RESUMO
Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the only curative therapy for the severe hematopoietic complications associated with Fanconi anemia (FA). In Germany, it is estimated that 10-15 transplants are performed annually for FA. However, because FA is a DNA repair disorder, standard conditioning regimens confer a high risk of excessive regimen-related toxicities and mortality, and reduced intensity regimens are linked with graft failure in some FA patients. Moreover, development of graft-versus-host disease is a major contributing factor for secondary solid tumors. The relative rarity of the disorder limits HSCT experience at any single center. Consensus meetings were convened to develop a national approach for HSCT in FA. This manuscript outlines current experience and knowledge about HSCT in FA and, based on this analysis, general recommendations reached at these meetings.
Assuntos
Anemia de Fanconi/terapia , Transplante de Células-Tronco Hematopoéticas , Criança , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Anemia de Fanconi/sangue , Alemanha , Sobrevivência de Enxerto , Doença Enxerto-Hospedeiro/prevenção & controle , Fidelidade a Diretrizes , Hospitais Especializados , Humanos , Terapia de Imunossupressão , Estudos Retrospectivos , Fatores de Risco , Condicionamento Pré-TransplanteRESUMO
X-linked inhibitor of apoptosis (XIAP) deficiency caused by mutations in BIRC4 was initially described in patients with X-linked lymphoproliferative syndrome (XLP) who had no mutations in SH2D1A. In the initial reports, EBV-associated hemophagocytic lymphohistiocytosis (HLH) was the predominant clinical phenotype. Among 25 symptomatic patients diagnosed with XIAP deficiency, we identified 17 patients who initially presented with manifestations other than HLH. These included Crohn-like bowel disease (n=6), severe infectious mononucleosis (n=4), isolated splenomegaly (n=3), uveitis (n=1), periodic fever (n=1), fistulating skin abscesses (n=1) and severe Giardia enteritis (n=1). Subsequent manifestations included celiac-like disease, antibody deficiency, splenomegaly and partial HLH. Screening by flow cytometry identified 14 of 17 patients in our cohort. However, neither genotype nor protein expression nor results from cell death studies were clearly associated with the clinical phenotype. Only mutation analysis can reliably identify affected patients. XIAP deficiency must be considered in a wide range of clinical presentations.
Assuntos
Síndromes de Imunodeficiência/genética , Linfo-Histiocitose Hemofagocítica/genética , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/deficiência , Adolescente , Adulto , Criança , Pré-Escolar , Genótipo , Humanos , Síndromes de Imunodeficiência/imunologia , Linfo-Histiocitose Hemofagocítica/imunologia , Masculino , Mutação , Células T Matadoras Naturais/imunologia , Fenótipo , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/genética , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/imunologia , Adulto JovemAssuntos
Anemia Refratária com Excesso de Blastos/terapia , Transplante de Células-Tronco Hematopoéticas , Hemofilia A/terapia , Síndromes Mielodisplásicas/terapia , Anemia Refratária com Excesso de Blastos/diagnóstico , Anemia Refratária com Excesso de Blastos/genética , Pré-Escolar , Éxons/genética , Fator VIII/genética , Seguimentos , Hemofilia A/sangue , Hemofilia A/diagnóstico , Hemofilia A/genética , Humanos , Masculino , Mutação de Sentido Incorreto/genética , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/genética , Tempo de Tromboplastina Parcial , Contagem de Plaquetas , Transfusão de Plaquetas , Resultado do TratamentoRESUMO
Myelodysplastic syndromes (MDS) are a heterogenous group of acquired hematopoietic stem cell disorders. Refractory cytopenia (RC) is the most common subtype of childhood MDS and hematopoietic stem cell transplantation (HSCT) is the only curative treatment. HSCT following a myeloablative preparative regimen is associated with a low probability of relapse and considerable transplant-related mortality. In the present European Working Groups of MDS pilot study, we investigated whether a reduced intensity conditioning regimen (RIC) is able to offer reduced toxicity without increased rates of graft failure or relapse. Nineteen children with RC were transplanted from an unrelated donor following RIC consisting of fludarabine, thiotepa and anti-thymocyte globulin. Three patients experienced graft failure. Neutrophil and platelet engraftment occurred at a median time of 23 and 30 days, respectively. Cumulative incidence of grade II-IV and grade III and IV acute graft-versus-host disease (GVHD) was 0.48 and 0.13, respectively; three patients developed extensive chronic GVHD. Although infections were the predominant complications, only one patient with extensive chronic GVHD died from infectious complications. Overall and event-free survival at 3 years were 0.84 and 0.74, respectively. In conclusion, our results were comparable to those of patients treated with myeloablative HSCT. Long-term follow-up is needed to demonstrate the expected reduction in long-term sequelae.
Assuntos
Anemia Refratária/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Condicionamento Pré-Transplante/métodos , Adolescente , Criança , Pré-Escolar , Feminino , Sobrevivência de Enxerto , Humanos , Lactente , Estimativa de Kaplan-Meier , Masculino , Projetos Piloto , Transplante HomólogoRESUMO
Allogeneic hematopoietic stem cell transplantation (HSCT) offers the potential to cure patients with an inherited bone marrow failure syndrome (IBMFS). However, the procedure involves the risk of treatment-related mortality and may be associated with significant early and late morbidity. For these reasons, the benefits should be carefully weighed against the risks. IBMFS are rare, whereas case reports and small series in the literature illustrate highly heterogeneous practices in terms of indications for HSCT, timing, stem cell source and conditioning regimens. A consensus meeting was therefore held in Vienna in September 2012 on behalf of the European Group for Blood and Marrow Transplantation to discuss HSCT in the setting of IBMFS. This report summarizes the recommendations from this expert panel, including indications for HSCT, timing, stem cell source and conditioning regimen.
Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Hemoglobinúria Paroxística/terapia , Condicionamento Pré-Transplante/métodos , Adolescente , Aloenxertos , Anemia Aplástica , Doenças da Medula Óssea , Transtornos da Insuficiência da Medula Óssea , Criança , Pré-Escolar , Feminino , Humanos , Lactente , MasculinoRESUMO
Glomerulopathy with predominant fibronectin deposits (GFD) is a newly recognized autosomal dominant renal disease that leads to albuminuria, microscopic hematuria, hypertension, renal tubular acidosis type IV, and end-stage renal disease in the second to fourth decade of life. Light microscopy documents extensive deposits in the subendothelial space, which on electron microscopy consist of non-oriented 12 x 125 nm fibers. Deposits are strongly immunoreactive for antibodies to fibronectin. We examined the hypothesis that a genetic defect in the gene for fibronectin is responsible for the disease. In a 197 member pedigree, 13 relatives developed end-stage renal failure from the disease. In 99 individuals haplotype analysis was performed using 6 microsatellite markers spanning a > 56 cM interval in chromosome region 2q34, where fibronectin, villin, and desmin map in close proximity. Haplotype analysis resulted in exclusion of the whole range of 78 cM covered by the markers examined. This result excludes fibronectin, villin, and desmin from being the causative genes for GFD in this large kindred.
Assuntos
Cromossomos Humanos Par 2 , Fibronectinas/genética , Nefropatias/genética , Glomérulos Renais/patologia , Proteínas de Ligação ao Cálcio/genética , Proteínas de Transporte/genética , Criança , Mapeamento Cromossômico , Desmina/genética , Família , Feminino , Fibronectinas/análise , Seguimentos , Marcadores Genéticos , Haplótipos , Humanos , Nefropatias/patologia , Falência Renal Crônica/etiologia , Falência Renal Crônica/genética , Falência Renal Crônica/patologia , Glomérulos Renais/diagnóstico por imagem , Masculino , Proteínas dos Microfilamentos/genética , Microscopia Eletrônica , Linhagem , UltrassonografiaRESUMO
Veno-occlusive disease (VOD) of the liver is a complication observed particularly in patients undergoing hematopoietic stem cell transplantation (HSCT). Defibrotide (DF) is a polydeoxyribonucleotide with aptameric activity on endothelium. We evaluated in a retrospective analysis the efficacy of DF in pediatric patients developing hepatic VOD after HSCT.A total of 45 patients between 0.2 and 20 years (median age: 8.2 years) with hepatic VOD were treated with DF: 22 patients (49%) met risk criteria for severe or progressive disease and 23 (51%) for moderately severe and mild disease. The median duration of DF treatment was 17 days. In all, 34 patients (76%) achieved complete response (CR) with a survival rate of 64% at day 100. CR rate in patients with severe disease was 50% with long-term survival of 36%. The average DF dose in the CR group was 45 mg/kg/day and in the no responder (NR) group 27 mg/kg/day. The use of additional drugs besides DF to treat VOD made no difference in the outcome compared to DF alone. The average interval from diagnosis to start of DF was 1 day in the CR and 5.5 days in NR group. In multivariate analysis, early intervention remained the only significant factor for a CR.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Hepatopatia Veno-Oclusiva/tratamento farmacológico , Inibidores da Agregação Plaquetária/administração & dosagem , Polidesoxirribonucleotídeos/administração & dosagem , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Hepatopatia Veno-Oclusiva/epidemiologia , Humanos , Lactente , Recém-Nascido , Masculino , Inibidores da Agregação Plaquetária/efeitos adversos , Polidesoxirribonucleotídeos/efeitos adversos , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Condicionamento Pré-Transplante , Resultado do TratamentoRESUMO
Based on the results from the AML-BFM 98 trial, hematopoietic SCT (HSCT) is recommended for children with AML in second CR only. Here, we retrospectively analyze interphase data of children who underwent HSCT after myeloablative conditioning with BU, CY, and melphalan (BuCyMel) for AML in second remission (CR2) between 1998 and 2009. Out of 152 children, transplant data were available on 109 individuals. Sixty out of 109 children (55%) received BuCyMel. Median age at HSCT was 12.2 years (range 3.0; 18.3). GVHD prophylaxis mostly consisted of CsA and short term MTX with or without antithymocyte globulin. Matched-sibling donors were used for 6/60 analyzed recipients, the remainder either received grafts from matched unrelated (30/60) or mismatched donors. OS after 5 years was 62% (s.e. 6%), relapse incidence 35% (18/60 children) and treatment-related mortality accounted for 12% (7/60) of fatal events. In conclusion, even taking into account possible selection bias in this retrospective analysis, HSCT in CR2 using BuCyMel resulted in a respectable OS. Based on this data the prospective, controlled and centrally monitored AML SCT-BFM 2007 trial has started to recruit patients in January 2010 aiming to generate valid outcome data for further strategy decisions.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/cirurgia , Condicionamento Pré-Transplante/métodos , Adolescente , Bussulfano/administração & dosagem , Criança , Pré-Escolar , Estudos de Coortes , Terapia Combinada , Ciclofosfamida , Feminino , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Doença Enxerto-Hospedeiro/terapia , Humanos , Masculino , Melfalan/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos RetrospectivosRESUMO
We report on the outcome of children with advanced primary myelodysplastic syndrome (MDS) transplanted from an HLA-matched sibling (MSD) or an unrelated donor (UD) following a preparative regimen with busulfan, cyclophosphamide and melphalan. Ninety-seven patients with refractory anemia with excess blasts (RAEB, n=53), RAEB in transformation (RAEB-T, n=29) and myelodysplasia-related acute myeloid leukemia (MDR-AML, n=15) enrolled in the European Working Group of MDS in Childhood (EWOG-MDS) 98 study and given hematopoietic stem cell transplantation (HSCT) were analyzed. Median age at HSCT was 11.1 years (range 1.4-19.0). Thirty-nine children were transplanted from an MSD, whereas 58 were given the allograft from a UD (n=57) or alternative family donor (n=1). Stem cell source was bone marrow (n=69) or peripheral blood (n=28). With a median follow-up of 3.9 years (range 0.1-10.9), the 5-year probability of overall survival is 63%, while the 5-year cumulative incidence of transplantation-related mortality (TRM) and relapse is 21% each. Age at HSCT greater than 12 years, interval between diagnosis and HSCT longer than 4 months, and occurrence of acute or extensive chronic graft-versus-host disease were associated with increased TRM. The risk of relapse increased with more advanced disease. This study indicates that HSCT following a myeloablative preparative regimen offers a high probability of survival for children with advanced MDS.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Síndromes Mielodisplásicas/cirurgia , Adolescente , Adulto , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro/mortalidade , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Lactente , Masculino , Síndromes Mielodisplásicas/mortalidade , RecidivaAssuntos
Sangue Fetal/transplante , Leucemia Mielomonocítica Juvenil/terapia , Criança , Humanos , Masculino , RecidivaRESUMO
Treatment of NRK 536 fibroblasts with EGF and transforming growth factor type beta (TGF-beta) is known to lead to the reversible induction of the transformed phenotype in a large percentage of cells. Maintenance of the transformed state is dependent on the continuous presence of the cytokines. Here we show that treatment of these cells with TGF-beta alone leads to the formation of a small percentage of colonies, the majority of which stably retain the transformed phenotype after removal of the cytokine. Colony induction is dependent on the concentration of TGF-beta originally present. Stably transformed cells grow in soft agar without further addition of exogenous TGF-beta, and exhibit criss-cross morphology in monolayer culture and a diffuse actin pattern. Transformation of NRK 536 cells can be demonstrated only for individualized cells treated with TGF-beta in soft agar, as treatment in monolayer leads to the induction of apoptosis in newly transformed cells by neighboring normal cells. Transformation of NRK 536 fibroblasts by TGF-beta is not due to the induction of point mutations by TGF-beta.
Assuntos
Fibroblastos/efeitos dos fármacos , Transformação Genética/efeitos dos fármacos , Fator de Crescimento Transformador beta/farmacologia , Ágar , Animais , Células Cultivadas , Fator de Crescimento Epidérmico/farmacologia , Fibroblastos/citologia , Fibroblastos/fisiologia , Fenótipo , Mutação Puntual , Ratos , Células-Tronco/efeitos dos fármacosRESUMO
Bartter syndrome, an autosomal recessive renal tubular disorder, is associated with hypokalemic metabolic alkalosis with high renin and aldosterone plasma concentrations with low or normal blood pressure and renal salt loss. Two genes, the gene encoding the furosemide-sensitive apical Na-K-2Cl cotransporter (NKCC2) and the gene encoding the luminal inwardly-rectifying potassium channel Kir 1.1 (ROMK), have been reported to cause the neonatal subtype of Bartter syndrome. In a patient with neonatal Bartter syndrome, we report two novel mutations resulting in amino acid exchanges Ala156Val and Leu220Phe in the gene for Kir 1.1 that have been identified by single-strand conformation polymorphism analysis and subsequent direct sequencing. Both mutations occur in functional relevant domains of the channel protein and are therefore highly suggestive of altering channel properties.
Assuntos
Síndrome de Bartter/genética , Canais de Potássio/genética , Canais de Potássio/metabolismo , Adulto , Substituição de Aminoácidos , DNA/análise , Feminino , Humanos , Recém-Nascido , Mutação , Polimorfismo Conformacional de Fita Simples , Gravidez , Transcrição GênicaRESUMO
Medullary cystic kidney disease (MCD) is characterized by multiple renal cysts at the corticomedullary boundary area, by autosomal dominant inheritance, and by onset of chronic renal failure in the third decade of life. We report on a family with three affected individuals of both sexes in two generations presenting with end-stage renal failure at age 22-31 years. Primarily diagnoses considered included unclassified hereditary nephropathy and autosomal dominant polycystic kidney disease. Careful evaluation of all findings, initiated after investigation of renal morphology with CT, revealed features characteristic for MCD and led to the final diagnosis of MCD. We conclude that MCD is an important differential diagnosis for polycystic kidney disease in young adults with end-stage renal failure. Establishing the correct diagnosis has considerable impact for genetic counselling.
Assuntos
Doenças Renais Císticas/diagnóstico , Medula Renal , Adulto , Diagnóstico Diferencial , Feminino , Humanos , Doenças Renais Císticas/genética , Doenças Renais Císticas/patologia , Medula Renal/patologia , Masculino , Pessoa de Meia-Idade , Doenças Renais Policísticas/diagnósticoAssuntos
Subunidade alfa 2 de Fator de Ligação ao Core/genética , Mutação em Linhagem Germinativa , Heterozigoto , Leucemia Mieloide Aguda/complicações , Modelos Biológicos , Síndromes Mielodisplásicas/genética , Adolescente , Feminino , Humanos , Cariotipagem , Masculino , Síndromes Mielodisplásicas/complicações , LinhagemRESUMO
Familial juvenile nephronophthisis (NPH) is an autosomal recessive cystic disease of the kidney that leads to end-stage renal failure in adolescence. NPH is the most common genetic cause of end-stage renal disease in children. A gene locus for nephronophthisis (NPH1) has been mapped by linkage analysis to chromosome 2q13. We report here the construction of a complete YAC contig in the minimum genetic region for NPH1 by STS content mapping using clones of the CEPH YAC libraries. A physical map of maximum distances between 32 STS markers was constructed, thereby defining the order of a total of 27 STS markers. Since D2S340 and D2S121 have previously been identified as flanking markers to the NPH1 gene, the new contig defines on a physical map the NPH1 minimum genetic region to a 6.4-Mb interval. As a novel assignment, expressed genes, some of which may be candidates for the disease, were localized to the NPH1 region. In addition, the known interstitial telomeric repeat on chromosome 2 was physically mapped to this region. This contig assembly provides the basis for closer definition of the NPH1 critical region through identification of more narrow flanking markers and for the construction of a transcriptional map of the region towards isolation of the NPH1 gene.
Assuntos
Cromossomos Artificiais de Levedura , Cromossomos Humanos Par 2 , Doenças Renais Císticas/genética , Sequência de Bases , Mapeamento Cromossômico , Primers do DNA , Marcadores Genéticos , Humanos , Dados de Sequência Molecular , Sitios de Sequências RotuladasRESUMO
Joubert syndrome type B (JSB) is a developmental disorder of the nephronophthisis (NPH) complex with multiple organ involvement, including NPH, coloboma of the eye, aplasia of the cerebellar vermis, and the facultative symptoms of psychomotor retardation, polydactyly, and neonatal tachypnea. In isolated autosomal recessive NPH type 1 (NPH1), homozygous deletions have been described as causative in more than 80% of patients. Since different combinations of the extrarenal symptoms with NPH occur in JSB, a contiguous gene deletion syndrome in the NPH1 genetic region would seem a highly likely cause for JSB. We therefore examined 11 families with JSB for the presence of extended deletions at the NPH1 locus. Genomic DNA was examined using four consecutive polymerase chain reaction (PCR) markers that are deleted in NPH1 and three PCR makers flanking the NPH1 deletion. In all seven markers examined, there was no homozygous deletion detected in any of the 11 JSB families studied. Since these markers saturate the NPH1 deletion region at high density, this finding excludes the presence of large homozygous deletions of the NPH1 region in these JSB families, making it unlikely that deletions of the NPH1 region are a primary cause for JSB.
Assuntos
Doenças Cerebelares/genética , Cerebelo/anormalidades , Deleção de Genes , Criança , DNA/análise , Marcadores Genéticos , Homozigoto , Humanos , Reação em Cadeia da Polimerase , SíndromeRESUMO
Familial juvenile nephronophthisis (NPH), an autosomal recessive cystic disease of the kidney, is the most common genetic cause of end-stage renal disease (ESRD) in the first two decades of life. A gene locus for nephronophthisis type 1 (NPH1) has been mapped by linkage analysis to chromosome 2q13. We performed a haplotype analysis in 16 NPH families with at least two affected patients with the typical history, clinical signs and histology of NPH using microsatellite markers of the NPH1 genetic region. By demonstration of a recombinant event marker D2S1893 was identified as a novel centromeric flanking marker to the NPH1 critical genetic region. Absence of linkage to the NPH1 locus in six NPH families confirmed the existence of at least one additional gene locus for NPH. Linkage to the NPH1 locus was demonstrated in 10 families. In 8 of these families a homozygous deletion was identified. These data permit for the first time the study of the development of renal failure in a subset of NPH1 families, which is most likely homogeneous with regard to the responsible gene locus. We present a statistical description of serial serum creatinine measurements in NPH1. Analysis of renal death revealed a median of 13.1 years. Age-dependent quartiles were generated for serum creatinine. In summary, the new marker provides a diagnostic tool to aid in the diagnosis of NPH, while the progression charts offer a standard for an assessment of the rate of progression to ESRD for patients with NPH1 to be used in future therapeutic trials and for a prediction of the individual course of the disease.
Assuntos
Doenças Renais Císticas/genética , Falência Renal Crônica/genética , DNA Satélite/análise , Progressão da Doença , Europa (Continente) , Feminino , Marcadores Genéticos , Genótipo , Haplótipos , Humanos , Doenças Renais Císticas/mortalidade , Falência Renal Crônica/mortalidade , Masculino , Linhagem , Análise de SobrevidaRESUMO
X-linked lymphoproliferative disease (XLP) is a primary immunodeficiency, which most often manifests itself after Epstein-Barr virus (EBV) infection. The main clinical phenotypes include fulminant or fatal infectious mononucleosis, dysgammaglobulinaemia and malignant lymphoma. We have recently cloned the SH2D1A gene, which has been shown to be mutated in approximately 70% of XLP patients. Now we report five novel SH2D1A mutations in patients from five unrelated XLP families. No mutations were found in another three XLP families. In three boys with early onset non-Hodgkin lymphoma (NHL) from two unrelated families a deletion of SH2D1A exon 1 and a splice site mutation were found, respectively. These patients did not show any laboratory or clinical signs of a previous EBV infection. A fourth EBV-uninfected and unrelated boy with a stop mutation in the SH2D1A gene shows only signs of dysgammaglobulinaemia. Development of dysgamma-globulinaemia and lymphoma without evidence of prior EBV infection in four of our patients suggests that EBV is unrelated to these phenotypes, in contrast to fulminant or fatal infectious mononucleosis. The role of SH2D1A as a putative tumour suppressor gene remains to be investigated.