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1.
Rinsho Ketsueki ; 60(6): 702-707, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31281163

RESUMO

Inherited bone marrow failure syndromes (IBMFS) are caused by mutations in genes associated with DNA repair and telomere maintenance. In addition, mutations in ribosome-related genes cause defective hematopoiesis. Patients with IBMFS exhibit a predisposition to developing hematological malignancy or solid tumor because of the defect in cellular and molecular hemostasis. The SAMD9 mutation causes the multisystem disorder, MIRAGE syndrome, characterized by congenital adrenal hypoplasia and loss of chromosome 7, providing a novel insight into the correlation between the germline and somatic mutations of SAMD9/SAMD9L and myelodysplastic syndrome (MDS) with monosomy 7. Primary immunodeficiency diseases (PID) are caused by inborn errors of the immune system. PID patients with inadequate tumor immunity are at an elevated risk of developing malignancies such as lymphoma, leukemia, and gastrointestinal cancer. Recently, monocytopenia and mycobacterial infection (MonoMAC) syndrome with the GATA2 gene mutation have been reported as PID related to bone marrow failure. Patients with MonoMAC syndrome often develop MDS and acute myeloid leukemia. Here, we present the pediatric-onset IBMFS and/or PID with cancer predisposition and briefly discuss the tumorigenesis in each monogenic disease.


Assuntos
Anemia Aplástica/complicações , Doenças da Medula Óssea/complicações , Predisposição Genética para Doença , Hemoglobinúria Paroxística/complicações , Síndromes de Imunodeficiência/complicações , Neoplasias/genética , Anemia Aplástica/genética , Doenças da Medula Óssea/genética , Criança , Hemoglobinúria Paroxística/genética , Humanos , Síndromes de Imunodeficiência/genética , Síndromes Mielodisplásicas
2.
Ann Lab Med ; 39(5): 438-446, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31037862

RESUMO

BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired pluripotent hematopoietic stem cell disorder associated with an increase in the number of glycosyl-phosphatidyl inositol (GPI)-deficient blood cells. We investigated PNH clonal proliferation in the three cell lineages-granulocytes, T lymphocytes, and red blood cells (RBCs)-by analyzing PIGA gene mutations and T-cell receptor (TCR) clonality. METHODS: Flow cytometry was used on peripheral blood samples from 24 PNH patients to measure the GPI-anchored protein (GPI-AP) deficient fraction in each blood cell lineage. PIGA gene mutations were analyzed in granulocytes and T lymphocytes by Sanger sequencing. A TCR clonality assay was performed in isolated GPI-AP deficient T lymphocytes. RESULTS: The GPI-AP deficient fraction among the three lineages was the highest in granulocytes, followed by RBCs and T lymphocytes. PIGA mutations were detected in both granulocytes and T lymphocytes of 19 patients (79.2%), with a higher mutation burden in granulocytes. The GPI-AP deficient fractions of granulocytes and T lymphocytes correlated moderately (rs=0.519, P=0.049) and strongly (rs=0.696, P=0.006) with PIGA mutation burden, respectively. PIGA mutations were more frequently observed in patients with clonal rearrangements in TCR genes (P=0.015). The PIGA mutation burden of T lymphocytes was higher in patients with clonal TCRB rearrangement. CONCLUSIONS: PIGA mutations were present in approximately 80% of PNH patients. PNH clone size varies according to blood cell lineage, and clonal cells may obtain proliferation potential or gain a survival advantage over normal cells.


Assuntos
Proliferação de Células , Granulócitos/citologia , Hemoglobinúria Paroxística/diagnóstico , Proteínas de Membrana/genética , Linfócitos T/citologia , Adolescente , Adulto , Idoso , Linhagem da Célula , Criança , Feminino , Proteínas Ligadas por GPI/deficiência , Proteínas Ligadas por GPI/genética , Rearranjo Gênico , Granulócitos/metabolismo , Hemoglobinúria Paroxística/genética , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T/metabolismo , Adulto Jovem
3.
Int J Lab Hematol ; 41 Suppl 1: 73-81, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31069981

RESUMO

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematopoietic stem cell disorder resulting from the somatic mutation of the X-linked phosphatidyl-inositol glycan complementation Class A (PIG-A) gene. Depending on the severity of the mutation in the PIG-A gene, there is a partial or absolute inability to make glycosylphosphatidyl-inositol (GPI)-anchored proteins including complement-defense structures such as CD55 and CD59 on RBCs and WBCs. Flow cytometric detection of PNH clones has become the gold standard and has played an increasingly important role in the diagnosis, monitoring, and clinical management of patients with PNH. Recently, a 4-part set of Consensus Guidelines have been published by flow experts in the field to address the key assay-specific considerations for the identification of PNH clones in RBC and WBC, how to report such data and a full validation document for the assays described. Below, we have summarized the most significant aspects of this International effort.


Assuntos
Antígenos CD55/sangue , Antígenos CD59/sangue , Citometria de Fluxo/métodos , Hemoglobinúria Paroxística/sangue , Hemoglobinúria Paroxística/líquido cefalorraquidiano , Proteínas de Membrana/sangue , Antígenos CD55/genética , Antígenos CD59/genética , Consenso , Citometria de Fluxo/normas , Hemoglobinúria Paroxística/diagnóstico , Hemoglobinúria Paroxística/genética , Humanos , Proteínas de Membrana/genética , Guias de Prática Clínica como Assunto
4.
Int J Lab Hematol ; 41(3): 424-432, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30970179

RESUMO

BACKGROUND: Thrombosis is a most common and lethal complication of paroxysmal nocturnal hemoglobinuria (PNH), which is a complex progression and its mechanism remains unclear. We tried to explore the possible genetic background of thrombosis in PNH patients and provide potential gene mutations associated with thrombosis in PNH patients. METHODS: The CD59- cells of 7 PNH and 6 PNH- aplastic anemia (AA) patients were sorted by flow cytometry and sequenced by whole-exome sequencing (WES). The sequencing results and target mutation genes were analyzed and screened, respectively, and Kyoto Encyclopedia of Genes and Genomes (KEGG) signal pathway enrichment analysis was carried out. Finally, the expression of target genes was detected in 22 PNH (including seven cases with thrombus) and 20 normal controls, and the correlation between the expression of mRNA and the clinical thrombus-related indexes was analyzed. RESULTS: The mutation genes screened from 4 PNH with thrombus were BMPR2, F8, ITGA2B, THBD, and THBS1. The pathways enriched by these genes included Notch, Wnt, and arachidonic acid metabolism signaling pathways, which may be related to the pathogenesis of thrombosis in PNH. The BMPR2, THBD, and THBS1 gene expression was significantly different between PNH with and without thrombus group, and the THBS1 gene expression was positively correlated with D-Dimer and su-PAR levels. CONCLUSIONS: Genetic defects have a non-negligible effect on the incidence of thrombosis, and therefore, gene mutations maybe a genetic risk factor in PNH, which increase the incidence of thrombosis.


Assuntos
Predisposição Genética para Doença , Hemoglobinúria Paroxística/complicações , Hemoglobinúria Paroxística/genética , Mutação , Trombose/etiologia , Sequenciamento Completo do Exoma , Adulto , Idoso , Biomarcadores , Biologia Computacional , Análise Mutacional de DNA , Feminino , Citometria de Fluxo , Expressão Gênica , Estudos de Associação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Trombose/diagnóstico , Adulto Jovem
5.
PLoS Comput Biol ; 14(6): e1006133, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29912864

RESUMO

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal blood disorder characterized by hemolysis and a high risk of thrombosis, that is due to a deficiency in several cell surface proteins that prevent complement activation. Its origin has been traced to a somatic mutation in the PIG-A gene within hematopoietic stem cells (HSC). However, to date the question of how this mutant clone expands in size to contribute significantly to hematopoiesis remains under debate. One hypothesis posits the existence of a selective advantage of PIG-A mutated cells due to an immune mediated attack on normal HSC, but the evidence supporting this hypothesis is inconclusive. An alternative (and simpler) explanation attributes clonal expansion to neutral drift, in which case selection neither favours nor inhibits expansion of PIG-A mutated HSC. Here we examine the implications of the neutral drift model by numerically evolving a Markov chain for the probabilities of all possible outcomes, and investigate the possible occurrence and evolution, within this framework, of multiple independently arising clones within the HSC pool. Predictions of the model agree well with the known incidence of the disease and average age at diagnosis. Notwithstanding the slight difference in clonal expansion rates between our results and those reported in the literature, our model results lead to a relative stability of clone size when averaging multiple cases, in accord with what has been observed in human trials. The probability of a patient harbouring a second clone in the HSC pool was found to be extremely low ([Formula: see text]). Thus our results suggest that in clinical cases of PNH where two independent clones of mutant cells are observed, only one of those is likely to have originated in the HSC pool.


Assuntos
Hemoglobinúria Paroxística/genética , Hemoglobinúria Paroxística/fisiopatologia , Células Clonais , Evolução Molecular , Hematopoese/genética , Células-Tronco Hematopoéticas , Hemoglobinúria/genética , Hemoglobinúria/fisiopatologia , Humanos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Modelos Biológicos , Mutação
6.
Mol Genet Genomic Med ; 6(3): 463-468, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29633571

RESUMO

BACKGROUND: ERCC6L2-associated disorder has recently been described and only five patients were reported so far. The described phenotype included bone marrow, cerebral, and craniofacial abnormalities. The aim of this study was to further define the genetic and phenotypic spectrum of the disorder by summarizing the five published cases and an additional case that we identified through whole-exome sequencing performed at the University of Toronto. METHODS: Clinical data was extracted from the Canadian Inherited Marrow Failure Registry. Whole exome sequencing was performed to identify causative mutations. RESULTS: All six cases had homozygous truncating mutations either at or upstream of the helicase domain of ERCC6L2. All patients displayed bone marrow failure, learning or developmental delay and microcephaly. Our patient was unique in displaying features of cerebellar disease, including ataxia and dysmetria as well as an interval deterioration of the corpus callosum and generalized volume loss on MRI. Another unique feature of our patient was retinal dystrophy with macular involvement. Along with one other patient, our patient displayed craniofacial abnormalities by presenting with low-set prominent ears, a pointed prominent chin, and deep-set eyes. Leukemia is common among patients with inherited bone marrow failure, but thus far, none of the patients have developed this complication. CONCLUSIONS: ERCC6L2-associated disorder is a multisystem disorder. The phenotype spectrum includes bone marrow failure, cerebral, and craniofacial abnormalities, as well as cerebellar and retinal abnormalities.


Assuntos
Anemia Aplástica/genética , Doenças da Medula Óssea/genética , DNA Helicases/genética , Hemoglobinúria Paroxística/genética , Adolescente , Adulto , Anemia Aplástica/fisiopatologia , Doenças da Medula Óssea/fisiopatologia , Canadá , Criança , Pré-Escolar , Anormalidades Craniofaciais/genética , DNA Helicases/fisiologia , Deficiências do Desenvolvimento/genética , Exoma , Feminino , Hemoglobinúria Paroxística/fisiopatologia , Homozigoto , Humanos , Lactente , Deficiência Intelectual/genética , Masculino , Microcefalia/genética , Mutação , Malformações do Sistema Nervoso/genética , Linhagem , Fenótipo
7.
Gene ; 659: 149-154, 2018 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-29551496

RESUMO

Patients with paroxysmal nocturnal hemoglobinuria (PNH) who have minor allele of the complement receptor 1 (CR1) gene, displayed more sub-optimal responder to eculizumab compared with major allele. To investigate polymorphism of the CR1 gene in Chinese patients with PNH and its correlation with clinical features and the potential impact on eculizumab efficiency, we genotyped CR1 rs2274567, rs3811381 and the intron 27 Hind III restriction fragment length polymorphism in 95patients with PNH and 96 controls. The results indicated that the genotypes of CR1 rs2274567, rs3811381 and the intron 27 Hind III in PNH patients and controls both consist with Hardy-Weinberg equilibrium. The minor allele frequency (MAF) of rs2274567 and rs3811381 in PNH patients and normal controls were lower compared with data from the dbSNP database. Further analysis showed that the MAF of Chinese patients was significantly lower than that of Caucasians (P < 0.0001, P = 0.0006 and P < 0.0001, respectively). The minor allele of CR1 rs2274567, rs3811381 and the intron 27 Hind III was associated with decreased of hemoglobin level (P = 0.007, P = 0.022,and P = 0.022, respectively) in our patients. However, there was no significantly difference found in other clinical parameters. In conclusion, the results demonstrated the minor alleles of CR1 polymorphisms were lower in Chinese patients than in Caucasians, with a decrease in hemoglobin level. These findings may indicate less sub-optimal responders to eculizumab in Chinese patients.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Grupo com Ancestrais do Continente Asiático/genética , Hemoglobinúria Paroxística/tratamento farmacológico , Polimorfismo de Nucleotídeo Único , Receptores de Complemento 3b/genética , Adulto , Idoso , Anticorpos Monoclonais Humanizados/uso terapêutico , Feminino , Frequência do Gene , Hemoglobinúria Paroxística/genética , Humanos , Íntrons , Masculino , Pessoa de Meia-Idade , Variantes Farmacogenômicos
8.
Gene ; 656: 86-94, 2018 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-29496554

RESUMO

Congenital hypoplastic bone marrow failure is a rare condition in neonates. The genetics and mechanisms behind are largely obscure. Here we characterize a neonate presenting with congenital thrombocytopenia and anemia. During the first 2-4 weeks after birth the neonate developed severe neutropenia while the lymphoid lineages were unaffected. The neonate was without dysmorphic signs. A de novo mono-allelic constitutional microdeletion of 175.1 kb at 3q26.2 affecting exon 2 of MECOM, involving MDS1 but not EVI1, was identified as the only copy number alteration by oligo-based array-CGH analysis. Expression analysis showed profoundly reduced expression of multiple MECOM transcripts in the bone marrow cells. Whole exome sequencing detected no pathogenic mutations in genes known to be associated with inherited bone marrow failure syndromes. The patient was successfully treated with hematopoietic stem cell transplantation at 5 months of age. Interstitial deletions encompassing the 3q26.2 region are very rare. A literature search revealed two previous cases with microdeletions involving this region, and the cases were associated with congenital thrombocytopenia and anemia, but unaffected lymphopoiesis. Together these data indicate that MECOM may be important for normal myeloid hematopoiesis in humans but dispensable for lymphoid differentiation. We suggest that partial deletion in MECOM may be a primary event associated with congenital pancytopenia.


Assuntos
Anemia Aplástica/genética , Anemia Hipoplástica Congênita/genética , Doenças da Medula Óssea/genética , Deleção Cromossômica , Cromossomos Humanos Par 3/genética , Hemoglobinúria Paroxística/genética , Proteína do Locus do Complexo MDS1 e EVI1/genética , Anemia Aplástica/patologia , Doenças da Medula Óssea/patologia , Variações do Número de Cópias de DNA , Deleção de Genes , Hemoglobinúria Paroxística/patologia , Humanos , Recém-Nascido , Masculino , Linhagem , Trombocitopenia/congênito , Trombocitopenia/genética
9.
Exp Hematol ; 59: 1-8, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29248612

RESUMO

Inherited bone marrow failure syndromes (IBMFS) represent a heterogeneous group of multisystem disorders that typically present with cytopenia in early childhood. Efforts to understand the underlying hematopoietic stem cell (HSC) losses have generally focused on postnatal hematopoiesis. However, reflecting the role of many of the involved genes in core cellular functions and the diverse nonhematologic abnormalities seen in patients at birth, studies have begun to explore IBMFS manifestations during fetal development. Here, I consider the current evidence for fetal deficits in the HSC pool and highlight emerging concepts regarding the origins and unique pathophysiology of hematopoietic failure in IBMFS.


Assuntos
Anemia Aplástica/embriologia , Anemia Aplástica/fisiopatologia , Doenças da Medula Óssea/embriologia , Doenças da Medula Óssea/fisiopatologia , Desenvolvimento Fetal , Doenças Genéticas Inatas/embriologia , Doenças Genéticas Inatas/fisiopatologia , Hematopoese , Hemoglobinúria Paroxística/embriologia , Hemoglobinúria Paroxística/fisiopatologia , Anemia Aplástica/genética , Animais , Doenças da Medula Óssea/genética , Doenças Genéticas Inatas/genética , Hemoglobinúria Paroxística/genética , Humanos , Camundongos , Peixe-Zebra
10.
Hematology Am Soc Hematol Educ Program ; 2017(1): 66-72, 2017 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-29222238

RESUMO

Recent technological advances in genomics have led to the discovery of new somatic mutations and have brought deeper insights into clonal diversity. This discovery has changed not only the understanding of disease mechanisms but also the diagnostics and clinical management of bone marrow failure. The clinical applications of genomics include enhancement of current prognostic schemas, prediction of sensitivity or refractoriness to treatments, and conceptualization and selective application of targeted therapies. However, beyond these traditional clinical aspects, complex hierarchical clonal architecture has been uncovered and linked to the current concepts of leukemogenesis and stem cell biology. Detection of clonal mutations, otherwise typical of myelodysplastic syndrome, in the course of aplastic anemia (AA) and paroxysmal nocturnal hemoglobinuria has led to new pathogenic concepts in these conditions and created a new link between AA and its clonal complications, such as post-AA and paroxysmal nocturnal hemoglobinuria. Distinctions among founder vs subclonal mutations, types of clonal evolution (linear or branching), and biological features of individual mutations (sweeping, persistent, or vanishing) will allow for better predictions of the biologic impact they impart in individual cases. As clonal markers, mutations can be used for monitoring clonal dynamics of the stem cell compartment during physiologic aging, disease processes, and leukemic evolution.


Assuntos
Anemia Aplástica/genética , Anemia Aplástica/metabolismo , Hemoglobinúria Paroxística/genética , Hemoglobinúria Paroxística/metabolismo , Mutação , Genômica , Humanos
11.
Blood ; 130(21): 2257-2264, 2017 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-29167174

RESUMO

Patients with inherited bone marrow failure syndromes are usually identified when they develop hematologic complications such as severe bone marrow failure, myelodysplastic syndrome, or acute myeloid leukemia. They often have specific birth defects or other physical abnormalities that suggest a syndrome, and sequencing of specific genes or next-generation sequencing can determine or confirm the particular syndrome. The 4 most frequent syndromes are Fanconi anemia, dyskeratosis congenita, Diamond Blackfan anemia, and Shwachman Diamond syndrome. This review discusses the major complications that develop as the patients with these syndromes age, as well as additional late effects following hematopoietic stem cell transplantation. The most common complications are iron overload in transfused patients and syndrome-specific malignancies in untransplanted patients, which may occur earlier and with higher risks in those who have received transplants.


Assuntos
Anemia Aplástica/genética , Anemia Aplástica/terapia , Doenças da Medula Óssea/genética , Doenças da Medula Óssea/terapia , Transplante de Células-Tronco Hematopoéticas , Hemoglobinúria Paroxística/genética , Hemoglobinúria Paroxística/terapia , Padrões de Herança/genética , Humanos
13.
Pediatr Blood Cancer ; 64(12)2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28708320

RESUMO

Inherited bone marrow failure syndromes (IBMFS) are rare cancer predisposition syndromes with an especially high risk of transformation to myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML). We performed a retrospective systematic review of reported MDS/AML arising in the eight most common IBMFS to determine the frequency and outcome of chromosome 7 abnormalities. We identified 738 MDS/AML cases of 4,293 individuals. Monosomy 7 or del (7q) occurred in ∼17%. Greater understanding of the roles played by sequential acquisition of genetic and cytogenetic changes will provide insights into myeloid leukemogenesis and improve the surveillance and hopefully outcomes for individuals with IBMFS.


Assuntos
Anemia Aplástica/genética , Doenças da Medula Óssea/genética , Deleção Cromossômica , Hemoglobinúria Paroxística/genética , Adolescente , Adulto , Criança , Pré-Escolar , Cromossomos Humanos Par 7 , Humanos , Lactente , Recém-Nascido , Estudos Retrospectivos , Adulto Jovem
14.
Eur J Haematol ; 99(4): 350-356, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28692147

RESUMO

BACKGROUND: Eculizumab-treated paroxysmal nocturnal hemoglobinuria (PNH) patients (pts) show a dramatic decrease in serum lactate dehydrogenase (LDH) activities and bilirubin concentrations. However, some pts remain hyperbilirubinemic, possibly indicating an inadequate response due to extravascular hemolysis. METHODS: Mutation analyses of hepatocanalicular transporter/nuclear receptor variants (ABCB4, ABCB11, ATP8B1, NR1H4) were performed in eight (five of eight males; mean age 38 years [range 26-68 years]) out of the 174 pts with PNH/-clone at our department due to a persistent increase in total bilirubin concentrations (median 3.4 mg/dL; range 2.1-8.1 mg/dL) during chronic eculizumab treatment and normal/or slightly increased serum aminotransferase activities. Median observation time was 70.1 months (range 10.6-135.2 months). All pts were treated according to German PNH guidelines. RESULTS: Homozygous and heterozygous procholestatic variants in the ABCB4, ABCB11, and ATP8B1 genes were identified in all eight pts. All carried the common ABCB4 c.787A>T polymorphism. The A(TA)7 TAA variant in the UGT1A1 promoter causing Gilbert syndrome was detected in three pts (5/8). CONCLUSIONS: Hyperbilirubinemia in PNH pts treated with eculizumab might not only be due to an insufficient response but rather a combination of mutations in hepatocanalicular transporter variants, Gilbert syndrome, and extravascular hemolysis. Our findings warrant further studies concerning transporter and enzyme variants in PNH to determine their clinical significance.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Hemoglobinúria Paroxística/complicações , Hemoglobinúria Paroxística/tratamento farmacológico , Hiperbilirrubinemia/etiologia , Adulto , Idoso , Alelos , Análise Mutacional de DNA , Feminino , Frequência do Gene , Genótipo , Hemoglobinúria Paroxística/sangue , Hemoglobinúria Paroxística/genética , Hemólise , Humanos , Hiperbilirrubinemia/diagnóstico , L-Lactato Desidrogenase/sangue , Masculino , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Pessoa de Meia-Idade , Mutação , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo
15.
Semin Hematol ; 54(2): 105-114, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28637614

RESUMO

The inherited marrow failure syndromes (IBMFS) are a heterogeneous group of diseases characterized by failure in the production of one or more blood lineage. The clinical manifestations of the IBMFS vary according to the type and number of blood cell lines involved, including different combinations of anemia, leukopenia, and thrombocytopenia. In some IBMFS, systemic non-hematologic manifestations, including congenital malformations, mucocutaneous abnormalities, developmental delay, and other medical complications, may be present. Fanconi anemia (FA), caused by germline pathogenic variants in the DNA repair genes comprising the FA/BRCA pathway is associated with congenital anomalies, bone marrow failure, and increased risk of myelodysplastic syndrome (MDS), acute myelogenous leukemia (AML), and solid tumors. Dyskeratosis congenita (DC) is a telomere biology disorder (TBD) caused by aberrations in key telomere biology genes. In addition to mucocutaneous manifestations, patients with DC are at increased risk of marrow failure, MDS, AML, pulmonary fibrosis, and other complications. Ribosomal biology defects are the primary causes of Diamond Blackfan anemia (DBA) and Shwachman Diamond syndrome (SDS). In addition to pure red blood cell aplasia, DBA is associated with elevated risk of solid tumors, AML, and MDS. Patients with SDS have pancreatic insufficiency, neutropenia, as well as MDS and AML risks. Patients with severe congenital neutropenia (SCN), caused by pathogenic variants in genes essential in myeloid development, have profound neutropenia and high risk of MDS and AML. Herein we review the genetic causes, clinical features, diagnostic modalities, predisposition to malignancies with focus on leukemogenic markers whenever available, and approaches to treatments of the classical IBMFS: FA, DC, SDS, DBA, and SCN.


Assuntos
Anemia Aplástica/complicações , Doenças da Medula Óssea/complicações , Hemoglobinúria Paroxística/complicações , Leucemia Mieloide Aguda/etiologia , Síndromes Mielodisplásicas/etiologia , Anemia Aplástica/genética , Doenças da Medula Óssea/genética , Hemoglobinúria Paroxística/genética , Humanos , Leucemia Mieloide Aguda/genética , Síndromes Mielodisplásicas/genética , Fatores de Risco
16.
Br J Haematol ; 178(6): 954-958, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28643364

RESUMO

The clinical significance of paroxysmal nocturnal haemoglobinuria (PNH) in children with aplastic anaemia (AA) remains unclear. We retrospectively studied 57 children with AA between 1992 and 2010. During the follow-up, five patients developed clinical PNH, in whom somatic PIGA mutations were detected by targeted sequencing. The 10-year probability of clinical PNH development was 10·2% (95% confidence interval, 3·6-20·7%). Furthermore, the detection of minor PNH clones by flow cytometry at AA diagnosis was a risk factor for the subsequent development of clinical PNH. These patients with PNH clones at AA diagnosis should undergo periodic monitoring for potential clinical PNH development.


Assuntos
Anemia Aplástica/complicações , Hemoglobinúria Paroxística/etiologia , Adolescente , Anemia Aplástica/tratamento farmacológico , Anemia Aplástica/genética , Criança , Pré-Escolar , Feminino , Seguimentos , Hemoglobinúria Paroxística/genética , Humanos , Imunossupressores/uso terapêutico , Lactente , Masculino , Proteínas de Membrana/genética , Mutação , Estudos Retrospectivos , Fatores de Risco
17.
Rinsho Ketsueki ; 58(4): 353-362, 2017.
Artigo em Japonês | MEDLINE | ID: mdl-28484166

RESUMO

Paroxysmal nocturnal hemoglobinuria (PNH) manifests by clonal expansion of mutant hematopoietic stem cells (HSCs) bearing a somatic mutation in the X-linked PIGA gene. PIGA mutations cause defective biosynthesis of GPI and cell surface deficiency of GPI-anchored proteins such as DAF and CD59, leading to intravascular hemolysis and thrombosis. These two major symptoms of PNH can be controlled by eculizumab, an anti-C5 monoclonal antibody. Bone marrow failure, the third major symptom of PNH, is autoimmune-mediated and contributes to the clonal expansion of GPI-defective HSCs by selectively attacking GPI-positive wild-type HSCs. GPI-defective erythrocytes, being protected from intravascular hemolysis by eculizumab, accumulate C3-derived fragments, C3b, iC3b, and C3dg, because of DAF deficiency and in turn become susceptible to CR3-mediated phagocytosis by spleen macrophages. Approximately 3% of Japanese patients with PNH are refractory to eculizumab therapy. Approximately 3% of Japanese people are heterozygous for a single nucleotide polymorphism that changes an amino acid near the eculizumab binding site. New therapeutic measures are needed to solve these issues.


Assuntos
Hemoglobinúria Paroxística/genética , Hemoglobinúria Paroxística/metabolismo , Anemia Hemolítica/complicações , Animais , Proteínas do Sistema Complemento/genética , Proteínas do Sistema Complemento/metabolismo , Hemoglobinúria Paroxística/complicações , Hemoglobinúria Paroxística/tratamento farmacológico , Humanos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Mutação , Ligação Proteica
18.
Pediatr Res ; 82(3): 458-464, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28486441

RESUMO

BackgroundPatients with inherited bone marrow failure syndromes (IBMFS) may have several risk factors for low bone mineral density (BMD). We aimed to evaluate the prevalence of low BMD in IBMFS and determine the associated risk factors.MethodsPatients with IBMFS with at least one dual-energy X-ray absorptiometry (DXA) scan were evaluated. Diagnosis of each IBMFS, Fanconi anemia (FA), dyskeratosis congenita, Diamond-Blackfan anemia, and Shwachman-Diamond syndrome was confirmed by syndrome-specific tests. Data were gathered on age, height, and clinical history. DXA scans were completed at the lumbar spine, femoral neck, and forearm. BMD was adjusted for height (HAZ) in children (age ≤20 years). Low BMD was defined as a BMD Z-score and HAZ ≤-2 in adults and children, respectively, in addition to patients currently on bisphosphonate therapy.ResultsNine of thirty-five adults (26%) and eleven of forty children (27%) had low BMD. Adults with FA had significantly lower BMD Z-scores than those with other diagnoses; however, HAZ did not vary significantly in children by diagnosis. Risk factors included hypogonadism, iron overload, and glucocorticoid use.ConclusionsAdults and children with IBMFS have high prevalence of low BMD. Prompt recognition of risk factors and management are essential to optimize bone health.


Assuntos
Anemia Aplástica/fisiopatologia , Densidade Óssea , Doenças da Medula Óssea/fisiopatologia , Hemoglobinúria Paroxística/fisiopatologia , Absorciometria de Fóton , Adolescente , Adulto , Anemia Aplástica/epidemiologia , Anemia Aplástica/genética , Doenças da Medula Óssea/epidemiologia , Doenças da Medula Óssea/genética , Criança , Feminino , Hemoglobinúria Paroxística/epidemiologia , Hemoglobinúria Paroxística/genética , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Fatores de Risco , Adulto Jovem
19.
Nat Rev Dis Primers ; 3: 17028, 2017 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-28516949

RESUMO

Paroxysmal nocturnal haemoglobinuria (PNH) is a clonal haematopoietic stem cell (HSC) disease that presents with haemolytic anaemia, thrombosis and smooth muscle dystonias, as well as bone marrow failure in some cases. PNH is caused by somatic mutations in PIGA (which encodes phosphatidylinositol N-acetylglucosaminyltransferase subunit A) in one or more HSC clones. The gene product of PIGA is required for the biosynthesis of glycosylphosphatidylinositol (GPI) anchors; thus, PIGA mutations lead to a deficiency of GPI-anchored proteins, such as complement decay-accelerating factor (also known as CD55) and CD59 glycoprotein (CD59), which are both complement inhibitors. Clinical manifestations of PNH occur when a HSC clone carrying somatic PIGA mutations acquires a growth advantage and differentiates, generating mature blood cells that are deficient of GPI-anchored proteins. The loss of CD55 and CD59 renders PNH erythrocytes susceptible to intravascular haemolysis, which can lead to thrombosis and to much of the morbidity and mortality of PNH. The accumulation of anaphylatoxins (such as C5a) from complement activation might also have a role. The natural history of PNH is highly variable, ranging from quiescent to life-threatening. Therapeutic strategies include terminal complement blockade and bone marrow transplantation. Eculizumab, a monoclonal antibody complement inhibitor, is highly effective and the only licensed therapy for PNH.


Assuntos
Hemoglobinúria Paroxística/patologia , Hemoglobinúria Paroxística/terapia , Proteínas de Membrana/genética , Anticorpos Monoclonais Humanizados/uso terapêutico , Transplante de Medula Óssea , Antígenos CD55/metabolismo , Antígenos CD59/metabolismo , Proteínas Inativadoras do Complemento/metabolismo , Hemoglobinúria Paroxística/genética , Hemoglobinúria Paroxística/metabolismo , Humanos , Mutação , Resultado do Tratamento
20.
Basic Clin Pharmacol Toxicol ; 121 Suppl 3: 78-92, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28481423

RESUMO

This MiniReview describes the principle of mutation assays based on the endogenous Pig-a gene and summarizes results for two species of toxicological interest, mice and human beings. The work summarized here largely avoids rat-based studies, as are summarized elsewhere. The Pig-a gene mutation assay has emerged as a valuable tool for quantifying in vivo and in vitro mutational events. The Pig-a locus is located at the X-chromosome, giving the advantage that one inactivated allele can give rise to a mutated phenotype, detectable by multicolour flow cytometry. For in vivo studies, only minute blood volumes are required, making it easily incorporated into ongoing studies or experiments with limited biological materials. Low blood volumes also allow individuals to serve as their own controls, providing temporal information of the mutagenic process, and/or outcome of intervention. These characteristics make it a promising exposure marker. To date, the Pig-a gene mutation assay has been most commonly performed in rats, while reports regarding its usefulness in other species are accumulating. Besides its applicability to in vivo studies, it holds promise for genotoxicity testing using cultured cells, as shown in recent studies. In addition to safety assessment roles, it is becoming a valuable tool in basic research to identify mutagenic effects of different interventions or to understand implications of various gene defects by investigating modified mouse models or cell systems. Human blood-based assays are also being developed that may be able to identify genotoxic environmental exposures, treatment- and lifestyle-related factors or endogenous host factors that contribute to mutagenesis.


Assuntos
Bioensaio/métodos , Exposição Ambiental/efeitos adversos , Proteínas de Membrana/genética , Mutagênicos/toxicidade , Cromossomo X/genética , Animais , Células Cultivadas , Dano ao DNA , Citometria de Fluxo , Hemoglobinúria Paroxística/genética , Humanos , Camundongos , Modelos Animais , Testes de Mutagenicidade/métodos , Mutação
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