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2.
Bone Marrow Transplant ; 55(8): 1614-1622, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31992846

RESUMO

ELANE neutropenia is associated with myelodysplasia and acute leukemia (MDS-AL), and severe infections. Because the MDS-AL risk has also been shown to be associated with exposure to GCSF, since 2005, in France, patients receiving high daily GCSF doses (>15 µg/kg/day) are eligible for HSCT, in addition to classic indications (MDS-AL or GCSF refractoriness). We analyzed the effect of this policy. Among 144 prospectively followed ELANE-neutropenia patients enrolled in the French Severe Congenital Neutropenia Registry, we defined two groups according to period: "before 2005" for those born before 2005 and followed until 31/12/2004 (1588 person-years); and "after 2005" comprised of those born after 2005 or born before 2005 but followed after 2005 until 31/03/2019 (1327 person-years). Sixteen of our cohort patients underwent HSCT (14 long-term survivors) and six developed MDS-ALs. Six leukemic transformations occurred in the before-2005 group and none after 2005 (respective frequencies 3.8 × 10-3 vs. 0; P < 0.01), while four HSCTs were done before 2005 and 12 since 2005 (respective HSCT rates increased 2.5 × 10-3 vs. 9 × 10-3; P < 0.01). Our results support early HSCT for patients with ELANE mutations who received high GCSF doses, as it might lower the risk of leukemic transformation.

3.
Blood ; 134(3): 277-290, 2019 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-31151987

RESUMO

Shwachman-Diamond syndrome (SDS) is a recessive disorder typified by bone marrow failure and predisposition to hematological malignancies. SDS is predominantly caused by deficiency of the allosteric regulator Shwachman-Bodian-Diamond syndrome that cooperates with elongation factor-like GTPase 1 (EFL1) to catalyze release of the ribosome antiassociation factor eIF6 and activate translation. Here, we report biallelic mutations in EFL1 in 3 unrelated individuals with clinical features of SDS. Cellular defects in these individuals include impaired ribosomal subunit joining and attenuated global protein translation as a consequence of defective eIF6 eviction. In mice, Efl1 deficiency recapitulates key aspects of the SDS phenotype. By identifying biallelic EFL1 mutations in SDS, we define this leukemia predisposition disorder as a ribosomopathy that is caused by corruption of a fundamental, conserved mechanism, which licenses entry of the large ribosomal subunit into translation.


Assuntos
Mutação , Fatores de Alongamento de Peptídeos/genética , Fatores de Iniciação de Peptídeos/biossíntese , Ribonucleoproteína Nuclear Pequena U5/genética , Síndrome de Shwachman-Diamond/genética , Síndrome de Shwachman-Diamond/metabolismo , Adolescente , Animais , Células Cultivadas , Análise Mutacional de DNA , Modelos Animais de Doenças , Suscetibilidade a Doenças , Feminino , Estudo de Associação Genômica Ampla , Humanos , Lactente , Masculino , Camundongos , Camundongos Transgênicos , Modelos Moleculares , Linhagem , Fatores de Alongamento de Peptídeos/química , Fatores de Alongamento de Peptídeos/metabolismo , Fenótipo , Conformação Proteica , Ribonucleoproteína Nuclear Pequena U5/química , Ribonucleoproteína Nuclear Pequena U5/metabolismo , Síndrome de Shwachman-Diamond/diagnóstico , Relação Estrutura-Atividade , Sequenciamento Completo do Genoma
4.
J Clin Immunol ; 39(2): 200-206, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30900095

RESUMO

PURPOSE: Neonatal immune neutropenia is observed in rare cases in newborns from mothers with idiopathic or autoimmune neutropenia, secondary to passive transfer of maternal granulocyte auto-antibodies. METHODS: We performed a literature review and report four supplementary cases from the French registry of neutropenia. RESULTS: Only 14 cases (11 mothers, 14 newborns) have been reported. Granulocyte aggregation (GAT) and granulocyte indirect immunofluorescence test (GIFT) are the recommended laboratory procedures for antibody detection. Monoclonal antibody-specific immobilization of granulocyte antigens (MAIGA)-confirmed antibody specificity. Antibody detection in newborns is not generally possible owing to extreme neutropenia. In half of the cases autoantibodies against neutrophils (AAN) were positive in maternal sera (7 out of 11). In some newborns tested, IgG+ AAN were also positive, with disappearance in parallel of spontaneous neutrophil count improvement. No correlation between maternal type of AAN and titer and neonatal neutropenia can be established. Neutropenia resolved spontaneously between 2 weeks and 4 months. Infections in newborns were observed in 43% of cases, with no deaths reported. Granulocyte colony-stimulating factor (G-CSF) was administered to some newborns (5 out of 14) in the case of infections. Low-dose G-CSF administered to childbearing women during pregnancy could be proposed to prevent neutropenia in newborns. CONCLUSIONS: From the few cases reported so far it is impossible to draw any conclusions regarding frequency, risk factors, and outcome, but the overall prognosis for newborns seems good. Because it can be associated with potentially severe neonatal infections, autoimmune neutropenia in childbearing mothers should be closely monitored in collaboration with gynecologists and pediatricians.


Assuntos
Neutropenia , Complicações Hematológicas na Gravidez , Adulto , Autoanticorpos/sangue , Feminino , França , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Granulócitos/imunologia , Humanos , Recém-Nascido , Infecções/tratamento farmacológico , Infecções/etiologia , Contagem de Leucócitos , Masculino , Mães , Neutropenia/sangue , Neutropenia/complicações , Neutropenia/imunologia , Gravidez , Complicações Hematológicas na Gravidez/sangue , Complicações Hematológicas na Gravidez/imunologia
5.
Blood ; 132(12): 1318-1331, 2018 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-29914977

RESUMO

Congenital neutropenias (CNs) are rare heterogeneous genetic disorders, with about 25% of patients without known genetic defects. Using whole-exome sequencing, we identified a heterozygous mutation in the SRP54 gene, encoding the signal recognition particle (SRP) 54 GTPase protein, in 3 sporadic cases and 1 autosomal dominant family. We subsequently sequenced the SRP54 gene in 66 probands from the French CN registry. In total, we identified 23 mutated cases (16 sporadic, 7 familial) with 7 distinct germ line SRP54 mutations including a recurrent in-frame deletion (Thr117del) in 14 cases. In nearly all patients, neutropenia was chronic and profound with promyelocytic maturation arrest, occurring within the first months of life, and required long-term granulocyte colony-stimulating factor therapy with a poor response. Neutropenia was sometimes associated with a severe neurodevelopmental delay (n = 5) and/or an exocrine pancreatic insufficiency requiring enzyme supplementation (n = 3). The SRP54 protein is a key component of the ribonucleoprotein complex that mediates the co-translational targeting of secretory and membrane proteins to the endoplasmic reticulum (ER). We showed that SRP54 was specifically upregulated during the in vitro granulocytic differentiation, and that SRP54 mutations or knockdown led to a drastically reduced proliferation of granulocytic cells associated with an enhanced P53-dependent apoptosis. Bone marrow examination of SRP54-mutated patients revealed a major dysgranulopoiesis and features of cellular ER stress and autophagy that were confirmed using SRP54-mutated primary cells and SRP54 knockdown cells. In conclusion, we characterized a pathological pathway, which represents the second most common cause of CN with maturation arrest in the French CN registry.


Assuntos
Doenças da Medula Óssea/genética , Estresse do Retículo Endoplasmático , Insuficiência Pancreática Exócrina/genética , Lipomatose/genética , Mutação , Neutropenia/congênito , Partícula de Reconhecimento de Sinal/genética , Adolescente , Adulto , Apoptose , Autofagia , Doenças da Medula Óssea/metabolismo , Doenças da Medula Óssea/patologia , Criança , Pré-Escolar , Síndrome Congênita de Insuficiência da Medula Óssea , Insuficiência Pancreática Exócrina/metabolismo , Insuficiência Pancreática Exócrina/patologia , Feminino , Humanos , Lactente , Recém-Nascido , Lipomatose/metabolismo , Lipomatose/patologia , Masculino , Pessoa de Meia-Idade , Neutropenia/genética , Neutropenia/metabolismo , Neutropenia/patologia , Síndrome de Shwachman-Diamond , Regulação para Cima , Adulto Jovem
6.
Haematologica ; 103(8): 1278-1287, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29724903

RESUMO

Heterozygous germline GATA2 mutations strongly predispose to leukemia, immunodeficiency, and/or lymphoedema. We describe a series of 79 patients (53 families) diagnosed since 2011, made up of all patients in France and Belgium, with a follow up of 2249 patients/years. Median age at first clinical symptoms was 18.6 years (range, 0-61 years). Severe infectious diseases (mycobacteria, fungus, and human papilloma virus) and hematologic malignancies were the most common first manifestations. The probability of remaining symptom-free was 8% at 40 years old. Among the 53 probands, 24 had missense mutations including 4 recurrent alleles, 21 had nonsense or frameshift mutations, 4 had a whole-gene deletion, 2 had splice defects, and 2 patients had complex mutations. There were significantly more cases of leukemia in patients with missense mutations (n=14 of 34) than in patients with nonsense or frameshift mutations (n=2 of 28). We also identify new features of the disease: acute lymphoblastic leukemia, juvenile myelomonocytic leukemia, fatal progressive multifocal leukoencephalopathy related to the JC virus, and immune/inflammatory diseases. A revised International Prognostic Scoring System (IPSS) score allowed a distinction to be made between a stable disease and hematologic transformation. Chemotherapy is of limited efficacy, and has a high toxicity with severe infectious complications. As the mortality rate is high in our cohort (up to 35% at the age of 40), hematopoietic stem cell transplantation (HSCT) remains the best choice of treatment to avoid severe infectious and/or hematologic complications. The timing of HSCT remains difficult to determine, but the earlier it is performed, the better the outcome.


Assuntos
Deficiência de GATA2/epidemiologia , Mutação em Linhagem Germinativa , Adulto Jovem , Adolescente , Adulto , Bélgica , Criança , Pré-Escolar , França , Deficiência de GATA2/complicações , Deficiência de GATA2/genética , Deficiência de GATA2/terapia , Neoplasias Hematológicas/etiologia , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Lactente , Recém-Nascido , Infecções/etiologia , Pessoa de Meia-Idade , Mortalidade , Prognóstico , Inquéritos e Questionários
7.
Br J Haematol ; 179(4): 557-574, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28875503

RESUMO

This review focuses on the classification, diagnosis and natural history of congenital neutropenia (CN). CN encompasses a number of genetic disorders with chronic neutropenia and, for some, affecting other organ systems, such as the pancreas, central nervous system, heart, bone and skin. To date, 24 distinct genes have been associated with CN. The number of genes involved makes gene screening difficult. This can be solved by next-generation sequencing (NGS) of targeted gene panels. One of the major complications of CN is spontaneous leukaemia, which is preceded by clonal somatic evolution, and can be screened by a targeted NGS panel focused on somatic events.


Assuntos
Genômica/métodos , Neutropenia/congênito , Transformação Celular Neoplásica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Leucemia/etiologia , Neutropenia/classificação , Neutropenia/complicações , Neutropenia/diagnóstico
8.
Pediatr Blood Cancer ; 64(12)2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28727239

RESUMO

OBJECTIVES: We developed a diagnostic score to differentiate congenital from noncongenital neutropenia at the time of diagnosis using reliable data collected at the first visit of a patients with neutropenia. STUDY DESIGN: In a pilot retrospective study, we included 120 patients diagnosed with chronic neutropenia; 61 had congenital and 59 had noncongenital neutropenia. We reviewed patient medical charts and collected the initial complete blood count (CBC) and other reliable data. We used logistic regression to determine the probability that the neutropenia was congenital. RESULTS: On the initial CBC, the degree of neutropenia had no predictive value; only monocytosis >1.5 × 109 /l, hemoglobin <90 g/l, or mild thrombocytopenia <150 × 109 /l suggested congenital neutropenia. The most predictive factors for congenital neutropenia were a medical history (consanguinity and patient history of neutropenia), severe infections, and oral stomatitis or gingivitis at the time of diagnosis. The age at diagnosis had limited predictive value. CONCLUSION: A diagnosis of congenital neutropenia may be reliably suspected based only on information from the CBC, some basic information from patient and parent interviews, and a clinical examination. A pilot score with six factors that could be readily, reliably collected, should facilitate the diagnosis of congenital neutropenia.


Assuntos
Neutropenia/diagnóstico , Doença Crônica , Diagnóstico Diferencial , Humanos , Modelos Logísticos , Neutropenia/congênito , Projetos Piloto , Sistema de Registros , Estudos Retrospectivos
9.
Blood ; 126(14): 1643-50, 2015 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-26261239

RESUMO

Severe chronic primary neutropenia (CPN) is a rare entity, and long-term outcome and risk factors for infections in severe CPN adults have not been described to date. We report the characteristics and outcomes of 108 severe adult CPN patients enrolled in a multi-institutional observational study. Severe CPN adults were mostly female (78%), and median age at diagnosis was 28.3 years. Diagnosis was fortuitous in 62% of cases. The median absolute neutrophil count (ANC) at diagnosis was 0.4 × 10(9)/L, and median ANC without granulocyte colony-stimulating factor (G-CSF) during follow-up was 0.5 × 10(9)/L. Twenty-three of 66 (34.8%) evaluable patients had neutrophil autoantibodies, and 6 of 47 (12.8%) a T-cell clone. The presence of neutrophil autoantibodies or T-cell clone was not associated with any specific clinical or biological characteristics. No death or hematologic malignancies occurred, and 44 severe bacterial infections were reported in 27 patients with a median follow-up of 8.3 years. Fifty patients received G-CSF either sporadically (n = 24) or continuously (n = 26) and responded (96%). Nineteen patients received immunosuppressive therapies: overall response (OR) was 41%, and median duration of response was 3 months. At diagnosis, the only predictive factor for the occurrence of severe bacterial infections was an ANC count below 0.2 × 10(9)/L (OR, 0.76). Severe CPN in adults is characterized by a female predominance and a benign outcome with a low rate of severe bacterial infections and no secondary malignancies. G-CSF is efficient and well tolerated but is not required in a majority of patients.


Assuntos
Neutropenia/sangue , Neutropenia/patologia , Adulto , Autoanticorpos/sangue , Feminino , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Humanos , Imunossupressores/uso terapêutico , Masculino , Neutropenia/tratamento farmacológico
10.
Orphanet J Rare Dis ; 9: 183, 2014 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-25491320

RESUMO

BACKGROUND: The purpose of this study was to describe the natural history of severe congenital neutropenia (SCN) in 14 patients with G6PC3 mutations and enrolled in the French SCN registry. METHODS: Among 605 patients included in the French SCN registry, we identified 8 pedigrees that included 14 patients with autosomal recessive G6PC3 mutations. RESULTS: Median age at the last visit was 22.4 years. All patients had developed various comordibities, including prominent veins (n = 12), cardiac malformations (n = 12), intellectual disability (n = 7), and myopathic syndrome with recurrent painful cramps (n = 1). Three patients developed Crohn's disease, and five had chronic diarrhea with steatorrhea. Neutropenia was profound (<0.5 × 109/l) in almost all cases at diagnosis and could marginally fluctuate. The bone marrow smears exhibited mild late-stage granulopoeitic defects. One patient developed myelodysplasia followed by acute myelogenous leukemia with translocation (18, 21) at age 14 years, cured by chemotherapy and hematopoietic stem cell transplantation. Four deaths occurred, including one from sepsis at age 5, one from pulmonary late-stage insufficiency at age 19, and two from sudden death, both at age 30 years. A new homozygous mutation (c.249G > A /p.Trp83*) was detected in one pedigree. CONCLUSIONS: Severe congenital neutropenia with autosomal recessive G6PC3 mutations is associated with considerable clinical heterogeneity. This series includes the first described case of malignancy in this neutropenia.


Assuntos
Glucose-6-Fosfatase/genética , Mutação/genética , Neutropenia/congênito , Sistema de Registros , Adulto , Síndrome Congênita de Insuficiência da Medula Óssea , Feminino , Seguimentos , França/epidemiologia , Humanos , Masculino , Neutropenia/diagnóstico , Neutropenia/genética , Neutropenia/mortalidade , Linhagem , Taxa de Sobrevida/tendências , Adulto Jovem
11.
Pediatr Blood Cancer ; 61(6): 1041-8, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24482108

RESUMO

OBJECTIVES: To describe the clinical profile and the prevalence of severe congenital neutropenia (SCN) and HAX1 mutations, so-called Kostmann syndrome, in France. STUDY DESIGN: Two pedigrees were identified from the French registry. RESULTS: The study included five subjects (three males), which represent 0.7% of the 759 SCN cases registered in France. The age at diagnosis was 0.3 years (range: 0.1-1.2 years) and the median age at the last follow-up was 7.3 years (range: 1.2-17.8 years). A novel large homozygous deletion of the HAX1 gene (exons 2-5) was found in one pedigree; while, a homozygous frameshift mutation was identified in exon 3 (c.430dupG, p.Val144fs) in the second pedigree. Severe bacterial infections were observed in four patients, including two cases of sepsis, one case of pancolitis, a lung abscess, and recurrent cellulitis and stomatitis. During routine follow-up, the median neutrophil value was 0.16 × 10(9)/L, associated with monocytosis (2 × 10(9)/L). Bone marrow (BM) smears revealed a decrease of the granulocytic lineage with no mature myeloid cells above the myelocytes. One patient died at age 2 from neurological complications, while two other patients, including one who underwent a hematopoietic stem cell transplantation (HSCT) at age 5, are living with very severe neurological retardation. CONCLUSIONS: SCN with HAX1 mutations, is a rare sub type of congenital neutropenia, mostly observed in population from Sweden and Asia minor, associating frequently neurological retardation, when the mutations involved the B isoform of the protein.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Neutropenia/congênito , Proteínas Adaptadoras de Transdução de Sinal/química , Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Atrofia , Infecções Bacterianas/etiologia , Encéfalo/patologia , Criança , Pré-Escolar , Síndrome Congênita de Insuficiência da Medula Óssea , Consanguinidade , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/patologia , Grupos Étnicos/genética , Éxons/genética , Feminino , França , Genes Recessivos , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Humanos , Hospedeiro Imunocomprometido , Lactente , Deficiência Intelectual/genética , Masculino , Mutação de Sentido Incorreto , Mielopoese/genética , Mielopoese/fisiologia , Neutropenia/sangue , Neutropenia/genética , Neutropenia/patologia , Neutropenia/cirurgia , Paquistão/etnologia , Linhagem , Polimorfismo de Nucleotídeo Único , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Isoformas de Proteínas/fisiologia , Deleção de Sequência
12.
Orphanet J Rare Dis ; 8: 70, 2013 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-23656970

RESUMO

BACKGROUND: This study describes the natural history of Barth syndrome (BTHS). METHODS: The medical records of all patients with BTHS living in France were identified in multiple sources and reviewed. RESULTS: We identified 16 BTHS pedigrees that included 22 patients. TAZ mutations were observed in 15 pedigrees. The estimated incidence of BTHS was 1.5 cases per million births (95%CI: 0.2-2.3). The median age at presentation was 3.1 weeks (range, 0-1.4 years), and the median age at last follow-up was 4.75 years (range, 3-15 years). Eleven patients died at a median age of 5.1 months; 9 deaths were related to cardiomyopathy and 2 to sepsis. The 5-year survival rate was 51%, and no deaths were observed in patients ≥3 years. Fourteen patients presented with cardiomyopathy, and cardiomyopathy was documented in 20 during follow-up. Left ventricular systolic function was very poor during the first year of life and tended to normalize over time. Nineteen patients had neutropenia. Metabolic investigations revealed inconstant moderate 3-methylglutaconic aciduria and plasma arginine levels that were reduced or in the low-normal range. Survival correlated with two prognostic factors: severe neutropenia at diagnosis (<0.5 × 109/L) and birth year. Specifically, the survival rate was 70% for patients born after 2000 and 20% for those born before 2000. CONCLUSIONS: This survey found that BTHS outcome was affected by cardiac events and by a risk of infection that was related to neutropenia. Modern management of heart failure and prevention of infection in infancy may improve the survival of patients with BTHS without the need for heart transplantation.


Assuntos
Síndrome de Barth/mortalidade , Síndrome de Barth/fisiopatologia , Adolescente , Síndrome de Barth/complicações , Síndrome de Barth/genética , Cardiomiopatias/complicações , Criança , Pré-Escolar , Estudos de Coortes , Feminino , França , Humanos , Masculino , Mutação , Neutropenia/complicações , Linhagem , Taxa de Sobrevida , Fatores de Transcrição/genética
13.
Hematol Oncol Clin North Am ; 27(1): 1-17, vii, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23351985

RESUMO

Epidemiologic investigations of congenital neutropenia aim to determine several important indicators related to the disease, such as incidence at birth, prevalence, and outcome in the population, including the rate of severe infections, leukemia, and survival. Genetic diagnosis is an important criterion for classifying patients and reliably determining the epidemiologic indicators. Patient registries were developed in the 1990s. The prevalence today is probably more than 10 cases per million inhabitants. The rate of infection and leukemia risk can now be calculated. Risk factors for leukemia seem to depend on both the genetic background and cumulative dose of granulocyte colony stimulating factor.


Assuntos
Neutropenia/congênito , Neutropenia/epidemiologia , Transformação Celular Neoplásica , Humanos , Incidência , Morbidade , Prevalência , Prognóstico , Sistema de Registros , Fatores de Risco
15.
Blood ; 121(5): 822-9, 2013 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-23223431

RESUMO

UNLABELLED: Congenital neutropenia is a group of genetic disorders that involve chronic neutropenia and susceptibility to infections. These neutropenias may be isolated or associated with immunologic defects or extra-hematopoietic manifestations. Complications may occur as infectious diseases, but also less frequently as myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Recently, the transcription factor GATA2 has been identified as a new predisposing gene for familial AML/MDS. In the present study, we describe the initial identification by exome sequencing of a GATA2 R396Q mutation in a family with a history of chronic mild neutropenia evolving to AML and/or MDS. The subsequent analysis of the French Severe Chronic Neutropenia Registry allowed the identification of 6 additional pedigrees and 10 patients with 6 different and not previously reportedGATA2 mutations (R204X, E224X, R330X, A372T, M388V, and a complete deletion of the GATA2 locus). The frequent evolution to MDS and AML in these patients reveals the importance of screening GATA2 in chronic neutropenia associated with monocytopenia because of the frequent hematopoietic transformation, variable clinical expression at onset, and the need for aggressive therapy in patients with poor clinical outcome. KEY POINTS: Mutations of key transcription factor in myeloid malignancies.


Assuntos
Fator de Transcrição GATA2/genética , Doenças Genéticas Inatas/genética , Leucemia Mieloide Aguda/genética , Mutação de Sentido Incorreto , Síndromes Mielodisplásicas/genética , Neutropenia/genética , Adolescente , Adulto , Substituição de Aminoácidos , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Criança , Pré-Escolar , Feminino , França , Fator de Transcrição GATA2/metabolismo , Doenças Genéticas Inatas/metabolismo , Doenças Genéticas Inatas/patologia , Doenças Genéticas Inatas/terapia , Loci Gênicos , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/terapia , Masculino , Síndromes Mielodisplásicas/metabolismo , Síndromes Mielodisplásicas/patologia , Síndromes Mielodisplásicas/terapia , Neutropenia/metabolismo , Linhagem , Sistema de Registros
16.
Orphanet J Rare Dis ; 7: 71, 2012 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-23009155

RESUMO

BACKGROUND: WHIM syndrome (WS), a rare congenital neutropenia due to mutations of the CXCR4 chemokine receptor, is associated with Human Papillomavirus (HPV)-induced Warts, Hypogammaglobulinemia, bacterial Infections and Myelokathexis. The long term follow up of eight patients highlights the clinical heterogeneity of this disease as well as the main therapeutic approaches and remaining challenges in the light of the recent development of new CXCR4 inhibitors. OBJECTIVE: This study aims to describe the natural history of WS based on a French cohort of 8 patients. METHODS: We have reviewed the clinical, biological and immunological features of patients with WS enrolled into the French Severe Chronic Neutropenia Registry. RESULTS: We identified four pedigrees with WS comprised of eight patients and one foetus. Estimated incidence for WS was of 0.23 per million births. Median age at the last visit was 29 years. Three pedigrees encompassing seven patients and the fetus displayed autosomal dominant heterozygous mutations of the CXCR4 gene, while one patient presented a wild-type CXCR4 gene. Two subjects exhibited congenital conotruncal heart malformations. In addition to neutropenia and myelokathexis, all patients presented deep monocytopenia and lymphopenia. Seven patients presented repeated bacterial Ears Nose Throat as well as severe bacterial infections that were curable with antibiotics. Four patients with late onset prophylaxis developed chronic obstructive pulmonary disease (COPD). Two patients reported atypical mycobacteria infections which in one case may have been responsible for one patient's death due to liver failure at the age of 40.6 years. HPV-related disease manifested in five subjects and progressed as invasive vulvar carcinoma with a fatal course in one patient at the age of 39.5 years. In addition, two patients developed T cell lymphoma skin cancer and basal cell carcinoma at the age of 38 and 65 years. CONCLUSIONS: Continuous prophylactic anti-infective measures, when started in early childhood, seem to effectively prevent further bacterial infections and the consequent development of COPD. Long-term follow up is needed to evaluate the effect of early anti-HPV targeted prophylaxis on the development of skin and genital warts.


Assuntos
Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/patologia , Verrugas/genética , Verrugas/patologia , Adolescente , Adulto , Antibacterianos/uso terapêutico , Infecções Bacterianas/etiologia , Infecções Bacterianas/prevenção & controle , Criança , Pré-Escolar , Feminino , Humanos , Síndromes de Imunodeficiência/complicações , Lactente , Masculino , Linhagem , Doenças da Imunodeficiência Primária , Receptores CXCR4/genética , Sistema de Registros , Verrugas/complicações , Adulto Jovem
17.
Haematologica ; 97(9): 1312-9, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22491737

RESUMO

BACKGROUND: Patients with the Shwachman-Diamond syndrome often develop hematologic complications. No risk factors for these complications have so far been identified. The aim of this study was to classify the hematologic complications occurring in patients with Shwachman-Diamond syndrome and to investigate the risk factors for these complications. DESIGN AND METHODS: One hundred and two patients with Shwachman-Diamond syndrome, with a median follow-up of 11.6 years, were studied. Major hematologic complications were considered in the case of definitive severe cytopenia (i.e. anemia <7 g/dL or thrombocytopenia <20 × 10(9)/L), classified as malignant (myelodysplasia/leukemia) according to the 2008 World Health Organization classification or as non-malignant. RESULTS: Severe cytopenia was observed in 21 patients and classified as malignant severe cytopenia (n=9), non-malignant severe cytopenia (n=9) and malignant severe cytopenia preceded by non-malignant severe cytopenia (n=3). The 20-year cumulative risk of severe cytopenia was 24.3% (95% confidence interval: 15.3%-38.5%). Young age at first symptoms (<3 months) and low hematologic parameters both at diagnosis of the disease and during the follow-up were associated with severe hematologic complications (P<0.001). Fifteen novel SBDS mutations were identified. Genotype analysis showed no discernible prognostic value. CONCLUSIONS Patients with Shwachman-Diamond syndrome with very early symptoms or cytopenia at diagnosis (even mild anemia or thrombocytopenia) should be considered at a high risk of severe hematologic complications, malignant or non-malignant. Transient severe cytopenia or an indolent cytogenetic clone had no deleterious value.


Assuntos
Doenças da Medula Óssea/complicações , Insuficiência Pancreática Exócrina/complicações , Doenças Hematológicas/classificação , Doenças Hematológicas/etiologia , Lipomatose/complicações , Doenças da Medula Óssea/mortalidade , Insuficiência Pancreática Exócrina/mortalidade , Feminino , Seguimentos , França , Doenças Hematológicas/mortalidade , Humanos , Lactente , Lipomatose/mortalidade , Masculino , Prognóstico , Estudos Prospectivos , Sistema de Registros , Fatores de Risco , Síndrome de Shwachman-Diamond , Taxa de Sobrevida
18.
J Exp Med ; 209(3): 565-80, 2012 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-22393124

RESUMO

Natural killer (NK) cells are bone marrow (BM)-derived granular lymphocytes involved in immune defense against microbial infections and tumors. In an N-ethyl N-nitrosourea (ENU) mutagenesis strategy, we identified a mouse mutant with impaired NK cell reactivity both in vitro and in vivo. Dissection of this phenotype showed that mature neutrophils were required both in the BM and in the periphery for proper NK cell development. In mice lacking neutrophils, NK cells displayed hyperproliferation and poor survival and were blocked at an immature stage associated with hyporesponsiveness. The role of neutrophils as key regulators of NK cell functions was confirmed in patients with severe congenital neutropenia and autoimmune neutropenia. In addition to their direct antimicrobial activity, mature neutrophils are thus endowed with immunoregulatory functions that are conserved across species. These findings reveal novel types of cooperation between cells of the innate immune system and prompt examination of NK cell functional deficiency in patients suffering from neutropenia-associated diseases.


Assuntos
Células Matadoras Naturais/imunologia , Neutropenia/imunologia , Neutrófilos/imunologia , Adulto , Animais , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Estudos de Casos e Controles , Diferenciação Celular , Criança , Pré-Escolar , Feminino , Homeostase , Humanos , Imunidade Inata , Lactente , Células Matadoras Naturais/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Camundongos Transgênicos , Pessoa de Meia-Idade , Neutropenia/congênito , Neutropenia/patologia , Neutrófilos/patologia , Adulto Jovem
19.
Orphanet J Rare Dis ; 6: 26, 2011 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-21595885

RESUMO

The term congenital neutropenia encompasses a family of neutropenic disorders, both permanent and intermittent, severe (<0.5 G/l) or mild (between 0.5-1.5 G/l), which may also affect other organ systems such as the pancreas, central nervous system, heart, muscle and skin. Neutropenia can lead to life-threatening pyogenic infections, acute gingivostomatitis and chronic parodontal disease, and each successive infection may leave permanent sequelae. The risk of infection is roughly inversely proportional to the circulating polymorphonuclear neutrophil count and is particularly high at counts below 0.2 G/l.When neutropenia is detected, an attempt should be made to establish the etiology, distinguishing between acquired forms (the most frequent, including post viral neutropenia and auto immune neutropenia) and congenital forms that may either be isolated or part of a complex genetic disease.Except for ethnic neutropenia, which is a frequent but mild congenital form, probably with polygenic inheritance, all other forms of congenital neutropenia are extremely rare and have monogenic inheritance, which may be X-linked or autosomal, recessive or dominant.About half the forms of congenital neutropenia with no extra-hematopoietic manifestations and normal adaptive immunity are due to neutrophil elastase (ELANE) mutations. Some patients have severe permanent neutropenia and frequent infections early in life, while others have mild intermittent neutropenia.Congenital neutropenia may also be associated with a wide range of organ dysfunctions, as for example in Shwachman-Diamond syndrome (associated with pancreatic insufficiency) and glycogen storage disease type Ib (associated with a glycogen storage syndrome). So far, the molecular bases of 12 neutropenic disorders have been identified.Treatment of severe chronic neutropenia should focus on prevention of infections. It includes antimicrobial prophylaxis, generally with trimethoprim-sulfamethoxazole, and also granulocyte-colony-stimulating factor (G-CSF). G-CSF has considerably improved these patients' outlook. It is usually well tolerated, but potential adverse effects include thrombocytopenia, glomerulonephritis, vasculitis and osteoporosis. Long-term treatment with G-CSF, especially at high doses, augments the spontaneous risk of leukemia in patients with congenital neutropenia.


Assuntos
Neutropenia/congênito , Neutropenia/etiologia , Antibacterianos/uso terapêutico , Predisposição Genética para Doença , Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Humanos , Neutropenia/genética , Neutropenia/terapia , Fatores de Risco
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