13 results on '"Inherited bone marrow failure syndromes"'
Search Results
2. Ataluren improves myelopoiesis and neutrophil chemotaxis by restoring ribosome biogenesis and reducing p53 levels in Shwachman–Diamond syndrome cells.
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Cipolli, Marco, Boni, Christian, Penzo, Marianna, Villa, Isabella, Bolamperti, Simona, Baldisseri, Elena, Frattini, Annalisa, Porta, Giovanni, Api, Martina, Selicato, Nora, Roccia, Pamela, Pollutri, Daniela, Marinelli Busilacchi, Elena, Poloni, Antonella, Caporelli, Nicole, D'Amico, Giovanna, Pegoraro, Anna, Cesaro, Simone, Oyarbide, Usua, and Vella, Antonio
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ORGANELLE formation , *BONE marrow cells , *NEUTROPHILS , *NONSENSE mutation , *CHEMOTAXIS , *EXOCRINE pancreatic insufficiency , *RIBOSOMAL proteins - Abstract
Summary: Shwachman–Diamond syndrome (SDS) is characterized by neutropenia, exocrine pancreatic insufficiency and skeletal abnormalities. SDS bone marrow haematopoietic progenitors show increased apoptosis and impairment in granulocytic differentiation. Loss of Shwachman–Bodian–Diamond syndrome (SBDS) expression results in reduced eukaryotic 80S ribosome maturation. Biallelic mutations in the SBDS gene are found in ~90% of SDS patients, ~55% of whom carry the c.183‐184TA>CT nonsense mutation. Several translational readthrough‐inducing drugs aimed at suppressing nonsense mutations have been developed. One of these, ataluren, has received approval in Europe for the treatment of Duchenne muscular dystrophy. We previously showed that ataluren can restore full‐length SBDS protein synthesis in SDS‐derived bone marrow cells. Here, we extend our preclinical study to assess the functional restoration of SBDS capabilities in vitro and ex vivo. Ataluren improved 80S ribosome assembly and total protein synthesis in SDS‐derived cells, restored myelopoiesis in myeloid progenitors, improved neutrophil chemotaxis in vitro and reduced neutrophil dysplastic markers ex vivo. Ataluren also restored full‐length SBDS synthesis in primary osteoblasts, suggesting that its beneficial role may go beyond the myeloid compartment. Altogether, our results strengthened the rationale for a Phase I/II clinical trial of ataluren in SDS patients who harbour the nonsense mutation. [ABSTRACT FROM AUTHOR]
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- 2024
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3. Human leucocyte antigen‐matched related haematopoietic stem cell transplantation using low‐dose cyclophosphamide, fludarabine and thymoglobulin in children with severe aplastic anaemia.
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Alsultan, Abdulrahman, Abujoub, Rodaina, Alsudairy, Reem, Memon, Shahbaz, Jarrar, Mohammad S., Alafghani, Sameera, Aldaama, Saad, Ballourah, Walid, Almanjomi, Fahd, and Essa, Mohammed F.
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HEMATOPOIETIC stem cell transplantation , *APLASTIC anemia , *LEUCOCYTES , *FLUDARABINE , *PATIENT experience - Abstract
Summary: 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. [ABSTRACT FROM AUTHOR]
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- 2023
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4. How to optimize outcome of patients undergoing HLA‐matched related haematopoietic stem cell transplantation in acquired and inherited bone marrow failure syndromes.
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Giardino, Stefano, Pierri, Filomena, and Faraci, Maura
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STEM cell transplantation , *HEMATOPOIETIC stem cell transplantation , *BONE marrow , *APLASTIC anemia , *PAROXYSMAL hemoglobinuria , *IMMUNOSUPPRESSION - Abstract
Up‐front allogeneic haematopoietic stem cell transplantation (allo‐HSCT) after a reduced intensity conditioning regimen is the standard treatment in children with acquired severe aplastic anaemia (aSAA) and inherited bone marrow failure syndromes (iBMFs) in the presence of a healthy matched related donor (MRD). The paper by Alsultan et al. report the safety and efficacy of MRD HSCT conditioned with low‐dose cyclophosphamide, fludarabine and thymoglobulin in both aSAA and non‐Fanconi iBMFs, strengthening the concept of the pivotal role of immunosuppressive approach in allo‐HSCT for specific subgroups of non‐malignant diseases requiring a reduced risk of toxicities, offering the opportunity to discuss the essential points for achieving patients' long‐term survival after MRD HSCT in BMF. Commentary on: Alsultan et al. Human leucocyte antigen‐matched related haematopoietic stem cell transplantation using low‐dose cyclophosphamide, fludarabine and thymoglobulin in children with severe aplastic anaemia. Br J Haematol 2023;203:255‐263. [ABSTRACT FROM AUTHOR]
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- 2023
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5. Poor outcome after hematopoietic stem cell transplantation of patients with unclassified inherited bone marrow failure syndromes.
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Lim, Yeon Jung, Arbiv, Omri A., Kalbfleisch, Melanie E., Klaassen, Robert J., Fernandez, Conrad, Rayar, Meera, Steele, MacGregor, Lipton, Jeffrey H., Cuvelier, Geoff, Pastore, Yves D., Silva, Mariana, Brossard, Josee, Michon, Bruno, Abish, Sharon, Sinha, Roona, Corriveau‐Bourque, Catherine, Breakey, Vicky R., Tole, Soumitra, Goodyear, Lisa, and Sung, Lillian
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HEMATOPOIETIC stem cell transplantation , *CORD blood transplantation , *BONE marrow , *CORD blood , *HEPATIC veno-occlusive disease - Abstract
Classification of inherited bone marrow failure syndromes (IBMFSs) according to clinical and genetic diagnoses enables proper adjustment of treatment. Unfortunately, 30% of patients enrolled in the Canadian Inherited Marrow Failure Registry (CIMFR) with features suggesting hereditability could not be classified with a specific syndromic diagnosis. We analyzed the outcome of hematopoietic stem cell transplantation (HSCT) in unclassified IBMFSs (uIBMFSs) and the factors associated with outcome. Twenty‐two patients with uIBMFSs and 70 patients with classified IBMFSs underwent HSCT. Five‐year overall survival of uIBMFS patients after HSCT was inferior to that of patients with classified IBMFSs (56% vs 76.5%). The outcome of patients with uIBMFS who received cord blood was significantly lower than that of patients who received other stem cell sources (14.8% vs 90.9%). Engraftment failure was higher among patients with uIBMFS who received cord blood than those who received bone marrow. None of the following factors were significantly associated with poor survival: transfusion load, transplant indication, the intensity of conditioning regimen, human leukocyte antigen‐identical sibling/alternative donor. We suggest that identifying the genetic diagnosis is essential to modulate the transplant procedure including conditioning agents and stem cell sources for better outcome and the standard cord blood transplantation (CBT) should be avoided in uIBMFS. [ABSTRACT FROM AUTHOR]
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- 2022
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6. Next‐generation sequencing in hypoplastic bone marrow failure: What difference does it make?
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Skibenes, Sofie T., Clausen, Ida, and Raaschou‐Jensen, Klas
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BONE marrow , *NUCLEOTIDE sequencing , *PAROXYSMAL hemoglobinuria , *SYMPTOMS , *APLASTIC anemia , *LITERATURE reviews - Abstract
Hypoplastic bone marrow failure is a diagnostic feature of multiple haematological disorders, which also share a substantial overlap of clinical symptoms. Hence, discrimination of underlying disorders in patients presenting with hypoplastic bone marrow failure remains a major challenge in the clinic. Recent next‐generation sequencing (NGS) studies have broadened our understanding of the varying molecular mechanisms and advanced diagnostics of disorders exhibiting hypoplastic bone marrow failure. In this article, we present a literature review of NGS studies of haematological disorders associated with hypoplastic bone marrow failure and highlight the relevance of NGS for improved clinical diagnostics and decision‐making. [ABSTRACT FROM AUTHOR]
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- 2021
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7. Molecular analysis and genotype‐phenotype correlation of Diamond‐Blackfan anemia.
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Arbiv, O. A., Cuvelier, G., Klaassen, R. J., Fernandez, C. V., Robitaille, N., Steele, M., Breakey, V., Abish, S., Wu, J., Sinha, R., Silva, M., Goodyear, L., Jardine, L., Lipton, J. H., Corriveau‐Bourque, C., Brossard, J., Michon, B., Ghemlas, I., Waespe, N., and Zlateska, B.
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APLASTIC anemia , *MOLECULAR diagnosis , *HUMAN abnormalities , *GENETIC mutation , *RIBOSOMAL proteins , *DIAGNOSIS - Abstract
Diamond‐Blackfan anemia (DBA) features hypoplastic anemia and congenital malformations, largely caused by mutations in various ribosomal proteins. The aim of this study was to characterize the spectrum of genetic lesions causing DBA and identify genotypes that correlate with phenotypes of clinical significance. Seventy‐four patients with DBA from across Canada were included. Nucleotide‐level mutations or large deletions were identified in 10 ribosomal genes in 45 cases. The
RPS19 mutation group was associated with higher requirement for chronic treatment for anemia than other DBA groups. Patients withRPS19 mutations, however, were more likely to maintain long‐term corticosteroid response without requirement for further chronic transfusions. Conversely, patients withRPL11 mutations were less likely to need chronic treatment. Birth defects, including cardiac, skeletal, hand, cleft lip or palate and genitourinary malformations, also varied among the various genetic groups. Patients withRPS19 mutations had the fewest number of defects, while patients withRPL5 had the greatest number of birth defects. This is the first study to show differences between DBA genetic groups with regards to treatment. Previously unreported differences in the rate and types of birth defects were also identified. These data allow better patient counseling, a more personalized monitoring plan, and may also suggest differential functions of DBA genes on ribosome and extra‐ribosomal functions. [ABSTRACT FROM AUTHOR]- Published
- 2018
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8. Genetic Information-Seeking Behaviors and Knowledge among Family Members and Patients with Inherited Bone Marrow Failure Syndromes.
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Hamilton, Jada, Hutson, Sadie, Frohnmayer, Amy, Han, Paul, Peters, June, Carr, Ann, and Alter, Blanche
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Inherited bone marrow failure syndromes (IBMFS) including Fanconi anemia, dyskeratosis congenita, Diamond-Blackfan anemia, and Shwachman-Diamond syndrome are rare genetic disorders characterized by hematologic complications and increased risk of cancer. Patients and their families likely experience obstacles in obtaining sufficient health information given their disorders' rarity. To investigate this possibility, we examined information-seeking behaviors and levels of general and disorder-specific genetic knowledge among 315 members of 174 families with an IBMFS, and how information-seeking behaviors and socio-demographic factors may be associated with their genetic knowledge. Cross-sectional survey data indicated that participants were most likely to have ever used the Internet or healthcare providers for genetic information. On average, participants correctly answered 57 % of items assessing general genetic knowledge and 49-59 % of disorder-specific knowledge items. Greater knowledge was associated with greater education and ever experiencing genetic counseling, attending a scientific meeting, and seeking information from the Internet and scientific literature. Among families with Fanconi anemia (whose family support organization has the longest history of providing information), greater disorder-specific genetic knowledge was also associated with seeking information from support groups and other affected families. Results suggest that families with IBMFS have uncertainty regarding genetic aspects of their disorder, and highlight potential channels for delivering educational resources. [ABSTRACT FROM AUTHOR]
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- 2015
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9. Cytokine production by bone marrow mononuclear cells in inherited bone marrow failure syndromes.
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Matsui, Ken, Giri, Neelam, Alter, Blanche P., and Pinto, Ligia A.
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FANCONI'S anemia , *DYSKERATOSIS congenita , *SHWACHMAN-Diamond Syndrome , *BONE marrow diseases , *TUMOR necrosis factors , *T cells , *MONONUCLEAR leukocytes , *LIPOPOLYSACCHARIDES - Abstract
Fanconi anaemia ( FA), dyskeratosis congenita ( DC), Diamond- Blackfan anaemia ( DBA), and Shwachman- Diamond syndrome ( SDS) are characterized by the progressive development of bone marrow failure. Overproduction of tumour necrosis factor-α ( TNF-α) from activated bone marrow T-cells has been proposed as a mechanism of FA-related aplasia. Whether such overproduction occurs in the other syndromes is unknown. We conducted a comparative study on bone marrow mononuclear cells to examine the cellular subset composition and cytokine production. We found lower proportions of haematopoietic stem cells in FA, DC, and SDS, and a lower proportion of monocytes in FA, DC, and DBA compared with controls. The T- and B-lymphocyte proportions were similar to controls, except for low B-cells in DC. We did not observe overproduction of TNF-α or IFN-γ by T-cells in any patients. Induction levels of TNF-α, interleukin ( IL)-6, IL-1β, IL-10, granulocyte colony-stimulating factor, and granulocyte-macrophage colony-stimulating factor in monocytes stimulated with high-dose lipopolysaccharide ( LPS) were similar at 4 h but lower at 24 h when compared to controls. Unexpectedly, patient samples showed a trend toward higher cytokine level in response to low-dose (0·001 μg/ml) LPS. Increased sensitivity to LPS may have clinical implications and could contribute to the development of pancytopenia by creating a chronic subclinical inflammatory micro-environment in the bone marrow. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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10. Genetic regulation of fetal haemoglobin in inherited bone marrow failure syndromes.
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Alter, Blanche P., Rosenberg, Philip S., Day, Thomas, Menzel, Stephan, Giri, Neelam, Savage, Sharon A., and Thein, Swee Lay
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BONE marrow , *ANEMIA , *ERYTHROPOIETIN , *FANCONI'S anemia , *DYSKERATOSIS congenita , *HEMOGLOBINS - Abstract
Patients with inherited bone marrow failure syndromes ( IBMFS) have 'stress erythropoiesis', with anaemia, macrocytosis, increased fetal haemoglobin (Hb F) and high erythropoietin levels. In haemoglobinopathies, Hb F levels are regulated by 3 quantitative trait loci, HBS1L- MYB, BCL11A and Xmn1 - HBG2. In our study of 97 patients with an IBMFS, increased Hb F was associated with young age, male gender, anaemia, high erythropoietin levels, and alternative alleles in Xmn1 - HBG2 [adjusted P = 0·04 for the total group, driven by Fanconi anaemia ( P = 0·02) and dyskeratosis congenita ( P = 0·09)]. Thus Hb F is regulated in IBMFS by Xmn1 - HBG2, as it is in the haemoglobinopathies. [ABSTRACT FROM AUTHOR]
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- 2013
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11. Comparative analysis of Shwachman-Diamond syndrome to other inherited bone marrow failure syndromes and genotype-phenotype correlation.
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Hashmi, S. K., Allen, C., Klaassen, R., Fernandez, C. V., Yanofsky, R., Shereck, E., Champagne, J., Silva, M., Lipton, J. H., Brossard, J., Samson, Y., Abish, S., Steele, M., Ali, K., Dower, N., Athale, U., Jardine, L., Hand, J. P., Beyene, J., and Dror, Y.
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COMPARATIVE studies , *GENETIC disorders , *BONE marrow diseases , *GENOTYPE-environment interaction , *PHENOTYPES , *MEDICAL genetics - Abstract
Hashmi SK, Allen C, Klaassen R, Fernandez CV, Yanofsky R, Shereck E, Champagne J, Silva M, Lipton JH, Brossard J, Samson Y, Abish S, Steele M, Ali K, Dower N, Athale U, Jardine L, Hand JP, Beyene J, Dror Y. Comparative analysis of Shwachman-Diamond syndrome to other inherited bone marrow failure syndromes and genotype-phenotype correlation. Our knowledge of the phenotypes of inherited bone marrow failure syndromes (IBMFSs) derives from case reports or case series in which only one IBMFS was studied. However, the substantial phenotypic overlap necessitates comparative analysis between the IBMFSs. Shwachman-Diamond syndrome (SDS) is an IBMFS that the appreciation of what comprises its clinical phenotype is still evolving. In this analysis we used data on 125 patients from the Canadian Inherited Marrow Failure Study (CIMFS), which is a prospective multicenter population-based study. Thirty-four cases of SDS patients were analyzed and compared to other patients with the four most common IBMFSs on the CIMFS: Diamond Blackfan anemia, Fanconi anemia (FA), Kostmann/severe congenital neutropenia and dyskeratosis congenita (DC). The diagnosis of SDS, FA and DC was often delayed relative to symptoms onset; indicating a major need for improving tools to establish a rapid diagnosis. We identified multiple phenotypic differences between SDS and other IBMFSs, including several novel differences. SBDS biallelic mutations were less frequent than in previous reports (81%). Importantly, compared to patients with biallelic mutations, patients with wild type SBDS had more severe hematological disease but milder pancreatic disease. In conclusion, comprehensive study of the IBMFSs can provide useful comparative data between the disorders. SBDS-negative SDS patients may have more severe hematological failure and milder pancreatic disease. [ABSTRACT FROM AUTHOR]
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- 2011
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12. The pathology of bone marrow failure R J Leguit & J G van den Tweel Pathology of bone marrow failure.
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Leguit, Roos J. and Van Den Tweel, Jan G.
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BONE marrow diseases , *BLOOD platelet disorders , *HEMATOLOGICAL manifestations of general diseases , *ANEMIA , *NEUTROPENIA , *HIV infections - Abstract
Leguit R J & van den Tweel J G (2010) Histopathology , 655-670 An important indication for bone marrow investigation is the presence of bone marrow failure, which manifests itself as (pan)cytopenia. The causes of cytopenia are varied and differ considerably between childhood and adulthood. In the paediatric age group inherited bone marrow failure syndromes are important causes of bone marrow failure, but they play only a minor role in later life. This review gives a comprehensive overview of bone marrow failure disorders in children and adults. We classified the causes of bone marrow failure according to the main presenting haematological abnormality, i.e. anaemia, neutropenia, thrombocytopenia or pancytopenia. The following red cell disorders are discussed: red cell aplasia, sideroblastic anaemia, congenital dyserythropoietic anaemia, haemolytic anaemia, paroxysmal nocturnal haemoglobinuria, iron deficiency anaemia, anaemia of chronic disease and megaloblastic anaemia. The neutropenias occur in the context of Shwachman-Diamond syndrome (SDS), severe congenital neutropenia, cyclic neutropenia, immune-related neutropenia and non-immune neutropenia. In addition, the following causes of thrombocytopenia are discussed: congenital amegakaryocytic thrombocytopenia, thrombocytopenia with absent radii, immune-related thrombocytopenia and non-immune thrombocytopenia. Finally, we pay attention to the following pancytopenic disorders: Fanconi anaemia, dyskeratosis congenita, aplastic anaemia, myelodysplastic syndromes and human immunodeficiency virus (HIV) infection. [ABSTRACT FROM AUTHOR]
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- 2010
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13. Advances in the understanding of congenital amegakaryocytic thrombocytopenia.
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Ballmaier, Matthias and Germeshausen, Manuela
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THROMBOCYTOPENIA , *STEM cell transplantation , *BONE marrow cells , *HEMATOPOIETIC stem cells , *BLOOD platelet disorders - Abstract
Congenital amegakaryocytic thrombocytopenia (MIM #604498) is an extremely rare inherited bone marrow failure syndrome, usually presenting as a severe thrombocytopenia at birth due to ineffective megakaryocytopoiesis and no characteristic physical anomalies. Usually the isolated thrombocytopenia progresses to pancytopenia during the first years of life. The only curative therapy to date is haematopoietic stem cell transplantation. Most of the cases of congenital amegakaryocytic thrombocytopenia are caused by defective expression or function of the thrombopoietin receptor due to homozygous or compound heterozygous mutations in the gene MPL. The essential roles of thrombopoietin as a lineage specific regulator of platelet production and as a regulator of haematopoietic stem cell function are reflected in the haematological defects seen in affected individuals. [ABSTRACT FROM AUTHOR]
- Published
- 2009
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