A Ferster

Hôpital Universitaire des Enfants Reine Fabiola, Bruxelles, Brussels Capital Region, Belgium

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Publications (162)730.87 Total impact

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    ABSTRACT: Objective Red cell exchange transfusion is frequently used in the management of patients with sickle cell disease (SCD) either electively or chronically to maintain hemoglobin S (HbS) <30%. The purpose of this retrospective study was to evaluate the results of manual chronic partial exchange transfusion (MCPET) on level of Hb and HbS, on iron load and on the need for chelation, on risk of immunization, monitoring transfusion-transmitted viral infection, and clinical outcome. Methods We reviewed the long-term effect of MCPET in 10 children (six men and four women) with SCD and evaluated the iron balance during a median follow-up of 20 months (range: 6-36) in which 248 exchanges were performed. Results The pre-exchange median Hb value was 9.5 g/dl (range: 7.7-10.9 g/dl) and the median post-exchange value was 9.4 g/dl (range: 8.4-11.1 g/dl).The majority of patients reached an HbS of <50% with a median HbS value of 40.04% (range: 30-54). At start of the MCPET program, the median ferritin was 439 ng/ml (range: 80-1704 ng/ml). In the final evaluation, the median value of ferritin was 531 ng/ml (range: 84-3840 ng/ml). The annual calculated iron balance was 0. 28 ± 0.08 mg/kg/day. MCPET was well tolerated, and adverse effects were limited. Discussion MCPET in children with SCD is safe to prevent iron overload, and is effective and easy to use in our cohort. Conclusion Indication for chronic exchange blood transfusion is essential for patients with SCD with recurrent and frequent crises who do not respond to hydroxyurea. However, there is no consensual study for the period at which chronic transfusion can safely be stopped and further research in large population of patients with SCD will need to clarify this question.
    Hematology (Amsterdam, Netherlands) 08/2014; · 1.33 Impact Factor
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    ABSTRACT: Viral infections are important causes of morbidity and mortality in patients after hematopoietic stem cell transplantation. The monitoring by PCR of Herpesviridae loads in blood samples has become a critical part of post-transplant follow-up representing mounting costs for the laboratory. In this study, we assessed the clinical performances of the multiplex PCR DNA microarray Clart® Entherpex kit for detection of CMV, EBV and HHV-6 as screening test for virological follow-up. 255 blood samples from 16 transplanted patients, prospectively tested by routine PCR assays, were analyzed by microarray. Routine PCR detected single or multiple viruses in 42% and 10 % of the samples respectively. Microarray detected single or multiple viruses in 34% and 18% of the samples. Microarray results correlated well with CMV and EBV detections by routine PCR (Kappa tests = 0.79 and 0.78 respectively), whereas a weak correlation was observed with HHV-6 (0.43). HHV-7 was also detected in 48 samples by microarray. In conclusion, the microarray is a reliable screening assay for a post-transplant virological follow-up to detect CMV and EBV infections in blood. However, positive samples must be subsequently confirmed and viral loads quantified by PCR assays. Limitations were identified regarding HHV-6 detection. Although promising, easy to use as first-line test and allowing a reduction in the cost of analysis without undue delay in the reporting of the final quantitative result to the clinician, some characteristics of this microarray should be improved, particularly regarding quality control and targeted virus panel such that it could then be used as a routine test.
    Journal of clinical microbiology 05/2014; · 4.16 Impact Factor
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    ABSTRACT: Pregnancy in women with inherited thrombocytopenias is a major matter of concern as both the mothers and the newborns are potentially at risk of bleeding. However, medical management of this condition cannot be based on evidence because of the lack of consistent information in the literature. To advance knowledge on this matter, we performed a multicentric, retrospective study evaluating 339 pregnancies in 181 women with 13 different forms of inherited thrombocytopenia. Neither the degree of thrombocytopenia nor the severity of bleeding tendency worsened during pregnancy, and the course of pregnancy was not different from that of healthy subjects in terms of miscarriages, fetal bleeding and preterm births. The degree of thrombocytopenia in the babies was similar to that in the mother. Only 7 of 156 affected newborns had delivery-related bleeding, but two of them died of cerebral hemorrhage. The frequency of delivery-related maternal bleeding ranged from 6.8 to 14.2% depending on the definition of abnormal blood loss, suggesting that the risk of risk of abnormal blood loss was increased with respect to the general population. However, no mother died or received hysterectomy to arrest bleeding. The search for parameters predicting delivery-related bleeding in the mother suggested that hemorrhages requiring blood transfusion were more frequent in women with history of severe bleedings before pregnancy and with platelet count at delivery lower than 50 x 10(9)/L.
    Haematologica 04/2014; · 5.94 Impact Factor
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    ABSTRACT: Dexamethasone could be more effective than prednisolone at similar anti-inflammatory doses in the treatment of childhood acute lymphoblastic leukemia. In order to check if this superiority of dexamethasone might be dose-dependent, we conducted a randomized phase III trial comparing dexamethasone (6 mg/m2/day) to prednisolone (60 mg/m2/day) in induction therapy. All newly diagnosed children and adolescents with acute lymphoblastic leukemia in 58951 EORTC trial were randomized either on prephase day 1 or day 8. The main endpoint was event-free survival; secondary endpoints were overall survival and toxicity. A total of 1947 acute lymphoblastic leukemia patients were randomized. At a median follow up of 6.9 years, the 8-year event-free survival rate was 81.5% in the dexamethasone arm and 81.2% in the prednisolone arm; the 8-year overall survival rates were 87.2% and 89.0% respectively. The 8-year central nervous system isolated or combined relapse incidence was 2.9% (dexamethasone) v 4.5% (prednisolone). The incidence of grade 3-4 toxicities during induction and the frequency of osteonecrosis were similar in the two arms. In conclusion, dexamethasone and prednisolone, used respectively at the doses of 6 and 60 mg/m2/day during induction, were equally effective and had a similar toxicity profile. Dexamethasone decreased the 8-year central nervous system relapse incidence by 1.6%. This trial was registered at www.clinicaltrials.gov as #NCT00003728.
    Haematologica 04/2014; · 5.94 Impact Factor
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    ABSTRACT: Despite improvements in medical management, sickle cell disease (SCD) remains associated with severe morbidity and decreased survival. Allogeneic haematopoietic stem cell transplantation (HSCT) remains the only curative approach. We report the outcome of 50 consecutive children with severe SCD that received HSCT in our unit between November 1988 and April 2013. The stem cell source was bone marrow (n = 39), cord blood (n = 3), bone marrow and cord blood (n = 7) and peripheral blood stem cells (n = 1). All patients had ≥1 severe manifestation: 37 presented with recurrent vaso-occlusive crises/acute chest syndrome, 27 cerebral vasculopathy and 1 nephropathy. The conditioning regimen consisted of busulfan + cyclophosphamide (BuCy) before November 1991 and BuCy + rabbit antithymocyte globulin after that date. Since 1995, all patients have been treated with hydroxycarbamide (HC) prior to transplantation for a median duration of 2·7 years. Median age at transplantation and median follow-up was 8·3 and 7·7 years, respectively. Acute graft-versus-host disease (GVHD) and chronic GVHD were observed in 11 and 10 patients, respectively. An excellent outcome was achieved, with 8-year overall survival and event-free survival (EFS) rates of 94·1% and 85·6%, respectively. Since HC introduction, no graft failure occurred and EFS reached 97·4%. Prior treatment with HC may have contributed to successful engraftment.
    British Journal of Haematology 01/2014; · 4.94 Impact Factor
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    ABSTRACT: The 6-minute walk test (6MWT) is used in adults and children affected by a wide range of chronic diseases to evaluate their sub-maximal exercise capacity. It reflects the global response of various physiological systems in a situation simulating a daily life activity.
    PLoS ONE 01/2014; 9(10):e108922. · 3.53 Impact Factor
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    ABSTRACT: OBJECTIVES:Clinical data are lacking on optimal levels of specific antipneumococcal antibodies (PnPsAbs) in patients with primary immunodeficiency (PID) receiving intravenous immunoglobulin (IVIG) replacement. Objectives were to conduct a prospective multicenter study providing data on total immunoglobulin G (IgG) and peak/trough levels of PnPsAbs specifically targeting the 16 most prevalent pneumococcal serotypes in IVIG-treated children with PID; to compare trough PnPsAb levels with those measured in healthy adults and the IVIG product; and to evaluate PnPsAb protection correlates with thresholds based on World Health Organization.METHODS:Patients received 7 consecutive IVIG infusions. Total IgG and PnPsAb levels were determined on plasma samples obtained before and after infusion.RESULTS:Twenty-two children with PID were treated with IVIG (mean weekly dose: 0.10 g/kg). The mean trough and peak levels of total IgG were 7.77 and 13.93 g/L, respectively. Trough and peak geometric mean concentrations and distribution curves differed between serotypes and showed wide dispersion (0.17-7.96 µg/mL). In patients (89%-100%), antibodies against most serotypes reached trough levels ≥0.2 µg/mL, a threshold considered protective against invasive pneumococcal infection. For several serotypes, trough levels reached ≥1.0 to 1.3 µg/mL, the level found in adults. Trough geometric mean concentrations correlated well with the PnPsAb contents of the IVIG product.CONCLUSIONS:In IVIG-treated children with PID, protective PnPsAb levels for most pathogenic serotypes were obtained. A correlation was observed between PnPsAb levels in patients and in the IVIG product. This offers the potential to improve infection prevention by adapting the IVIG product and dose according to epidemiology.
    PEDIATRICS 12/2013; · 4.47 Impact Factor
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    ABSTRACT: Transient neonatal leukemia occurs almost exclusively in Down syndrome babies. We report here the unusual case of a newborn without Down syndrome who presented neonatal transient leukemia and who achieved spontaneously complete remission. Trisomy 21 and GATA1 mutation were both present in leukemic cells. While close follow-up is advised since true leukemia may develop later, the patient is still in remission for 2.5 years. We performed a literature review of 15 other similar cases. Conclusion: Our case of transient leukemia without Down syndrome and the literature review highlight the important role of trisomy 21 and GATA1 mutation in the development of transient neonatal leukemia.
    European Journal of Pediatrics 11/2013; · 1.98 Impact Factor
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    ABSTRACT: Oncogenic subtypes in childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) are used for risk-stratification. However, a significant number of BCP-ALL patients are still genetically unassigned. Using array-CGH in a selected BCP-ALL cohort, we characterized a recurrent V(D)J-mediated intragenic deletion of the ERG gene (ERG(del)). A breakpoint-specific PCR assay was designed and used to screen an independent non-selected cohort of 897 children aged 1-17 years treated for BCP-ALL in the EORTC-CLG 58951 trial. ERG(del) was found in 29/897 patients (3.2%) and was mutually exclusive of known classifying genetic lesions, suggesting that it characterized a distinct leukemia entity. ERG(del) was associated with higher age (median 7.0 years vs 4.0 years, P=0.004), aberrant CD2 expression (43.5% vs 3.7%, P<0.001) and frequent IKZF1 Δ4-7 deletions (37.9% vs 5.3%, P<0.001). However, ERG(del) patients had a very good outcome, with an 8-year event-free survival (8-y EFS) and overall survival (8-y OS) of 86.4% and 95.6%, respectively, suggesting that the IKZF1 deletion had no impact on prognosis in this genetic subtype. Accordingly, within patients with an IKZF1 Δ4-7 deletion, those with ERG(del) had a better outcome (8-y EFS, 85.7% vs 51.3%, HR: 0.16, 95% CI: 0.02-1.20, P=0.04). These findings have implications for further stratification including IKZF1 status.Leukemia accepted article preview online, 25 September 2013. doi:10.1038/leu.2013.277.
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 09/2013; · 10.16 Impact Factor
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    ABSTRACT: INTRODUCTION: Increased thrombin generation (TG) was described in sickle cell (SCD) children. The aim of this study was to characterize TG at the individual level and assess its relationship with age, hemolysis transcranial Doppler velocity (TCD) and hydroxyurea treatment. PATIENTS AND METHODS: TG was triggered in the platelet-poor plasma using tissue factor and phospholipids with addition of thrombomodulin in 97 SCD at steady-state and 80 control children. Patients and controls were aged from 2 to 20 years and they were distributed in 4 categories of age: [2-5], [6-10], [11-15] and [16-20] years. For each subject, ratio of endogenous thrombin potential (rETP) and peak height (rPeak) was calculated as subject's value divided by the mean value of controls of the same age range. rETP and rPeak of patients were considered abnormal when > mean +2SD of controls. LDH, total hemoglobin and reticulocyte count were measured as markers of hemolysis. Data on hydroxyurea treatment and TCD were collected from medical records. RESULTS: Overall 38.1% and 44.3% of patients showed elevated rETP and rPeak respectively. rETP and rPeak decreased significantly with increasing age. In SS patients, TCD velocities and all markers of hemolysis correlated significantly with both rETp and rPeak. Negative correlations were observed between these ratios and the duration of hydroxyurea treatment. CONCLUSION: Elevated TG in SCD children is mainly related to younger age and to the intensity of hemolysis. There is a link between TG and cerebral vasculopathy in these patients. Hydroxyurea may have a beneficial effect which could be related to the duration of treatment. © 2013 John Wiley & Sons A/S.
    European Journal Of Haematology 03/2013; · 2.55 Impact Factor
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    ABSTRACT: Immunodeficiency with centromeric instability and facial anomalies (ICF) syndrome is a primary immunodeficiency, predominantly characterized by agammaglobulinemia or hypoimmunoglobulinemia, centromere instability and facial anomalies. Mutations in two genes have been discovered to cause ICF syndrome: DNMT3B and ZBTB24. To characterize the clinical features of this syndrome, as well as genotype-phenotype correlations, we compared clinical and genetic data of 44 ICF patients. Of them, 23 had mutations in DNMT3B (ICF1), 13 patients had mutations in ZBTB24 (ICF2), whereas for 8 patients, the gene defect has not yet been identified (ICFX). While at first sight these patients share the same immunological, morphological and epigenetic hallmarks of the disease, systematic evaluation of all reported informative cases shows that: (1) the humoral immunodeficiency is generally more pronounced in ICF1 patients, (2) B- and T-cell compartments are both involved in ICF1 and ICF2, (3) ICF2 patients have a significantly higher incidence of intellectual disability and (4) congenital malformations can be observed in some ICF1 and ICF2 cases. It is expected that these observations on prevalence and clinical presentation will facilitate mutation-screening strategies and help in diagnostic counseling.European Journal of Human Genetics advance online publication, 13 March 2013; doi:10.1038/ejhg.2013.40.
    European journal of human genetics: EJHG 03/2013; · 3.56 Impact Factor
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    ABSTRACT: Hydroxycarbamide, well known in clinical settings as hydroxyurea (HU), is an antineoplastic agent inhibiting the ribonucleotide reductase enzyme, and thus, the conversion of ribonucleotides into deoxyribonucleotides. A concern about long term side effects of HU treatment in sickle cell disease patients, particularly genotoxicity, has often been evoked. The present study assessed two suitable methods to evaluate oxidative DNA damage associated with HU: the comet assay on blood lymphocytes and the quantification of urinary excretion of 8-oxodeoxyguanosine (8-oxodG). Both methods were applied in a preliminary study including seven sickle cell disease patients treated with HU, seven untreated sickle cell disease patients and five healthy volunteers. Concerning DNA damage, the comet assay and the 8-oxodG assay did not reveal any significant differences among the three groups. Methodologies used in this pilot study could be suitable to carry out further research in this area including a larger size sample setting.
    Hemoglobin 10/2012; · 0.89 Impact Factor
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    ABSTRACT: We describe a 27-month-old girl with COG6 deficiency. She is the first child of healthy consanguineous Moroccan parents. She presented at birth with dysmorphic features including microcephaly, post-axial polydactyly, broad palpebral fissures, retrognathia, and anal anteposition. The clinical phenotype was further characterised by multiorgan involvement including mild psychomotor retardation, and microcephaly, chronic inflammatory bowel disease, micronodular liver cirrhosis, associated with life-threatening and recurrent infections due to combined T- and B-cell dysfunction and neutrophil dysfunction.Mutation analysis showed the patient to be homozygous for the c.G1646T mutation in the COG6 gene. She is the second reported patient with a deficiency of subunit 6 of the COG complex. Although both patients are homozygous for the same mutation, they present a markedly different clinical picture. Indeed immunodeficiency as well as inflammatory bowel disease has not been described previously in patients with any COG-CDG.
    JIMD reports. 01/2012; 4:103-8.
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    ABSTRACT: The mechanisms of hypercoagulability in sickle cell disease (SCD) are poorly understood. We aimed to explore the procoagulant activity of endogenous phospholipids (ePL) in the platelet-free plasma of SCD children. A factor Xa clotting time (XACT), thrombin generation (TG) and a capture-based assay for the detection of procoagulant microparticles (PMP) were used. Forty three SCD children (35 SS, 6 SC and 2 Sβ+) were evaluated at steady-state and compared to 20 controls. Fourteen patients were also evaluated during vaso-occlusive crisis. TG was performed using 10 pM tissue factor without addition of exogenous phospholipids. A control condition was also performed using 10 pM tissue factor and 4 μM phospholipids. Percentages of the test/control conditions were calculated for the peak height (% peak), endogenous thrombin potential (% ETP) and velocity index (% VI). XACT times were shorter, PMP levels, peak height and velocity index of thrombin generation were higher in SCD patients than controls. Lag time and ETP were not different between the two groups. % peak, % ETP and % VI were higher in patients than controls. Significant correlations were found between PMP levels and XACT, also between PMP levels and peak height, velocity index, ETP and their respective percentages to the control condition, but not with lag time. Double heterozygous patients showed intermediate values for XACT and TG parameters. No significant difference was observed when comparing patients at steady-state versus vaso-occlusive crisis. High procoagulant activity of ePL was observed in the platelet-free plasma of SCD children, probably borne by procoagulant microparticles. This may contribute to a high hemostatic potential and predisposition to thrombotic complications in these patients.
    Thrombosis Research 11/2011; 130(2):259-64. · 3.13 Impact Factor
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    ABSTRACT: Changes in several components of the clotting system are well documented in sickle cell disease (SCD) patients. However, whether the global hemostatic potential of these patients is altered is still unclear. Calibrated automated thrombogram® method of thrombin generation (TG) was used to characterize the hemostatic potential of 83 SCD children (75 SS, 6 SC, and 2 Sβ (thal) ) at steady-state as compared with 50 controls of the same range of age. TG was triggered using 1 pM tissue factor and 4 μM phospholipids with and without thrombomodulin. Thirteen SCD children were also evaluated during vaso-occlusive crisis. Protein C activity, free protein S and D-dimers levels were measured in parallel. SCD patients showed higher rates of thrombin formation, higher thrombin peak height (with and without thrombomodulin), and higher endogenous thrombin potential (ETP) than controls in the presence of thrombomodulin. Reduction of ETP (RETP) in the presence of thrombomodulin was lower in SCD group compared with controls and correlated both with protein C and protein S levels. ETP, RETP, peak height, and velocity index of TG correlated with D-dimers. Compound heterozygous patients showed an intermediate hemostatic phenotype at steady-state. No significant difference was observed when comparing TG parameters during vaso-occlusive crisis to those obtained at steady-state in the same patients. The global hemostatic potential is increased and reflects the hypercoagulable state of SCD patients even at steady-state. The relevance of this finding with respect to the risk of thrombotic complications of the disease needs further investigation. Am. J. Hematol. 2011. © 2011 Wiley-Liss, Inc.
    American Journal of Hematology 09/2011; · 4.00 Impact Factor
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    ABSTRACT: We present a 9-month-old boy with megaloblastic anaemia, neutropenia and hypogammaglobulinaemia due to vitamin B12 deficiency. The deficiency was secondary to prolonged exclusive breastfeeding with inadequate nutritional amounts of vitamin B12 from the mother. There were no clinical or biological signs of maternal anaemia or macrocytosis. Treatment with oral vitamin B12 rapidly improved the biological findings of the child. Vitamin B12 deficiency should be considered in infants older than 2 months presenting with failure to thrive, neurocognitive retardation or even pancytopenia and hypogammaglobulinaemia, even in the absence of any signs of maternal anaemia or macrocytosis. Therefore, evaluation of vitamin B12 status during pregnancy and lactation is necessary in order to prevent B12 deficiency and its possible long-term effects in infants. CONCLUSION: Further studies should be conducted to evaluate the optimal oral dosage of vitamin B12 in children since limited data on the use of oral B12 substitution are available.
    European Journal of Pediatrics 09/2011; 171(1):193-5. · 1.98 Impact Factor
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    ABSTRACT: In the present work, we explored the way in which cromoglycate, a drug used to treat allergies acts on ion movements in sickle cells. Cells were either slowly deoxygenated by overnight exposure to nitrogen or acutely deoxygenated by exposure to metabisulfite, a strong reducing agent which induces sickling of red blood sickle cells. Flushing the cells with nitrogen increased the intracellular concentration of Na(+) and decreased the intracellular concentration of K(+) and the sum of the concentrations of the two cations. One hundred nM cromoglycate inhibited the decrease of intracellular K(+) and the increase of intracellular Na(+) induced by deoxygenation (n=17). Metabisulfite (100mM) increased the intracellular concentration of Ca(2+) (measured by Fura Red) (n=15) and the shape of the cells (measured by light scattering) (n=9). One μM cromoglycate partially inhibited these two responses. In conclusion, cromoglycate partially inhibits abnormal K(+) loss, Ca(2+) entry pathways or Ca(2+) channels opened by cell deoxygenation and ensuing membrane modifications and prevents cell sickling.
    European journal of pharmacology 08/2011; 665(1-3):13-8. · 2.59 Impact Factor
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    ABSTRACT: Autosomal-recessive immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is mainly characterized by recurrent, often fatal, respiratory and gastrointestinal infections. About 50% of patients carry mutations in the DNA methyltransferase 3B gene (DNMT3B) (ICF1). The remaining patients carry unknown genetic defects (ICF2) but share with ICF1 patients the same immunological and epigenetic features, including hypomethylation of juxtacentromeric repeat sequences. We performed homozygosity mapping in five unrelated ICF2 patients with consanguineous parents and then performed whole-exome sequencing in one of these patients and Sanger sequencing in all to identify mutations in the zinc-finger- and BTB (bric-a-bric, tramtrack, broad complex)-domain-containing 24 (ZBTB24) gene in four consanguineously descended ICF2 patients. Additionally, we found ZBTB24 mutations in an affected sibling pair and in one patient for whom it was not known whether his parents were consanguineous. ZBTB24 belongs to a large family of transcriptional repressors that include members, such as BCL6 and PATZ1, with prominent regulatory roles in hematopoietic development and malignancy. These data thus indicate that ZBTB24 is involved in DNA methylation of juxtacentromeric DNA and in B cell development and/or B and T cell interactions. Because ZBTB24 is a putative DNA-binding protein highly expressed in the lymphoid lineage, we predict that by studying the molecular function of ZBTB24, we will improve our understanding of the molecular pathophysiology of ICF syndrome and of lymphocyte biology in general.
    The American Journal of Human Genetics 06/2011; 88(6):796-804. · 11.20 Impact Factor
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    ABSTRACT: We describe the incidence of malignancy in patients with primary immunodeficiency disorders (PIDD) following hematopoietic cell transplantation (HCT). From the Center for International Blood and Marrow Transplant Research, 2266 PIDD patients who had undergone allogeneic HCT between 1968 and 2003 were identified. Patient, disease, and transplant factors for development of malignancy were examined and pathology reports for reported malignancies reviewed independently by a pathologist for confirmation. The incidence of malignancy was highest for Wiskott-Aldrich syndrome (3.3%), with an overall incidence of 2.3% for PIDD. Post-HCT malignancy was confirmed for 52 of 63 reported cases. Forty-five of 52 patients developed posttransplant lymphoproliferative disorders (PTLD) at a median of 3 months post-HCT. Of these, 26 had received T cell-depleted (TCD) bone marrow. Three patients who developed myelodysplastic syndrome had received TCD marrow and total body irradiation. Three patients developed a solid tumor. Patients with PIDD are at a relatively low risk of developing malignancies post-HCT compared with their historic risk of cancer. The most frequent malignancy or lymphoproliferative disorder was early-onset PTLD. As in other HCT recipients, TCD appears to correlate with PTLD development. Our results lend support to the hypothesis that immune reconstitution in PIDD following HCT leads to a decrease in cancer risk.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 05/2011; 17(12):1783-9. · 3.15 Impact Factor
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    ABSTRACT: Immunoglobulin superfamily (IgSF) domains are conserved structures present in many proteins in eukaryotes and prokaryotes. These domains are well-capable of facilitating sequence variation, which is most clearly illustrated by the variable regions in immunoglobulins (Igs) and T cell receptors (TRs). We studied an antibody-deficient patient suffering from recurrent respiratory infections and with impaired antibody responses to vaccinations. Patient's B cells showed impaired Ca(2+) influx upon stimulation with anti-IgM and lacked detectable CD19 membrane expression. CD19 sequence analysis revealed a homozygous missense mutation resulting in a tryptophan to cystein (W52C) amino acid change. The affected tryptophan is CONSERVED-TRP 41 located on the C-strand of the first extracellular IgSF domain of CD19 and was found to be highly conserved, not only in mammalian CD19 proteins, but in nearly all characterized IgSF domains. Furthermore, the tryptophan is present in all variable domains in Ig and TR and was not mutated in 117 Ig class-switched transcripts of B cells from controls, despite an overall 10% amino acid change frequency. In vitro complementation studies and CD19 western blotting of patient's B cells demonstrated that the mutated protein remained immaturely glycosylated. This first missense mutation resulting in a CD19 deficiency demonstrates the crucial role of a highly conserved tryptophan in proper folding or stability of IgSF domains.
    Human Molecular Genetics 02/2011; 20(9):1854-63. · 7.69 Impact Factor

Publication Stats

2k Citations
730.87 Total Impact Points

Institutions

  • 1988–2014
    • Hôpital Universitaire des Enfants Reine Fabiola
      • • Department of Hemato-Oncology
      • • Department of Pediatrics
      • • Department of Neurology
      Bruxelles, Brussels Capital Region, Belgium
  • 2011–2013
    • Centre Hospitalier Universitaire de Charleroi
      Charleroi, Walloon Region, Belgium
  • 1990–2013
    • Université Libre de Bruxelles
      • Department of Hematology
      Bruxelles, Brussels Capital Region, Belgium
  • 2008
    • Ministère de la Santé du Burkina Faso
      Wagadugu, Centre, Burkina Faso
    • Centre Hospitalier Monkole
      Leopoldstad, Kinshasa, Democratic Republic of the Congo
  • 2007
    • Medical College of Wisconsin
      • Division of Hematology/Oncology/ Blood and Marrow Transplant
      Milwaukee, WI, United States
  • 1998–2004
    • University-Hospital Brugmann UVC
      Bruxelles, Brussels Capital Region, Belgium
    • Catholic University of Louvain
      Walloon Region, Belgium
  • 1997–2001
    • Université de Poitiers
      Poitiers, Poitou-Charentes, France
    • Clinique Saint-Pierre
      Walloon Region, Belgium
  • 2000
    • Hôpital Universitaire Robert Debré
      Lutetia Parisorum, Île-de-France, France
  • 1993–1999
    • Cliniques Universitaires Saint-Luc
      • Division of Hematology and Pediatric Oncology
      Bruxelles, Brussels Capital Region, Belgium
  • 1996
    • Centre Hospitalier Universitaire Saint-Pierre
      Bruxelles, Brussels Capital Region, Belgium
  • 1994
    • European Organisation for Research and Treatment of Cancer
      Bruxelles, Brussels Capital Region, Belgium
  • 1986–1994
    • Vrije Universiteit Brussel
      • • Department of Hematology
      • • Department of Pediatrics
      Bruxelles, Brussels Capital Region, Belgium