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1.
Haematologica ; 106(9): 2439-2448, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32703794

RESUMO

Congenital amegakaryocytic thrombocytopenia caused by deleterious homozygous or compound heterozygous mutations in MPL (CAMT-MPL) is a rare inherited bone marrow failure syndrome presenting as an isolated thrombocytopenia at birth progressing to pancytopenia due to exhaustion of hematopoietic progenitors. The analysis of samples and clinical data from a large cohort of 56 patients with CAMT-MPL resulted in a detailed description of the clinical picture and reliable genotype-phenotype correlations for this rare disease. We extended the spectrum of CAMT causing MPL mutations regarding number (17 novel mutations) and impact. The clinical courses showed a great variability with respect to the severity of thrombocytopenia, the development of pancytopenia and the consequences from bleedings. The most severe clinical problems were (1) intracranial bleedings pre- and perinatally and the resulting long-term consequences, and (2) the development of aplastic anemia in the later course of the disease. An important and new finding was that thrombocytopenia was not detected at birth in a quarter of the patients. The rate of non-hematological abnormalities in CAMT-MPL was higher than described so far. Most of the anomalies were related to the head region (brain anomalies, ocular and orbital anomalies) and consequences of intracranial bleedings. The present study demonstrates a higher variability of clinical courses than described so far and has important implications on diagnosis and therapy. The diagnosis CAMT-MPL has to be considered even for those patients who are inconspicuous in the first months of life or show somatic anomalies typical for other inherited bone marrow failure syndromes.


Assuntos
Receptores de Trombopoetina , Trombocitopenia , Síndrome Congênita de Insuficiência da Medula Óssea , Humanos , Megacariócitos , Mutação , Receptores de Trombopoetina/genética , Trombocitopenia/genética
2.
Blood ; 127(23): 2791-803, 2016 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-27084890

RESUMO

Inherited bleeding, thrombotic, and platelet disorders (BPDs) are diseases that affect ∼300 individuals per million births. With the exception of hemophilia and von Willebrand disease patients, a molecular analysis for patients with a BPD is often unavailable. Many specialized tests are usually required to reach a putative diagnosis and they are typically performed in a step-wise manner to control costs. This approach causes delays and a conclusive molecular diagnosis is often never reached, which can compromise treatment and impede rapid identification of affected relatives. To address this unmet diagnostic need, we designed a high-throughput sequencing platform targeting 63 genes relevant for BPDs. The platform can call single nucleotide variants, short insertions/deletions, and large copy number variants (though not inversions) which are subjected to automated filtering for diagnostic prioritization, resulting in an average of 5.34 candidate variants per individual. We sequenced 159 and 137 samples, respectively, from cases with and without previously known causal variants. Among the latter group, 61 cases had clinical and laboratory phenotypes indicative of a particular molecular etiology, whereas the remainder had an a priori highly uncertain etiology. All previously detected variants were recapitulated and, when the etiology was suspected but unknown or uncertain, a molecular diagnosis was reached in 56 of 61 and only 8 of 76 cases, respectively. The latter category highlights the need for further research into novel causes of BPDs. The ThromboGenomics platform thus provides an affordable DNA-based test to diagnose patients suspected of having a known inherited BPD.


Assuntos
Transtornos Plaquetários/genética , Predisposição Genética para Doença , Hemorragia/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Trombose/genética , Estudos de Casos e Controles , Variações do Número de Cópias de DNA , Feminino , Estudos de Associação Genética/métodos , Humanos , Masculino , Mutação , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA/métodos
3.
Nat Genet ; 39(1): 86-92, 2007 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17187068

RESUMO

Autosomal recessive severe congenital neutropenia (SCN) constitutes a primary immunodeficiency syndrome associated with increased apoptosis in myeloid cells, yet the underlying genetic defect remains unknown. Using a positional cloning approach and candidate gene evaluation, we identified a recurrent homozygous germline mutation in HAX1 in three pedigrees. After further molecular screening of individuals with SCN, we identified 19 additional affected individuals with homozygous HAX1 mutations, including three belonging to the original pedigree described by Kostmann. HAX1 encodes the mitochondrial protein HAX1, which has been assigned functions in signal transduction and cytoskeletal control. Here, we show that HAX1 is critical for maintaining the inner mitochondrial membrane potential and protecting against apoptosis in myeloid cells. Our findings suggest that HAX1 is a major regulator of myeloid homeostasis and underline the significance of genetic control of apoptosis in neutrophil development.


Assuntos
Genes Recessivos , Neutropenia/congênito , Neutropenia/genética , Proteínas/genética , Proteínas Adaptadoras de Transdução de Sinal , Adolescente , Adulto , Apoptose , Células Cultivadas , Criança , Pré-Escolar , Mapeamento Cromossômico , Análise Mutacional de DNA , Feminino , Testes Genéticos , Humanos , Lactente , Masculino , Potencial da Membrana Mitocondrial/genética , Mutação , Células Mieloides/metabolismo , Linhagem , Síndrome
4.
Eur J Haematol ; 94(1): 79-82, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24750412

RESUMO

Glucose-6-phosphatase catalytic subunit 3 (G6PC3) deficiency is a newly described syndrome characterized by severe congenital neutropenia associated with multiple organ abnormalities including cardiac and urogenital malformations. The underlying pathophysiology of increased apoptosis of myeloid cells and of neutrophil dysfunction in G6PC3 deficiency involves disturbed glucose metabolism, increased endoplasmic reticulum stress and deficient protein folding. Here, we report a new case of G6PC3 deficiency caused by a novel homozygous G6PC3 gene mutation p.Trp59Arg. The patient showed pancytopenia and a variable bone marrow phenotype with maturation arrest and vacuolization in myeloid lineage cells and a normocellular marrow, respectively. She also showed persistent lymphopenia with low CD4 T- and CD19 B-cell counts. Lymphopenia and even pancytopenia as well as a variable bone marrow phenotype can be part of this syndrome. These clinical findings in a patient with chronic neutropenia should alert the clinician to consider a diagnosis of G6PC3 deficiency.


Assuntos
Glucose-6-Fosfatase/genética , Mutação , Neutropenia/congênito , Medula Óssea/patologia , Pré-Escolar , Síndrome Congênita de Insuficiência da Medula Óssea , Feminino , Humanos , Neutropenia/diagnóstico , Neutropenia/genética , Pancitopenia , Fenótipo , Síndrome
5.
Hum Mutat ; 34(6): 905-14, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23463630

RESUMO

Neutrophil elastase gene (ELANE) mutations are responsible for the majority of cases of severe congenital neutropenia (CN) and cyclic neutropenia (CyN). We screened CN (n = 395) or CyN (n = 92) patients for ELANE mutations and investigated the impact of mutations on mRNA expression, protein expression, and activity. We found 116 different mutations in 162 (41%) CN patients and 26 in 51 (55%) CyN patients, 69 of them were novel. CyN-associated mutations were predicted to be more benign than CN-associated mutations, but the mutation severity largely overlapped. The frequency of acquired CSF3R mutations, malignant transformation, and the need for hematopoietic stem cell transplantation was significantly higher in CN patients with ELANE mutation than in ELANE mutation negative patients. Cellular elastase activity was reduced in neutrophils from CN/CyN patients, irrespective of the mutation status. In CN, enzymatic activity was significantly lower in patients with ELANE mutations compared with those with wild-type ELANE. Despite differences in the spectrum of mutations in CN or CyN, type or localization of mutation only partially determine the clinical phenotype. Specific ELANE mutations have limited predictive value for leukemogenesis; the risk for leukemia was correlated with disease severity rather than with occurrence of an ELANE mutation.


Assuntos
Elastase de Leucócito/genética , Mutação , Neutropenia/congênito , Neutropenia/genética , Códon de Iniciação , Ativação Enzimática , Éxons , Expressão Gênica , Genótipo , Neoplasias Hematológicas/etiologia , Humanos , Elastase de Leucócito/metabolismo , Neutropenia/complicações , Neutropenia/metabolismo , Neutrófilos/metabolismo , Polimorfismo Genético , Regiões Promotoras Genéticas , Transporte Proteico , Sítios de Splice de RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
6.
Pediatr Blood Cancer ; 60(9): E94-6, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23625800

RESUMO

Congenital amegakaryocytic thrombocytopenia (CAMT) is characterised by neonatal thrombocytopenia, with reduced or absent bone marrow megakaryocytes, leading eventually to pancytopenia. The mean age for progression to bone marrow failure is four years, with the earliest reported being six months. We describe a CAMT patient with compound heterozygous mutations of the causative MPL gene (one being a previously unreported splice site mutation in intron 11) who developed pancytopenia within the first month of life. This report emphasises the importance of considering CAMT in the differential diagnosis of congenital aplastic anaemia or idiopathic aplastic anaemia in babies.


Assuntos
Mutação , Pancitopenia/diagnóstico , Pancitopenia/genética , Receptores de Trombopoetina/genética , Trombocitopenia/diagnóstico , Trombocitopenia/genética , Síndrome Congênita de Insuficiência da Medula Óssea , Diagnóstico Diferencial , Feminino , Humanos , Recém-Nascido , Íntrons/genética , Pancitopenia/complicações , Pancitopenia/patologia , Sítios de Splice de RNA/genética , Trombocitopenia/complicações , Trombocitopenia/patologia
7.
Nat Med ; 12(10): 1191-7, 2006 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17063141

RESUMO

We demonstrate here that lymphoid enhancer-binding factor 1 (LEF-1) mediates the proliferation, survival and differentiation of granulocyte progenitor cells. We initially documented the importance of this transcription factor in the bone marrow of individuals with severe congenital neutropenia (CN) with a 'differentiation block' at the promyelocytic stage of myelopoiesis. LEF-1 expression was greatly reduced or even absent in CN arrested promyelocytes, resulting in defective expression of the LEF-1 target genes CCND1, MYC and BIRC5, encoding cyclin D1 (ref. 2), c-Myc and survivin, respectively. In contrast, healthy individuals showed highest LEF-1 expression in promyelocytes. Reconstitution of LEF-1 in early hematopoietic progenitors of two individuals with CN corrected the defective myelopoiesis and resulted in the differentiation of these progenitors into mature granulocytes. Repression of endogenous LEF-1 by specific short hairpin RNA inhibited proliferation and induced apoptosis of CD34(+) progenitors from healthy individuals and of cells from two myeloid lines (HL-60 and K562). C/EBPalpha, a key transcription factor in granulopoiesis, was directly regulated by LEF-1. These observations indicate that LEF-1 is an instructive factor regulating neutrophilic granulopoiesis whose absence plays a critical role in the defective maturation program of myeloid progenitors in individuals with CN.


Assuntos
Regulação da Expressão Gênica , Granulócitos/citologia , Fator 1 de Ligação ao Facilitador Linfoide/fisiologia , Neutropenia/congênito , Neutropenia/patologia , Neutrófilos/citologia , Antígenos CD/biossíntese , Antígenos CD34/biossíntese , Antígenos de Diferenciação Mielomonocítica/biossíntese , Sequência de Bases , Ciclina D1/biossíntese , Granulócitos/metabolismo , Células HL-60 , Células-Tronco Hematopoéticas/citologia , Humanos , Células K562 , Fator 1 de Ligação ao Facilitador Linfoide/metabolismo , Dados de Sequência Molecular , Neutrófilos/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico
8.
J Pediatr Hematol Oncol ; 35(2): e81-3, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23018568

RESUMO

Glucose-6-phosphatase catalytic subunit 3 (G6PC3) deficiency is a newly described syndromic type of severe congenital neutropenia, associated with multiple organ abnormalities including facial, cardiac, and urogenital abnormalities, and increased visibility of superficial veins. The molecular pathophysiology of G6PC3 deficiency is associated with the disturbed glucose homeostasis, increased endoplasmic reticulum stress, and apoptosis in neutrophils. We report a new case of G6PC3 deficiency caused by a novel homozygous G6PC3 gene mutation (p.Leu154Pro). Most remarkable is that the chronic neutropenia that originated from this novel G6PC3 genetic defect is also accompanied by some other unusual manifestations in this patient: myelokathexis and hypercholesterolemia.


Assuntos
Glucose-6-Fosfatase/genética , Mutação , Neutropenia/congênito , Adolescente , Síndrome Congênita de Insuficiência da Medula Óssea , Feminino , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Humanos , Neutropenia/tratamento farmacológico , Neutropenia/genética
9.
Hamostaseologie ; 2023 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-37918839

RESUMO

Inherited platelet disorders (IPDs) represent a heterogeneous group of disorders that include both quantitative (thrombocytopenia or thrombocytosis) and qualitative (thrombocytopathy) defects. To gain better knowledge about the prevalence, pathogenesis, and clinical consequences of specific diseases, to improve diagnosis and treatment of patients with IPD, and to support translational research on a genetic, molecular, and physiological basis, the THROMKIDplus study group currently comprising 24 sites in Germany, Austria, and Switzerland decided to establish a patient registry with associated biomaterial banking for children. This registry is designed as a retrospective-prospective, multicenter observational study and supposed to launch in the second half of 2023. Blood smears, plasma, platelet pellets, and DNA of patients will be stored in certified biomaterial banks for future translational research projects. The main inclusion criteria are (1) diagnosis of or highly suspected IPD after assessment of a THROMKIDplus competence center and (2) patients aged 0 to 17 years. Initial and follow-up data on patient history, laboratory parameters, standardized documentation of bleeding tendency, and congenital defects are collected according to good clinical practice and current data protection acts by using the MARVIN platform, a broadly used data management system supported by the German Society for Pediatric Oncology Hematology (GPOH). The THROMKIDplus study group intends to enroll ∼200 patients retrospectively and an annual amount of ∼50 patients prospectively.

10.
N Engl J Med ; 360(1): 32-43, 2009 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-19118303

RESUMO

BACKGROUND: The main features of severe congenital neutropenia are the onset of severe bacterial infections early in life, a paucity of mature neutrophils, and an increased risk of leukemia. In many patients, the genetic causes of severe congenital neutropenia are unknown. METHODS: We performed genomewide genotyping and linkage analysis on two consanguineous pedigrees with a total of five children affected with severe congenital neutropenia. Candidate genes from the linkage interval were sequenced. Functional assays and reconstitution experiments were carried out. RESULTS: All index patients were susceptible to bacterial infections and had very few mature neutrophils in the bone marrow; structural heart defects, urogenital abnormalities, and venous angiectasia on the trunk and extremities were additional features. Linkage analysis of the two index families yielded a combined multipoint lod score of 5.74 on a linkage interval on chromosome 17q21. Sequencing of G6PC3, the candidate gene encoding glucose-6-phosphatase, catalytic subunit 3, revealed a homozygous missense mutation in exon 6 that abolished the enzymatic activity of glucose-6-phosphatase in all affected children in the two families. The patients' neutrophils and fibroblasts had increased susceptibility to apoptosis. The myeloid cells showed evidence of increased endoplasmic reticulum stress and increased activity of glycogen synthase kinase 3beta (GSK-3beta). We identified seven additional, unrelated patients who had severe congenital neutropenia with syndromic features and distinct biallelic mutations in G6PC3. CONCLUSIONS: Defective function of glucose-6-phosphatase, catalytic subunit 3, underlies a severe congenital neutropenia syndrome associated with cardiac and urogenital malformations.


Assuntos
Anormalidades Múltiplas/genética , Glucose-6-Fosfatase/genética , Cardiopatias Congênitas/genética , Mutação de Sentido Incorreto , Neutropenia/genética , Anormalidades Urogenitais/genética , Adolescente , Apoptose/genética , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Estudo de Associação Genômica Ampla , Glucose-6-Fosfatase/metabolismo , Doença de Depósito de Glicogênio Tipo I/genética , Humanos , Lactente , Escore Lod , Masculino , Neutropenia/congênito , Neutropenia/fisiopatologia , Neutrófilos/fisiologia , Linhagem , Síndrome , Telangiectasia/genética
11.
Semin Thromb Hemost ; 37(6): 673-81, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22102270

RESUMO

Congenital amegakaryocytic thrombocytopenia (CAMT, MIM #604498) is a rare inherited bone marrow failure syndrome presenting as isolated hypomegakaryocytic thrombocytopenia at birth without other characteristic physical anomalies. Most of the patients develop a severe aplastic anemia and trilineage cytopenia during the first years of life and hematopoietic stem cell transplantation is the only curative treatment. In most of the cases the disease is caused by homozygous or compound heterozygous mutations in the gene MPL encoding the receptor for the hematopoietic growth factor thrombopoietin. The present review summarizes clinical and laboratory data for 96 patients with CAMT, reported since 1990.


Assuntos
Trombocitopenia/diagnóstico , Trombocitopenia/cirurgia , Anemia Aplástica/diagnóstico , Síndrome Congênita de Insuficiência da Medula Óssea , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Lactente , Recém-Nascido , Mutação , Pancitopenia/diagnóstico , Receptores de Trombopoetina/genética , Trombocitopenia/genética , Resultado do Tratamento
12.
Blood ; 113(3): 668-70, 2009 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-19020310

RESUMO

Severe congenital neutropenia (CN) is a rare bone marrow failure syndrome with a high incidence of acute leukemia. In previous studies, we could show that point mutations in the gene for the granulocyte colony-stimulating factor (G-CSF) receptor CSF3R are a highly predictive marker for leukemic development in CN patients. To find out at which stage of hematopoietic development these mutations emerge and how they are propagated during hematopoietic differentiation, we analyzed single cells of different hematopoietic subpopulations from CN patients with CSF3R mutations. We found that CSF3R mutations are not restricted to the myeloid compartment but are also detectable in lymphoid cells, although at a much lower percentage. From our observations, we conclude that CSF3R mutations are acquired in multipotent hematopoietic progenitor cells in CN patients and that they are clonally expanded in myeloid cells expressing the G-CSF receptor due to the growth advantage mediated by the CSF3R mutation.


Assuntos
Transformação Celular Neoplásica/genética , Neutropenia/genética , Lesões Pré-Cancerosas/genética , Receptores de Fator Estimulador de Colônias/genética , Adolescente , Adulto , Progressão da Doença , Citometria de Fluxo , Humanos , Leucemia/genética , Mutação , Neutropenia/congênito , Reação em Cadeia da Polimerase Via Transcriptase Reversa
13.
Best Pract Res Clin Haematol ; 34(2): 101286, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34404532

RESUMO

Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare inherited bone marrow failure syndrome (IBMFS) that is characterized by severe thrombocytopenia at birth due to ineffective megakaryopoiesis and development towards aplastic anemia during the first years of life. CAMT is not a single monogenetic disorder; rather, many descriptions of CAMT include different entities with different etiologies. CAMT in a narrow sense, which is primarily restricted to the hematopoietic system, is caused mainly by mutations in the gene for the thrombopoietin receptor (MPL), sometimes in the gene for its ligand (THPO). CAMT in association with radio-ulnar synostosis, which is not always clinically apparent, is mostly caused by mutations in MECOM, rarely in HOXA11. Patients affected by other IBMFS - especially Fanconi anemia or dyskeratosis congenita - may be misdiagnosed as having CAMT when they lack typical disease features of these syndromes or have only mild symptoms. This article reviews scientific and clinical aspects of the various disorders associated with the term "CAMT" with a main focus on the disease caused by mutations in the MPL gene.


Assuntos
Trombocitopenia , Síndrome Congênita de Insuficiência da Medula Óssea , Humanos , Recém-Nascido , Mutação , Trombocitopenia/diagnóstico , Trombocitopenia/genética
14.
Blood ; 111(10): 4954-7, 2008 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-18337561

RESUMO

Homozygous mutations in HAX1 cause an autosomal recessive form of severe congenital neutropenia (CN). By screening 88 patients with CN, we identified 6 additional patients with HAX1 mutations carrying 4 novel mutations. Of these, 2 affect both published transcript variants of HAX1; the other 2 mutations affect only transcript variant 1. Analysis of the patients' genotypes and phenotypes revealed a striking correlation: Mutations affecting transcript variant 1 only were associated with CN (23 of 23 patients), whereas mutations affecting both transcript variants caused CN and neurologic symptoms, including epilepsy and neurodevelopmental delay (6 of 6 patients). In contrast to peripheral blood, transcript variant 2 was markedly expressed in human brain tissue. The clinical phenotype of HAX1 deficiency appears to depend on the localization of the mutation and their influence on the transcript variants. Therefore, our findings suggest that HAX1 isoforms may play a distinctive role in the neuronal system.


Assuntos
Mutação , Neutropenia/genética , Proteínas/genética , RNA Mensageiro/análise , Proteínas Adaptadoras de Transdução de Sinal , Adolescente , Adulto , Química Encefálica , Criança , Análise Mutacional de DNA , Frequência do Gene , Genótipo , Humanos , Lactente , Proteínas Mutantes , Neutropenia/congênito , Neutropenia/etnologia , Fenótipo , Isoformas de Proteínas/análise , Isoformas de Proteínas/genética , RNA Mensageiro/genética , Distribuição Tecidual
16.
Haematologica ; 95(7): 1207-10, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20220065

RESUMO

Severe congenital neutropenia a clinically and genetically heterogeneous disorder. Mutations in different genes have been described as causative for severe neutropenia, e.g. ELANE, HAX1 and G6PC3. Although congenital neutropenia is considered to be a group of monogenic disorders, the phenotypic heterogeneity even within the yet defined genetic subtypes points to additional genetic and/or epigenetic influences on the disease phenotype. We describe congenital neutropenia patients with mutations in two candidate genes each, including 6 novel mutations. Two of them had a heterozygous ELANE mutation combined with a homozygous mutation in G6PC3 or HAX1, respectively. The other 2 patients combined homozygous or compound heterozygous mutations in G6PC3 or HAX1 with a heterozygous mutation in the respective other gene. Our results suggest that digenicity may underlie this disorder of myelopoiesis at least in some congenital neutropenia patients.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Glucose-6-Fosfatase/genética , Mutação , Neutropenia/congênito , Criança , Genótipo , Humanos , Neutropenia/genética
17.
Eur J Pediatr ; 169(6): 759-62, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20177699

RESUMO

Kostmann disease is a rare autosomal recessive form of severe congenital neutropenia characterized by maturation arrest at the stage of promyelocytes/myelocytes in bone marrow with peripheral blood absolute neutrophil counts below 0.5 x 10(9)/L and severe recurrent bacterial infections from early infancy. Kostmann disease is caused by homozygous mutations in the gene encoding the mitochondrial protein HCLS1-associated X1. Here, we report three patients with Kostmann disease who, besides recurrent infections, have developmental delay.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/deficiência , Deficiências do Desenvolvimento , Síndromes de Imunodeficiência , Neutropenia/congênito , Proteínas Adaptadoras de Transdução de Sinal/genética , Idade de Início , Pré-Escolar , Consanguinidade , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/terapia , Feminino , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Humanos , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/terapia , Lactente , Masculino , Neutropenia/diagnóstico , Neutropenia/genética , Neutropenia/terapia , Síndrome , Turquia
18.
Eur J Pediatr ; 169(6): 657-60, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20165869

RESUMO

Rolf Kostmann (1909-1982) was a Swedish pediatrician and army doctor. He was the first to describe an inherited form of chronic neutropenia in childhood. In 1956, Kostmann published his article "Infantile genetic agranulocytosis" in Acta Paediatrica. "Infantile agranulocytosis," as Rolf Kostmann named this hereditary syndrome, has been known for more than half a century, yet the underlying genetic mutations have remained unknown for many decades. Fifty years later, homozygous mutations in the gene encoding the mitochondrial protein HCLS1-associated X1 were found in affected members of the original Kostmann pedigree. Therefore, the eponym "Kostmann disease" best fits this specific mutation and mode of inheritance. The identification of genetic cause now allows the analysis of genotype-phenotype correlations. After the development of recombinant human granulocyte colony-stimulating factor (G-CSF), the prognosis and quality of life improved dramatically. Hematopoietic stem cell transplantation remains the only currently available treatment for refractory cases to G-CSF and patients who have transformed into leukemia.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/deficiência , Epônimos , Neutropenia/congênito , Neutropenia/história , Proteínas Adaptadoras de Transdução de Sinal/genética , História do Século XX , Humanos , Mutação , Neutropenia/genética , Síndrome
19.
Br J Haematol ; 146(1): 3-16, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19388932

RESUMO

Congenital amegakaryocytic thrombocytopenia (MIM #604498) is an extremely rare inherited bone marrow failure syndrome, usually presenting as a severe thrombocytopenia at birth due to ineffective megakaryocytopoiesis and no characteristic physical anomalies. Usually the isolated thrombocytopenia progresses to pancytopenia during the first years of life. The only curative therapy to date is haematopoietic stem cell transplantation. Most of the cases of congenital amegakaryocytic thrombocytopenia are caused by defective expression or function of the thrombopoietin receptor due to homozygous or compound heterozygous mutations in the gene MPL. The essential roles of thrombopoietin as a lineage specific regulator of platelet production and as a regulator of haematopoietic stem cell function are reflected in the haematological defects seen in affected individuals.


Assuntos
Megacariócitos/patologia , Trombocitopenia/congênito , Trombocitopenia/patologia , Diagnóstico Diferencial , Progressão da Doença , Transplante de Células-Tronco Hematopoéticas , Humanos , Recém-Nascido , Mutação , Pancitopenia/genética , Receptores de Trombopoetina/genética , Trombocitopenia/cirurgia , Trombopoese/genética , Trombopoetina/genética
20.
Br J Haematol ; 144(4): 459-67, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19120359

RESUMO

Congenital Neutropenia (CN) is a heterogeneous bone marrow failure syndrome characterized by a maturation arrest of myelopoiesis at the level of the promyelocyte/myelocyte stage with peripheral blood absolute neutrophil counts below 0.5 x 10(9)/l. There are two major subtypes of CN as judged by inheritance: an autosomal dominant subtype, e.g. defined by neutrophil elastase mutations (approximately 60% of patients) and an autosomal recessive subtype (approximately 30% of patients), both presenting with the same clinical and morphological phenotype. Different mutations have been described (e.g. HAX1, p14 etc) in autosomal recessive CN, with HAX1 mutations in the majority of these patients. CN in common is considered as a preleukemic syndrome, since the cumulative incidence for leukemia is more than 25% after 20 years of observation. Leukemias occur in both, the autosomal dominant and recessive subtypes of CN. The individual risk for each genetic subtype needs to be further evaluated. Numbers of patients tested for the underlying genetic defect are still limited. Acquired G-CSFR (CSF3R) mutations are detected in approximately 80% of CN patients who developed acute myeloid leukemia independent of the ELA2 or HAX1 genetic subtype, suggesting that these mutations are involved in leukemogenesis. As the majority of patients benefit from G-CSF administration, HSCT should be restricted to non-responders and patients with leukaemic transformation.


Assuntos
Mutação , Neutropenia/genética , Proteínas/genética , Receptores de Fator Estimulador de Colônias de Granulócitos/genética , Serina Endopeptidases/genética , Proteínas Adaptadoras de Transdução de Sinal , Criança , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Humanos , Leucemia/etiologia , Neutropenia/congênito , Neutropenia/fisiopatologia , Neutropenia/terapia , Proteínas Recombinantes
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