The Experts below are selected from a list of 312 Experts worldwide ranked by ideXlab platform
Yoshihiro Komada - One of the best experts on this subject based on the ideXlab platform.
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Successful unrelated BMT in a patient with Kostmann Syndrome complicated by pre-transplant pulmonary 'bacterial' abscesses.
Bone marrow transplantation, 2001Co-Authors: Hidemi Toyoda, Eichi Azuma, Hiroki Hori, Masahiro Hirayama, Michihiro Kobayashi, K Isogai, Naomi Kondo, Yoshihiro KomadaAbstract:Kostmann Syndrome, severe congenital neutropenia, is often associated with life-threatening bacterial infections. A 5-year-old girl with Kostmann Syndrome developed pulmonary abscesses. She was refractory to granulocyte colony-stimulating factor and antibiotics. She underwent unrelated HLA-matched BMT. Myeloablative conditioning consisted of 12-Gy TBI with lung shielding, antithymocyte globulin, etoposide, and cyclophosphamide. After successful engraftment, the pulmonary abscesses resolved by day 75 post-transplant. Although the option of transplantation is not established in the setting of unrelated HLA-matched BMT in Kostmann Syndrome, this case may provide useful information. Furthermore, pre-transplant pulmonary bacterial abscesses may not be a contraindication for BMT in some patients with Kostmann Syndrome.
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Successful unrelated BMT in a patient with Kostmann Syndrome complicated by pre-transplant pulmonary ‘bacterial’ abscesses
Bone Marrow Transplantation, 2001Co-Authors: Hidemi Toyoda, Eichi Azuma, Hiroki Hori, Masahiro Hirayama, Michihiro Kobayashi, K Isogai, Naomi Kondo, Yoshihiro KomadaAbstract:Kostmann Syndrome, severe congenital neutropenia, is often associated with life-threatening bacterial infections. A 5-year-old girl with Kostmann Syndrome developed pulmonary abscesses. She was refractory to granulocyte colony-stimulating factor and antibiotics. She underwent unrelated HLA-matched BMT. Myeloablative conditioning consisted of 12-Gy TBI with lung shielding, antithymocyte globulin, etoposide, and cyclophosphamide. After successful engraftment, the pulmonary abscesses resolved by day 75 post-transplant. Although the option of transplantation is not established in the setting of unrelated HLA-matched BMT in Kostmann Syndrome, this case may provide useful information. Furthermore, pre-transplant pulmonary bacterial abscesses may not be a contraindication for BMT in some patients with Kostmann Syndrome. Bone Marrow Transplantation (2001) 28, 413–415.
Karl Welte - One of the best experts on this subject based on the ideXlab platform.
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Angeborene Störungen der Blutbildung
Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz, 2007Co-Authors: Cornelia Zeidler, Karl WelteAbstract:Congenital bone marrow failure Syndromes are rare diseases characterised by a reduction of mature blood cells (erythrocytes, platelets, neutrophils). Examples of such disorders include congenital aplastic anemia (Fanconi anemia), congenital hypoplastic anemia (Diamond-Blackfan anemia), congenital neutropenias (Kostmann Syndrome, cyclic neutropenia, Shwachman-Diamond Syndrome and others), and congenital thrombocytopenias (TAR Syndrome, amegacaryocytic thrombocytopenia). In Germany the prevalence of congenital bone marrow failure Syndromes can be estimated to be 10/1,000,000 children and adolescents. Although rare, these diseases contributed significantly to the current knowledge on normal haematopoiesis. The documentation of rare diseases by patient registries and the cooperation of clinical centres within networks are most important for the resolution of such disorders. In the following, congenital neutropenia will be presented as an example: Until the 1980s congenital neutropenia could only be classified clinically. Few cases had been reported in the literature. All subtypes were therefore collected under the general term "congenital neutropenia". The establishment of an international network of experts and the long-term documentation of the courses of disease in a common database allowed for statistically workable data in response to therapy, secondary diagnoses and the long-term prognosis. A close cooperation with scientists finally led to the characterisation of genetically different disorders with common pathomechanisms. Angeborene Störungen der Blutbildung umfassen eine Gruppe seltener Erkrankungen, die durch eine Verminderung reifer Blutzellen (Erythrozyten, Granulozyten, Thrombozyten) gekennzeichnet sind. Zu diesen Erkrankungen gehören die angeborene aplastische Anämie (Fanconi-Anämie), kongenitale hypoplastische Anämie (Diamond-Blackfan-Anämie), kongenitale Neutropenien (Kostmann-Syndrom, zyklische Neutropenie, Shwachman-Diamond-Syndrom und viele andere) sowie kongenitale Thrombozytopenien (TAR-Syndrom, amegakaryozytäre Thrombozytopenie). Insgesamt ist in Deutschland von einer Prävalenz dieser Erkrankungen von 10/1.000.000 Kindern und Jugendlichen auszugehen. Trotz ihrer Seltenheit ist ihr Verständnis für die Erforschung der normalen und pathologischen Hämatopoese von immenser Bedeutung. Zu diesem Zweck sind die Dokumentation dieser seltenen Erkrankungen in Patientenregistern und der Zusammenschluss von Behandlungszentren in Netzwerken wichtig. Im Folgenden soll dies am Beispiel der angeborenen Neutropenien beschrieben werden: Bis in die 1980er-Jahre war eine Klassifikation der angeborenen Neutropenien ausschließlich klinisch möglich, es existierten nur wenige Fallbeschreibungen. Daher wurden die unterschiedlichen Formen unter dem Sammelbegriff "schwere kongenitale Neutropenie" zusammengefasst. Erst durch den Aufbau eines internationalen Expertennetzwerkes und die Langzeitdokumentation von Krankheitsverläufen in einer gemeinsamen Datenbank konnten statistisch tragfähige Daten zu Therapieansprechen, Begleiterkrankungen und Langzeitprognose gesammelt werden. Die enge Kooperation mit Wissenschaftlern führte letztlich zur Charakterisierung genetisch unterschiedlicher Erkrankungen mit gemeinsamen Pathomechanismen.
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defective expression of neutrophil serine proteases in myeloid progenitors of congenital neutropenia patients carrying either ela2 or hax1 mutations
Blood, 2007Co-Authors: Julia Skokowa, Johnpaul Fobiwe, Manuela Germeshausen, Karl WelteAbstract:Severe congenital neutropenia (CN) is a heterogeneous disorder of myelopoiesis with two major types of inheritance: 1. autosomal dominant CN defined by mutations in ELA2 gene encoding neutrophil elastase (NE) (Horwitz M., et al., Nat Genet. 1999;23:433) and 2. autosomal recessive CN (including Kostmann Syndrome) carrying HAX-1 mutations (Klein C., et al., Nat Genet. 2007;39:86), both characterized by a maturation arrest of granulopoiesis at the level of promyelocytes. In the present study we aimed to evaluate the expression profile of genes specifically expressed in the CD33+ bone marrow promyelocytes of both patient groups harbouring ELA2 or HAX1 mutations. In healthy individuals mRNA expression levels of neutrophil serine proteases (neutrophil elastase (ELA2), cathepsin G, cathepsin D, proteinase 3 and azurocidin) as well as of myeloperoxidase (MPO) and defensins reached highest levels in the azurophil granules at the promyelocytic stage of neutrophil differentiation (Borregaard N., et al., Curr Opin Hematol. 2001;8:23). We found downregulation of mRNA expression levels of ELA2 (8.9 fold), cathepsin G (7.6 fold), cathepsin D (11.2 fold), proteinase 3 (9.2 fold) and defensin B1 (6.5 fold) in both groups of CN patients (with ELA2 or HAX1 mutations), in comparison to G-CSF-treated patients with idiopathic neutropenia (IN) and G-CSF-treated healthy controls. In contrast, there were no difference in mRNA expression levels of azurocidin and only slight decrease in the expression of MPO mRNA in CN patients. Additionally, we found significantly reduced protein levels of neutrophil elastase (NE) in plasma of CN patients irrespective of “ELA2 or HAX1” inheritance, in comparison to cyclic neutropenia (CyN) patients, IN patients and G-CSF-treated healthy controls. Taken together, both ELA2 and HAX1 mutations are associated with defective expression of neutrophil serine proteases such as NE, cathepsin G, cathepsin D, proteinase 3 as well as of defensin B1 in CD33+ myeloid progenitor cells of CN patients, suggesting a common pathway for both patient groups. Intriguingly, ELA2 expression is directly regulated by LEF-1, suggesting that abrogated LEF-1 expression in CN promyelocytes (Skokowa J., et al., Nat. Med. 2006;12:1191) may be responsible for defective serine proteases expression in both groups, since all are regulated by a similar mechanism.
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Severe congenital neutropenia.
Seminars in hematology, 2006Co-Authors: Karl Welte, Cornelia Zeidler, David C. DaleAbstract:Severe congenital neutropenia (CN) includes a variety of hematologic disorders characterized by severe neutropenia, with absolute neutrophil counts (ANC) below 0.5 × 10 9 /L, and associated with severe systemic bacterial infections from early infancy. One subtype of CN, Kostmann Syndrome, is an autosomal recessive disorder, characterized histopathologically by early-stage maturation arrest of myeloid differentiation. CN with similar clinical features occurs as an autosomal dominant disorder and many sporadic cases also have been reported. This genetic heterogeneity suggests that several pathophysiological mechanisms may lead to this common clinical phenotype. Recent studies on the genetic bases of CN have detected inherited or spontaneous point mutations in the neutrophil elastase gene ( ELA 2 ) in about 60% to 80% of patients and, less commonly, mutations in other genes. Acquisition of additional genetic defects during the course of the disease, for example, granulocyte colony-stimulating factor (G-CSF) receptor gene mutations and cytogenetic aberrations, indicates an underlying genetic instability as a common feature for all congenital neutropenia subtypes. Data on more than 600 patients with CN collected by the Severe Chronic Neutropenia International Registry (SCNIR) demonstrate that, regardless of the particular CN subtype, more than 95% of these patients respond to recombinant human (rHu)G-CSF with ANCs that can be maintained above 1.0 × 10 9 /L. Adverse events include mild splenomegaly, osteoporosis, and malignant transformation into myelodysplasia (MDS)/leukemia. If and how G-CSF treatment impacts on these adverse events is not fully understood. In recent analyses the influence of the G-CSF dose required to achieve neutrophil response (ANC >1,000/μL) in the risk of developing acute myeloid leukemia (AML) has been reported. Hematopoietic stem cell transplantation (HSCT) is still the only treatment available for patients who are refractory to G-CSF treatment.
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Administration of Granulocyte Colony-Stimulating Factor Does Not Restore Defective Expression of bcl-2 and bcl-2-xL in Myeloid Progenitor Cells of Patients with Severe Congenital Neutropenia (Kostmann Syndrome).
Blood, 2004Co-Authors: Gunnar Cario, Cornelia Zeidler, Julia Skokowa, Zheng Wang, Vesna Bucan, Martin Stanulla, Martin Schrappe, Karl WelteAbstract:Severe congenital neutropenia (SCN; Kostmann Syndrome) is characterized by a maturation block in the myelopoiesis at the promyelocytic/myelocytic stage leading to decreased amounts of neutrophils in bone marrow and peripheral blood. This maturation arrest was previously associated with an accelerated apoptosis. Administration of recombinant human granulocyte colony-stimulating factor (G-CSF) sufficiently increases neutrophil numbers in most patients. Recently, it was demonstrated that the elevated degree of apoptosis was accompanied by a selective decreased expression of the anti-apoptotic Bcl-2 protein in myeloid progenitor cells in 4 surviving members of the original “Kostmann family” and 1 patient with SCN of unknown inheritance (Carlsson et al., Blood2004; 103: 3355–3361). In these patients, it was shown that the administration of G-CSF restored Bcl-2 expression and corrected the abnormal acceleration of apoptosis. To test whether this observation is a common feature of SCN patients myeloid progenitor cells, we analyzed the mRNA and protein expression of bcl-2 in CD33 + bone marrow myeloid progenitor cells from 6 G-CSF treated SCN patients not related to the original “Kostmann family” in comparison to that of 2 long-term G-CSF treated patients with neutropenia other than SCN and healthy controls without and after administration of G-CSF (4 and 3, respectively). Additionally, the mRNA expression of the Bcl-2-related genes, bcl-xL (anti-apoptotic) and bax (pro-apoptotic), and the expression of caspase 9, an important intracellular amplifier of apoptotic signaling was investigated. Gene expression was measured by quantitative real-time PCR, and protein expression by immunofluorescence and confocal microscopy. We observed a significant increase of bcl-2 expression after administration of G-CSF in CD33 + cells of healthy controls (fold change (FC) = 1.7, p = 0.0011, t-test). In contrast, bcl-2 was significantly lower expressed in CD33 + cells from long-term G-CSF treated SCN patients as compared to that of long-term G-CSF treated patients with neutropenia other than SCN (FC = 20, p = 0.015, t-test), and healthy controls without (FC = 7, p bcl-xL did show a similar pattern with a significant difference comparing SCN patients and healthy controls without G-CSF (FC = 4.4, p = 0.018). In contrast, the expression of caspase 9 was significantly upregulated in CD33 + cells of SCN patients as well as G-CSF treated controls compared to healthy controls without G-CSF administration (FC = 8.9, p = 0.002). Bax was similarly expressed in all groups. The expression pattern of bcl-2 was confirmed on the protein level. In summary, the expression of bcl-2 was defective in SCN patients as it was described by Carlsson et al., and a similar pattern was observed for bcl-xL. In contrast to published data, long-time administration of G-CSF did not normalize the expression of both anti-apoptotic Bcl-2 family members in our patients. We conclude, that a mechanism other than the restoration of Bcl-2 and Bcl-xL expression is responsible for the increase of neutrophils after G-CSF treatment in our patient sample.
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Kostmann Syndrome and severe congenital neutropenia.
Seminars in hematology, 2002Co-Authors: Cornelia Zeidler, Karl WelteAbstract:Abstract Congenital neutropenia (CN) includes hematologic disorders characterized by severe neutropenia with an absolute neutrophil count (ANC) below 0.5 × 10 9 /L associated with severe systemic bacterial infections from early infancy. One subtype of CN, Kostmann Syndrome, was originally described as an autosomal-recessive disorder, characterized by early-stage maturation arrest of myelopoiesis. Autosomal-dominant and sporadic cases have also been reported. Recent studies on the genetic bases of CN have detected different inherited or spontaneous point mutations in the neutrophil elastase gene. Development of additional genetic defects during the course of disease, such as granulocyte colony-stimulating factor (G-CSF)-receptor gene mutations and cytogenetic aberrations, indicates an underlying genetic instability. Data on more than 300 patients with CN collected by the Severe Chronic Neutropenia International Registry (SCNIR) since 1994 demonstrate that, independent of the CN subtype, more than 90% of patients respond to recombinant human (rHu)G-CSF with ANCs that can be maintained at approximately 1.0 × 10 9 /L. Adverse events include mild splenomegaly, moderate thrombocytopenia, osteoporosis, and malignant transformation into myelodysplasia (MDS)/leukemia. If and how rHuG-CSF treatment impacts on these adverse events remains unclear since there are no historical controls for comparison. Hematopoietic stem cell transplantation (HSCT) is still the only available treatment for patients refractory to rHuG-CSF treatment. Semin Hematol 39:82-88. Copyright 2002, Elsevier Science (USA). All rights reserved.
Elio Castagnola - One of the best experts on this subject based on the ideXlab platform.
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uneventful outcome of unrelated hematopoietic stem cell transplantation in a patient with leukemic transformation of Kostmann Syndrome and long lasting invasive pulmonary mycosis
European Journal of Haematology, 2003Co-Authors: Sandro Dallorso, Carla Manzitti, P. Dodero, Maura Faraci, Cristina Rosanda, Elio CastagnolaAbstract:Kostmann Syndrome (KS) is an inherited hematological disorder characterized by an absolute neutrophil count (ANC) <0.2 x 109/L and life-threatening bacterial infections. Granulocyte-colony stimulating factor (G-CSF) makes it possible to reach an ANC of 1.0 x 109/L and consequently to reduce significantly the occurrence of severe infections. Absence of response to G-CSF, G-CSF receptor mutation, and leukemic transformation are absolute indications to perform hematopoietic stem cell transplantation (HSCT). Pulmonary mycosis does not represent an absolute contraindication to bone marrow transplantation (BMT), although a relapse rate of 30-50% has been reported, despite adequate medical and surgical treatment. Mycotic pneumonia recurrence shows a mortality rate above 80%, especially in the presence of persisting immunosuppression. We report on a KS patient with long-lasting fungal pneumonia who developed myelodysplasia and subsequent acute myeliod leukemia (AML) conversion resistant to antiblastic therapy. Despite surgical excision and secondary prophylaxis, recurrence of the pulmonary lesion occurred prior to the unrelated HSCT. In spite of these poor prognostic characteristics, outcome was uneventful and the patient is alive and well in continuous complete remission with no signs of fungal infection.
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Uneventful outcome of unrelated hematopoietic stem cell transplantation in a patient with leukemic transformation of Kostmann Syndrome and long-lasting invasive pulmonary mycosis.
European journal of haematology, 2003Co-Authors: Sandro Dallorso, Carla Manzitti, P. Dodero, Maura Faraci, Cristina Rosanda, Elio CastagnolaAbstract:Kostmann Syndrome (KS) is an inherited hematological disorder characterized by an absolute neutrophil count (ANC)
Hidemi Toyoda - One of the best experts on this subject based on the ideXlab platform.
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Successful unrelated BMT in a patient with Kostmann Syndrome complicated by pre-transplant pulmonary 'bacterial' abscesses.
Bone marrow transplantation, 2001Co-Authors: Hidemi Toyoda, Eichi Azuma, Hiroki Hori, Masahiro Hirayama, Michihiro Kobayashi, K Isogai, Naomi Kondo, Yoshihiro KomadaAbstract:Kostmann Syndrome, severe congenital neutropenia, is often associated with life-threatening bacterial infections. A 5-year-old girl with Kostmann Syndrome developed pulmonary abscesses. She was refractory to granulocyte colony-stimulating factor and antibiotics. She underwent unrelated HLA-matched BMT. Myeloablative conditioning consisted of 12-Gy TBI with lung shielding, antithymocyte globulin, etoposide, and cyclophosphamide. After successful engraftment, the pulmonary abscesses resolved by day 75 post-transplant. Although the option of transplantation is not established in the setting of unrelated HLA-matched BMT in Kostmann Syndrome, this case may provide useful information. Furthermore, pre-transplant pulmonary bacterial abscesses may not be a contraindication for BMT in some patients with Kostmann Syndrome.
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Successful unrelated BMT in a patient with Kostmann Syndrome complicated by pre-transplant pulmonary ‘bacterial’ abscesses
Bone Marrow Transplantation, 2001Co-Authors: Hidemi Toyoda, Eichi Azuma, Hiroki Hori, Masahiro Hirayama, Michihiro Kobayashi, K Isogai, Naomi Kondo, Yoshihiro KomadaAbstract:Kostmann Syndrome, severe congenital neutropenia, is often associated with life-threatening bacterial infections. A 5-year-old girl with Kostmann Syndrome developed pulmonary abscesses. She was refractory to granulocyte colony-stimulating factor and antibiotics. She underwent unrelated HLA-matched BMT. Myeloablative conditioning consisted of 12-Gy TBI with lung shielding, antithymocyte globulin, etoposide, and cyclophosphamide. After successful engraftment, the pulmonary abscesses resolved by day 75 post-transplant. Although the option of transplantation is not established in the setting of unrelated HLA-matched BMT in Kostmann Syndrome, this case may provide useful information. Furthermore, pre-transplant pulmonary bacterial abscesses may not be a contraindication for BMT in some patients with Kostmann Syndrome. Bone Marrow Transplantation (2001) 28, 413–415.
Yuichi Akiyama - One of the best experts on this subject based on the ideXlab platform.
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Unrelated Donor Marrow Transplantation for Congenital Immunodeficiency and Metabolic Disease: An Update of the Experience of the Japan Marrow Donor Program
International Journal of Hematology, 2004Co-Authors: Naoki Sakata, Keisei Kawa, Koji Kato, Hiromasa Yabe, Miharu Yabe, Masayuki Nagasawa, Hideo Mugishima, Hisato Kigasawa, Masahiro Tsuchida, Yuichi AkiyamaAbstract:We retrospectively analyzed the clinical results of 81 patients with congenital genetic diseases who were treated with bone marrow transplantation (BMT) from unrelated donors identified through the Japan Marrow Donor Program.The patients were aged between 1 and 38 years (median, 4 years).Thirty-five patients underwent transplantation for metabolic disease (MD), ie, mucopolysaccharidosis (n = 25), adrenoleukodystrophy (n = 7), and others (n = 3). The remaining 46 patients had Wiskott-Aldrich Syndrome (n = 16), hemophagocytic Syndrome including the inherited type (n = 9), severe combined immunodeficiency (n = 6), hyper-IgM Syndrome (n = 4), Chédiak-Higashi Syndrome (n = 3),Kostmann Syndrome (n = 3), and others (n = 5). Fiftytwo donor-patient pairs were fully matched at HLA-A, HLA-B, and HLA-DRB1 alleles. The remaining 24 patients received allele-mismatched grafts (20 matched at 5 of 6 loci and 4 matched at 4 of 6 loci). Engraftment occurred in 82.4% of the MD group and 90.7% of the other genetic disease (OGD) group; however, 14 patients (18.2%) experienced either early or late graft failure.The cumulative incidence of grade II to IV acute graft-versus-host disease (GVHD) was 35.5% _ 9.8% in the MD group and 47.3% _ 9.5% in the OGD group, and the rate of chronic GVHD was 20% in both groups. Forty-nine patients have survived for 3 to 96 months (median, 20 months).The probabilities of 5-year overall survival and event-free survival were 72.6% _ 11.5% and 65.3% _ 8.6%, respectively, for MD (n = 35) and 72.5% _ 7.3% and 63.6% _ 7.3% for OGD (n = 46). Although patient status before BMT and the occurrence of grade III to IV acute GVHD significantly affected outcome, unrelated BMT is a curative therapeutic option for children with congenital genetic diseases who have no HLA-matched family donors.
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Unrelated donor marrow transplantation for congenital immunodeficiency and metabolic disease: An update of the experience of the Japan marrow donor program
International journal of hematology, 2004Co-Authors: Naoki Sakata, Keisei Kawa, Koji Kato, Hiromasa Yabe, Miharu Yabe, Masayuki Nagasawa, Hideo Mugishima, Hisato Kigasawa, Masahiro Tsuchida, Yuichi AkiyamaAbstract:We retrospectively analyzed the clinical results of 81 patients with congenital genetic diseases who were treated with bone marrow transplantation (BMT) from unrelated donors identified through the Japan Marrow Donor Program.The patients were aged between 1 and 38 years (median, 4 years).Thirty-five patients underwent transplantation for metabolic disease (MD), ie, mucopolysaccharidosis (n = 25), adrenoleukodystrophy (n = 7), and others (n = 3). The remaining 46 patients had Wiskott-Aldrich Syndrome (n = 16), hemophagocytic Syndrome including the inherited type (n = 9), severe combined immunodeficiency (n = 6), hyper-IgM Syndrome (n = 4), Chediak-Higashi Syndrome (n = 3),Kostmann Syndrome (n = 3), and others (n = 5). Fiftytwo donor-patient pairs were fully matched at HLA-A, HLA-B, and HLA-DRB1 alleles. The remaining 24 patients received allele-mismatched grafts (20 matched at 5 of 6 loci and 4 matched at 4 of 6 loci). Engraftment occurred in 82.4% of the MD group and 90.7% of the other genetic disease (OGD) group; however, 14 patients (18.2%) experienced either early or late graft failure.The cumulative incidence of grade II to IV acute graft-versus-host disease (GVHD) was 35.5% _ 9.8% in the MD group and 47.3% _ 9.5% in the OGD group, and the rate of chronic GVHD was 20% in both groups. Forty-nine patients have survived for 3 to 96 months (median, 20 months).The probabilities of 5-year overall survival and event-free survival were 72.6% _ 11.5% and 65.3% _ 8.6%, respectively, for MD (n = 35) and 72.5% _ 7.3% and 63.6% _ 7.3% for OGD (n = 46). Although patient status before BMT and the occurrence of grade III to IV acute GVHD significantly affected outcome, unrelated BMT is a curative therapeutic option for children with congenital genetic diseases who have no HLA-matched family donors.
