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Study Objective The aim of the study was to examine the effect of heavy menstrual bleeding (HMB) and dysmenorrhea on daily activity and quality of life (QoL) in young women engaged in demanding activities. Design Cross-sectional study. Participants A total of 422 Israeli women soldiers in combat and non-combat roles. Interventions Participants were asked to provide consent and to complete study questionnaires. Main Outcome Measures A pictorial bleeding assessment chart (PBAC), visual analog scale (VAS), verbal multidimensional scoring system for assessment of dysmenorrhea, and approved Hebrew-translated age-appropriate Pediatric Quality of Life Inventory (PedsQL). Results HMB (PBAC >100) and severe HMB (PBAC >185) were demonstrated in 181 (50%) and 96 (26%) participants, respectively. A high PBAC score was recorded in 20% who answered “no” or “unknown” in the questionnaire on having HMB. Mild, moderate, and severe dysmenorrhea were demonstrated in 80 (21.5%), 115 (31%), and 142 (38%) participants, respectively. The prevalence of HMB and dysmenorrhea was similar in soldiers in combat and non-combat roles. Diagnosis of HMB was related to the lower fitness-for-service score, history of bleeding, and dysmenorrhea. Daily activity and QoL were both affected by the severity of HMB and dysmenorrhea. Conclusion Underdiagnosis of HMB and dysmenorrhea results from a combination of unawareness from the women's side and inattention from the system. In an era of female empowerment, each woman should be at the optimal physiological and psychological level to start her career; thus, addressing the menstrual burden and providing effective treatment is needed in the military scenario and other settings with demanding activities.

Introduction For the last three decades, enzyme replacement therapy (ERT) for Gaucher disease (GD) has been available. We aimed to evaluate the effect of ERT on the pregnancy and obstetric outcome in a unique group of multiparous women with type 1 GD (GD1) who had pregnancies with and without ERT. Study design The Gaucher Unit database (1987-2019) was searched for multiparous women who had pregnancies before and after the institution of ERT. Data were collected from the clinic files and study-specific questionnaires. Descriptive, correlation analysis and generalized estimating equations (GEE) were used to study the effect of ERT and confounding variables on study outcomes. Results We identified 19 women with 105 pregnancies, among which 26 (24.7%) terminated in first-trimester miscarriage. The risk for miscarriage was associated with the severity of GD1 genotype and phenotype, but not with ERT usage. Early postpartum hemorrhage (PPH) was reported in 16 (84%) women after 25 deliveries (31.6%, 95% CI 21.6%-43.1%). The risks of early PPH and red blood cell (RBC) transfusions were significantly lower when ERT was used during pregnancy, OR (95% CI) 0.13 (0.03-0.54) and 0.27 (0.08-0.94), respectively, compared to pregnancies without the use of ERT. Conclusion Enzyme replacement therapy during pregnancy is risk reducing for early PPH and RBC transfusions in women with GD1. We suggest considering ERT for the benefit of all pregnant women with GD1, including mild GD1. This article is protected by copyright. All rights reserved.

Ambroxol hydrochloride is an oral mucolytic drug available over-the-counter for many years as cough medicine. In 2009 it was identified as a pharmacological chaperone for mutant glucocerebrosidase, albeit in a several-fold higher dose. Unfortunately, there have been no pharma-driven clinical trials to establish its use. Thus, real-world observational data are needed on the safety and efficacy of ambroxol for patients with Gaucher disease (GD) and GBA-Parkinson disease (GBA-PD). Clinicians treating patients with ambroxol for GD and GBA-PD were approached to collaborate in an investigator-initiated registry. Anonymized data were collected, including demographics, GD type, GD-specific therapy (when applicable), adverse events (AEs), and, when available, efficacy data. We report the data of the first 41 patients (25 females) at a median (range) age 17 (1.5-74) from 13 centers; 11 with GD type 1(four diagnosed with PD), 27 with neuronopathic GD (nGD), and three GBA mutation carriers with PD. The median (range) treatment period and maximum dose of ambroxol were 19 (1-76) months and 435 (75-1485) mg/day, respectively. One patient with type 2 GD died of her disease. No other severe AEs were reported. Twelve patients experienced AE, including minor bowel discomfort, cough, allergic reaction, mild proteinuria, dizziness and disease progression. Clinical benefits were reported in 25 patients, including stable or improved neurological status, increased physical activity, and reduced fatigue. Until the approval of specific therapies for nGD and disease-modification for GBA-PD, these preliminary data may be encouraging to physicians and patients who consider an off-label use of ambroxol.

Background Bleeding disorders (BD) are under-recognized in adolescents with heavy menstrual bleeding (HMB). Objectives The lack of clinical guidelines and variable symptomatic management of HMB created the imperative to standardize HMB care to identify and manage BD in adolescents. Methods We convened an international working group (WG), utilized the results of a literature review to define knowledge gaps in HMB care, and used the collective clinical experience of the WG to develop care considerations for adolescents with BD and HMB. We then solicited input on the appropriateness of HMB care considerations from expert stakeholders representing hematology, adolescent medicine, and obstetrics-gynecology. We conducted an expert panel online, using the ExpertLens platform. During a 3-round online modified-Delphi process, the expert panel rated the appropriateness of 21 care considerations using a 9-point scale to designate care as appropriate (7-9), uncertain (4-6), or inappropriate (1-3) covering screening for BD, the laboratory work-up, and management of adolescents with BD that present with HMB. We used the RAND/UCLA appropriateness method to determine the existence of consensus among the interdisciplinary panel of experts. Results Thirty-nine experts participated in the panel. The experts rated fifteen HMB care considerations as appropriate, six as uncertain, and none as inappropriate. Conclusions The HMB care statements represent the first set of HMB care considerations in adolescents with BD, developed with broad expert input on appropriateness. Although likely to be of interest to a range of clinicians who routinely manage adolescents with HMB, additional research is required in many key areas.

For years, the gold standard for diagnosing Gaucher disease (GD) has been detecting reduced β-glucocerebrosidase (GCase) activity in peripheral blood cells combined with GBA1 mutation analysis. The use of dried blood spot (DBS) specimens offers many advantages, including easy collection, the need for a small amount of blood, and simpler transportation. However, DBS has limitations for measuring GCase activity. In this paper, we recount our cross-sectional study and publish seven years of experience using DBS samples and levels of the deacylated form of glucocerebroside, glucosylsphingosine (lyso-Gb1), for GD diagnosis. Of 444 screened subjects, 99 (22.3%) were diagnosed with GD at a median (range) age of 21 (1–78) years. Lyso-Gb levels for genetically confirmed GD patients vs. subjects negative to GD diagnosis were 252 (9–1340) ng/mL and 5.4 (1.5–16) ng/mL, respectively. Patients diagnosed with GD1 and mild GBA1 variants had lower median (range) lyso-Gb1, 194 (9–1050), compared to GD1 and severe GBA1 variants, 447 (38–1340) ng/mL, and neuronopathic GD, 325 (116–1270) ng/mL (p = 0.001). Subjects with heterozygous GBA1 variants (carrier) had higher lyso-Gb1 levels, 5.8 (2.5–15.3) ng/mL, compared to wild-type GBA1, 4.9 (1.5–16), ng/mL (p = 0.001). Lyso-Gb1 levels, median (range), were 5 (2.7–10.7) in heterozygous GBA1 carriers with Parkinson’s disease (PD), similar to lyso-Gb1 levels in subjects without PD. We call for a paradigm change for the diagnosis of GD based on lyso-Gb1 measurements and confirmatory GBA1 mutation analyses in DBS. Lyso-Gb1 levels could not be used to differentiate between heterozygous GBA1 carriers and wild type.

BACKGROUND: Dabigatran etexilate is a direct oral anticoagulant with potential to overcome the limitations of standard of care in children with venous thromboembolism. The aims of this clinical trial were to study the appropriateness of a paediatric dabigatran dosing algorithm, and the efficacy and safety of dabigatran dosed according to that algorithm versus standard of care in treating children with venous thromboembolism. METHODS: DIVERSITY is a randomised, controlled, open-label, parallel-group, phase 2b/3 non-inferiority trial done in 65 centres in 26 countries. Standard of care (low-molecular-weight heparins, unfractionated heparin, vitamin K antagonists or fondaparinux) was compared with a paediatric oral dabigatran dosing regimen (an age-adjusted and weight-adjusted nomogram) in children younger than 18 years with acute venous thromboembolism initially treated (5-21 days) with parenteral anticoagulation, requiring anticoagulation therapy for at least 3 months. Patients were randomised 1:2 (standard of care:dabigatran) and stratified by age (12 to

Patients with Gaucher disease (GD), a rare autosomal recessive glycosphingolipid storage disease, commonly present to hematologists with unexplained splenomegaly, thrombocytopenia, anemia, and bone symptoms. Patients with GD may develop other manifestations, such as autoimmune thrombocytopenia, monoclonal gammopathy, multiple myeloma, or, even more rarely, other hematological malignancies; sometimes they are first diagnosed during an assessment of those disorders. Although the diagnosis and management of patients with GD have significantly evolved over the last 30 years, some patients remain poor responders to GD-specific therapy, needing novel and investigational therapies. Ideally, patients with GD, like patients with other rare diseases, should be managed by a multidisciplinary team expert with the diverse clinical manifestations and potential GD-related or -unrelated comorbidities. The hematology community should be knowledgeable regarding the presentation and the variety of hematologic complications and comorbidities associated with Gaucher disease.

Background It is now acknowledged that the input of patients in health outcome assessment is vital to understanding the impact of diseases and interventions for those diseases. This study is the first report of patient-reported outcome measures (PROM) in a large cohort of patients with type 1 Gaucher disease (GD1) enabling us to study predictors of the reported outcomes. Method The PROM was sent via a mobile phone survey to 405 adult patients with GD1. Demographics, clinical data, and treatment status were extracted from clinic charts. Age, sex, severity score index (SSI) at presentation and treatment status were used as variables to assess outcomes. Results A total of 192 patients with GD1 (111 females) responded (47.4% response rate), of whom 124 (64.5%) had received GD1-specific therapy. Around 40% of patients reported that GD had restricted their education/job and fun activities and were concerned about being emotional and financial burdens on others. Concerns regarding the risk of bone disease and Parkinson disease were also high (60%). The severity of GD1 (reflected by the need for GD1-specific therapy and a high SSI) was associated with GD1-related restrictions and concerns, fatigue, physical weakness, bone pain, and worry regarding the future. Conclusions The use of GD1 specific PROM highlights personal problems that are not captured by traditional outcome parameters and that need to be addressed to improve health-related quality of life. Validated PROM should be included among the outcome measures in clinical practice and future prospective studies for patients with chronic and rare diseases.

Type-1 Gaucher disease (GD1) is considered to be non- neuronopathic however recent evidence of neurological involvement continues to accumulate. There is limited evidence of retinal abnormalities in GD1. The purpose of this study was to evaluate the retinal findings of patients with GD1. Thirty GD1 individuals and 30 healthy volunteers between the ages 40–75 years were prospectively enrolled. Macular and optic nerve optical coherence tomography (OCT) scans of both eyes of each patient were performed and thickness maps were compared between groups. Patients with a known neurodegenerative disease, glaucoma, high myopia and previous intraocular surgeries were excluded. It was shown that patients with GD1 presented with higher incidence of abnormal pRNFL OCT scan and showed significantly thinner areas of pRNFL and macular ganglion cell complex (GCC) when compared to a healthy control population. Changes in retinal thickness were not associated with GD1 genotype, treatment status, disease monitoring biomarker (lyso-Gb1) and severity score index (Zimran SSI). Further investigations are needed to determine whether these findings possess functional visual implications and if retinal thinning may serve as biomarker for the development of future neurodegenerative disease in this population.

Data on non-fermentative Gram-negative rods (NFGNR) bacteremia in children with malignancies are limited. The aim of this study was to present clinical picture, antimicrobial susceptibility pattern, risk factors for resistance and outcome in NFGNR bacteremia in children with cancer. All episodes of NFGNR bacteremia occurring during 2001–2014 in children with cancer in a tertiary-care hospital were retrospectively analyzed. Pseudomonas and Acinetobacter spp. resistant to three or more antibiotic classes and all Stenotrophomonas maltophilia (SM) were defined as multidrug-resistant bacteria (MDR). A total of 80 children (44 males, 0.8–18 years, median 5 years) developed 107 episodes (116 pathogens) of NFGNR bacteremia; Pseudomonas aeruginosa (PA) (51; 43.9%), Acinetobacter baumannii (AB) (21, 18.1%), SM (18, 15.5%); and others (27, 25.2%). The rate of NFGNR bacteremia in children with certain solid tumors (e.g. sarcoma, 12/134 (9.0%)) was comparable to that of hematological malignancies (52/429 (12.2%). Focal infection and septic shock occurred in 16 (14.9%) and four (3.7%) episodes, respectively. Thirty (25.8%) of 116 NFGNR were MDR. The most significant predictors of bacteremia with MDR PA or AB were severe neutropenia (

Contains fulltext : 219893.pdf (Publisher’s version ) (Closed access) BACKGROUND: Treatment of venous thromboembolism in children is based on data obtained in adults with little direct documentation of its efficacy and safety in children. The aim of our study was to compare the efficacy and safety of rivaroxaban versus standard anticoagulants in children with venous thromboembolism. METHODS: In a multicentre, parallel-group, open-label, randomised study, children (aged 0-17 years) attending 107 paediatric hospitals in 28 countries with documented acute venous thromboembolism who had started heparinisation were assigned (2:1) to bodyweight-adjusted rivaroxaban (tablets or suspension) in a 20-mg equivalent dose or standard anticoagulants (heparin or switched to vitamin K antagonist). Randomisation was stratified by age and venous thromboembolism site. The main treatment period was 3 months (1 month in children /=1 dose), were centrally assessed by investigators who were unaware of treatment assignment. Repeat imaging was obtained at the end of the main treatment period and compared with baseline imaging tests. This trial is registered with ClinicalTrials.gov, number NCT02234843 and has been completed. FINDINGS: From Nov 14, 2014, to Sept 28, 2018, 500 (96%) of the 520 children screened for eligibility were enrolled. After a median follow-up of 91 days (IQR 87-95) in children who had a study treatment period of 3 months (n=463) and 31 days (IQR 29-35) in children who had a study treatment period of 1 month (n=37), symptomatic recurrent venous thromboembolism occurred in four (1%) of 335 children receiving rivaroxaban and five (3%) of 165 receiving standard anticoagulants (hazard ratio [HR] 0.40, 95% CI 0.11-1.41). Repeat imaging showed an improved effect of rivaroxaban on thrombotic burden as compared with standard anticoagulants (p=0.012). Major or clinically relevant non-major bleeding in participants who received >/=1 dose occurred in ten (3%) of 329 children (all non-major) receiving rivaroxaban and in three (2%) of 162 children (two major and one non-major) receiving standard anticoagulants (HR 1.58, 95% CI 0.51-6.27). Absolute and relative efficacy and safety estimates of rivaroxaban versus standard anticoagulation estimates were similar to those in rivaroxaban studies in adults. There were no treatment-related deaths. INTERPRETATION: In children with acute venous thromboembolism, treatment with rivaroxaban resulted in a similarly low recurrence risk and reduced thrombotic burden without increased bleeding, as compared with standard anticoagulants. FUNDING: Bayer AG and Janssen Research & Development. 01 januari 2020

A targeted high-throughput sequencing (HTS) panel test for clinical diagnostics requires careful consideration of the inclusion of appropriate diagnostic-grade genes, the ability to detect multiple types of genomic variation with high levels of analytic sensitivity and reproducibility, and variant interpretation by a multidisciplinary team (MDT) in the context of the clinical phenotype. We have sequenced 2396 index patients using the ThromboGenomics HTS panel test of diagnostic-grade genes known to harbor variants associated with rare bleeding, thrombotic, or platelet disorders (BTPDs). The molecular diagnostic rate was determined by the clinical phenotype, with an overall rate of 49.2% for all thrombotic, coagulation, platelet count, and function disorder patients and a rate of 3.2% for patients with unexplained bleeding disorders characterized by normal hemostasis test results. The MDT classified 745 unique variants, including copy number variants (CNVs) and intronic variants, as pathogenic, likely pathogenic, or variants of uncertain significance. Half of these variants (50.9%) are novel and 41 unique variants were identified in 7 genes recently found to be implicated in BTPDs. Inspection of canonical hemostasis pathways identified 29 patients with evidence of oligogenic inheritance. A molecular diagnosis has been reported for 894 index patients providing evidence that introducing an HTS genetic test is a valuable addition to laboratory diagnostics in patients with a high likelihood of having an inherited BTPD. ispartof: BLOOD vol:134 issue:23 pages:2082-2091 ispartof: location:United States status: published

Background Essential thrombocythemia (ET) is rare in children, and pediatric guidelines are lacking. Therefore, we aimed to evaluate ET diagnosis and treatment in a pediatric cohort. Procedure Data of patients with ET from three hospitals were reviewed. Molecular diagnosis included JAK2V617F, CALR, and MPL mutations. Patients were evaluated for acquired von Willebrand syndrome (AVWS). Follow-up included clinical symptoms, adverse events, and treatment. Results Twelve children (median age: 8 years, range 1-14.5) were included. Mean lag period between the first documentation of thrombocytosis until ET diagnosis was 36 months. Six patients were positive for JAK2V617F and two for CALR mutations. In six of nine patients, AVWS was diagnosed. At diagnosis, only 33% of patients started therapy with aspirin (n = 4) and hydroxyurea (n = 2). In three of eight untreated patients, therapy was added during follow-up. The cohort was followed for a median of 32.5 months (range: 4-108 months). Clinical follow-up disclosed vascular complications in 4 of 12 patients (deep vein thrombosis, n = 1; transient ischemic attack, n = 3). Two females experienced excessive bleeding; both were diagnosed with AVWS. Neither leukemia nor myelofibrosis evolved in our cohort. Conclusion Increased awareness to pediatric ET is warranted, as delayed diagnosis is common. Compared to adults, AVWS may be more prevalent among children with ET.

Background Rivaroxaban has been shown to be efficacious for treatment of venous thromboembolism in adults, and has a reduced risk of bleeding compared with standard anticoagulants. We aimed to develop paediatric rivaroxaban regimens for the treatment of venous thromboembolism in children and adolescents. Methods In this phase 2 programme, we did three studies to evaluate rivaroxaban treatment in children younger than 6 months, aged 6 months to 5 years, and aged 6-17 years. Our studies used a multicentre, single-arm design at 54 sites in Australia, Europe, Israel, Japan, and north America. We included children with objectively confirmed venous thromboembolism previously treated with low-molecular weight heparin, fondaparinux, or a vitamin K antagonist for at least 2 months or, in children who had catheter-related venous thromboembolism for at least 6 weeks. We administered rivaroxaban orally in a bodyweight-adjusted 20 mg-equivalent dose, based on physiologically-based pharmacokinetic modelling predictions and EINSTEIN-Jr phase 1 data in young adults, in either a once-daily (tablets; for those aged 6-17 years), twice-daily (in suspension; for those aged 6 months to 11 years), or three times-daily (in suspension; for those younger than 6 months) dosing regimen for 30 days (or 7 days for those younger than 6 months). The primary aim was to define rivaroxaban treatment regimens that match the target adult exposure range. The principal safety outcome was major bleeding and clinically relevant non-major bleeding. Analyses were per-protocol. The predefined efficacy outcomes were symptomatic recurrent venous thromboembolism, asymptomatic deterioration on repeat imaging at the end of the study treatment period. These trials are registered at ClinicalTrials.gov, numbers NCT02564718, NCT02309411, and NCT02234843. Findings Between Feb 11, 2013, and Dec 20, 2017, we enrolled 93 children (ten children younger than 6 months; 15 children aged 6 months to 1 year; 25 children aged 2-5 years; 32 children aged 6-11 years; and 11 children aged 12-17 years) into our study. 89 (96%) children completed study treatment (30 days of treatment, or 7 days in those younger than 6 months), and 93 (100%) children received at least one dose of study treatment and were evaluable for the primary endpoints. None of the children had a major bleed, and four (4%, 95% CI 1.2-10.6) of these children had a clinically relevant non-major bleed (three children aged 12-17 years with menorrhagia and one child aged 6-11 years with gingival bleeding). We found no symptomatic recurrent venous thromboembolism in any patients (0%, 0.0-3.9). 24 (32%) of 75 patients with repeat imaging had their thrombotic burden resolved, 43 (57%) patients improved, and eight (11%) patients were unchanged. No patient deteriorated. We confirmed therapeutic rivaroxaban exposures with once-daily dosing in children with bodyweights of at least 30 kg and with twice-daily dosing in children with bodyweights of at least 20 kg and less than 30 kg. Children with low bodyweights (

The role of glucosylsphingosine (lyso-Gb1), a downstream metabolic product of glucosylceramide, for monitoring treated and untreated children with Gaucher disease (GD) has not yet been studied. We reviewed the clinical charts of 81 children (

Adenosine deaminase 2 deficiency is an autoinflammatory disease, characterized by various forms of vasculitis. We describe 5 patients with adenosine deaminase 2 deficiency with various hematologic manifestations, including pure red cell aplasia, with no evidence for vasculitis.

Nasopharyngeal carcinoma (NPC) is a rare and locally aggressive form of childhood cancer. Treatment of NPC includes chemotherapy and radiotherapy. With current treatment protocols, survival rates for patients with nonmetastatic disease is over 80%. Data regarding very late events including long-term treatment-related morbidities and second malignancies are scarce. We present our data on 42 patients with NPC treated in Israel between 1989 and 2014, and followed until 2019. During follow up, five patients had disease recurrence, and four children developed secondary malignancy. Median time to diagnosis of secondary malignancy was 105 months. Eighty-eight percent of patients have long-term treatment-related morbidities.

Next-generation sequencing has been invaluable in the elucidation of the genetic etiology of many subtypes of intellectual disability in recent years. Here, using exome sequencing and whole-genome sequencing, we identified three de novo truncating mutations in WAS protein family member 1 (WASF1) in five unrelated individuals with moderate to profound intellectual disability with autistic features and seizures. WASF1, also known as WAVE1, is part of the WAVE complex and acts as a mediator between Rac-GTPase and actin to induce actin polymerization. The three mutations connected by Matchmaker Exchange were c.1516C>T (p.Arg506Ter), which occurs in three unrelated individuals, c.1558C>T (p.Gln520Ter), and c.1482delinsGCCAGG (p.Ile494MetfsTer23). All three variants are predicted to partially or fully disrupt the C-terminal actin-binding WCA domain. Functional studies using fibroblast cells from two affected individuals with the c.1516C>T mutation showed a truncated WASF1 and a defect in actin remodeling. This study provides evidence that de novo heterozygous mutations in WASF1 cause a rare form of intellectual disability. ispartof: AMERICAN JOURNAL OF HUMAN GENETICS vol:103 issue:1 pages:144-153 ispartof: location:United States status: published

SummaryThe maturation and postnatal development of the human coagulation system results in significant and important differences in the coagulation and fibrinolysis of neonates and young children compared to older children and adults. Importantly, these differences, which mostly reflect the immaturity of the neonatal haemostasis system, are functionally balanced. Healthy neonates show no signs of easy bruising or other bleeding diathesis and no increased tendency to thrombosis for any given stimulus compared to adults.Systemic diseases may affect haemostasis, thus predisposing ill neonates to increased risk for haemorrhagic or thrombotic complications. In hospitalized children, neonates have increased risk of developing thrombosis compared to infants and children, mostly associated with the presence of central venous catheter. For diagnosis of haemostasis disorders, diagnostic laboratories processing pediatric samples should use age, analyzer and reagent appropriate reference ranges. Age specific guidelines should be followed for the management of neonates with hemostatic disorders.

Evaluate a potential association between Wilms' tumour (WT) and renal cystic lesions.Digital records and imaging files of consecutive patients diagnosed with WT between 2004 and 2014 were retrospectively reviewed under an Institutional Review Board waiver of informed consent. The locations of renal cysts seen on US, CT, and/or MRI were recorded and compared with the locations of newly developed WT.A total of 48 patients (mean age 3 years 9 months) presented with newly diagnosed WT in the study period. Mean follow-up was 4.5 (range 1-10) years. WT was unilateral in 40 children, bilateral in 8. Renal cysts were identified in only one of the forty patients (2.5 %) with unilateral disease - in the contralateral kidney. In contrast, renal cysts were found in seven of eight patients with bilateral WT (87.5 %), in two of whom, new tumours developed in the same location where cysts had been seen on previous imaging studies.Renal cystic lesions in patients with Wilms' tumour should be regarded as potential tumour precursors, and followed with frequent imaging.• Cortical renal cystic lesions have a high association with bilateral Wilms' tumour. • In children with Wilms' tumour renal cysts are possible tumour precursors. • MRI appears to be the best modality in depicting the cortical cysts.

Hematopoietic stem cell transplantation (HSCT) remains the leading treatment for the majority of severe primary immune deficiency (PID). This study aims to analyze changes in outcome over time. We conducted a retrospective analysis of HSCT in children with PID in a tertiary medical center over the period of 1983 to 2012. We identified 93 children with PID with a median follow-up of 3.6 years (range, 29 d to 21.2 y) after HSCT. The 2-year survival rates after HSCT for children with severe combined immune deficiency, hemophagocytic lymphohistiocytosis/lymphoproliferative disease, Wiskott-Aldrich syndrome, granulocyte defect, and undefined PID were 65.7%±6.8%, 80%±10.3%, 83.3%±15.2%, 75%±12.5%, and 25%±21.7%, respectively. Survival was associated with year of HSCT and matching. The hazard ratio (HR) (95% CI) for HSCT done in 1983 to 1999 compared with 2000 to 2012 and for matched (related and unrelated) compared with mismatched donor were 2.14 (0.99 to 4.653) and 3.07 (1.46 to 6.4), respectively. Survival was not associated with age, sex of the recipient, underlying PID, conditioning regimen, and presence of acute graft-versus-host disease. After adjustment to the underlying PID, donor and use of fludarabine-based conditioning, the HR (95% CI) for HSCT from the year 2000 was 4.69 (range, 1.4 to 15.45). Advances in HSCT over time have improved the survival of children with PID.

Autoimmune lymphoproliferative syndrome is frequently caused by mutations in genes involved in the Fas death receptor pathway, but for 20–30% of patients the genetic defect is unknown. We observed that treatment of healthy T cells with interleukin-12 induces upregulation of Fas ligand and Fas ligand-dependent apoptosis. Consistently, interleukin-12 could not induce apoptosis in Fas ligand-deficient T cells from patients with autoimmune lymphoproliferative syndrome. We hypothesized that defects in the interleukin-12 signaling pathway may cause a similar phenotype as that caused by mutations of the Fas ligand gene. To test this, we analyzed 20 patients with autoimmune lymphoproliferative syndrome of unknown cause by whole-exome sequencing. We identified a homozygous nonsense mutation (c.698G>A, p.R212*) in the interleukin-12/interleukin-23 receptor-component IL12RB1 in one of these patients. The mutation led to IL12RB1 protein truncation and loss of cell surface expression. Interleukin-12 and -23 signaling was completely abrogated as demonstrated by deficient STAT4 phosphorylation and interferon γ production. Interleukin-12-mediated expression of membrane-bound and soluble Fas ligand was lacking and basal expression was much lower than in healthy controls. The patient presented with the classical symptoms of autoimmune lymphoproliferative syndrome: chronic non-malignant, non-infectious lymphadenopathy, splenomegaly, hepatomegaly, elevated numbers of double-negative T cells, autoimmune cytopenias, and increased levels of vitamin B12 and interleukin-10. Sanger sequencing and whole-exome sequencing excluded the presence of germline or somatic mutations in genes known to be associated with the autoimmune lymphoproliferative syndrome. Our data suggest that deficient regulation of Fas ligand expression by regulators such as the interleukin-12 signaling pathway may be an alternative cause of autoimmune lymphoproliferative syndrome-like disease.

Teratomas of the liver are exceedingly rare. Neuroblastoma is the most common, extracranial solid tumor of infancy. We describe the case of a 2-month-old, female infant who presented with an abdominal mass arising in the right lobe of the liver, and a severe coagulopathy, which necessitated cryoprecipitate infusion. Biopsy was interpreted as hepatoblastoma. Following resection, difficulty classifying the mass led to several consultations, and an eventual diagnosis of teratoma. During follow-up, the patient was diagnosed with right adrenal neuroblastoma, which, in retrospect, had been present before the hepatic resection. To our knowledge, these 2 tumors have never been reported together, or in combination with isolated hypofibrinogenemia.

Preliminary data suggest a positive effect of taliglucerase alfa on the bone marrow infiltration of Gaucher cells. In this investigator-initiated study, we report the impact of taliglucerase alfa on the bone marrow fat fraction (FF) in 26 patients assessed by quantitative chemical shift imaging (QCSI). Of 15 treatment-naïve patients (median age 48 [range 24–68] years), eight had baseline FF ≤ 0.3, six of those with a FF ≤ 0.23 (‘bone at risk’). All significantly improved from a median baseline FF of 0.24 (0.15–0.32) to 1st year FF of 0.37 (0.25–0.54) and 2nd year FF of 0.42 (0.27–0.59) (p = 0.01). Among the 11 ‘switch-over’ patients (median age 42 [range 33–69] years; median imiglucerase exposure 8 [range 1–17] years), eight had baseline FF ≤ 0.3, five of those with FF < 0.23. All, but one, significantly improved from a median baseline FF of 0.17 (0.08–0.28) to 1st year FF of 0.3 (0.05–0.34) and 2nd year FF of 0.34 (0.08–0.44) (p = 0.03). Two elderly female patients (age 43 and 58 years, with 17 years imiglucerase exposure) who remained at the same enzyme replacement therapy dose, increased from baseline FF of 0.13 and 0.19 to 0.26 at 1 year. Although the number of observations is small, we hypothesize that switching to taliglucerase may result in an improved bone marrow response. A larger study is needed to assess the early benefit of taliglucerase alfa in adult patients with type 1 Gaucher disease on the bone marrow compartment.

Autoimmune cytopenia is a frequent manifestation of primary immunodeficiencies. Two siblings presented with Evans syndrome, viral infections, and progressive leukopenia. DNA available from one patient showed a homozygous frameshift mutation in tripeptidyl peptidase II (TPP2) abolishing protein expression. TPP2 is a serine exopeptidase involved in extralysosomal peptide degradation. Its deficiency in mice activates cell death programs and premature senescence. Similar to cells from naïve, uninfected TPP2-deficient mice, patient cells showed increased major histocompatibility complex I expression and most CD8(+) T-cells had a senescent CCR7-CD127(-)CD28(-)CD57(+) phenotype with poor proliferative responses and enhanced staurosporine-induced apoptosis. T-cells showed increased expression of the effector molecules perforin and interferon-γ with high expression of the transcription factor T-bet. Age-associated B-cells with a CD21(-) CD11c(+) phenotype expressing T-bet were increased in humans and mice, combined with antinuclear antibodies. Moreover, markers of senescence were also present in human and murine TPP2-deficient fibroblasts. Telomere lengths were normal in patient fibroblasts and granulocytes, and low normal in lymphocytes, which were compatible with activation of stress-induced rather than replicative senescence programs. TPP2 deficiency is the first primary immunodeficiency linking premature immunosenescence to severe autoimmunity. Determination of senescent lymphocytes should be part of the diagnostic evaluation of children with refractory multilineage cytopenias.

International audience; Heritable platelet function disorders (PFDs) are genetically heterogeneous and poorly characterised. Pathogenic variants in RASGRP2, which encodes calcium and diacylglycerol-regulated guanine exchange factor I (CalDAG-GEFI), have been reported previously in three pedigrees with bleeding and reduced platelet aggregation responses. To better define the phenotype associated with pathogenic RASGRP2 variants, we compared high-throughput sequencing and phenotype data from 2,042 cases in pedigrees with unexplained bleeding or platelet disorders to data from 5,422 controls. Eleven cases harboured 11 different, previously unreported RASGRP2 variants that were biallelic and likely pathogenic. The variants included five high-impact variants predicted to prevent CalDAG-GEFI expression and six missense variants affecting the CalDAG-GEFI CDC25 domain, which mediates Rap1 activation during platelet inside-out αIIbβ3 signalling. Cases with biallelic RASGRP2 variants had abnormal mucocutaneous, surgical and dental bleeding from childhood, requiring at least one blood or platelet transfusion in 78% of cases. Platelets displayed reduced aggregation in response to ADP and epinephrine, but variable aggregation defects with other agonists. There were no other consistent clinical or laboratory features. These data enable definition of human CalDAG-GEFI deficiency as a non-syndromic, recessive PFD associated with a moderate or severe bleeding phenotype and complex defects in platelet aggregation.

Eleven pedigrees were identified with biallelic pathogenic variants in RASGPR2, which encodes platelet CalDAG-GEFI.CalDAG-GEFI deficiency is a severe, recessive, nonsyndromic platelet function disorder with defective aggregation to multiple agonists.

Background Cytochrome P450 1A2 (CYP1A2) is a cytochrome enzyme with a pivotal role in hepatic drug metabolism. Data from CYP1A2(−/−) mouse suggest that CYP1A2 plays a role in aspects of hepatic iron toxicity. The aim of this study was to assess the activity of CYP1A2 in relation to hepatic iron load in patients with transfusion-dependent β-thalassaemia major. Methods The 13C-methacetin continuous breath test was performed on 30 consecutive patients with transfusion-dependent β-thalassaemia major. CYP1A2 activity was measured by the rate at which the 13C substrate is metabolized and exhaled expressed as percentage dose recovery (PDR) per hour. CYP1A2 activity was correlated with clinical and laboratory parameters and hepatic iron accumulation by T2* magnetic resonance imaging (T2*MRI). Results Cytochrome P450 1A2 activity in patients with transfusion-dependent β- thalassaemia major was positivity correlated with plasma ferritin levels. No correlation was found with age, duration and amount of red blood cell transfusion and type of iron chelation therapy. Low CYP1A2 activity was negatively associated with hepatic iron accumulation (T2*MRI ≤ 6·3 ms); adjusted odds ratio (OR; 95% CI) for hepatic iron accumulation in patients with low CYP1A2 activity was 0·047 (0·003–0·72; P = 0·021). Of the six patients with decreased activity of CYP1A2, five had no hepatic iron accumulation and one had mild hepatic iron accumulation by T2*MRI. Conclusion Activity of CYP1A2 is associated with hepatic iron accumulation in patients with transfusion-depended β-thalassaemia major. Further studies are needed to assess the exact role of CYP1A2 in iron metabolism in human.

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.

Mutations in the IL-2-inducible T-cell kinase gene have recently been shown to cause an autosomal recessive fatal Epstein Barr virus (EBV) associated lymphoproliferation. We report 3 cases from a single family who presented with EBV-positive B-cell proliferation diagnosed as Hodgkin’s lymphoma. Single nucleotide polymorphism array-based genome-wide linkage analysis revealed IL-2-inducible T-cell kinase as a candidate gene for this disorder. All 3 patients harbored the same novel homozygous nonsense mutation C1764G which causes a premature stop-codon in the kinase domain. All cases were initially treated with chemotherapy. One patient remains in durable remission, the second patient subsequently developed severe hemophagocytic lymphohistiocytosis with multi-organ failure and died, and the third patient underwent a successful allogeneic bone marrow transplantation. IL-2-inducible T-cell kinase deficiency underlies a new primary immune deficiency which may account for part of the spectrum of Epstein Barr virus related lymphoproliferative disorders which can be successfully corrected by bone marrow transplantation.

Objective To determine whether oocyte retrieval and in vitro maturation (IVM) is effective in girls undergoing fertility preservation before cancer treatment. Design Cohort study. Setting Tertiary university medical center. Patient(s) Patients ≤20 years old before gonadotoxic chemotherapy undergoing ovarian cortex cryopreservation. Intervention(s) Before ovarian cortex cryopreservation, oocytes in all observed follicles were aspirated, matured in vitro, and cryopreserved. Main Outcome Measure(s) Maturation of oocytes. Result(s) One hundred seventy-nine oocytes were detected in 17/19 patients (89%) aged 5–20 years. We found 7, 8, and 17 oocytes in patients 5, 8, and 10 years old, respectively. The median number of oocytes per patient was 9 (0–37). Maturation rate was 45/133 oocytes (34%). In total, 81 oocytes were cryopreserved. We cryopreserved 4 of 12 detected, 4 of 9 detected, 1 of 8 detected, and 4 of 9 detected IVM oocytes for patients aged 5–10, 11–14, 15–17, and 18–20 years old, respectively. Conclusion(s) Patients undergoing ovarian cryopreservation could benefit from supplementary oocyte aspiration from the cortex. Surprisingly, oocytes were detected even in young premenarcheal girls. The number of oocytes detected, matured, and cryopreserved was not age dependent. Retrieved oocytes can be matured in vitro and cryopreserved. Because no pregnancy has yet resulted from this procedure it should be considered to be experimental. We describe the youngest patients to undergo ovum collection, IVM, and oocyte cryopreservation.

Inherited bleeding, thrombotic and platelet disorders (BPDs) are diseases affecting approximately 300 individuals per million births. With the exception of haemophilia and von Willebrand disease patients, a molecular analysis for patients with a BPD is often unavailable. Many specialised tests are usually required to reach a putative diagnosis and they are typically performed in a step-wise manner to control costs. This approach causes delays and a conclusive molecular diagnosis is often never reached which can compromise treatment and impede rapid identification of affected relatives. To address this unmet diagnostic need, we designed a high-throughput sequencing (HTS) platform targeting 63 genes relevant for BPDs. The platform can call single nucleotide variants (SNVs), short insertions/deletions (indels) and large copy number variants (CNVs), though not inversions, which are subjected to automated filtering for diagnostic prioritization, resulting in an average of 5.34 candidate variants per individual. We sequenced 159 and 137 samples respectively from cases with and without previously known causal variants. Among the latter group, 61 cases had clinical and laboratory phenotypes indicative of a particular molecular etiology while the remainder had ana priorihighly uncertain etiology. All previously detected variants were recapitulated and, when the etiology was suspected but unknown or uncertain, a molecular diagnosis was reached in 56 of 61 and only eight of 76 cases, respectively. The latter category highlights the need for further research into novel causes of BPDs. The ThromboGenomics platform thus provides an affordable DNA-based test to diagnose patients suspected of having a known inherited BPD.

Item does not contain fulltext BACKGROUND: LPS-responsive beige-like anchor protein (LRBA) deficiency is a primary immunodeficiency caused by biallelic mutations in LRBA that abolish LRBA protein expression. OBJECTIVE: We sought to report the extended phenotype of LRBA deficiency in a cohort of 22 LRBA-deficient patients. METHODS: Clinical criteria, protein detection, and genetic sequencing were applied to diagnose LRBA deficiency. RESULTS: Ninety-three patients met the inclusion criteria and were considered to have possible LRBA deficiency. Twenty-four patients did not express LRBA protein and were labeled as having probable LRBA deficiency, whereas 22 were genetically confirmed as having definitive LRBA deficiency, with biallelic mutations in LRBA. Seventeen of these were novel and included homozygous or compound heterozygous mutations. Immune dysregulation (95%), organomegaly (86%), recurrent infections (71%), and hypogammaglobulinemia (57%) were the main clinical complications observed in LRBA-deficient patients. Although 81% of LRBA-deficient patients had normal T-cell counts, 73% had reduced regulatory T (Treg) cell numbers. Most LRBA-deficient patients had low B-cell subset counts, mainly in switched memory B cells (80%) and plasmablasts (92%), with a defective specific antibody response in 67%. Of the 22 patients, 3 are deceased, 2 were treated successfully with hematopoietic stem cell transplantation, 7 are receiving immunoglobulin replacement, and 15 are receiving immunosuppressive treatment with systemic corticosteroids alone or in combination with steroid-sparing agents. CONCLUSION: This report describes the largest cohort of patients with LRBA deficiency and offers guidelines for physicians to identify LRBA deficiency, supporting appropriate clinical management.

Ewing sarcoma (ES) is the second most common bone tumor in children. Current chemotherapeutic regimens include high-dose anthracyclines and alkylating agents with significant variation in treatment length. The Memorial Sloan Kettering Cancer Center P6 regimen (MSKCC P6) treatment protocol is a highly aggressive regimen given over 21 weeks only. We present the outcome of ES patients treated in our center with this protocol over the last 15 years.We retrospectively analyzed data on the presentation, patient characteristics, treatment, and outcome of all ES patients treated according to the MSKCC P6 regimen from 1999 to 2014.Of 48 patients, 37 (77%) presented with a nonmetastatic disease and 26 (54%) with tumor located in the extremities. The 5-year overall survival (OS) of the entire cohort was 55.9% ± 8%. Nonmetastatic disease conferred a better prognosis with a 5-year OS of 68.4% ± 8.5%. Patients with a nonmetastatic extremity tumor had the most favorable outcome with 5-year OS of 72.2% ± 9.8%.The outcome of ES patients after a short aggressive course of chemotherapy (the MSKCC P6 protocol), is comparable to that following other first-line treatment regimens in use, with potentially fewer long-term adverse events.

Purpura fulminans (PF) is a very rare clinicopathologic skin disorder comprising dermal microvascular thrombosis associated with perivascular hemorrhage of multiple origins. It may occur as the presenting symptom of severe congenital deficiency of protein C (PC) or protein S (PS) during the newborn period, or later in life following oral anticoagulant therapy with vitamin K antagonists, or of sepsis that may be associated with disseminated intravascular coagulation. Treatment consists of anticoagulants and PC concentrates during acute episodes. We report our experience in the diagnosis and management of pediatric PF. The medical records of the 6 children aged 2-16 years (median: 5 years) who presented with PF to our tertiary care center between 1996 and 2013 were studied. The thrombophilia workup revealed either the presence of congenital homozygous PC deficiency, prothrombotic polymorphisms (factor V Leiden and FIIG20210A heterozygosity), acquired PC/PS deficiency, or no discernible thrombophilia. The skin necrosis resolved following conservative fresh-frozen plasma/anticoagulant therapy in 2 cases, whereas 3 children required interventional plastic surgery. The sixth case, a 10-year-old child with severe PC deficiency, heterozygous factor V Leiden, and FIIG20210A, received recombinant activated PC. PF in childhood is rare and has multiple etiologies. Understanding of the variable pathogenesis and risk factors will facilitate diagnosis and appropriate clinical management.

Venous thromboembolism (VTE) is an increasingly recognized problem among children and adolescents. Although inferior vena cava (IVC) filter placement for pulmonary embolism prevention is well reported in adults, data regarding safety and efficacy in the pediatric age group are lacking.At a large university hospital with a level I trauma center, medical records of children and adolescents who underwent IVC filter insertion were reviewed. Appropriateness of referral for retrieval was assessed in each case.Fifty-nine children and adolescents (mean age 16 years) successfully underwent IVC filter insertion. All filters placed were retrievable. In 47 patients (79.7%), prophylactic filters were placed in the absence of acute VTE in the setting of trauma. In eight patients (13.5%), filters were placed due to contraindication to anticoagulation therapy with concomitant lower extremity deep vein thrombosis or pulmonary embolism. Filters were successfully retrieved in only 12 patients (20.3%), although an attempt at removal was appropriate and feasible in over 90% of cases. Mean duration of follow-up was 2.1 (range 0.4-7.3) years. A significantly higher retrieval rate was found in patients followed at our thrombosis clinic (P0.01). Ten patients (17%) experienced at least one filter-related complication.Although in most cases, IVC filters were placed for prophylactic indications, the evidence to support their role in this setting is limited. Their low retrieval rate and high filter-related complication rate question their extensive utilization in children. Dedicated follow-up is necessary to detect complications and to ensure that an attempt at retrieval is made when feasible.

Central venous lines are used in critically ill children and in children with chronic conditions for the administration of intravenous therapy, such as fluids, medications, total parenteral nutrition and blood products. Although the use of central venous lines has greatly improved the quality of care in these children, these catheters may cause serious mechanical, infectious and thrombotic complications. The reported frequency of catheter thrombosis in children is low as 5% in studies including only symptomatic cases and high as 50% in studies where patients are systematically screened for catheter-related thrombosis. The risk factors for catheter-related thrombosis in children are associated with the methods used for catheter insertion and with individual patient characteristics, underlying diagnosis and treatment. The management of catheter-related thrombosis is largely dependent on the requirement of the catheter. If no longer required or nonfunctioning the catheter should be removed. If access is still required and the catheter is functioning, treatment with anticoagulation is recommended in the absence of contraindications. The management of radiographically detected asymptomatic thrombosis in children is less clear. Clinical studies of prophylaxis for catheter-related thrombosis are inconclusive and no definitive recommendations for prophylaxis in adults or in children with central venous thrombosis can be made. Properly designed studies are needed to assess the role of prophylactic anticoagulation for preventing catheter-related thrombosis.

The diagnosis of type 1 von Willebrand disease (VWD), the most common inherited bleeding disorder in humans, is greatly dependent on an accurate diagnosis of significant mucocutaneous bleeding. In a previous study, the authors modified the criteria of the International Society on Thrombosis and Haemostasis for significant mucocutaneous bleeding to a format, the Hospital for Sick Children (HSC) criteria, that was more applicable to diagnose significant mucocutaneous bleeding in children. To assess the reliability and reproducibility of classification of subjects as "bleeders" versus "non-bleeders" using a questionnaire for significant mucocutaneous bleeding targeted to children, 39 subjects interviewed for a previous HSC VWD study were reinterviewed for the current study. The original bleeding classification was confirmed in 80% of subjects interviewed for a second time, indicating that this method of classification is reproducible (kappa = 0.65), with a "substantial" agreement among the investigators who reviewed the questionnaire responses (kappa = 0.71). The validity and utility of the HSC questionnaire for primary screening of children with suspected mucocutaneous bleeding disorders merits assessment in further clinical studies.

Stage 4s neuroblastoma (NB) is a unique entity seen in infants less than 1 year of age, with metastatic disease confined to liver, skin, or bone marrow. Despite metastatic spread, stage 4s NB has a favorable outcome. An exception to this is seen in neonates who present with progressive enlargement of the liver with secondary respiratory compromise and liver failure. We describe a 4-week-old neonate who presented with 4s NB, with a rapidly enlarging liver, resulting in respiratory and hepatic failure, who had a rapid, sustained, and ongoing response to chemoembolization of the hepatic artery. This approach is feasible at this age, and may be effective in improving the outcome in this group of patients.

To determine the pattern and predictors of response to desmopressin (DDAVP) in children with von Willebrand disease (VWD).The authors reviewed the hospital records of all children with type 1 (n = 70) and type 2A (n = 5) VWD who were followed in the institution's Bleeding Disorders Clinic from January 1989 to June 2001 and who had a DDAVP challenge test after diagnosis. The major outcome evaluated was response to DDAVP, defined as an increase of greater than twofold over baseline of von Willebrand factor, ristocetin cofactor (VWF:RCo), and factor VIII coagulant (FVIII:C) and levels above 0.3 IU/mL.Response to DDAVP was observed in 56 (80%) of the 70 children with type 1 VWD. Age and baseline VWF:RCo and FVIII:C levels were positively associated with DDAVP response. A total of 36 children (28 responders, 8 nonresponders) with type 1 VWD were treated for bleeding episodes or for prophylaxis; of these 75% (6/8) of the nonresponders compared with 7% (2/28) of the responders to a DDAVP challenge test received blood component therapy (P0.01). One of the five children with type 2A VWD responded to DDAVP.DDAVP challenge tests are recommended in children with newly diagnosed VWD to identify responders in whom DDAVP may be used for the prevention or treatment of bleeding, thus avoiding exposure to blood products. The association of DDAVP response with age merits further investigation.

This study aimed at reviewing our experience with infections caused by Fusobacterium in children. A retrospective analysis of medical records of children admitted to Hadassah-Hebrew University Medical Center from 2000 to 2013, in whom Fusobacterium spp. was identified in any specimen. A total of 22 patients (males = 12) at a mean ± SE age of 5 ± 1 (range 1–17) years, were identified. The most common complication was abscess formation (n = 11, 50 %). Eight children (36.4 %) had intracranial complications, including brain abscess (n = 4), meningitis (n = 4) and cerebral sinus vein thrombosis (CSVT, n = 5). Seventeen children (77 %) had bacteremia. Primary site of infection was otogenic (n = 9), oropharyngeal (n = 7), respiratory (n = 2), sinuses (n = 2), intra-abdominal (n = 1) and mucositis (n = 1). Fourteen cases were caused by Fusobacterium necrophorum, including four cases with CSVT, 7/8 cases of mastoiditis, four of them with subperiosteal abscess formation; all four cases with meningitis and two brain abscesses. Fifteen (68 %) patients required surgical intervention and 3 (14 %) received anti-coagulation therapy. Excluding one patient with overwhelming sepsis with fatal outcome, all patients recovered. Fusobacterium infections in children can cause a diverse spectrum of disease and is associated with high rates of abscess formation and intracranial complications. Although Fusobacterium nucleatum is abundant in the oral cavity, F. necrophorum is the main pathogen that causes severe infections in healthy children.

A cross-sectional retrospective study was performed to question the utility of coagulation screening to prevent procedure-related bleeding before oocyte retrieval in IVF. Among 1,032 patients evaluated we found that 534 coagulation tests were needed to prevent one case of bleeding associated with an abnormal coagulation test result.

Iron studies are difficult to interpret in patients with chronic inflammatory states such as inflammatory bowel disease (IBD). Serum transferrin receptor (TfR) has been reported to be a reliable tool for the diagnosis of iron deficiency in adults. Our aim was to evaluate the role of serum TfR in diagnosing iron deficiency in children and adolescents with IBD. A total of 63 consecutive patients with IBD, aged 9 to 22 years (median 15 years), were tested for serum haemoglobin level, mean corpuscular volume (MCV), and serum iron, transferrin, ferritin and serum TfR levels. Those found to be anaemic were compared with seven age-matched subjects with iron deficiency anaemia (IDA) and 24 age-matched children without signs of anaemia or inflammation. Of the 63 patients with IBD, 26 had anaemia. Based on ferritin levels and MCV indices, anaemia was classified as IDA in 11 patients and as anaemia of chronic disease (ACD) in 15 patients. Mean serum TfR level in normal controls was 3.5 mg/l (range 1.2-8.2 mg/l). Mean (+/-SD) serum TfR levels were significantly lower in the IBD patients with ACD (5.3 +/- 2.3 mg/l) than in the IBD patients with IDA (8.2 +/- 3.1 mg/l) (P0.05). Serum TfR levels above 5 mg/l identified 10/11 IBD patients with IDA. The calculated TfR/ferritin ratio was 84 (range 17-367) for controls and 133 (range 6.4-1840) for IBD patients. A cut-off level of 350 (91% sensitivity, 100% specificity, 100% positive predictive value, 98% negative predictive value) was established for the diagnosis of IDA in IBD.The results suggest that serum transferrin receptor is a useful parameter for the diagnosis of iron deficiency in inflammatory bowel disease, in particular, the transferrin receptor/ferritin ratio with a cut-off levelor = 350.

The need to recognize infants that are at high risk for developing significant jaundice is apparent in the era of routine early discharge. The aim of the present study was to prospectively determine the ability to predict severe hyperbilirubinemia in term healthy newborns (defined as total serum bilirubin of10.0 mg/dl at day 2,14.0 mg/dl at day 3, and17.0 mg/dl at days 4 and 5 of life).Prospective study of 1177 healthy term newborns.Two university-affiliated community hospitals in Jerusalem.Using a multiple logistic regression analysis, neonatal jaundice was best predicted (p0.0001) by day 1 serum bilirubin (adjusted odds ratio of 3.1 [per mg/dl] [95% confidence limits of 2.4 to 4.1]) and by a change in serum bilirubin from the first to the second day of life (2.4 [per mg/dl] [1.9 to 3.0]). Maternal blood type 0 (2.9 [1.5 to 5.8]), age (1.1 [per year] [1.0 to 1.2]), schooling (0.8 [per year] [0.7 to 0.9]), and full breastfeeding (0.4 [0.2 to 0.9]) were also associated with jaundice (p0.005). Other factors considered in the regression model but not found to be significantly related to jaundice included maternal ethnic origin, smoking, hypertension, diabetes mellitus, intranatal administration of oxytocin, meperidine, anesthesia, premature rupture of the membranes, parity, newborn sex, birth weight, gestational age, presentation. Apgar scores, blood type, hematocrit, cephalohematoma, and history of jaundice in other siblings. A model for predicting neonatal jaundice based on the above factors had a sensitivity of 81.8%, a specificity of 82.9%, a false positive rate of 80.2%, and a false negative rate of 1.1%.Individual risk assessment on discharge in association with day 1 total serum bilirubin is of value in identifying infants at greater risk for neonatal jaundice.

Retinoblastoma is the most common eye tumor in children and is highly curable. Patients with hereditary retinoblastoma, have an increased risk of developing additional tumors, predominantly sarcomas. Most chemotherapy regimens used in retinoblastoma include etoposide, an epipodophyllotoxin associated with a risk of secondary myeloid leukemia. The use of etoposide in patients with a cancer predisposition syndrome such as retinoblastoma is potentially harmful, however, reports of secondary acute myeloid leukemia in patients treated with etoposide for retinoblastoma are rare. We report a case of a patient who developed secondary acute myeloid leukemia after etoposide treatment for retinoblastoma.

Oral mucositis is a common complication of cancer therapy. Animal models suggest that curcumin may prevent oral mucositis. To date, no clinical studies have been reported.The primary aim of this pilot study was to assess the tolerability of a curcumin mouthwash. The secondary aim was to describe oral mucositis in pediatric patients undergoing doxorubicin-containing chemotherapy who were using the curcumin mouthwash.The research team had originally designed a placebo-controlled study, but gastrointestinal adverse events (nausea and vomiting) affected the compliance of the first three participants who entered the study. An independent researcher found that all three had received the placebo. Believing it unethical to continue using the study's original design, the research team discontinued the control group, and the resulting study is comparable to a case series.The research team performed the study at Hadassah University Medical Center in Jerusalem, Israel.Participants were seven pediatric and young-adult oncology patients.In addition to standard, preventive oral care (chlorhexidine 0.2% mouthwash for 30 s twice per day), participants also used 10 drops of Curcumall twice per day in a mouthwash during treatment with highdose chemotherapy.Oral mucositis was assessed on days 0, 7, 10, 14, and 21. The World Health Organization (WHO) scale, the Oral Mucositis Assessment Scale (OMAS), and a Visual Analog pain scale (VAS; patient reporting scale of 0-10) were used. Adverse events were tracked.No oral adverse events were documented. No systemic adverse events that possibly could be related to the use of the curcumin mouthwash were observed. In the four patients who fulfilled the compliance criteria, the WHO, OMAS and VAS scores were lower than the severity of oral mucositis previously reported in the literature. Four out of the five participants developed OM, but the values were low, reflecting a relatively mild case.In this study, the research team suggested that curcumin mouthwash was safe and well-tolerated. More research is warranted about the efficacy of topical curcumin in the prevention of oral mucositis.

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.

Infants with 4s neuroblastoma (NB) and massive hepatomegaly have a guarded prognosis and mortality approaches 30%. We report on eight patients with 4s NB and massive hepatomegaly treated with multiple modalities. One patient had spontaneous tumor regression. Three patients had progressive disease and responded to chemotherapy. Four patients progressed despite intravenous chemotherapy, of whom two died, and two were salvaged with hepatic intra-arterial chemoembolization. Treatment of infants with stage 4s NB with massive hepatomegaly should be individualized based on disease course. A sequential approach with observation, intravenous chemotherapy, and intra-arterial chemoembolization, may improve the outcome of these infants. Pediatr Blood Cancer 2012; 59: 182–184. © 2011 Wiley Periodicals, Inc.