin lesions and bacteremia. Bacterial isolates were mostly gram negative, predominantly Pseudomonas species (13/32, 40.6% of isolates) (Figure 1). Prevalence of significant skin infections, especially in the genital region, was very high (20% of infections). There were only 3 episodes of bacteremia out of 559 total febrile illnesses (0.5%). Discussion and conclusions: A standard treatment protocol for AIN is lacking, possibly due to a paucity of data in the literature. Severe bacterial infections in AIN are less common than in severe congenital neutropenia or chemotherapy induced neutropenia. The prevalence of bacteremia in AIN is not well defined in the post-pneumococcal vaccine era. In our cohort bacteremia was uncommon, while bacterial skin infections were much more prevalent, especially involving the genital area, with a high isolation rate of gram negative bacteria, especially Pseudomonas sp. This finding was surprising as ecthymal lesions are more commonly associated with hypoproductive neutropenias. The common practice of treating febrile illnesses in AIN with broad spectrum antibiotics may be unnecessary for a proportion of patients, while a subset of patients seems to be susceptible to gram negative skin infections and should be covered with anti-pseudomonal antibiotics. We recommend that patients with AIN and a febrile illness undergo a careful daily physical examination in addition to laboratory studies including blood counts and cultures of blood, urine and any other suspected sites of infection. Antibiotic therapy should be prescribed according to the clinical picture and the laboratory results. Disclosures No relevant conflicts of interest to declare.

Deferasirox is a recently approved oral iron chelator for treatment of patients with transfusion-related iron overload. Although renal function disturbances were recognized, proximal renal tubulopathy was not addressed in published safety reports for deferasirox. Although subclinical proximal tubulopathy was described in β-thalassemia homozygotes, overt Fanconi kidney is not an established disease complication. We describe 4 cases out of 50 children and adults with transfusion-dependent β-thalassemia, treated with deferasirox for iron overload, who developed clinically significant Fanconi syndrome. Three had concomitant infectious events; the fourth case was entirely spontaneous. In addition, all 4 patients were moderately to well chelated. Cessation of deferasirox resulted in prompt recovery. We propose the necessity for diligent monitoring for proximal tubule nephropathy, possibly related to infectious events, during treatment with deferasirox.

BACKGROUND: The use of central venous catheters (CVCs) has greatly improved the quality of care in children with cancer, yet these catheters may cause serious infectious and thrombotic complications. The aim of this prospective registry study was to assess the host and CVC-related risk factors for CVC-created thrombotic complications. METHODS: Patients undergoing CVC insertion for chemotherapy were followed prospectively for CVC complications. At the time of enrollment, demographic, clinical, and CVC-related data, and family history of thrombosis were collected. Survival and Cox regression analyses were performed. RESULTS: A total of 423 CVCs were inserted into 262 patients for a total of 76,540 catheter days. The incidence of CVC-related deep-vein thrombosis (DVT) was 0.13 per 1000 catheter-days (95% confidence interval [CI], 0.06-0.24). Insertion of peripherally inserted central catheters (PICCs) and insertion in an angiography suite significantly increased the risk of symptomatic CVC-related DVT. The incidence of CVC occlusion was 1.35 per 1000 catheter-days (95% CI, 1.1-1.63). Positive family history of thrombosis significantly increased the risk of CVC occlusion (hazard ratio [HR], 2.16; 95% CI, 1.2-3.8). The CVC-related risk factors were insertion of Hickman catheters, insertion in angiography suite, and proximal-tip location. Patients developing at least 1 episode of both CVC occlusion and infection had an increased risk for developing symptomatic CVC-related DVT (HR, 4.15; 95% CI, 1.2-14.4). CONCLUSIONS: Both patient-related and CVC-related factors are associated with higher risk of symptomatic thrombotic complications. These risk factors could be used in the clinical setting and in developing future studies for CVC thromboprophylaxis. Cancer 2010;116:4197–205. V C 2010 American Cancer Society.

Background Inherited bone marrow failure syndromes are rare genetic disorders characterized by bone marrow failure, congenital anomalies, and cancer predisposition. Available single disease registries provide reliable information regarding natural history, efficacy and side effects of treatments, and contribute to the discovery of the causative genes. However, these registries could not shed light on the true incidence of the various syndromes. We, therefore, established an Israeli national registry in order to investigate the relative frequency of each of these syndromes and their complications. Design and methods Patients were registered by their hematologists in all 16 medical centers in Israel. We included patients with Fanconi anemia, severe congenital neutropenia, Diamond-Blackfan anemia, congenital amegakaryocytic thrombocytopenia, dyskeratosis congenita, Shwachman-Diamond syndrome, and thrombocytopenia with absent radii. Results One hundred and twenty-seven patients diagnosed between 1966 and 2007 were registered. Fifty-two percent were found to have Fanconi anemia, 17% severe congenital neutropenia, 14% Diamond-Blackfan anemia, 6% congenital amegakaryocytic thrombocytopenia, 5% dyskeratosis congenita, 2% Shwachman-Diamond syndrome, and 2% thrombocytopenia with absent radii. No specific diagnosis was made in only 2 patients. Of the thirty patients (24%) developing severe bone marrow failure, 80% had Fanconi anemia. Seven of 9 patients with leukemia had Fanconi anemia, as did all 6 with solid tumors. Thirty-four patients died from their disease; 25 (74%) had Fanconi anemia and 6 (17%) had severe congenital neutropenia. Conclusions This is the first comprehensive population-based study evaluating the incidence and complications of the different inherited bone marrow failure syndromes. By far the most common disease was Fanconi anemia, followed by severe congenital neutropenia and Diamond-Blackfan anemia. Fanconi anemia carried the worst prognosis, with severe bone marrow failure and cancer susceptibility. Diamond-Blackfan anemia had the best prognosis. The data presented provide a rational basis for prevention programs and longitudinal surveillance of the complications of inherited bone marrow failure syndromes.

Aims: The aim of the study was to characterize the clinical course of post-varicella idiopathic thrombocytopenic purpura (ITP) and to asses the risk of acquiring ITP after varicella infection. Methods: A retrospective study of all children diagnosed with ITP in a tertiary medical centre during 1998–2008. Findings were compared with the Intercontinental Childhood ITP Study Group database. The risk of acquiring ITP after a varicella infection was assessed. Results: Ten children were diagnosed with post-varicella ITP. The incidence of post-varicella ITP was 1.9% amongst children diagnosed with ITP and 1.1% amongst children hospitalized for varicella. ITP was diagnosed, on average, 8.5 days after the onset of the varicella rash. The female-to-male ratio was 1:1.5. The average minimal platelet count was 9.5 × 109 platelets/L. Post-varicella ITP had an acute course in 80% of cases and a chronic course in the remaining 20%. Bleeding episodes occurred in three patients. During the follow-up period, 11 patients with previously diagnosed ITP developed varicella. The infection had no apparent affect on the platelet count of the children with acute ITP, but caused a relapse in 71% of the patients with chronic ITP. Conclusions: Post-varicella ITP has similar clinical features and course to non-varicella associated ITP. The calculated risk of ITP as a complication of varicella infections is approximately 1:25 000.

Neutral lipid storage disease (Chanarin-Dorfman syndrome) is a rare autosomal recessive disorder of lipid metabolism, characterized by systemic accumulation of neutral lipids in multiple tissues. We report a case of a 14-year-old girl with generalized ichthyosis, liver cirrhosis, and a hearing impairment. A peripheral blood smear demonstrated marked cytoplasmatic vacuoles in most polymorphonuclear cells (Jordan's anomaly). Bone marrow examination revealed vacuoles in myeloid precursors. Genetic analysis showed that the patient was homozygous for the p.Arg312Ter mutation in the CGI-58 gene, a key enzyme in lipid metabolism. The peripheral blood smear is diagnostic, and should be performed in any patient with ichthyosis.

Background The course of hereditary spherocytosis (HS) may be subject to hemolytic episodes, sometimes requiring blood transfusion. The aim of this study was to evaluate the efficacy of a short course of steroid therapy in elevating hemoglobin levels during hemolytic crisis. Procedure The files of all patients followed for HS from 1968 to 2009 at our hospital were reviewed. Outcome of hemolytic crises was compared between steroid-treated and untreated patients; patients given packed red blood cell transfusion(s) or erythropoietin treatment were excluded. A good outcome was defined as an increase of at least 20% in hemoglobin level from the nadir within 1 week. Results Of the 118 patients with HS who attended our hospital during the study period, 20 were treated with steroids and 9 received no treatment. Mean nadir hemoglobin level in both groups was 6.9 g/dl. The study group had a total of 50 steroid-treated hemolytic crises of which 37 (74%) responded favorably to treatment. Treatment failure was significantly associated with a low dose (

The molecular basis of α-thalassemia (α-thal) is complex. The use of multiplex ligation-dependent probe amplification (MLPA) has offered the possibility of identifying more gene deletions causing α-thal. Our objective was to determine the molecular basis of two patients with Hb H (β4) disease. By using MLPA in combination with comparative genomic hybridization (CGH) we identified two novel α-globin gene cluster deletions: a 30 kb deletion (patient 1) we refer to as - -(JAL) and a large 216 kb deletion (patient 2) we refer to as - -(LOD). Patient 1 was a compound heterozygote for - -(JAL) and -α(3.7) (rightward deletion). Twelve family members of patient 1 carrying the - -(JAL) deletion were available for evaluation: five with - -(JAL)/-α(3.7), four with - -(JAL)/α(Hph I)α and three with - -(JAL)/αα. Their clinical picture of compound heterozygosity was compatible with moderate Hb H disease. In patient 2 (- -(LOD)/-α(3.7)), no additional symptoms were present despite the heterozygous deletion of seven known genes, three non coding RNAs (ncRNAs), four unknown genes and two pseudo genes. Further analysis of more patients with α-thal deletions will have implications for genetic counseling and appropriate therapy.

The use of central venous catheters (CVCs) has greatly improved the quality of care in children receiving chemotherapy, yet these catheters may cause serious infectious complications. The aim of this prospective registry study was to assess the host and CVC-related risk factors for blood stream infections (BSIs).Patients undergoing CVC insertion for chemotherapy were followed prospectively for CVC complications. At the time of enrollment demographic-, clinical- and CVC-related data were collected. Survival and Cox-regression analysis were performed.A total of 423 CVCs were inserted into 262 patients for a total of 76,540 catheter-days. The incidence of BSIs was 1.95 per 1,000 patient-days (95% CI 1.66-2.29). Myeloid leukemia and younger age were associated with higher risk for BSI. At least one BSI occurred in 187 CVCs with an incidence of 2.84 per 1,000 catheter-days (95% CI 2.47-3.24). Externalized CVCs, that is, tunneled externalized catheters and peripheral inserted central catheters, were associated with higher risk for BSI in the group of diseases with relatively lower rate of infection. However, in diseases with high rate of infection no such association was found. The type of BSI was associated with the diagnosis and the CVC type. CVC occlusion was associated with higher risk for recurrent BSI and for coagulase negative staph BSI.Both patient and CVC-related factors are associated with higher risk of BSI in children receiving chemotherapy. The results of this study could be used in developing studies aiming to reduce the rate of BSIs in children with cancer.

The relative frequency of mutated genes among patients with severe congenital neutropenia (SCN) may differ between various ethnic groups. To date, few population-based genetic studies have been reported. This study describes the genetic analysis of 32 Israeli patients with SCN.Clinical data were retrieved from the prospective Israeli Inherited Bone Marrow Failure Registry. Recruitment included living and deceased patients who were diagnosed between 1982 and 2012, for whom molecular diagnosis was performed. ELANE, HAX1 and G6PC3 genes were sequenced in all patients, and GFI-1 and WAS genes were sequenced if other genes were wildtype.Eleven patients (34%) had heterozygous mutations in ELANE (10 kindreds), eight (25%) had homozygous mutations in G6PC3 (5 kindreds) and 13 (41%) had no detected mutations. No patients had mutations in HAX1 or WAS. Four of the eight patients with G6PC3 mutations had congenital anomalies. The probability of survival for all patients was 50% at age of 18. Deaths were mainly due to sepsis (5 patients, 4/5 not responding to G-CSF, none with G6PC3 mutation). Two patients developed acute myelogenous leukemia (AML) and one myelodysplastic syndrome (MDS), none with G6PC3 mutation.We found a unique pattern of SCN mutations in Israel with homozygous G6PC3 mutations in eight (25%) patients, the highest frequency described so far. HAX1 mutations, reported mainly in Sweden and Iran, were absent. Patients with G6PC3 mutations had congenital anomalies, appeared to have a better response to G-CSF, and so far have not developed AML or MDS.

Elective splenectomy in childhood can ameliorate the clinical manifestations of non-malignant hematological diseases such as beta-thalassemia, hereditary spherocytosis and chronic immune thrombocytopenia. The advantages however, must be weighed against possible adverse effects. The incidence of infectious complications post splenectomy has decreased as a result of the introduction of novel vaccinations and antibiotic prophylaxis, however this depends on patient compliance. The risk of thromboembolism appears to be related to the underlying diagnosis, although the exact long-term risk has not been well documented. There is a paucity of reports describing large cohorts and long term follow-up of splenectomized hematological patients. We present herein four decades, comprising 1652 patient years, of follow-up of patients who underwent splenectomy in childhood for non-malignant hematological diseases, evaluating the risk of infection and thromboembolic complications. Medical records were screened for the diagnosis of splenectomy among patients previously or currently treated in our pediatric hematology clinic. Demographic, clinical and laboratory data, including the diagnosis, age at time of surgery, infectious and thrombotic complications were recorded. Bacterial infection was defined as positive blood cultures taken due to febrile illness. Thrombotic events included venous thrombosis diagnosed by appropriate imaging. For patients lost to follow up, a telephone follow-up visit was performed using a brief questionnaire focusing on the complications of interest. One hundred and four (104) patients underwent splenectomy between 1974-2015 for the diagnoses of beta-thalassemia major (TM)(33), beta-thalassemia intermedia (TI)(7), sickle-thalassemia (ST)(4), hereditary spherocytosis (HS)(42) or immune thrombocytopenia (ITP)(18). The follow-up period encompasses a total of 1652 years (mean=16, range=1-40 per patient). Mean age at splenectomy was 11.4 years (0.5-25). Vaccinations according to the recommended protocol at time of surgery were administered to 98% of patients. Forty-four bacterial infections occurred in 21 patients. Twenty four percent of the first infections occurred in the first year post-splenectomy, while 67% were within five years post-splenectomy. Only 1 of 7 reported deaths was due to sepsis, in a ST patient. Eight thrombotic events occurred in the cohort, 7 among TM patients with central venous lines (CVL) and 1 case of a postoperative portal vein thrombosis (PVT) in a patient with HS. In univariate analysis, CVL and thalassemia diagnoses were each predictive for both infectious and thrombotic complications (p Our study of 104 patients with 1652 years of cumulative follow-up shows an extremely low risk for infectious and thrombotic complications: 1.3 and 0.5 per 100 years at risk, respectively. Only one patient each among the ITP and HS groups developed bacterial infection and the only thrombotic event in a non-thalassemic patient was an immediately post splenectomy PVT in a patient with HS. The majority (19/21) of infections occurred in thalassemic patients, 63% of which had a CVL. Thrombosis beyond the post-operative period occurred exclusively among thalassemic patients with CVL. Infection occurred primarily within 5 years after splenectomy and was fatal in only 1 case. Splenectomy in pediatric patients with non-malignant hematological diseases is a safe procedure with minimal infectious and thrombotic complications particularly among patients with HS or ITP. Abiding by the pre-splenectomy vaccination guidelines for all patients and prudent use of CVLs in splenectomized thalassemic patients should contribute to minimizing long term complications. Disclosures No relevant conflicts of interest to declare.

Thrombocytosis is a common finding and is a frequent cause of referral for further investigation. The MPL Baltimore (Lys39Asn) mutation has been reported as a cause of thrombocytosis in 7% of African Americans. We describe an 11-month-old Ethiopian Jewish boy referred for evaluation of thrombocytosis who was found to be homozygous for MPL Baltimore. So far, there is no indication whether patients with thrombocytosis who have this mutation, particularly homozygotes, are at increased risk of thrombotic or hemorrhagic complications. Nevertheless, this entity should be considered in the differential diagnosis of every patient with thrombocytosis, particularly those of African origin.

To evaluate the predictive value of clinical features at diagnosis of immune thrombocytopenia (ITP) for resolution of disease.Hospital records of 472 consecutive children (18 years old) with ITP cared for at 2 participating centers were reviewed retrospectively and data related to the initial presentation were recorded. Logistic regression analysis was used for calculating prediction of resolution at 3, 6, and 12 months from diagnosis.The most significant predictors for resolution of ITP at 3, 6, and 12 months were age at onset10 years and abrupt onset (history of2 weeks of bleeding). We designed a prediction rule for ITP chronicity based on these criteria. The rate of developing chronic ITP for low, intermediate, and high risk children at diagnosis of ITP was 11%, 39%, and 63%, respectively. Recovery rate at 3 months for low, intermediate, and high risk children was 72%, 43% and 30%, respectively.We present a simple rule to predict recovery from ITP at 3, 6, and 12 months from diagnosis. For prediction of resolution at 3 months, our rule was in agreement with the more complex, previously described Nordic score. Prediction of resolution of ITP may enable practitioners to better inform children and parents at the time of diagnosis, resulting in reduced anxiety and improved quality of life.

Thrombotic thrombocytopenic purpura is caused by an imbalance of von Willebrand factor and its cleaving protease, which leads to the formation of microthrombi in end-organs. It rarely occurs in the pediatric population. Plasma exchange can significantly reduce mortality and morbidity. We present a 14-month-old infant in whom clinical and laboratory abnormalities compatible with thrombotic thrombocytopenic purpura were noted several days after resection of a large pelvic tumor. Treatment with double volume plasma exchange on postoperative day 5 led to complete resolution of the renal failure, thrombocytopenia, anemia, and neurological manifestations. ADAMTS13 inhibitors were negative and no mutations were found in factor H, factor I, membrane cofactor protein, and thrombomodulin to account for genetic predisposition to thrombotic thrombocytopenic purpura or atypical hemolytic uremic syndrome. Postoperative anemia, thrombocytopenia, fever, and neurological deficits in children should raise the suspicion of thrombotic thrombocytopenic purpura. Early diagnosis is important because the disorder is readily and efficiently treated with plasma exchange.

Severe congenital neutropenia type 4 (SCN4) is an autosomal recessive condition, which was defined recently with identification of the causative mutations in G6PC3. To date there are only three reports in the literature describing patients with SCN4 with mutations in the G6PC3 gene. We report four individuals with SCN4 who belong to a single large consanguineous kindred. We provide an overview of the non-haematological features of the condition with a focus on the adult phenotype, which has not been previously described in detail. We show that the superficial venous changes seen in SCN4 patients can develop into varicose veins and venous ulcers in adulthood. We review the range of congenital anomalies associated with SCN4. We demonstrate that secundum atrial septal defect, patent ductus arteriosus and valvular defects are the most frequent cardiac anomalies in SCN4. Drawing parallels with type 1 glycogen storage disease, we propose that poor growth of prenatal onset, mild-to-moderate learning disability, primary pulmonary hypertension, delayed or incomplete puberty, hypothyroidism and dysmorphism likely represent features of this syndrome. We also suggest monitoring for lipid anomalies, and kidney and liver function in affected patients. Delineation of the SCN4 phenotype may help in appropriate treatment and management and provide further insights into the pathogenesis of this multisystem disease.

The course of hereditary spherocytosis (HS) may be subject to hemolytic episodes, sometimes requiring blood transfusion. The aim of this study was to evaluate the efficacy of a short course of steroid therapy in elevating hemoglobin levels during hemolytic crisis.The files of all patients followed for HS from 1968 to 2009 at our hospital were reviewed. Outcome of hemolytic crises was compared between steroid-treated and untreated patients; patients given packed red blood cell transfusion(s) or erythropoietin treatment were excluded. A good outcome was defined as an increase of at least 20% in hemoglobin level from the nadir within 1 week.Of the 118 patients with HS who attended our hospital during the study period, 20 were treated with steroids and 9 received no treatment. Mean nadir hemoglobin level in both groups was 6.9 g/dl. The study group had a total of 50 steroid-treated hemolytic crises of which 37 (74%) responded favorably to treatment. Treatment failure was significantly associated with a low dose (1 mg/kg/day) or short duration (1 week) of treatment. The nine untreated patients had 16 hemolytic crises, of which 25% had a good outcome. Steroid therapy was significantly more effective than no therapy in increasing hemoglobin level (P = 0.015) in these hemolytic crises.Steroid therapy may be effective in augmenting hemoglobin levels during hemolytic crises in patients with moderate HS and eventually will result in a reduced need for RBC transfusion.

Yunis-Varon syndrome (YVS) is a rare autosomal recessive condition characterized by limb defects, ossification defects, generalized hypotrichosis and, frequently, a severe neonatal course. The molecular basis is unknown. We report on a newborn infant with previously undescribed findings, including hydrops fetalis, primary pulmonary hypertension and unusually severe abnormalities of toes. We review clinical data on 22 published cases in order to delineate the phenotype of this condition. Clinical recommendations for prenatal and postnatal evaluation of patients and fetuses at risk are discussed.

Familial hemophagocytic lymphohistiocytosis is usually diagnosed in the first 2 years of life and, if untreated, is rapidly fatal. We describe a 10-year-old boy with a 9-year history of prolonged fever and progressive hepatosplenomegaly who was diagnosed as having hemophagocytic lymphohistiocytosis 2, being homozygote to a previously described mutation in the PRF1 gene, and cured by the HLH-2004 protocol and allogenic bone marrow transplantation. This unique case emphasizes the heterogeneity of this disease and the diversity of its clinical presentations.

The risk of later development of systemic lupus erythematosus (SLE) in childhood idiopathic thrombocytopenic purpura (ITP) is currently unknown. We retrospectively evaluated the incidence and risk factors of this complication in 222 children with ITP who were followed for a mean of 4.2+/-4.9 years. During that time 3.6% of the children (8/222) developed SLE; all were females with positive anti-nuclear antibody (ANA), older (12.7+/-3.6 vs. 6.4+/-4.3 years old; P

Exserohilum is a dematiaceous fungus that may cause a spectrum of diseases in humans, including skin and corneal infection, invasive disease, and allergic fungal sinusitis. The aim of this work is to describe two new cases of Exserohilum infection and to review the literature. The review yielded 33 cases of Exserohilum infection, of which 23 were reported since 1993. Most occurred in regions with hot climates, such as India, Israel, and the southern USA. Impaired immunity was present in the majority of patients with invasive and skin infections, whereas local trauma and atopy were the predisposing factors in those with corneal infections and allergic fungal sinusitis, respectively. Surgical debridement was the principal mode of therapy for allergic fungal sinusitis. Amphotericin B was the initial single antifungal agent used in all cases of invasive disease; the response rate was low but improved with the addition of triazole agents. Outcome appeared to be better than for other mold infections and depended mainly on the underlying diseases.

Background: The prolonged survival in patients with beta thalassemia major and other transfusion dependent disorders has exposed the multi-organ effects of multiple transfusions and chelation therapy. Renal deficits were described with the focus on tubular and glomerular function. Nephrolithiasis has not been systematically explored in these patients. Contributing factors to stone formation may include hypercalcuria, abnormal vitamin D homeostasis, and proximal tubulopathy. Objective: We analyzed hematologic and nephrologic parameters of 22 transfusion- dependent pediatric patients to investigate contributors to nephrolithiasis. Methods: The study included patients with beta thalassemia major (TM) (13), transfusion-dependent beta thalassemia intermedia (TDTI) (4), Diamond-Blackfan anemia (DBA) (3), other transfusion-dependent hemoglobinopathies (2). Patients' ages were from 4-20 years (overall median -11 years, TM/TDTI median - 11.5, DBA median - 7.5 years). At the time of analysis 11 received iron chelation with deferasirox, 8 with combined desferoxamine & deferiprone, 2 with combined desferoxamine & deferasirox and one patient received desferoxamine alone. All patients had previously been treated with deferasirox alone and due to either significant adverse events or failure to control iron overload were switched to an alternate regimen. Seven patients were treated with vitamin D supplements for a median of 3 years (range: 0.2-4.3), 6 patients received vitamin D+calcium for a median of 4.5 years (range: 4.3-10). Venous blood samples, 24-hour urine collections and spot urine samples were collected to assess urine chemistry, vitamin D metabolism, electrolytes and renal function. Renal sonography and directed computerized tomography were used to diagnose nephrolithiasis/nephrocalcinosis. Results: Three patients, all with TM/TDTI, had symptomatic and radiographically identified renal stones, an additional TM patient had symptomatic nephrocalcinosis (Table 1). Among the entire cohort hypercalcuria was identified in 75% with increased Ca/Cr in 68%. 25(OH)D3 was abnormal in 81% of patients, mostly in the "insufficient" range (25-75 mmol/L). No significant relationship between presence of nephrolithiasis and chelation regimen, Ca mg/kg/d, Ca/Cr, renal fractional excretion (Fe) of phosphate (FePhos(, FeNa, FeUA, oxalate, cystein, citrate, 25(OH)D3, or treatment with vitamin D± calcium was identified, possibly in part due to the small sample size. Conclusions: The incidence rate of nephrolithiasis in our pediatric transfusion-dependent population was 1000x that published in various pediatric populations. Hypercalcuria and relatively low vitamin D levels were found in the majority of our patients, notably in all with nephrolithiasis. All 4 patients with nephrolithiasis/calcinosis were ≥ 13 years old, receiving vitamin D±calcium supplements and had received deferasirox chelation. Of note none of the patients not receiving vitamin D±calcium therapy presented with renal stones or calcinosis. The pathophysiology of nephrolithiasis/calcinosis is unclear among these adolescents; however the role of vitamin D±calcium supplemental therapy and the contribution of deferasirox must be further studied to find the proper formulation needed to maintain bone health without increasing the risk for renal stones. Abstract 4895. Table 1- Characteristics of patients with nephrolithiasis/nephrocalcinosis Patient Diagnoses Age at onset (years) Chelation (at onset) Duration of vitamin D+Ca supplement (years) Low vitamin D levels (mmol/L) Urine calcium (mg/kg/d) 1 TM/NL 16 DFX 2.3 + 7.6 2 TM/NL 16 DFX 5 - 6.9 3 TDTI/NL 13 DFO&DFP (prior DFX) 0.25 (vitamin D only) + 4.4 4 TM/NC 18 DFX 4 + 2.7 TM-thalassemia major, TDTI-transfusion-dependent thalassemia intermedia, NL-nephrolithiasis, NC-nephrocalcinosis, DFX-deferasirox, DFO-desferoxamine, DFP-deferiprone, Ca-calcium, normal values: vitamin D>75mmol/L, urine calcium Disclosures No relevant conflicts of interest to declare.

Hemoglobin Taybe is an unstable alpha-chain hemoglobin variant caused by a deletion of a threonine residue at codon 38 or 39 of the alpha-1 globin chain. We describe preterm infant triplets born with hydrops fetalis and anemia who were found by DNA analysis to be homozygous for hemoglobin Taybe. All three infants developed intrauterine hemolytic anemia, which subsequently led to hydrops fetalis. To the best of our knowledge, this is the first description of hydrops fetalis associated with this hemoglobinopathy. We suggest that hemoglobin Taybe be considered in the differential diagnosis of hydrops fetalis and that known affected fetuses be carefully followed both antenatally and postnatally.

Inherited bone marrow failures syndromes (IBMFS) are rare genetic disorders usually characterized by congenital anomalies, development of bone marrow failure and a tendency to develop malignant diseases. Although single disease registries for Fanconi anemia (FA), Diamond-Blackfan Anemia (DBA), Severe Congenital Neutropenia (SCN) and Dyskeratois Congenita (DC) have been established the true incidence of many of the IBMFS is still unknown. To investigate the prevalence of each of the IBMFS and to the types and frequencies of complications we set up a retrospective national registry of these disorders in Israel. We reviewed charts of 127 patients with IBMFS diagnosed between 1964 and 2005. This represents the majority of such patients in the country. Consanguinity was recorded in 50 (40%) patients. Median time since diagnosis was 6 years (range: 1 month-39 years). Genetic analysis was available in 60 (47%) patients. The number of patients within each disease category is presented in the Table. The majority of patients who succumbed to their disease had FA. Of the 29 patients who developed malignancies (hematological and solid) the majority 23 (79%) had FA. All of the 6 patients who developed solid tumors had FA. The solid tumors were squamous cell carcinoma of head and neck, esophagus, cervix and vulva. Table: Israeli Inherited Bone Marrow Failure Cohort - Diagnosis, Complications and Survival No. of pts. FA DBA SCN CAMT DC SDS TAR NOS All Total (%) 66 (52) 18 (14) 21 (16.5) 8 (6) 6 (5) 3 (2) 3 (2) 2 (1.5) 127 (100) Per 106 people 5.3 2.6 2.1 1.1 0.86 0.43 0.29 Deceased (%) 24 (36) - 6 (29) - 2 (33) 1 (33) - - 33 (26) Molecular diagnosis (%) 34 (51) 6 (33) 7 (33) 8 (100) 4 (67) 1 (33) - - 60 (47) MDS/AML/ALL (%) 19 (29) - 4 (19) 2 (25) - - - - 25 (20) Solid tumor (%) 6 (9) - - - - - - - 6 (5) CAMT, Congenital Amegakaryocytic Thrombocytopenia; SDS-Shwachman-Diamond Syndrome; TAR, Thrombocytopenia Absent Radii; NOS-not otherwise specified. This is the largest population-based study which has examined the relative frequency of each of the IBMFS. In this cohort, FA was by far the most common form of an IBMFS (52% of pts), followed by DBA (16.5%) and SCN (14%), while CAMT, DC, SDS and TAR were far less common. These findings agree with the frequencies of FA, DBA and SCN reported by individual disease registries, and contrast with the results from the Canadian inherited marrow failure registry (Pediatr Blood Cancer47:918, 2006), where among a smaller number (39) of patients with an IBMFS the frequencies of FA, SDS, DBA and SCN were similar (12% each). One caveat is that the Israeli cohort has a large proportion of consanguineous families, which differs from most cohorts in other countries. The number of undiagnosed patients with IBMFS in our study was very small. SDS and DC are either rare in our region or under-diagnosed. The implementation of new diagnostic tests will help to resolve this issue. These data provide a rational basis for longitudinal surveillance and prevention of complications in the severe forms of IBMFS.

The use of central venous lines (CVLs) has greatly improved the quality of care in children with cancer, yet these catheters may cause serious mechanical, infectious and thrombotic complications, both deep vein thrombosis (DVT) and catheter occlusion. The aim of this prospective study is to ascertain the incidence of thrombotic complications and their risk factors. A registry was started in June 2006 for all children undergoing CVL insertion for treatment of cancer in the three largest pediatric cancer centers in Israel. After informed consent was signed, a registration form, that included questions regarding demographic-, clinical- and CVL-related data, and family history of thrombosis, was completed. Blood samples for baseline thrombophilia work-up, i.e. protein C, protein S, anti-thrombin, APCR, Factor V Leiden, Prothrombin gene mutation and MTHFR, were collected with separate consent. The following events were reported to the registry: immediate post insertion complications, venous thrombosis confirmed by imaging, occlusion of the CVL, i.e. inability to infuse and/or withdraw blood, requiring medical or surgical intervention, and CVL infections. The maintenance of CVLs and management of CVL occlusion and infection remained in accordance with institutional protocols. Responsible oncologists decided whether a dysfunctional or an infected CVL was to be removed or replaced, and whether radiographic evaluation for thrombotic complications was indicated. Patients were enrolled until December 2007, and data analysis was completed in June 2008. A total of 414 CVLs, i.e. peripherally inserted central catheters (PICCs) (45%), Hickman catheters (25%) and Port-a-Caths (30%), were inserted into 262 children for a total of 71,241 catheter-days. Fourteen events of venous thrombosis occurred in 13 children (4.9%, 95% confidence interval (CI) 2.6% to 8.3%), including 10 events of CVL-related DVT. The occurrence of CVL-related DVT was significantly higher for PICCs, 4.5%, compared to other types of CVLs, 0.9% (p=0.02, odds ratio (OR) 5.4 (95% CI 1.13 to 25.8)). CVL-related DVT was not associated with age at diagnosis, side of insertion (right vs. left), vessel cannulated, type of cancer (acute lymphoblastic leukemia vs. others), ethnic origin or family history of thrombosis. Occlusion of the CVL occurred at least once in 90 children (34%, 95% CI 29% to 40%). Children with family history of thrombosis were more likely to have CVL occlusion, 62.5%, compared to children without family history of thrombosis, 30.4% (P=0.01, OR 3.8 (95% CI 1.3 to 10.8)). Occlusion was reported in 102 CVLs (24%, 95% CI 20% to 28%). The occurrence of occlusion was higher for Port-a-Caths, 42%, and Hickman catheters, 35%, compared to PICCs, 23% (P