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1.
Haematologica ; 104(10): 1974-1983, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30948484

RESUMO

Quality of response to immunosuppressive therapy and long-term outcomes for pediatric severe aplastic anemia remain incompletely characterized. Contemporary evidence to inform treatment of relapsed or refractory severe aplastic anemia for pediatric patients is also limited. The clinical features and outcomes for 314 children treated from 2002 to 2014 with immunosuppressive therapy for acquired severe aplastic anemia were analyzed retrospectively from 25 institutions in the North American Pediatric Aplastic Anemia Consortium. The majority of subjects (n=264) received horse anti-thymocyte globulin (hATG) plus cyclosporine (CyA) with a median 61 months follow up. Following hATG/CyA, 71.2% (95%CI: 65.3,76.6) achieved an objective response. In contrast to adult studies, the quality of response achieved in pediatric patients was high, with 59.8% (95%CI: 53.7,65.8) complete response and 68.2% (95%CI: 62.2,73.8) achieving at least a very good partial response with a platelet count ≥50×109L. At five years post-hATG/CyA, overall survival was 93% (95%CI: 89,96), but event-free survival without subsequent treatment was only 64% (95%CI: 57,69) without a plateau. Twelve of 171 evaluable patients (7%) acquired clonal abnormalities after diagnosis after a median 25.2 months (range: 4.3-71 months) post treatment. Myelodysplastic syndrome or leukemia developed in 6 of 314 (1.9%). For relapsed/refractory disease, treatment with a hematopoietic stem cell transplant had a superior event-free survival compared to second immunosuppressive therapy treatment in a multivariate analysis (HR=0.19, 95%CI: 0.08,0.47; P=0.0003). This study highlights the need for improved therapies to achieve sustained high-quality remission for children with severe aplastic anemia.

3.
Am J Hum Genet ; 2018 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-30503522

RESUMO

Diamond-Blackfan anemia (DBA) is a rare bone marrow failure disorder that affects 7 out of 1,000,000 live births and has been associated with mutations in components of the ribosome. In order to characterize the genetic landscape of this heterogeneous disorder, we recruited a cohort of 472 individuals with a clinical diagnosis of DBA and performed whole-exome sequencing (WES). We identified relevant rare and predicted damaging mutations for 78% of individuals. The majority of mutations were singletons, absent from population databases, predicted to cause loss of function, and located in 1 of 19 previously reported ribosomal protein (RP)-encoding genes. Using exon coverage estimates, we identified and validated 31 deletions in RP genes. We also observed an enrichment for extended splice site mutations and validated their diverse effects using RNA sequencing in cell lines obtained from individuals with DBA. Leveraging the size of our cohort, we observed robust genotype-phenotype associations with congenital abnormalities and treatment outcomes. We further identified rare mutations in seven previously unreported RP genes that may cause DBA, as well as several distinct disorders that appear to phenocopy DBA, including nine individuals with biallelic CECR1 mutations that result in deficiency of ADA2. However, no new genes were identified at exome-wide significance, suggesting that there are no unidentified genes containing mutations readily identified by WES that explain >5% of DBA-affected case subjects. Overall, this report should inform not only clinical practice for DBA-affected individuals, but also the design and analysis of rare variant studies for heterogeneous Mendelian disorders.

6.
Hum Mutat ; 39(8): 1102-1111, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29766597

RESUMO

Diamond-Blackfan anemia (DBA) is a rare genetic hypoplasia of erythroid progenitors characterized by mild to severe anemia and associated with congenital malformations. Clinical manifestations in DBA patients are quite variable and genetic testing has become a critical factor in establishing a diagnosis of DBA. The majority of DBA cases are due to heterozygous loss-of-function mutations in ribosomal protein (RP) genes. Causative mutations are fairly straightforward to identify in the case of large deletions and frameshift and nonsense mutations found early in a protein coding sequence, but diagnosis becomes more challenging in the case of missense mutations and small in-frame indels. Our group recently characterized the phenotype of lymphoblastoid cell lines established from DBA patients with pathogenic lesions in RPS19 and observed that defective pre-rRNA processing, a hallmark of the disease, was rescued by lentiviral vectors expressing wild-type RPS19. Here, we use this complementation assay to determine whether RPS19 variants of unknown significance are capable of rescuing pre-rRNA processing defects in these lymphoblastoid cells as a means of assessing the effects of these sequence changes on the function of the RPS19 protein. This approach will be useful in differentiating pathogenic mutations from benign polymorphisms in identifying causative genes in DBA patients.

7.
Blood ; 131(4): 408-416, 2018 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-29092827

RESUMO

Severe congenital neutropenia (SCN) and Shwachman-Diamond syndrome (SDS) are congenital neutropenia syndromes with a high rate of leukemic transformation. Hematopoietic stressors may contribute to leukemic transformation by increasing the mutation rate in hematopoietic stem/progenitor cells (HSPCs) and/or by promoting clonal hematopoiesis. We sequenced the exome of individual hematopoietic colonies derived from 13 patients with congenital neutropenia to measure total mutation burden and performed error-corrected sequencing on a panel of 46 genes on 80 patients with congenital neutropenia to assess for clonal hematopoiesis. An average of 3.6 ± 1.2 somatic mutations per exome was identified in HSPCs from patients with SCN compared with 3.9 ± 0.4 for healthy controls (P = NS). Clonal hematopoiesis due to mutations in TP53 was present in 48% (13/27) of patients with SDS but was not seen in healthy controls (0/17, P < .001) or patients with SCN (0/40, P < .001). Our SDS cohort was young (median age 6.3 years), and many of the patients had multiple TP53 mutations. Conversely, clonal hematopoiesis due to mutations of CSF3R was present in patients with SCN but was not detected in healthy controls or patients with SDS. These data show that hematopoietic stress, including granulocyte colony-stimulating factor, do not increase the mutation burden in HSPCs in congenital neutropenia. Rather, distinct hematopoietic stressors result in the selective expansion of HSPCs carrying specific gene mutations. In particular, in SDS there is enormous selective pressure to expand TP53-mutated HSPCs, suggesting that acquisition of TP53 mutations is an early, likely initiating event, in the transformation to myelodysplastic syndrome/acute myeloid leukemia in patients with SDS.

8.
Mol Genet Genomic Med ; 6(1): 77-91, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29193904

RESUMO

BACKGROUND: Fanconi anemia (FA) is a rare disorder characterized by congenital malformations, progressive bone marrow failure, and predisposition to cancer. Patients harboring X-linked FANCB pathogenic variants usually present with severe congenital malformations resembling VACTERL syndrome with hydrocephalus. METHODS: We employed the diepoxybutane (DEB) test for FA diagnosis, arrayCGH for detection of duplication, targeted capture and next-gen sequencing for defining the duplication breakpoint, PacBio sequencing of full-length FANCB aberrant transcript, FANCD2 ubiquitination and foci formation assays for the evaluation of FANCB protein function by viral transduction of FANCB-null cells with lentiviral FANCB WT and mutant expression constructs, and droplet digital PCR for quantitation of the duplication in the genomic DNA and cDNA. RESULTS: We describe here an FA-B patient with a mild phenotype. The DEB diagnostic test for FA revealed somatic mosaicism. We identified a 9154 bp intragenic duplication in FANCB, covering the first coding exon 3 and the flanking regions. A four bp homology (GTAG) present at both ends of the breakpoint is consistent with microhomology-mediated duplication mechanism. The duplicated allele gives rise to an aberrant transcript containing exon 3 duplication, predicted to introduce a stop codon in FANCB protein (p.A319*). Duplication levels in the peripheral blood DNA declined from 93% to 7.9% in the span of eleven years. Moreover, the patient fibroblasts have shown 8% of wild-type (WT) allele and his carrier mother showed higher than expected levels of WT allele (79% vs. 50%) in peripheral blood, suggesting that the duplication was highly unstable. CONCLUSION: Unlike sequence point variants, intragenic duplications are difficult to precisely define, accurately quantify, and may be very unstable, challenging the proper diagnosis. The reversion of genomic duplication to the WT allele results in somatic mosaicism and may explain the relatively milder phenotype displayed by the FA-B patient described here.


Assuntos
Proteínas de Grupos de Complementação da Anemia de Fanconi/genética , Anemia de Fanconi/genética , Adolescente , Alelos , Sequência de Bases/genética , Células Sanguíneas/metabolismo , Éxons/genética , Proteínas de Grupos de Complementação da Anemia de Fanconi/metabolismo , Fibroblastos , Duplicação Gênica/genética , Genes Ligados ao Cromossomo X/genética , Genótipo , Humanos , Masculino , Mosaicismo , Fenótipo
9.
Hematology Am Soc Hematol Educ Program ; 2017(1): 716-719, 2017 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-29222326

RESUMO

A mutation in the gene encoding the small subunit-associated ribosomal protein RPS19, leading to RPS19 haploinsufficiency, is one of the ribosomal protein gene defects responsible for the rare inherited bone marrow failure syndrome Diamond Blackfan anemia (DBA). Additional inherited and acquired defects in ribosomal proteins (RPs) continue to be identified and are the basis for a new class of diseases called the ribosomopathies. Acquired RPS14 haploinsufficiency has been found to be causative of the bone marrow failure found in 5q- myelodysplastic syndromes. Both under- and overexpression of RPs have also been implicated in several malignancies. This review will describe the somatic ribosomopathies that have been found to be associated with a variety of solid tumors as well as leukemia and will review cancers in which over- or underexpression of these proteins seem to be associated with outcome.


Assuntos
Anemia de Diamond-Blackfan/genética , Haploinsuficiência , Leucemia/genética , Mutação , Síndromes Mielodisplásicas/genética , Ribossomos/genética , Anemia de Diamond-Blackfan/metabolismo , Anemia de Diamond-Blackfan/patologia , Humanos , Leucemia/metabolismo , Leucemia/patologia , Síndromes Mielodisplásicas/metabolismo , Síndromes Mielodisplásicas/patologia , Proteínas Ribossômicas/genética , Proteínas Ribossômicas/metabolismo , Ribossomos/metabolismo , Ribossomos/patologia
10.
Biol Blood Marrow Transplant ; 23(9): 1422-1428, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28533057

RESUMO

Patients with inherited bone marrow failure syndromes (IBMFS), such as Fanconi anemia (FA), dyskeratosis congenita (DC), or Diamond Blackfan anemia (DBA), can have hematologic manifestations cured through hematopoietic cell transplantation (HCT). Subsequent late effects seen in these patients arise from a combination of the underlying disease, the pre-HCT therapy, and the HCT process. During the international consensus conference sponsored by the Pediatric Blood and Marrow Transplant Consortium on late effects screening and recommendations following allogeneic hematopoietic cell transplantation for immune deficiency and nonmalignant hematologic diseases held in Minneapolis, Minnesota in May 2016, a half-day session was focused specifically on the unmet needs for these patients with IBMFS. This multidisciplinary group of experts in rare diseases and transplantation late effects has already published on the state of the science in this area, along with discussion of an agenda for future research. This companion article outlines consensus disease-specific long-term follow-up screening guidelines for patients with IMBFS.


Assuntos
Anemia Aplástica/diagnóstico , Anemia de Diamond-Blackfan/diagnóstico , Doenças da Medula Óssea/diagnóstico , Disceratose Congênita/diagnóstico , Anemia de Fanconi/diagnóstico , Transplante de Células-Tronco Hematopoéticas , Hemoglobinúria Paroxística/diagnóstico , Anemia Aplástica/imunologia , Anemia Aplástica/patologia , Anemia Aplástica/terapia , Anemia de Diamond-Blackfan/imunologia , Anemia de Diamond-Blackfan/mortalidade , Anemia de Diamond-Blackfan/terapia , Doenças da Medula Óssea/imunologia , Doenças da Medula Óssea/patologia , Doenças da Medula Óssea/terapia , Criança , Consenso , Conferências de Consenso como Assunto , Disceratose Congênita/imunologia , Disceratose Congênita/mortalidade , Disceratose Congênita/terapia , Anemia de Fanconi/imunologia , Anemia de Fanconi/mortalidade , Anemia de Fanconi/terapia , Hemoglobinúria Paroxística/imunologia , Hemoglobinúria Paroxística/patologia , Hemoglobinúria Paroxística/terapia , Humanos , Cooperação Internacional , Análise de Sobrevida , Transplante Homólogo
11.
Blood ; 129(23): 3111-3120, 2017 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-28377399

RESUMO

Diamond-Blackfan anemia (DBA) is a congenital bone marrow failure syndrome characterized by erythroid hypoplasia, usually without perturbation of other hematopoietic lineages. Approximately 65% of DBA patients with autosomal dominant inheritance have heterozygous mutations or deletions in ribosomal protein (RP) genes while <1% of patients with X-linked inheritance have been identified with mutations in the transcription factor GATA1 Erythroid cells from patients with DBA have not been well characterized, and the mechanisms underlying the erythroid specific effects of either RP or GATA1 associated DBA remain unclear. We have developed an ex vivo culture system to expand peripheral blood CD34+ progenitor cells from patients with DBA and differentiate them into erythroid cells. Cells from patients with RP or GATA1 mutations showed decreased proliferation and delayed erythroid differentiation in comparison with controls. RNA transcript analyses of erythroid cells from controls and patients with RP or GATA1 mutations showed distinctive differences, with upregulation of heme biosynthesis genes prominently in RP-mediated DBA and failure to upregulate components of the translational apparatus in GATA1-mediated DBA. Our data show that dysregulation of translation is a common feature of DBA caused by both RP and GATA1 mutations. This trial was registered at www.clinicaltrials.gov as #NCT00106015.


Assuntos
Anemia de Diamond-Blackfan/genética , Adolescente , Adulto , Anemia de Diamond-Blackfan/sangue , Anemia de Diamond-Blackfan/metabolismo , Estudos de Casos e Controles , Diferenciação Celular/genética , Proliferação de Células/genética , Células Cultivadas , Criança , Pré-Escolar , Células Eritroides/metabolismo , Células Eritroides/patologia , Eritropoese/genética , Feminino , Fator de Transcrição GATA1/genética , Genes Dominantes , Genes Ligados ao Cromossomo X , Humanos , Masculino , Modelos Genéticos , Mutação , Proteínas Ribossômicas/genética , Transcriptoma , Adulto Jovem
12.
Biol Blood Marrow Transplant ; 23(5): 726-735, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28115275

RESUMO

Fanconi anemia (FA), dyskeratosis congenita (DC), and Diamond Blackfan anemia (DBA) are 3 of the most common inherited bone marrow failure syndromes (IBMFS), in which the hematologic manifestations can be cured with hematopoietic cell transplantation (HCT). Later in life, these patients face a variety of medical conditions, which may be a manifestation of underlying disease or due to pre-HCT therapy, the HCT, or a combination of all these elements. Very limited long-term follow-up data exist in these populations, with FA the only IBMFS that has specific published data. During the international consensus conference sponsored by the Pediatric Blood and Marrow Transplant Consortium entitled "Late Effects Screening and Recommendations following Allogeneic Hematopoietic Cell Transplant (HCT) for Immune Deficiency and Nonmalignant Hematologic Disease" held in Minneapolis, Minnesota in May of 2016, a half-day session was focused specifically on the unmet needs for these patients with IBMFS. A multidisciplinary group of experts discussed what is currently known, outlined an agenda for future research, and laid out long-term follow-up guidelines based on a combination of evidence in the literature as well as expert opinion. This article addresses the state of science in that area as well as consensus regarding the agenda for future research, with specific screening guidelines to follow in the next article from this group.


Assuntos
Anemia Aplástica/terapia , Doenças da Medula Óssea/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Hemoglobinúria Paroxística/terapia , Efeitos Adversos de Longa Duração , Anemia Aplástica/complicações , Anemia de Diamond-Blackfan/complicações , Anemia de Diamond-Blackfan/terapia , Pesquisa Biomédica/métodos , Pesquisa Biomédica/tendências , Doenças da Medula Óssea/complicações , Criança , Disceratose Congênita/complicações , Disceratose Congênita/terapia , Anemia de Fanconi/complicações , Anemia de Fanconi/terapia , Previsões , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Hemoglobinúria Paroxística/complicações , Humanos , Guias de Prática Clínica como Assunto/normas
13.
Pediatr Blood Cancer ; 63(2): 306-12, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26496000

RESUMO

BACKGROUND: Diamond-Blackfan anemia (DBA) is a rare inherited bone marrow failure syndrome. The mainstays of treatment involve chronic red cell transfusions, long-term glucocorticoid therapy, and stem cell transplantation. Systematic data concerning endocrine function in DBA are limited. We studied patients in the DBA Registry (DBAR) of North America to assess the prevalence of various endocrinopathies. PROCEDURE: In a pilot study, retrospective data were collected for 12 patients with DBA. Subsequently, patients with DBA aged 1-39 years were recruited prospectively. Combined, 57 patients were studied; 38 chronically transfused, 12 glucocorticoid-dependent, and seven in remission. Data were collected on anthropometric measurements, systematic screening of pituitary, thyroid, parathyroid, adrenal, pancreatic, and gonadal function, and ferritin levels. Descriptive statistics were tabulated and group differences were assessed. RESULTS: Fifty-three percent of patients had ≥ 1 endocrine disorder, including adrenal insufficiency (32%), hypogonadism (29%), hypothyroidism (14%), growth hormone dysfunction (7%), diabetes mellitus (2%), and/or diabetes insipidus (2%). Ten of the 33 patients with available heights had height standard deviation less than -2. Low 25-hydroxy vitamin D (25(OH)D) levels were present in 50%. A small proportion also had osteopenia, osteoporosis, or hypercalciuria. Most with adrenal insufficiency were glucocorticoid dependent; other endocrinopathies were more common in chronically transfused patients. CONCLUSIONS: Endocrine dysfunction is common in DBA, as early as the teenage years. Although prevalence is highest in transfused patients, patients taking glucocorticoids or in remission also have endocrine dysfunction. Longitudinal studies are needed to better understand the etiology and true prevalence of these disorders.


Assuntos
Anemia de Diamond-Blackfan/complicações , Doenças do Sistema Endócrino/epidemiologia , Doenças do Sistema Endócrino/etiologia , Adolescente , Adulto , Anemia de Diamond-Blackfan/terapia , Transfusão de Sangue , Criança , Pré-Escolar , Feminino , Glucocorticoides/uso terapêutico , Humanos , Lactente , Masculino , Projetos Piloto , Prevalência , Sistema de Registros , Estudos Retrospectivos , Adulto Jovem
14.
Blood ; 127(11): 1481-92, 2016 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-26679864

RESUMO

Current therapeutic strategies for sickle cell anemia are aimed at reactivating fetal hemoglobin. Pomalidomide, a third-generation immunomodulatory drug, was proposed to induce fetal hemoglobin production by an unknown mechanism. Here, we report that pomalidomide induced a fetal-like erythroid differentiation program, leading to a reversion of γ-globin silencing in adult human erythroblasts. Pomalidomide acted early by transiently delaying erythropoiesis at the burst-forming unit-erythroid/colony-forming unit-erythroid transition, but without affecting terminal differentiation. Further, the transcription networks involved in γ-globin repression were selectively and differentially affected by pomalidomide including BCL11A, SOX6, IKZF1, KLF1, and LSD1. IKAROS (IKZF1), a known target of pomalidomide, was degraded by the proteasome, but was not the key effector of this program, because genetic ablation of IKZF1 did not phenocopy pomalidomide treatment. Notably, the pomalidomide-induced reprogramming was conserved in hematopoietic progenitors from individuals with sickle cell anemia. Moreover, multiple myeloma patients treated with pomalidomide demonstrated increased in vivo γ-globin levels in their erythrocytes. Together, these data reveal the molecular mechanisms by which pomalidomide reactivates fetal hemoglobin, reinforcing its potential as a treatment for patients with ß-hemoglobinopathies.


Assuntos
Células-Tronco Hematopoéticas/efeitos dos fármacos , Talidomida/análogos & derivados , Transcrição Genética/efeitos dos fármacos , gama-Globinas/genética , Adulto , Anemia Falciforme/sangue , Anemia Falciforme/genética , Proteínas de Transporte/sangue , Células Precursoras Eritroides/citologia , Células Precursoras Eritroides/efeitos dos fármacos , Células Precursoras Eritroides/metabolismo , Eritropoese/efeitos dos fármacos , Hemoglobina Fetal/biossíntese , Regulação da Expressão Gênica no Desenvolvimento , Vetores Genéticos/genética , Células-Tronco Hematopoéticas/metabolismo , Histona Desmetilases/sangue , Humanos , Fator de Transcrição Ikaros/sangue , Fator de Transcrição Ikaros/efeitos dos fármacos , Fatores de Transcrição Kruppel-Like/sangue , Lentivirus/genética , Mieloma Múltiplo/sangue , Mieloma Múltiplo/genética , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Proteínas Nucleares/sangue , Complexo de Endopeptidases do Proteassoma/metabolismo , Interferência de RNA , RNA Interferente Pequeno/genética , Fatores de Transcrição SOXD/sangue , Talidomida/farmacologia , Globinas beta/biossíntese , Globinas beta/genética , gama-Globinas/biossíntese
16.
Am J Hematol ; 89(10): 985-91, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25042156

RESUMO

Diamond Blackfan anemia (DBA), a syndrome primarily characterized by anemia and physical abnormalities, is one among a group of related inherited bone marrow failure syndromes (IBMFS) which share overlapping clinical features. Heterozygous mutations or single-copy deletions have been identified in 12 ribosomal protein genes in approximately 60% of DBA cases, with the genetic etiology unexplained in most remaining patients. Unlike many IBMFS, for which functional screening assays complement clinical and genetic findings, suspected DBA in the absence of typical alterations of the known genes must frequently be diagnosed after exclusion of other IBMFS. We report here a novel deletion in a child that presented such a diagnostic challenge and prompted development of a novel functional assay that can assist in the diagnosis of a significant fraction of patients with DBA. The ribosomal proteins affected in DBA are required for pre-rRNA processing, a process which can be interrogated to monitor steps in the maturation of 40S and 60S ribosomal subunits. In contrast to prior methods used to assess pre-rRNA processing, the assay reported here, based on capillary electrophoresis measurement of the maturation of rRNA in pre-60S ribosomal subunits, would be readily amenable to use in diagnostic laboratories. In addition to utility as a diagnostic tool, we applied this technique to gene discovery in DBA, resulting in the identification of RPL31 as a novel DBA gene.


Assuntos
Precursores de RNA , Processamento Pós-Transcricional do RNA/genética , RNA Ribossômico , Proteínas Ribossômicas , Anemia de Diamond-Blackfan/genética , Anemia de Diamond-Blackfan/metabolismo , Feminino , Humanos , Lactente , Células K562 , Precursores de RNA/genética , Precursores de RNA/metabolismo , RNA Ribossômico/metabolismo , Proteínas Ribossômicas/genética , Proteínas Ribossômicas/metabolismo , Subunidades Ribossômicas Maiores de Eucariotos/genética , Subunidades Ribossômicas Maiores de Eucariotos/metabolismo , Subunidades Ribossômicas Menores de Eucariotos/genética , Subunidades Ribossômicas Menores de Eucariotos/metabolismo
17.
Expert Rev Hematol ; 7(3): 359-72, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24665981

RESUMO

Diamond Blackfan anemia (DBA) is an inherited bone marrow failure syndrome. As with the other rare inherited bone marrow failure syndromes, the study of these disorders provides important insights into basic biology and, in the case of DBA, ribosome biology; the disruption of which characterizes the disorder. Thus DBA serves as a paradigm for translational medicine in which the efforts of clinicians to manage DBA have informed laboratory scientists who, in turn, have stimulated clinical researchers to utilize scientific discovery to provide improved care. In this review we describe the clinical syndrome Diamond Blackfan anemia and, in particular, we demonstrate how the study of DBA has allowed scientific inquiry to create opportunities for progress in its understanding and treatment.


Assuntos
Anemia de Diamond-Blackfan/diagnóstico , Anemia de Diamond-Blackfan/terapia , Animais , Humanos , Pesquisa Médica Translacional
18.
Pediatr Blood Cancer ; 61(5): 869-74, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24285674

RESUMO

BACKGROUND: Randomized clinical trials in pediatric aplastic anemia (AA) are rare and data to guide standards of care are scarce. PROCEDURE: Eighteen pediatric institutions formed the North American Pediatric Aplastic Anemia Consortium to foster collaborative studies in AA. The initial goal of NAPAAC was to survey the diagnostic studies and therapies utilized in AA. RESULTS: Our survey indicates considerable variability among institutions in the diagnosis and treatment of AA. There were areas of general consensus, including the need for a bone marrow evaluation, cytogenetic and specific fluorescent in situ hybridization assays to establish diagnosis and exclude genetic etiologies with many institutions requiring results prior to initiation of immunosuppressive therapy (IST); uniform referral for hematopoietic stem cell transplantation as first line therapy if an HLA-identical sibling is identified; the use of first-line IST containing horse anti-thymocyte globulin and cyclosporine A (CSA) if an HLA-identical sibling donor is not identified; supportive care measures; and slow taper of CSA after response. Areas of controversy included the need for telomere length results prior to IST, the time after IST initiation defining a treatment failure; use of hematopoietic growth factors; the preferred rescue therapy after failure of IST; the use of specific hemoglobin and platelet levels as triggers for transfusion support; the use of prophylactic antibiotics; and follow-up monitoring after completion of treatment. CONCLUSIONS: These initial survey results reflect heterogeneity in diagnosis and care amongst pediatric centers and emphasize the need to develop evidence-based diagnosis and treatment approaches in this rare disease.


Assuntos
Anemia Aplástica/diagnóstico , Anemia Aplástica/tratamento farmacológico , Pesquisas sobre Serviços de Saúde , Imunossupressores/uso terapêutico , Padrões de Prática Médica , Adolescente , Anemia Aplástica/epidemiologia , Soro Antilinfocitário/uso terapêutico , Criança , Pré-Escolar , Ciclosporina/uso terapêutico , Feminino , Seguimentos , Humanos , Lactente , Masculino , América do Norte/epidemiologia , Prognóstico , Irmãos
19.
Blood ; 122(14): 2487-90, 2013 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-23943650

RESUMO

Classical 5q- syndrome is an acquired macrocytic anemia of the elderly. Similar to Diamond Blackfan anemia (DBA), an inherited red cell aplasia, the bone marrow is characterized by a paucity of erythroid precursors. RPS14 deletions in combination with other deletions in the region have been implicated as causative of the 5q- syndrome phenotype. We asked whether smaller, less easily detectable deletions could account for a syndrome with a modified phenotype. We employed single-nucleotide polymorphism array genotyping to identify small deletions in patients diagnosed with DBA and other anemias lacking molecular diagnoses. Diminutive mosaic deletions involving RPS14 were identified in a 5-year-old patient with nonclassical DBA and in a 17-year-old patient with myelodysplastic syndrome. Patients with nonclassical DBA and other hypoproliferative anemias may have somatically acquired 5q deletions with RPS14 haploinsufficiency not identified by fluorescence in situ hybridization or cytogenetic testing, thus refining the spectrum of disorders with 5q- deletions.


Assuntos
Anemia de Diamond-Blackfan/genética , Anemia Macrocítica/genética , Análise Citogenética/métodos , Proteínas Ribossômicas/genética , Adolescente , Anemia de Diamond-Blackfan/diagnóstico , Anemia Macrocítica/diagnóstico , Anemia Macrocítica/tratamento farmacológico , Pré-Escolar , Deleção Cromossômica , Cromossomos Humanos Par 5/genética , Feminino , Genótipo , Humanos , Fatores Imunológicos/uso terapêutico , Lenalidomida , Fenótipo , Polimorfismo de Nucleotídeo Único , Reação em Cadeia da Polimerase em Tempo Real , Talidomida/análogos & derivados , Talidomida/uso terapêutico
20.
Hum Genet ; 132(11): 1265-74, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23812780

RESUMO

Diamond-Blackfan anemia (DBA) is an inherited red blood cell aplasia that usually presents during the first year of life. The main features of the disease are normochromic and macrocytic anemia, reticulocytopenia, and nearly absent erythroid progenitors in the bone marrow. The patients also present with growth retardation and craniofacial, upper limb, heart and urinary system congenital malformations in ~30-50 % of cases. The disease has been associated with point mutations and large deletions in ten ribosomal protein (RP) genes RPS19, RPS24, RPS17, RPL35A, RPL5, RPL11, RPS7, RPS10, RPS26, and RPL26 and GATA1 in about 60-65 % of patients. Here, we report a novel large deletion in RPL15, a gene not previously implicated to be causative in DBA. Like RPL26, RPL15 presents the distinctive feature of being required both for 60S subunit formation and for efficient cleavage of the internal transcribed spacer 1. In addition, we detected five deletions in RP genes in which mutations have been previously shown to cause DBA: one each in RPS19, RPS24, and RPS26, and two in RPS17. Pre-ribosomal RNA processing was affected in cells established from the patients bearing these deletions, suggesting a possible molecular basis for their pathological effect. These data identify RPL15 as a new gene involved in DBA and further support the presence of large deletions in RP genes in DBA patients.


Assuntos
Anemia de Diamond-Blackfan/genética , Deleção de Genes , Proteínas Ribossômicas/genética , Hibridização Genômica Comparativa , Variações do Número de Cópias de DNA , Técnicas de Silenciamento de Genes , Células HeLa , Humanos , Mutação , RNA Ribossômico/análise , RNA Ribossômico/genética , RNA Interferente Pequeno , Proteínas Ribossômicas/metabolismo
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