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  • 1
    Online-Ressource
    Online-Ressource
    Genotype and Phenotype of Adenosine Deaminase 2 Deficiency: a Report from Saudi Arabia
    Springer Science and Business Media LLC ; 2023
    In:  Journal of Clinical Immunology Vol. 43, No. 2 ( 2023-02), p. 338-349
    Details
    In: Journal of Clinical Immunology, Springer Science and Business Media LLC, Vol. 43, No. 2 ( 2023-02), p. 338-349
    Materialart: Online-Ressource
    ISSN: 0271-9142 , 1573-2592
    URL: Article
    DOI: 10.1007/s10875-022-01364-9
    RVK:
    XA 10000
    Sprache: Englisch
    Verlag: Springer Science and Business Media LLC
    Publikationsdatum: 2023
    ZDB Id: 2016755-6
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 2
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    LPS-responsive beige-like anchor (LRBA) gene mutation in a family with inflammatory bowel disease and combined immunodeficiency
    Elsevier BV ; 2012
    In:  Journal of Allergy and Clinical Immunology Vol. 130, No. 2 ( 2012-8), p. 481-488.e2
    Details
    In: Journal of Allergy and Clinical Immunology, Elsevier BV, Vol. 130, No. 2 ( 2012-8), p. 481-488.e2
    Materialart: Online-Ressource
    ISSN: 0091-6749
    URL: Article
    DOI: 10.1016/j.jaci.2012.05.043
    RVK:
    XA 52000
    Sprache: Englisch
    Verlag: Elsevier BV
    Publikationsdatum: 2012
    ZDB Id: 2006613-2
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 3
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    Impact of Red Blood Cell Transfusions on Height and Growth of Adolescents with Sickle Cell Disease & Short Stature
    American Society of Hematology ; 2018
    In:  Blood Vol. 132, No. Supplement 1 ( 2018-11-29), p. 4935-4935
    Details
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 4935-4935
    Kurzfassung: BACKGROUND: Children with sickle cell disease (SCD) commonly have delayed or impaired growth. There are no clear guidelines as how to manage these patients. Current evidence suggests that children who are treated long term with red blood cell (RBC) transfusions (simple red cell or exchange transfusions) for different SCD related complications, achieve better height and growth, although, it is not clear when to start such treatment for the maximum benefit. Timing of such treatment(s) may be critical as to achieve optimum height and growth. Children with SCD who are started transfusion therapy before the age of 14 years, may achieve better height velocity. However, some children may present late during adolescence and whether to adopt measures like regular blood transfusions to improve their growth, remains challenging. We treated adolescents with SCD and delayed growth with regular RBC transfusions and observed the effect on their growth. The major concern of the parents was short stature, and our aim was achievement of better height. Methods : Adolescent patients with SCD being followed at our department, who were observed to have short stature or were referred to us for this problem and received RBC transfusion therapy to improve their growth, were included in this study. They were started on regular RBC transfusions after thorough counseling (parents and patients). They were informed of the likely benefits and possible side effects including usual transfusion related adverse events and particularly the likelihood of iron overload and possible need for iron chelation therapy in future. A chart review was performed recording weight, height, and body mass index (BMI) measurements, timing and length of transfusion therapy along with laboratory parameters. When iron overload (defined as a serum ferritin ≥ 1000 µgm/l) developed, it was treated with deferasirox at an average dose of 20-30mg/kg body weight. RBC transfusions were continued for 3-6 months after achieving the maximum height (plateau phase). Patients were either already receiving hydroxyurea (HU) or were started at the beginning of transfusion therapy. The average dose of HU was 500 mg daily (20mg/kg body weight) at the start of transfusion therapy in all patients and was increased according to the weight gain. Two patients also received growth hormone for a short period. RESULTS: Six patients received RBC transfusion therapy for short stature (5 males). Median age at start of therapy was 15.5 years (range 13.9 -17.4). Patients were treated for a median duration of 32 months (range 23-53). One (female) patient continues to have ongoing transfusions as she has not achieved the maximum height. Median height at start of therapy was 137.25 cm and 152.25 cm at the end of therapy. Pre-therapy median weight was 28 kg and post therapy 38.2 kg. Median increase in height was 16.25 cm (p 〈 0.025) and median increase in weight 10.15 kg (p=0.007). BMI measurements showed improvement in 5 patients but the increase was modest, likely due to better height gain as compared to weight gain. Five patients received regular RBC transfusions while one patient received exchange transfusions after one year of simple transfusions because of high base line Hb. Four patients were already receiving HU for one year or more, while 2 patients started HU shortly after commencing transfusion therapy. There were no significant SCD related or transfusion related complications during transfusion therapy but all patients developed iron overload and received chelation therapy. However, 3 patients had s/ferritin around or above 1000 µgm/l at the base line. Mean pre-transfusion s/ferritin was 901 µgm/l and 2304 µgm/l at the end of transfusion therapy. CONCLUSIONS: RBC transfusion therapy improved height of all patients with SCD & short stature, even if started during late adolescence. However, the improvement was variable. There were no significant adverse events except iron overload, which developed in all patients and required chelation therapy. RBC Transfusion therapy should be considered in adolescent children with SCD and short stature, even if they present during late adolescence. RBC exchange therapy may be an alternative option to reduce the complication of iron overload and should be explored in further studies. Disclosures No relevant conflicts of interest to declare.
    Materialart: Online-Ressource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2018-99-111591
    RVK:
    XA 33000
    RVK:
    XA 10000
    Sprache: Englisch
    Verlag: American Society of Hematology
    Publikationsdatum: 2018
    ZDB Id: 1468538-3
    ZDB Id: 80069-7
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  • 4
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    Outcome of Hematopoietic Stem Cell Transplantation in Children with Primary Hemophagocytic Lymphohistiocytosis: A Single Institution Experience Using Reduced Intensity Conditioning
    American Society of Hematology ; 2020
    In:  Blood Vol. 136, No. Supplement 1 ( 2020-11-5), p. 43-44
    Details
    In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 43-44
    Kurzfassung: Hematopoietic stem cell transplantation (HSCT) is the only curative therapy for primary hemophagocytic lymphohistiocytosis (HLH). Conventional myeloablative conditioning regimen using busulfan, cyclophosphamide with or without etoposide was associated with high rate of transplant-related mortality (Horne et al. BJH 2005). Reduced intensity conditioning (RIC) is used in HLH to minimize transplant-related toxicities. The use of alemtuzumab, fludarabine, and melphalan in HLH was associated with low mortality; however, mixed donor chimerism and graft failure were frequent (Allen et al. Blood 2018). A recent report in 25 HLH patients who underwent HSCT from HLA matched donors using targeted busulfan (45-65 mg/L X h), fludarabine, and serotherapy resulted in adequate stable donor chimerism, no graft rejection, and no mortality (Felber et al. Blood Adv. 2020). In this study, we reviewed the outcome of 16 HLH patients who underwent HSCT from HLA matched donors using RIC. All patients were initially treated using HLH-2004 protocol. They subsequently underwent HSCT from 10/10 HLA matched related or unrelated donor using RIC regimens. We initially used AFM conditioning regimen that included alemtuzumab (1 mg/kg), fludarabine (150 mg/m2), and melphalan (140 mg/m2) with or without thiotepa (10 mg/kg). GVHD prophylaxis included cyclosporine (CSA) and steroids. Given the high rate of low donor chimerism with AFM regimen, we subsequently used BF conditioning regimen that included busulfan (weight-based dosing for total of 16 doses) and fludarabine (160 mg/m2). Therapeutic drug monitoring of busulfan was performed. Thymoglobulin (10 mg/kg) was added in matched unrelated donor (MUD). GVHD prophylaxis included CSA and steroids in matched related donors (MRD) and CSA and methotrexate in MUD. Bone marrow was the stem cell source in all patients except one who underwent second transplant using peripheral blood stem cells. Supportive care was consistent among all patients. Defibrotide prophylaxis was administered to prevent sinusoidal obstruction syndrome (SOS). Donor chimerism & lt;5% from whole blood or & lt;20% in T-cell, graft failure, and death from any cause were considered as events. A total of 16 HSCT transplants were performed, 5 received AFM regimen and 11 received BF regimen. Patient and transplant characteristics are shown in Table. All patients had successful neutrophil and platelet engraftments. Among the five patients who underwent AFM conditioning, one patient with SH2D1A mutation is 8 years post transplant with stable full donor chimerism and another patient with PRF1 mutation who received AFM with thiotepa has stable sufficient donor chimerism 3 years post transplant. Both patients did not require donor leukocyte infusions (DLI). The remaining 3 patients had declining donor chimerism beyond the first year of transplant despite the frequent use of DLI, one of them had disease reactivation and underwent second HSCT using BF regimen. Event free survival (EFS) at 3 years was 60% and overall survival (OS) was 100%. Among the 11 patients who underwent BF regimen, 7 were transplanted using MRD and 4 MUD. The median cumulative area under the curve of busulfan was 64 mg/L X h (range, 56-73). Median donor myeloid chimerism was 97% (range, 83-100) and median T-cell chimerism was 78% (range, 40-93). One patient who underwent MUD had grade III acute GVHD and none had chronic GVHD. Two patients had mild SOS. There were no events among BF group with median follow up duration of 393 days (151-2080). The use of BF regimen in HLH was associated with excellent outcome and stable donor chimerism with no graft failure in comparison to AFM regimen. Longer follow up is needed to confirm our findings. Disclosures No relevant conflicts of interest to declare.
    Materialart: Online-Ressource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2020-142988
    RVK:
    XA 33000
    RVK:
    XA 10000
    Sprache: Englisch
    Verlag: American Society of Hematology
    Publikationsdatum: 2020
    ZDB Id: 1468538-3
    ZDB Id: 80069-7
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 5
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    A Library of Sickle Cell Anemia Induced Pluripotent Stem Cells of Diverse Haplotypes and Ethnicities
    American Society of Hematology ; 2015
    In:  Blood Vol. 126, No. 23 ( 2015-12-03), p. 2354-2354
    Details
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 2354-2354
    Kurzfassung: The mutation causing sickle cell anemia (rs334, GAG-GTG, glu6val) had several independent origins in Africa, the Middle East and India and spread throughout parts of the world by wars, slave trading and population migrations. The genetic background upon which the HbS mutation occurred, or the β-globin gene (HBB) haplotype, is associated with differences in the phenotype of this disease and the ability of affected individuals to synthesize fetal hemoglobin (HbF). The main modifier of the disease phenotype is the level of HbF in the blood of affected individuals. HbF inhibits the polymerization of HbS, the proximate cause of disease pathophysiology. As part of the NHLBI NextGen consortium (U01HL107443) we established a library of induced pluripotent stem cells (iPSC) from patients with sickle cell anemia of diverse HBB haplotypes and HbF phenotypes. The purpose of establishing this library was to allow genetic studies of globin gene expression during the erythroid differentiation of iPSC of diverse genotypes. During these studies we have implemented an efficient and highly reproducible platform for the production of large numbers of sickle cell anemia-specific iPSC, derived and characterized a novel in vitro system for the production of an unlimited supply of erythroid lineage cells from the directed differentiation of normal and disease-specific iPSC and used this system to recapitulate erythroid-lineage ontogeny in vitro with the sequential development of primitive and definitive erythropoiesis, accompanied by the appropriate expression of stage-specific globin genes. We have recently finished whole genome DNA and RNA sequencing analysis in some of these lines aimed at identifying developmental gene expression profile differences between erythroid precursors that produce primarily HbF and those that produce primarily HbA or HbS as part of our search for novel HbF genetic modifiers associated with markedly elevated HbF levels found in sickle cell anemia patients naturally, or in response to hydroxyurea treatment. Furthermore, our labs are also focusing on using a CRISPR-based gene editing platform to study the effect of novel HbF genetic modifiers and explore globin switching. Cell lines established are shown in the table. Table 1. Number of subjects recruited to date 98 Number of subjects with iPSC lines established 56 Average number of iPSC lines per subject 3 (total of 158 lines generated) Quality control status of iPSC lines All lines are expanded and banked, mycoplasma free, express pluripotency markers Subjects with target cells differentiated (erythrocytes) 25 Samples have been collected on African American patients with sickle cell anemia with diverse HBB haplotypes, predominantly homozygotes and compound heterozygotes for the Benin and Bantu haplotypes, Saudi Arabian patients with the Arab-Indian haplotype and the Saudi Benin haplotype that is characterized by HbF levels about twice as high as in African Benin haplotype patients and from Brazilian patients who are predominantly homozygotes for the Bantu haplotype that typically is associated with the lowest HbF of all HBB haplotypes. This iPSC-based library and the data associated with it represents a valuable readily available resource for the sickle cell research community and all the generated lines will be available for distribution early in 2016 through WiCell. Disclosures No relevant conflicts of interest to declare.
    Materialart: Online-Ressource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V126.23.2354.2354
    RVK:
    XA 33000
    RVK:
    XA 10000
    Sprache: Englisch
    Verlag: American Society of Hematology
    Publikationsdatum: 2015
    ZDB Id: 1468538-3
    ZDB Id: 80069-7
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  • 6
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    Fetal Hemoglobin In Sickle Cell Anemia: Molecular Characterization of Saudi Patients From the Eastern Province
    American Society of Hematology ; 2010
    In:  Blood Vol. 116, No. 21 ( 2010-11-19), p. 1627-1627
    Details
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 1627-1627
    Kurzfassung: Abstract 1627 In the Eastern Province of Saudi Arabia, sickle cell anemia (HbSS) is associated with the Saudi Indian (SI) HBB-gene cluster haplotype, high levels of fetal hemoglobin (HbF) and milder disease, when compared with Southwestern Province HbSS patients who have lower HbF levels and different HBB haplotypes. An association between HbF and the Xmn1 restriction site in the HBG2 promoter present in both the SI and African-derived Senegal haplotypes is well known, but the causal elements of this association are unknown. Moreover, among individuals with the SI haplotype, only HbSS patients have high HbF while individuals with sickle cell trait (HbAS) or normal hemoglobin (HbAA) do not. Furthermore, HbF levels are far higher in SI haplotype patients, as shown below, compared with Senegal haplotype homozygotes. For example African patients homozygous for the Senegal haplotype had 12.3±5.3% HbF. To better understand the genetic basis for high HbF in SI haplotype HbSS cases, we compared sequences in the HBB gene cluster in patients with SI and Senegal haplotypes. We hypothesized that the causal elements that modify HbF in Saudi patients are in linkage disequilibrium (LD) with the βS globin gene in this population. Accordingly, we studied 5 Saudi families from the Eastern Province. Seven SI haplotype patients with HbSS (median age 5 yrs, range 2.5–49 yrs) were homozygous for the Xmn I site and had Hb 9.7 ± 1.6 g/dL, MCV 76.5 ± 8.3 fl and median Hb F 30.3 (range 18–41). Seventeen SI haplotype individuals had HbAS (median HbF 1.2, range 0–4.2); and 2 were normal. We first determined the genotypes of 3 known HbF QTLs, BCL11A (rs766432); HBS1L-MYB (rs7775698 and rs9399137); and OR51B5/6 (rs5006884). There were no consistent genotypes among these 7 patients to explain their universal high HbF. Next, we performed homozygosity mapping using Illumina Human610-Quad SNP array and identified runs of homozygosity (RoH) of variable length (from 160 kb to nearly 2 mb) within and surrounding the HBB cluster only in HbSS patients. RoH were absent elsewhere in the genome in HbSS. The RoH that was shared by all HbSS patients was 126.6 kb in chr11:5153026-5279647 (NCBI36/hg18) and contains SNPs from rs11036090 to rs7118113 of the Illumina Human610-Quad SNP array. This region contains: OR51B4, the complete HBB cluster, and OR51V1. Homozygosity mapping in 6 Senegal haplotype homozygotes showed a slightly larger RoH from chr11:4909490-5314457 and SNPs rs840713-rs10837822. Both the Saudi patients and Senegal homozygotes had the same homozygous genotypes for the overlapping region of chr11:5205580-5235931 ranging from rs11036364 to rs5010981.To identify potential genetic modifiers of HbF level in the region detected in the Saudi cases, we sequenced areas within or near the Corfu deletion that is known to cause HPFH, the HBD-HBG1 intergenic region, and core regions of HS- 2, 3, and 4 in the LCR. Core regions of HS-3 and HS-4 were identical to the reference sequences. In the core of HS-2, the 10TA.2CA.2TA.CG.12TA motif was present. This motif is known to be associated with the SI haplotype but not with any other haplotypes. Within the region of the Corfu deletion, many polymorphisms were identified highlighting the complexity of SI haplotype and HBB haplotypes in general. Many of these polymorphisms lead to creation or abolition of transcription factor binding sites when this was examined in silico using the TFBS search program ConSite (consite.genereg.net). Some of these putative sites bind transcription factors presumed to have regulatory roles in globin gene expression. Complete sequencing of the 126.6 kb interval with comparison to other HBB haplotypes associated with high and low HbF might focus attention on areas of interest that can be examined in functional studies. Disclosures: No relevant conflicts of interest to declare.
    Materialart: Online-Ressource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V116.21.1627.1627
    RVK:
    XA 33000
    RVK:
    XA 10000
    Sprache: Englisch
    Verlag: American Society of Hematology
    Publikationsdatum: 2010
    ZDB Id: 1468538-3
    ZDB Id: 80069-7
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  • 7
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    A Novel Homozygous Mutation in G6PC3 Presenting as Cyclic Neutropenia and Severe Congenital Neutropenia in the Same Family
    Springer Science and Business Media LLC ; 2013
    In:  Journal of Clinical Immunology Vol. 33, No. 8 ( 2013-11), p. 1403-1406
    Details
    In: Journal of Clinical Immunology, Springer Science and Business Media LLC, Vol. 33, No. 8 ( 2013-11), p. 1403-1406
    Materialart: Online-Ressource
    ISSN: 0271-9142 , 1573-2592
    URL: Article
    DOI: 10.1007/s10875-013-9945-7
    RVK:
    XA 10000
    Sprache: Englisch
    Verlag: Springer Science and Business Media LLC
    Publikationsdatum: 2013
    ZDB Id: 2016755-6
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 8
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    Human leucocyte antigen‐matched related haematopoietic stem cell transplantation using low‐dose cyclophosphamide, fludarabine and thymoglobulin in children with severe aplastic anaemia
    Wiley ; 2023
    In:  British Journal of Haematology Vol. 203, No. 2 ( 2023-10), p. 255-263
    Details
    In: British Journal of Haematology, Wiley, Vol. 203, No. 2 ( 2023-10), p. 255-263
    Kurzfassung: When human leucocyte antigen‐matched related donors are available, haematopoietic stem cell transplantation (HSCT) in children with severe aplastic anaemia (SAA) represents the standard of care. Cyclophosphamide (Cy) 200 mg/kg and anti‐thymocyte globulin (ATG) are frequently administered, but to‐date, no standard conditioning regimen exists. In this study, we investigated the efficacy of a unified HSCT conditioning protocol consisting of low‐dose Cy 80 mg/kg, fludarabine and ATG. Data were reviewed from children aged ≤14 years with either acquired SAA or non‐Fanconi anaemia inherited bone marrow failure syndrome (IBMFS) between 2011 and 2022 at various Saudi institutions. Graft‐versus‐host disease (GVHD) prophylaxis included mycophenolate mofetil and calcineurin inhibitors. HSCT was performed in 32 children (17 females and 15 males). Nine patients had deleterious mutations (two ERCC6L2 , two ANKRD26 , two TINF2 , one LZTFL1 , one RTEL1 and one DNAJC21 ). Four patients had short telomeres. All 32 patients engrafted successfully. At 3 years post‐transplant, the event‐free survival was 93% and overall survival was 95%. Two patients experienced secondary graft failure or myelodysplastic syndrome. A low probability of GVHD was observed (one acute GVHD II and one mild chronic GVHD). These data highlight how HSCT using low‐dose Cy as part of a fludarabine‐based regimen is safe and effective in SAA/non‐Fanconi anaemia IBMFS.
    Materialart: Online-Ressource
    ISSN: 0007-1048 , 1365-2141
    URL: Issue
    URL: Article
    DOI: 10.1111/bjh.v203.2
    DOI: 10.1111/bjh.19004
    RVK:
    XA 34100
    Sprache: Englisch
    Verlag: Wiley
    Publikationsdatum: 2023
    ZDB Id: 1475751-5
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  • 9
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    HLA-matched HSCT using targeted busulfan-based conditioning in children with primary hemophagocytic lymphohistiocytosis
    Springer Science and Business Media LLC ; 2021
    In:  Bone Marrow Transplantation Vol. 56, No. 12 ( 2021-12), p. 3097-3099
    Details
    In: Bone Marrow Transplantation, Springer Science and Business Media LLC, Vol. 56, No. 12 ( 2021-12), p. 3097-3099
    Materialart: Online-Ressource
    ISSN: 0268-3369 , 1476-5365
    URL: Article
    DOI: 10.1038/s41409-021-01468-7
    RVK:
    XA 10000
    RVK:
    XA 33180
    Sprache: Englisch
    Verlag: Springer Science and Business Media LLC
    Publikationsdatum: 2021
    ZDB Id: 2004030-1
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  • 10
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    HLA-identical related hematopoietic stem cell transplantation in severe sickle cell disease: age is not a barrier to successful outcome
    Springer Science and Business Media LLC ; 2022
    In:  Bone Marrow Transplantation Vol. 57, No. 2 ( 2022-02), p. 292-294
    Details
    In: Bone Marrow Transplantation, Springer Science and Business Media LLC, Vol. 57, No. 2 ( 2022-02), p. 292-294
    Materialart: Online-Ressource
    ISSN: 0268-3369 , 1476-5365
    URL: Article
    DOI: 10.1038/s41409-021-01513-5
    RVK:
    XA 10000
    RVK:
    XA 33180
    Sprache: Englisch
    Verlag: Springer Science and Business Media LLC
    Publikationsdatum: 2022
    ZDB Id: 2004030-1
    Standort Signatur Einschränkungen Verfügbarkeit
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