27 results on '"Charlotte M. Niemeyer"'
Search Results
2. Spontaneous remission and loss of monosomy 7: a window of opportunity for young children with SAMD9L syndrome
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Miriam Erlacher, Felicia Andresen, Martina Sukova, Jan Stary, Barbara de Moerloose, Jutte van der Werff Ten Bosch, Michael Dworzak, Markus G. Seidel, Sophia Polychronopoulou, Rita Beier, Christian P. Kratz, Michaela Nathrath, Michael C. Frühwald, Gudrun Göhring, Anke K. Bergmann, Christina Mayerhofer, Dirk Lebrecht, Senthilkumar Ramamoorthy, Ayami Yoshimi, Brigitte Strahm, Marcin W. Wlodarski, and Charlotte M. Niemeyer
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Monosomy 7 is the most common cytogenetic abnormality in pediatric myelodysplastic syndrome (MDS) and associated with a high risk of disease progression. However, in young children, spontaneous loss of monosomy 7 with concomitant hematologic recovery has been described, especially in the presence of germline mutations in SAMD9 and SAMD9L genes. Here, we report on our experience of close surveillance instead of upfront hematopoietic stem cell transplantation (HSCT) in seven patients diagnosed with SAMD9L syndrome and monosomy 7 at a median age of 0.6 years (range, 0.4-2.9). Within 14 months from diagnosis, three children experienced spontaneous hematological remission accompanied by a decrease in monosomy 7 clone size. Subclones with somatic SAMD9L mutations in cis were identified in five patients, three of whom attained hematological remission. Two patients acquired RUNX1 and EZH2 mutations during the observation period, of whom one progressed to myelodysplastic syndrome with excess of blasts (MDS-EB). Four patients underwent allogeneic HSCT at a median time of 26 months (range, 14-40) from diagnosis for MDSEB, necrotizing granulomatous lymphadenitis, persistent monosomy 7, and severe neutropenia. At last follow-up, six patients were alive, while one passed away due to transplant-related causes. These data confirm previous observations that monosomy 7 can be transient in young children with SAMD9L syndrome. However, they also indicate that delaying HSCT poses a substantial risk of severe infection and disease progression. Finally, surveillance of patients with SAMD9L syndrome and monosomy 7 is critical to define the evolving genetic landscape and to determine the appropriate timing of HSCT (clinicaltrials gov. Identifier: NCT00662090).
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- 2023
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3. Guideline for management of non-Down syndrome neonates with a myeloproliferative disease on behalf of the I-BFM AML Study Group and EWOG-MDS
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Eline J.M. Bertrums, C. Michel Zwaan, Daisuke Hasegawa, Valerie de Haas, Dirk N. Reinhardt, Franco Locatelli, Barbara de Moerloose, Michael Dworzak, Arjan Buijs, Petr Smisek, Alexandra Kolenova, Cornelis Jan Pronk, Jan-Henning Klusmann, Ana Carboné, Alina Ferster, Evangelia Antoniou, Soheil Meshinchi, Susana C. Raimondi, Charlotte M. Niemeyer, Henrik Hasle, Marry M. van den Heuvel-Eibrink, and Bianca F. Goemans
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2021
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4. A novel classification of hematologic conditions in patients with Fanconi anemia
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Yvonne Lisa Behrens, Gudrun Göhring, Randa Bawadi, Sümeyye Cöktü, Christina Reimer, Beatrice Hoffmann, Birte Sänger, Simon Käfer, Felicitas Thol, Miriam Erlacher, Charlotte M. Niemeyer, Irith Baumann, Reinhard Kalb, Detlev Schindler, and Christian Peter Kratz
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2021
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5. Genotype-phenotype association and variant characterization in Diamond-Blackfan anemia caused by pathogenic variants in RPL35A
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D. Matthew Gianferante, Marcin W. Wlodarski, Evangelia Atsidaftos, Lydie Da Costa, Polyxeni Delaporta, Jason E. Farrar, Frederick D. Goldman, Maryam Hussain, Antonis Kattamis, Thierry Leblanc, Jeffrey M. Lipton, Charlotte M. Niemeyer, Dagmar Pospisilova, Paola Quarello, Ugo Ramenghi, Vijay G. Sankaran, Adrianna Vlachos, Jana Volejnikova, Blanche P. Alter, Sharon A. Savage, and Neelam Giri
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Diamond Blackfan anemia (DBA) is predominantly an autosomal dominant inherited red cell aplasia primarily caused by pathogenic germline variants in ribosomal protein genes. DBA due to pathogenic RPL35A variants has been associated with large 3q29 deletions and phenotypes not common in DBA. We conducted a multi-institutional genotype-phenotype study of 45 patients with DBA associated with pathogenic RPL35A germline variants and curated the variant data on 21 additional cases from the literature. Genotype-phenotype analyses were conducted comparing patients with large deletions versus all other pathogenic variants in RPL35A. Twenty-two of the 45 cases had large deletions in RPL35A. After adjusting for multiple tests, a statistically significant association was observed between patients with a large deletion and steroid-resistant anemia, neutropenia, craniofacial abnormalities, chronic gastrointestinal problems, and intellectual disabilities (p
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- 2020
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6. Recurring mutations in RPL15 are linked to hydrops fetalis and treatment independence in Diamond-Blackfan anemia
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Marcin W. Wlodarski, Lydie Da Costa, Marie-Françoise O’Donohue, Marc Gastou, Narjesse Karboul, Nathalie Montel-Lehry, Ina Hainmann, Dominika Danda, Amina Szvetnik, Victor Pastor, Nahuel Paolini, Franca M. di Summa, Hannah Tamary, Abed Abu Quider, Anna Aspesi, Riekelt H. Houtkooper, Thierry Leblanc, Charlotte M. Niemeyer, Pierre-Emmanuel Gleizes, and Alyson W. MacInnes
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Diamond-Blackfan anemia (DBA) is a rare inherited bone marrow failure disorder linked predominantly to ribosomal protein gene mutations. Here the European DBA consortium reports novel mutations identified in the RPL15 gene in 6 unrelated individuals diagnosed with DBA. Although point mutations have not been previously reported for RPL15, we identified 4 individuals with truncating mutations p.Tyr81* (in 3 of 4) and p.Gln29*, and 2 with missense variants p.Leu10Pro and p.Lys153Thr. Notably, 75% (3 of 4) of truncating mutation carriers manifested with severe hydrops fetalis and required intrauterine transfusions. Even more remarkable is the observation that the 3 carriers of p.Tyr81* mutation became treatment-independent between four and 16 months of life and maintained normal blood counts until their last follow up. Genetic reversion at the DNA level as a potential mechanism of remission was not observed in our patients. In vitro studies revealed that cells carrying RPL15 mutations have pre-rRNA processing defects, reduced 60S ribosomal subunit formation, and severe proliferation defects. Red cell culture assays of RPL15-mutated primary erythroblast cells also showed a severe reduction in cell proliferation, delayed erythroid differentiation, elevated TP53 activity, and increased apoptosis. This study identifies a novel subgroup of DBA with mutations in the RPL15 gene with an unexpected high rate of hydrops fetalis and spontaneous, long-lasting remission.
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- 2018
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7. Constitutional SAMD9L mutations cause familial myelodysplastic syndrome and transient monosomy 7
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Victor B. Pastor, Sushree S. Sahoo, Jessica Boklan, Georg C. Schwabe, Ebru Saribeyoglu, Brigitte Strahm, Dirk Lebrecht, Matthias Voss, Yenan T. Bryceson, Miriam Erlacher, Gerhard Ehninger, Marena Niewisch, Brigitte Schlegelberger, Irith Baumann, John C. Achermann, Akiko Shimamura, Jochen Hochrein, Ulf Tedgård, Lars Nilsson, Henrik Hasle, Melanie Boerries, Hauke Busch, Charlotte M. Niemeyer, and Marcin W. Wlodarski
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Familial myelodysplastic syndromes arise from haploinsufficiency of genes involved in hematopoiesis and are primarily associated with early-onset disease. Here we describe a familial syndrome in seven patients from four unrelated pedigrees presenting with myelodysplastic syndrome and loss of chromosome 7/7q. Their median age at diagnosis was 2.1 years (range, 1–42). All patients presented with thrombocytopenia with or without additional cytopenias and a hypocellular marrow without an increase of blasts. Genomic studies identified constitutional mutations (p.H880Q, p.R986H, p.R986C and p.V1512M) in the SAMD9L gene on 7q21, with decreased allele frequency in hematopoiesis. The non-random loss of mutated SAMD9L alleles was attained via monosomy 7, deletion 7q, UPD7q, or acquired truncating SAMD9L variants p.R1188X and p.S1317RfsX21. Incomplete penetrance was noted in 30% (3/10) of mutation carriers. Long-term observation revealed divergent outcomes with either progression to leukemia and/or accumulation of driver mutations (n=2), persistent monosomy 7 (n=4), and transient monosomy 7 followed by spontaneous recovery with SAMD9L-wildtype UPD7q (n=2). Dysmorphic features or neurological symptoms were absent in our patients, pointing to the notion that myelodysplasia with monosomy 7 can be a sole manifestation of SAMD9L disease. Collectively, our results define a new subtype of familial myelodysplastic syndrome and provide an explanation for the phenomenon of transient monosomy 7. Registered at: www.clinicaltrials.gov; #NCT00047268.
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- 2018
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8. Long-term serial xenotransplantation of juvenile myelomonocytic leukemia recapitulates human disease in Rag2−/−γc−/− mice
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Christopher Felix Krombholz, Konrad Aumann, Matthias Kollek, Daniela Bertele, Silvia Fluhr, Mirjam Kunze, Charlotte M. Niemeyer, Christian Flotho, and Miriam Erlacher
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Juvenile myelomonocytic leukemia is a clonal malignant disease affecting young children. Current cure rates, even with allogeneic hematopoietic stem cell transplantation, are no better than 50%–60%. Pre-clinical research on juvenile myelomonocytic leukemia is urgently needed for the identification of novel therapies but is hampered by the unavailability of culture systems. Here we report a xenotransplantation model that allows long-term in vivo propagation of primary juvenile myelomonocytic leukemia cells. Persistent engraftment of leukemic cells was achieved by intrahepatic injection of 1×106 cells into newborn Rag2−/−γc−/− mice or intravenous injection of 5×106 cells into 5-week old mice. Key characteristics of juvenile myelomonocytic leukemia were reproduced, including cachexia and clonal expansion of myelomonocytic progenitor cells that infiltrated bone marrow, spleen, liver and, notably, lung. Xenografted leukemia cells led to reduced survival of recipient mice. The stem cell character of juvenile myelomonocytic leukemia was confirmed by successful serial transplantation that resulted in leukemia cell propagation for more than one year. Independence of exogenous cytokines, low donor cell number and slowly progressing leukemia are advantages of the model, which will serve as an important tool to research the pathophysiology of juvenile myelomonocytic leukemia and test novel pharmaceutical strategies such as DNA methyltransferase inhibition.
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- 2016
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9. Bone marrow immunophenotyping by flow cytometry in refractory cytopenia of childhood
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Anna M. Aalbers, Marry M. van den Heuvel-Eibrink, Irith Baumann, Michael Dworzak, Henrik Hasle, Franco Locatelli, Barbara De Moerloose, Markus Schmugge, Ester Mejstrikova, Michaela Nováková, Marco Zecca, C. Michel Zwaan, Jeroen G. te Marvelde, Anton W. Langerak, Jacques J.M. van Dongen, Rob Pieters, Charlotte M. Niemeyer, and Vincent H.J. van der Velden
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Refractory cytopenia of childhood is the most common type of childhood myelodysplastic syndrome. Because the majority of children with refractory cytopenia have a normal karyotype and a hypocellular bone marrow, differentiating refractory cytopenia from the immune-mediated bone marrow failure syndrome (very) severe aplastic anemia can be challenging. Flow cytometric immunophenotyping of bone marrow has been shown to be a valuable diagnostic tool in differentiating myelodysplastic syndrome from non-clonal cytopenias in adults. Here, we performed the first comprehensive flow cytometric analysis of immature myeloid, lymphoid cells and erythroid cells, and granulocytes, monocytes, and lymphoid cells in bone marrow obtained from a large prospective cohort of 81 children with refractory cytopenia. Children with refractory cyotopenia had a strongly reduced myeloid compartment, but not as severe as children with aplastic anemia. Furthermore, the number of flow cytometric abnormalities was significantly higher in children with refractory cytopenia than in healthy controls and in children with aplastic anemia, but lower than in advanced myelodysplastic syndrome. We conclude that flow cytometric immunophenotyping could be a relevant addition to histopathology in the diagnosis of refractory cytopenia of childhood. (The multi-center studies EWOG-MDS RC06 and EWOG-MDS 2006 are registered at clinicaltrials.gov identifiers 00499070 and 00662090, respectively).
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- 2015
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10. Criteria for evaluating response and outcome in clinical trials for children with juvenile myelomonocytic leukemia
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Charlotte M. Niemeyer, Mignon L. Loh, Annamaria Cseh, Todd Cooper, Christopher C. Dvorak, Rebecca Chan, Blanca Xicoy, Ulrich Germing, Seiji Kojima, Atsushi Manabe, Michael Dworzak, Barbara De Moerloose, Jan Starý, Owen P. Smith, Riccardo Masetti, Albert Catala, Eva Bergstraesser, Marek Ussowicz, Oskana Fabri, André Baruchel, Hélène Cavé, Michel Zwaan, Franco Locatelli, Henrik Hasle, Marry M. van den Heuvel-Eibrink, Christian Flotho, and Ayami Yoshimi
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Juvenile myelomonocytic leukemia is a rare myeloproliferative disease in young children. While hematopoietic stem cell transplantation remains the only curative therapeutic option for most patients, children with juvenile myelomonocytic leukemia increasingly receive novel agents in phase I–II clinical trials as pre-transplant therapy or therapy for relapse after transplantation. However, response criteria or definitions of outcome for standardized evaluation of treatment effect in patients with juvenile myelomonocytic leukemia are currently lacking. Here we propose criteria to evaluate the response to the non-transplant therapy and definitions of remission status after hematopoietic stem cell transplantation. For the evaluation of non-transplant therapy, we defined 6 clinical variables (white blood cell count, platelet count, hematopoietic precursors and blasts in peripheral blood, bone marrow blast percentage, spleen size and extramedullary disease) and 3 genetic variables (cytogenetic, molecular and chimerism response) which serve to describe the heterogeneous picture of response to therapy in each individual case. It is hoped that these criteria will facilitate the comparison of results between clinical trials in juvenile myelomonocytic leukemia.
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- 2015
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11. RAS diseases in children
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Charlotte M. Niemeyer
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
RAS genes encode a family of 21 kDa proteins that are an essential hub for a number of survival, proliferation, differentiation and senescence pathways. Signaling of the RAS-GTPases through the RAF-MEK-ERK pathway, the first identified mitogen-associated protein kinase (MAPK) cascade is essential in development. A group of genetic syndromes, named “RASopathies”, had been identified which are caused by heterozygosity for germline mutations in genes that encode protein components of the RAS/MAPK pathway. Several of these clinically overlapping disorders, including Noonan syndrome, Noonan-like CBL syndrome, Costello syndrome, cardio-facio-cutaneous (CFC) syndrome, neurofibromatosis type I, and Legius syndrome, predispose to cancer and abnormal myelopoiesis in infancy. This review focuses on juvenile myelomonocytic leukemia (JMML), a malignancy of early childhood characterized by initiating germline and/or somatic mutations in five genes of the RAS/MAPK pathway: PTPN11, CBL, NF-1, KRAS and NRAS. Natural courses of these five subtypes differ, although hematopoietic stem cell transplantation remains the only curative therapy option for most children with JMML. With whole-exome sequencing studies revealing few secondary lesions it will be crucial to better understand the RAS/MAPK signaling network with its crosstalks and feed-back loops to carefully design early clinical trials with novel pharmacological agents in this still puzzling leukemia.
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- 2014
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12. Comparison of horse and rabbit antithymocyte globulin in immunosuppressive therapy for refractory cytopenia of childhood
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Ayami Yoshimi, Marry M. van den Heuvel-Eibrink, Irith Baumann, Stephan Schwarz, Ingrid Simonitsch-Klupp, Pascale de Paepe, Vit Campr, Gitte Birk Kerndrup, Maureen O’Sullivan, Rita Devito, Roos Leguit, Miguel Hernandez, Michael Dworzak, Barbara de Moerloose, Jan Starý, Henrik Hasle, Owen P. Smith, Marco Zecca, Albert Catala, Markus Schmugge, Franco Locatelli, Monika Führer, Alexandra Fischer, Anne Guderle, Peter Nöllke, Brigitte Strahm, and Charlotte M. Niemeyer
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Refractory cytopenia of childhood is the most common subtype of myelodysplastic syndrome in children. In this study, we compared the outcome of immunosuppressive therapy using horse antithymocyte globulin (n=46) with that using rabbit antithymocyte globulin (n=49) in 95 patients with refractory cytopenia of childhood and hypocellular bone marrow. The response rate at 6 months was 74% for horse antithymocyte globulin and 53% for rabbit antithymocyte globulin (P=0.04). The inferior response in the rabbit antithymocyte globulin group resulted in lower 4-year transplantation-free (69% versus 46%; P=0.003) and failure-free (58% versus 48%; P=0.04) survival rates in this group compared with those in the horse antithymocyte globulin group. However, because of successful second-line hematopoietic stem cell transplantation, overall survival was comparable between groups (91% versus 85%; P=ns). The cumulative incidence of relapse (15% versus 9%; P=ns) and clonal evolution (12% versus 4%; P=ns) at 4 years was comparable between groups. Our results suggest that the outcome of immunosuppressive therapy with rabbit antithymocyte globulin is inferior to that of horse antithymocyte globulin. Although immunosuppressive therapy is an effective therapy in selected patients with refractory cytopenia of childhood, the long-term risk of relapse or clonal evolution remains. (ClinicalTrial.gov identifiers: NCT00662090)
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- 2014
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13. Mutations in the let-7 binding site - a mechanism of RAS activation in juvenile myelomonocytic leukemia?
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Doris Steinemann, Marcel Tauscher, Inka Praulich, Charlotte M. Niemeyer, Christian Flotho, and Brigitte Schlegelberger
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2010
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14. Mutations of the Shwachman-Bodian-Diamond syndrome gene in patients presenting with refractory cytopenia – do we have to screen?
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Axel Karow, Christian Flotho, Michaela Schneider, Manfred Fliegauf, and Charlotte M. Niemeyer
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2010
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15. Mitotic recombination and compound-heterozygous mutations are predominant NF1-inactivating mechanisms in children with juvenile myelomonocytic leukemia and neurofibromatosis type 1
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Doris Steinemann, Larissa Arning, Inka Praulich, Manfred Stuhrmann, Henrik Hasle, Jan Starý, Brigitte Schlegelberger, Charlotte M. Niemeyer, and Christian Flotho
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Children with neurofibromatosis type 1 (NF-1), being constitutionally deficient for one allele of the NF1 gene, are at greatly increased risk of juvenile myelomonocytic leukemia (JMML). NF1 is a negative regulator of RAS pathway activity, which has a central role in JMML. To further clarify the role of biallelic NF1 gene inactivation in the pathogenesis of JMML, we investigated the somatic NF1 lesion in 10 samples from children with JMML/NF-1. We report that two-thirds of somatic events involved loss of heterozygosity (LOH) at the NF1 locus, predominantly caused by segmental uniparental disomy of large parts of chromosome arm 17q. One-third of leukemias showed compound-heterozygous NF1-inactivating mutations. A minority of cases exhibited somatic interstitial deletions. The findings reinforce the emerging role of somatic mitotic recombination as a leukemogenic mechanism. In addition, they support the concept that biallelic NF1 inactivation in hematopoietic progenitor cells is required for transformation to JMML in children with NF-1.
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- 2010
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16. HLA-identical umbilical cord blood transplantation from a sibling donor in juvenile myelomonocytic leukemia
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Andrica C.H. de Vries, Robbert G.M. Bredius, Arjan C. Lankester, Marc Bierings, Monika Trebo, Petr Sedlacek, Charlotte M. Niemeyer, Marco Zecca, Franco Locatelli, and Marry M. van den Heuvel-Eibrink
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2009
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17. Diagnosis and classification of myelodysplastic syndrome: International Working Group on Morphology of myelodysplastic syndrome (IWGM-MDS) consensus proposals for the definition and enumeration of myeloblasts and ring sideroblasts
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Ghulam J. Mufti, John M. Bennett, Jean Goasguen, Barbara J. Bain, Irith Baumann, Richard Brunning, Mario Cazzola, Pierre Fenaux, Ulrich Germing, Eva Hellström-Lindberg, Itsuro Jinnai, Atsushi Manabe, Akira Matsuda, Charlotte M. Niemeyer, Guillermo Sanz, Masao Tomonaga, Teresa Vallespi, and Ayami Yoshimi
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
The classification of myelodysplastic syndromes is based on the morphological criteria proposed by the French-American-British (FAB) and World Health Organization (WHO) groups. Accurate enumeration of blast cells, although essential for diagnosis of myelodysplastic syndrome and for assignment to prognostic groups, is often difficult, due to imprecise criteria for the morphological definition of blasts and promyelocytes. An International Working Group on Morphology of Myelodysplastic Syndrome (IWGM-MDS) of hematopathologists and hematologists expert in the field of myelodysplastic syndrome reviewed the morphological features of bone marrows from all subtypes of myelodysplastic syndrome and agreed on a set of recommendations, including recommendations for the definition and enumeration of blast cells and ring sideroblasts. It is recommended that (1) agranular or granular blast cells be defined (replacing the previous type I, II and III blasts), (2) dysplastic promyelocytes be distinguished from cytologically normal promyelocytes and from granular blast cells, (3) sufficient cells be counted to give a precise blast percentage, particularly at thresholds that are important for diagnosis or prognosis and (4) ring sideroblasts be defined as erythroblasts in which there are a minimum of 5 siderotic granules covering at least a third of the nuclear circumference. Clear definitions and a differential count of a sufficient number of cells is likely to improve precision in the diagnosis and classification of myelodysplastic syndrome. Recommendations should be applied in the context of the WHO classification.
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- 2008
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18. Mutation analysis of the BRAF oncogene in juvenile myelomonocytic leukemia
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Andrica C.H. de Vries, Ronald W. Stam, Christian P. Kratz, Martin Zenker, Charlotte M. Niemeyer, and Marry M. van den Heuvel-Eibrink
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Juvenile myelomonocytic leukemia (JMML) is a myeloproliferative/myelodysplastic disorder associated with mutations in the Ras-Raf-MEK-ERK-signaling pathway. B-Raf plays a central role in this pathway. In 65 screened JMML patients we identified no BRAF mutations and we conclude that this gene is unlikely to play a role in the pathogenesis of JMML.
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- 2007
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19. Role of mutation independent constitutive activation of FLT3 in juvenile myelomonocytic leukemia
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Andrica C.H. de Vries, Ronald W. Stam, Pauline Schneider, Charlotte M. Niemeyer, Elisabeth R. van Wering, Oskar A. Haas, Christian P. Kratz, Monique L. den Boer, Rob Pieters, and Marry M. van den Heuvel-Eibrink
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
FLT3 gene mutations have been identified as prognostic factors in myeloid malignancies. Furthermore, FLT3 can be activated by wild type overexpression or ligand-dependent in leukemic cells co-expressing FLT3 ligand (FLT3L). So far no data are available on FLT3/FLT3L expression and activation in JMML. In 51 clinical JMML samples, activating mutations were screened, FLT3 and FLT3L mRNA levels were assessed and the sensitivity of JMML cells to the FLT3 inhibitor PKC412 was tested by MTT assays. No evidence for constitutively activation of FLT3/FLT3L was found in JMML, indicating that FLT3 inhibitors are unlikely to be effective in JMML.
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- 2007
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20. How a rare pediatric neoplasia can give important insights into biological concepts: a perspective on juvenile myelomonocytic leukemia
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Christian Flotho, Christian P. Kratz, and Charlotte M. Niemeyer
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2007
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21. Constitutional SAMD9L mutations cause familial myelodysplastic syndrome and transient monosomy 7
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Brigitte Schlegelberger, Melanie Boerries, Ulf Tedgård, Brigitte Strahm, Gerhard Ehninger, Miriam Erlacher, John C. Achermann, Matthias Voss, Hauke Busch, Jochen Hochrein, Irith Baumann, Victor B Pastor, Lennart Nilsson, Marena R. Niewisch, Yenan T. Bryceson, Dirk Lebrecht, Jessica Boklan, Georg C. Schwabe, Ebru Tugrul Saribeyoglu, Charlotte M. Niemeyer, Henrik Hasle, Sushree Sangita Sahoo, Akiko Shimamura, and Marcin W. Wlodarski
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0301 basic medicine ,Oncology ,Adult ,Male ,medicine.medical_specialty ,Adolescent ,Penetrance ,Tumor Suppressor Proteins/genetics ,Article ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Internal medicine ,Medicine ,Humans ,Allele ,Child ,Allele frequency ,Myelodysplastic Syndromes/genetics ,Chromosome 7 (human) ,Family Health ,business.industry ,Myelodysplastic syndromes ,Tumor Suppressor Proteins ,Bone marrow failure ,Infant ,Hematology ,medicine.disease ,Thrombocytopenia ,3. Good health ,Pedigree ,Leukemia ,030104 developmental biology ,030220 oncology & carcinogenesis ,Myelodysplastic Syndromes ,Child, Preschool ,Female ,Chromosome Deletion ,business ,Haploinsufficiency ,Chromosomes, Human, Pair 7 - Abstract
Familial myelodysplastic syndromes arise from haploinsufficiency of genes involved in hematopoiesis and are primarily associated with early-onset disease. Here we describe a familial syndrome in seven patients from four unrelated pedigrees presenting with myelodysplastic syndrome and loss of chromosome 7/7q. Their median age at diagnosis was 2.1 years (range, 1-42). All patients presented with thrombocytopenia with or without additional cytopenias and a hypocellular marrow without an increase of blasts. Genomic studies identified constitutional mutations (p.H880Q, p.R986H, p.R986C and p.V1512M) in the SAMD9L gene on 7q21, with decreased allele frequency in hematopoiesis. The non-random loss of mutated SAMD9L alleles was attained via monosomy 7, deletion 7q, UPD7q, or acquired truncating SAMD9L variants p.R1188X and p.S1317RfsX21. Incomplete penetrance was noted in 30% (3/10) of mutation carriers. Long-term observation revealed divergent outcomes with either progression to leukemia and/or accumulation of driver mutations (n=2), persistent monosomy 7 (n=4), and transient monosomy 7 followed by spontaneous recovery with SAMD9L-wildtype UPD7q (n=2). Dysmorphic features or neurological symptoms were absent in our patients, pointing to the notion that myelodysplasia with monosomy 7 can be a sole manifestation of SAMD9L disease. Collectively, our results define a new subtype of familial myelodysplastic syndrome and provide an explanation for the phenomenon of transient monosomy 7. Registered at: www.clinicaltrials.gov; #NCT00047268.
- Published
- 2018
22. LIN28B is over-expressed in specific subtypes of pediatric leukemia and regulates lncRNA H19
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Steven Goossens, Veerle Labarque, Barbara De Moerloose, Tim Pieters, Valerie de Haas, Jan Stary, Johannes H. Schulte, Pieter Van Vlierberghe, Jody J. Haigh, Pascale De Paepe, Christian Flotho, Geert Berx, Tim Lammens, Andrica C H de Vries, Marry M. van den Heuvel-Eibrink, Hélène Cavé, Hetty Helsmoortel, Yves Benoit, Nadine Van Roy, Frank Speleman, Silvia Bresolin, Charlotte M. Niemeyer, Farzaneh Ghazavi, and Pediatrics
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0301 basic medicine ,IncRNA H19 regulation ,LIN28B overexpression ,Pediatric leukemia ,Adolescent ,Child ,Child, Preschool ,Female ,Humans ,Infant ,Leukemia ,Male ,Neoplasm Proteins ,RNA, Long Noncoding ,RNA, Neoplasm ,RNA-Binding Proteins ,Gene Expression Regulation, Leukemic ,Medizin ,RNA-binding protein ,Biology ,medicine.disease_cause ,03 medical and health sciences ,Promyelocytic leukemia protein ,medicine ,Human embryogenesis ,Lymphopoiesis ,Online Only Articles ,Preschool ,Leukemic ,Hematology ,Methylation ,medicine.disease ,030104 developmental biology ,Gene Expression Regulation ,Immunology ,biology.protein ,Cancer research ,RNA ,Neoplasm ,Long Noncoding ,Stem cell ,Carcinogenesis - Abstract
LIN28B is an RNA-binding protein with an oncofetal expression pattern. High LIN28B expression is crucial during human embryogenesis and is down-regulated in most tissues after birth.[1][1] However, reactivation during oncogenesis is common in a plethora of adult cancers, including leukemia, and was
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- 2016
23. The long non-coding RNA landscape in juvenile myelomonocytic leukemia
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Barbara De Moerloose, Tim Lammens, Jan Stary, Mattias Hofmans, Jan Philippé, Silvia Bresolin, Pieter Van Vlierberghe, Nadine Van Roy, Christian Flotho, Hetty Helsmoortel, Hélène Cavé, Charlotte M. Niemeyer, Marry M. van den Heuvel-Eibrink, and Henrik Hasle
- Subjects
0301 basic medicine ,EXPRESSION ,Male ,medicine.medical_specialty ,Standard of care ,medicine.medical_treatment ,Hematopoietic stem cell transplantation ,Biology ,03 medical and health sciences ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Medicine and Health Sciences ,Humans ,RNA, Neoplasm ,Online Only Articles ,Child ,Hematology ,Juvenile myelomonocytic leukemia ,Gene Expression Regulation, Leukemic ,medicine.disease ,Long non-coding RNA ,surgical procedures, operative ,030104 developmental biology ,Leukemia, Myelomonocytic, Juvenile ,Child, Preschool ,Cancer research ,Female ,RNA, Long Noncoding - Abstract
Juvenile myelomonocytic leukemia (JMML) is a rare and aggressive myelodysplastic and myeloproliferative disorder of early childhood. It is characterized by proliferation of granulocytic and monocytic cells.[1][1] Currently, hematopoietic stem cell transplantation (HSCT) is the standard of care and
- Published
- 2018
24. Bone marrow immunophenotyping by flow cytometry in refractory cytopenia of childhood
- Author
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Irith Baumann, Michael Dworzak, Jacques J.M. van Dongen, Franco Locatelli, Marry M. van den Heuvel-Eibrink, Rob Pieters, Anna M. Aalbers, Ester Mejstrikova, Jeroen G. te Marvelde, Vincent H.J. van der Velden, Marco Zecca, C. Michel Zwaan, Barbara De Moerloose, Charlotte M. Niemeyer, Michaela Novakova, Henrik Hasle, Markus Schmugge, Anton W. Langerak, University of Zurich, Pediatrics, and Immunology
- Subjects
Pathology ,Myeloid ,SEVERE APLASTIC-ANEMIA ,Pancytopenia ,2720 Hematology ,acute myeloid-leukemia ,paroxysmal-nocturnal hemoglobinuria ,grade myelodysplastic syndromes ,severe aplastic-anemia ,immunosuppressive therapy ,sporadic monocytopenia ,autosomal-dominant ,multicenter validation ,european leukemianet ,diagnostic utility ,Severity of Illness Index ,GRADE MYELODYSPLASTIC SYNDROMES ,Monocytes ,Immunophenotyping ,Bone Marrow ,hemic and lymphatic diseases ,Medicine and Health Sciences ,Lymphocytes ,refractory cytopenia ,Child ,MULTICENTER VALIDATION ,Anemia, Aplastic ,Hematology ,Articles ,Flow Cytometry ,SPORADIC MONOCYTOPENIA ,medicine.anatomical_structure ,Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA ,Child, Preschool ,Female ,medicine.medical_specialty ,Hypocellular Bone Marrow ,Adolescent ,610 Medicine & health ,ACUTE MYELOID-LEUKEMIA ,Diagnosis, Differential ,EUROPEAN LEUKEMIANET ,Erythroid Cells ,PAROXYSMAL-NOCTURNAL HEMOGLOBINURIA ,Antigens, CD ,medicine ,Humans ,IMMUNOSUPPRESSIVE THERAPY ,Aplastic anemia ,Cytopenia ,business.industry ,Myelodysplastic syndromes ,Bone marrow failure ,Infant ,medicine.disease ,10036 Medical Clinic ,Myelodysplastic Syndromes ,Immunology ,DIAGNOSTIC UTILITY ,Bone marrow ,AUTOSOMAL-DOMINANT ,business ,Granulocytes - Abstract
Refractory cytopenia of childhood is the most common type of childhood myelodysplastic syndrome. Because the majority of children with refractory cytopenia have a normal karyotype and a hypocellular bone marrow, differentiating refractory cytopenia from the immune-mediated bone marrow failure syndrome (very) severe aplastic anemia can be challenging. Flow cytometric immunophenotyping of bone marrow has been shown to be a valuable diagnostic tool in differentiating myelodysplastic syndrome from non-clonal cytopenias in adults. Here, we performed the first comprehensive flow cytometric analysis of immature myeloid, lymphoid cells and erythroid cells, and granulocytes, monocytes, and lymphoid cells in bone marrow obtained from a large prospective cohort of 81 children with refractory cytopenia. Children with refractory cyotopenia had a strongly reduced myeloid compartment, but not as severe as children with aplastic anemia. Furthermore, the number of flow cytometric abnormalities was significantly higher in children with refractory cytopenia than in healthy controls and in children with aplastic anemia, but lower than in advanced myelodysplastic syndrome. We conclude that flow cytometric immunophenotyping could be a relevant addition to histopathology in the diagnosis of refractory cytopenia of childhood. (The multi-center studies EWOG-MDS RC06 and EWOG-MDS 2006 are registered at clinicaltrials.gov identifiers 00499070 and 00662090, respectively).
- Published
- 2015
25. Comparison of horse and rabbit antithymocyte globulin in immunosuppressive therapy for refractory cytopenia of childhood
- Author
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Charlotte M. Niemeyer, Henrik Hasle, Michael Dworzak, Maureen J. O'Sullivan, Roos J Leguit, Barbara De Moerloose, Gitte Kerndrup, Markus Schmugge, Marco Zecca, Rita Devito, Owen P. Smith, Anne Guderle, Peter Nöllke, Vit Campr, Miguel T. Hernandez, Alexandra Fischer, Ingrid Simonitsch-Klupp, Brigitte Strahm, Jan Starý, Ayami Yoshimi, Albert Català, Marry M. van den Heuvel-Eibrink, Pascale De Paepe, Monika Führer, Stephan Schwarz, Irith Baumann, Franco Locatelli, University of Zurich, Yoshimi, Ayami, Pediatrics, and Erasmus MC other
- Subjects
medicine.medical_specialty ,Globulin ,medicine.medical_treatment ,2720 Hematology ,610 Medicine & health ,Hematopoietic stem cell transplantation ,Gastroenterology ,Refractory ,Internal medicine ,medicine ,Cumulative incidence ,Cytopenia ,biology ,business.industry ,Horse ,Immunosuppression ,Hematology ,Articles ,medicine.disease ,Anti-thymocyte globulin ,N/A ,Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA ,10036 Medical Clinic ,Immunology ,biology.protein ,business - Abstract
Refractory cytopenia of childhood is the most common subtype of myelodysplastic syndrome in children. In this paper, we compared the outcome of immunosuppressive therapy using horse anti-thymocyte globulin (n = 46) with that using rabbit anti-thymocyte globulin (n = 49) in 95 patients with refractory cytopenia of childhood and hypocellular bone marrow. The response rate at 6 months was 74% for horse anti-thymocyte globulin and 53% for rabbit anti-thymocyte globulin (p = 0.04). The inferior response in the rabbit anti-thymocyte globulin group resulted in lower 4-year-transplantation-free (69% vs. 46%; p = 0.003) and failure-free (58% vs. 48%; p = 0.04) survival in this group compared with those in the horse anti-thymocyte globulin group. However, because of successful second-line hematopoietic stem cell transplantation, overall survival was comparable between groups (91% vs. 85%, p = ns). The cumulative incidence of relapse (15% vs. 9%, p = ns) and clonal evolution (12% vs. 4%, p = ns) at 4 years was comparable between groups. Our results suggest that the outcome of immunosuppressive therapy with rabbit anti-thymocyte globulin is inferior to that of horse anti-thymocyte globulin. Although immunosuppressive therapy is an effective therapy in selected patients with refractory cytopenia of childhood, the long-term risk of relapse or clonal evolution remains. (ClinicalTrial.gov identifiers: NCT00662090).
- Published
- 2014
26. Sequential decisions on FAS sequencing guided by biomarkers in patients with lymphoproliferation and autoimmune cytopenia
- Author
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Petr Smisek, Karina Butler, Andrew J. Cant, Anne Rensing-Ehl, Sophie Hambleton, Markus G. Seidel, Ester Mejstrikova, Sigune Goldacker, Kai Lehmberg, Volker Schuster, Stephen Owens, Benjamin Gathmann, Werner Vach, Myriam Ricarda Lorenz, Charlotte M. Niemeyer, Olaf Neth, Ilka Fuchs, Stephan Ehl, Annamaria Cseh, Carsten Speckmann, Martina Sukova, Ales Janda, Michael H. Albert, Thomas Wiesel, Peter Svec, Klaus Schwarz, Gregor Dückers, Milen Minkov, Freimut H. Schilling, Leonora Houet, Joachim Rösler, Martin Ebinger, Mario Abinun, Beryl Primrose Gladstone, Holger Hebart, Ingrid Kühnle, and Karim Kentouche
- Subjects
Male ,Fas Ligand Protein ,Adolescent ,CD3 ,Lymphoproliferative disorders ,medicine.disease_cause ,Germline ,Autoimmune Diseases ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Sequential decisions ,FAS sequencing ,biomarkers ,lymphoproliferation ,autoimmune cytopenia ,medicine ,Humans ,Vitamin B12 ,030304 developmental biology ,0303 health sciences ,Mutation ,biology ,business.industry ,Genetic heterogeneity ,Autoimmune Cytopenia ,Hematology ,Articles ,medicine.disease ,Lymphoproliferative Disorders ,3. Good health ,Vitamin B 12 ,Autoimmune lymphoproliferative syndrome ,Immunology ,biology.protein ,Biological Markers ,Female ,business ,Biomarkers ,030215 immunology - Abstract
Clinical and genetic heterogeneity renders confirmation or exclusion of autoimmune lymphoproliferative syndrome difficult. To re-evaluate and improve the currently suggested diagnostic approach to patients with suspected FAS mutation, the most frequent cause of autoimmune lymphoproliferative syndrome, we prospectively determined 11 biomarkers in 163 patients with splenomegaly or lymphadenopathy and presumed or proven autoimmune cytopenia(s). Among 98 patients sequenced for FAS mutations in CD3(+)TCRα/β(+)CD4(-)CD8(-) "double negative" T cells, 32 had germline and six had somatic FAS mutations. The best a priori predictor of FAS mutations was the combination of vitamin B12 and soluble FAS ligand (cut-offs 1255 pg/mL and 559 pg/mL, respectively), which had a positive predictive value of 92% and a negative predictive value of 97%. We used these data to develop a web-based probability calculator for FAS mutations using the three most discriminatory biomarkers (vitamin B12, soluble FAS ligand, interleukin-10) of the 11 tested. Since more than 60% of patients with lymphoproliferation and autoimmune cytopenia(s) in our cohort did not harbor FAS mutations, 15% had somatic FAS mutations, and the predictive value of double-negative T-cell values was rather low (positive and negative predictive values of 61% and 77%, respectively), we argue that the previously suggested diagnostic algorithm based on determination of double-negative T cells and germline FAS sequencing, followed by biomarker analysis, is not efficient. We propose vitamin B12 and soluble FAS ligand assessment as the initial diagnostic step with subsequent decision on FAS sequencing supported by a probability-calculating tool. peerReviewed
- Published
- 2013
27. Mutations of the Shwachman-Bodian-Diamond syndrome gene in patients presenting with refractory cytopenia – do we have to screen?
- Author
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Michaela Schneider, Charlotte M. Niemeyer, Axel Karow, Christian Flotho, and Manfred Fliegauf
- Subjects
congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,Pathology ,Refractory ,hemic and lymphatic diseases ,medicine ,Humans ,Mass Screening ,In patient ,Abnormalities, Multiple ,Letters to the Editor ,Mass screening ,Cytopenia ,business.industry ,Shwachman-Bodian-Diamond Syndrome Gene ,Anemia, Refractory ,Bone marrow failure ,Hypocellular Myelodysplastic Syndrome ,Proteins ,Hematology ,medicine.disease ,Prognosis ,Dermatology ,eye diseases ,Mutation ,business - Abstract
Children diagnosed with acquired hypocellular myelodysplastic syndrome (MDS), such as refractory cytopenia (RC), share clinical features with patients suffering from inherited bone marrow failure (IBMF). The Shwachman-Diamond syndrome (SDS; OMIM #260400) is an autosomal recessive disorder associated
- Published
- 2009
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