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1.
Blood ; 139(5): 779-791, 2022 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-34115842

RESUMO

Severe congenital neutropenia is an inborn disorder of granulopoiesis. Approximately one third of cases do not have a known genetic cause. Exome sequencing of 104 persons with congenital neutropenia identified heterozygous missense variants of CLPB (caseinolytic peptidase B) in 5 severe congenital neutropenia cases, with 5 more cases identified through additional sequencing efforts or clinical sequencing. CLPB encodes an adenosine triphosphatase that is implicated in protein folding and mitochondrial function. Prior studies showed that biallelic mutations of CLPB are associated with a syndrome of 3-methylglutaconic aciduria, cataracts, neurologic disease, and variable neutropenia. However, 3-methylglutaconic aciduria was not observed and, other than neutropenia, these clinical features were uncommon in our series. Moreover, the CLPB variants are distinct, consisting of heterozygous variants that cluster near the adenosine triphosphate-binding pocket. Both genetic loss of CLPB and expression of CLPB variants result in impaired granulocytic differentiation of human hematopoietic progenitor cells and increased apoptosis. These CLPB variants associate with wild-type CLPB and inhibit its adenosine triphosphatase and disaggregase activity in a dominant-negative fashion. Finally, expression of CLPB variants is associated with impaired mitochondrial function but does not render cells more sensitive to endoplasmic reticulum stress. Together, these data show that heterozygous CLPB variants are a new and relatively common cause of congenital neutropenia and should be considered in the evaluation of patients with congenital neutropenia.


Assuntos
Síndrome Congênita de Insuficiência da Medula Óssea/genética , Endopeptidase Clp/genética , Neutropenia/congênito , Células Cultivadas , Endopeptidase Clp/química , Exoma , Feminino , Variação Genética , Heterozigoto , Humanos , Lactente , Masculino , Modelos Moleculares , Mutação , Neutropenia/genética
2.
J Clin Immunol ; 42(8): 1748-1765, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35947323

RESUMO

Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome (WS) is a combined immunodeficiency caused by gain-of-function mutations in the C-X-C chemokine receptor type 4 (CXCR4) gene. We characterize a unique international cohort of 66 patients, including 57 (86%) cases previously unreported, with variable clinical phenotypes. Of 17 distinct CXCR4 genetic variants within our cohort, 11 were novel pathogenic variants affecting 15 individuals (23%). All variants affect the same CXCR4 region and impair CXCR4 internalization resulting in hyperactive signaling. The median age of diagnosis in our cohort (5.5 years) indicates WHIM syndrome can commonly present in childhood, although some patients are not diagnosed until adulthood. The prevalence and mean age of recognition and/or onset of clinical manifestations within our cohort were infections 88%/1.6 years, neutropenia 98%/3.8 years, lymphopenia 88%/5.0 years, and warts 40%/12.1 years. However, we report greater prevalence and variety of autoimmune complications of WHIM syndrome (21.2%) than reported previously. Patients with versus without family history of WHIM syndrome were diagnosed earlier (22%, average age 1.3 years versus 78%, average age 5 years, respectively). Patients with a family history of WHIM syndrome also received earlier treatment, experienced less hospitalization, and had less end-organ damage. This observation reinforces previous reports that early treatment for WHIM syndrome improves outcomes. Only one patient died; death was attributed to complications of hematopoietic stem cell transplantation. The variable expressivity of WHIM syndrome in pediatric patients delays their diagnosis and therapy. Early-onset bacterial infections with severe neutropenia and/or lymphopenia should prompt genetic testing for WHIM syndrome, even in the absence of warts.


Assuntos
Agamaglobulinemia , Síndromes de Imunodeficiência , Linfopenia , Neutropenia , Verrugas , Humanos , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/epidemiologia , Síndromes de Imunodeficiência/genética , Verrugas/diagnóstico , Verrugas/epidemiologia , Verrugas/genética , Agamaglobulinemia/genética , Receptores CXCR4/genética , Neutropenia/genética , Linfopenia/complicações , Progressão da Doença
3.
Blood ; 136(26): 2994-3003, 2020 12 24.
Artigo em Inglês | MEDLINE | ID: mdl-32870250

RESUMO

Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a rare primary immunodeficiency caused by gain-of-function mutations in the CXCR4 gene. We report the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of mavorixafor from a phase 2 open-label dose-escalation and extension study in 8 adult patients with genetically confirmed WHIM syndrome. Mavorixafor is an oral small molecule selective antagonist of the CXCR4 receptor that increases mobilization and trafficking of white blood cells from the bone marrow. Patients received escalating doses of mavorixafor, up to 400 mg once daily. Five patients continued on the extension study for up to 28.6 months. Mavorixafor was well tolerated with no treatment-related serious adverse events. At a median follow-up of 16.5 months, we observed dose-dependent increases in absolute neutrophil count (ANC) and absolute lymphocyte count (ALC). At doses ≥300 mg/d, ANC was maintained at >500 cells per microliter for a median of 12.6 hours, and ALC was maintained at >1000 cells per microliter for up to 16.9 hours. Continued follow-up on the extension study resulted in a yearly infection rate that decreased from 4.63 events (95% confidence interval, 3.3-6.3) in the 12 months prior to the trial to 2.27 events (95% confidence interval, 1.4-3.5) for patients on effective doses. We observed an average 75% reduction in the number of cutaneous warts. This study demonstrates that mavorixafor, 400 mg once daily, mobilizes neutrophil and lymphocytes in adult patients with WHIM syndrome and provides preliminary evidence of clinical benefit for patients on long-term therapy. The trial was registered at www.clinicaltrials.gov as #NCT03005327.


Assuntos
Aminoquinolinas/administração & dosagem , Benzimidazóis/administração & dosagem , Butilaminas/administração & dosagem , Doenças da Imunodeficiência Primária/tratamento farmacológico , Receptores CXCR4/antagonistas & inibidores , Verrugas/tratamento farmacológico , Administração Oral , Adolescente , Adulto , Aminoquinolinas/efeitos adversos , Benzimidazóis/efeitos adversos , Butilaminas/efeitos adversos , Feminino , Humanos , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Neutrófilos , Doenças da Imunodeficiência Primária/sangue , Doenças da Imunodeficiência Primária/genética , Estudos Prospectivos , Receptores CXCR4/genética , Verrugas/sangue , Verrugas/genética
4.
Curr Opin Hematol ; 27(1): 11-17, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31652152

RESUMO

PURPOSE OF REVIEW: WHIM syndrome (warts, hypogammaglobulinemia, immunodeficiency, myelokathexis, or WHIMs) is a very rare autosomal dominant immunodeficiency disorder attributable to mutations in CXCR4. We reviewed clinical manifestations in 24 patients in 9 families to expand understanding of this syndrome. RECENT FINDINGS: Warts, cellulitis and respiratory infections are common in patients with WHIMs. Less commonly these patients have congenital heart disease, human papilloma virus-associated malignancies (cervical and vulvular) and lymphomas. Hearing loss because of recurrent otitis media is another important complication. Treatment with granulocyte colony-stimulating factor is controversial; this review indicates that it is effective to prevent and treat infections based upon long-term observations of patients enrolled in the Severe Chronic Neutropenia International Registry. Understanding the natural history and diversity of this syndrome are important for ongoing clinical trials of novel agents to treat WHIMs. SUMMARY: WHIM syndrome has diverse manifestations; some features occur consistently in almost all patients, for example, neutropenia, lymphocytopenia and mild hypogammaglobulinemia. However, the clinical consequences are quite variable across patient cohorts and within families. Each complication is important as a cause for morbidity and a source for patient and family concerns.


Assuntos
Agamaglobulinemia , Família , Mutação , Doenças da Imunodeficiência Primária , Receptores CXCR4/genética , Sistema de Registros , Verrugas , Agamaglobulinemia/diagnóstico , Agamaglobulinemia/genética , Agamaglobulinemia/patologia , Agamaglobulinemia/terapia , Feminino , Humanos , Masculino , Doenças da Imunodeficiência Primária/diagnóstico , Doenças da Imunodeficiência Primária/genética , Doenças da Imunodeficiência Primária/patologia , Doenças da Imunodeficiência Primária/terapia , Fatores de Risco , Verrugas/diagnóstico , Verrugas/genética , Verrugas/patologia , Verrugas/terapia
5.
Curr Opin Hematol ; 27(1): 18-26, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31764167

RESUMO

PURPOSE OF REVIEW: Registries provide 'real world' perspectives on the natural history and outcomes for many clinical conditions. The purpose of this review is to identify registries for nonmalignant hematological disease and to describe the operation of a successful long-term registry for patients with severe chronic neutropenia. RECENT FINDINGS: There was an upswing in registries about 20 years ago, based on optimism about their utility to improve patient care. To show value, registries must define outcomes for populations of patients with specific medical conditions and the effects of treatment. This is challenging for many reasons. The Severe Chronic Neutropenia International Registry is an example of a successful registry. This report describes underlying reasons for its success. SUMMARY: Registries are important to organize and analyze clinical information across geographic, ethnic and social boundaries. They are also challenging to organize, administer and support.


Assuntos
Neutropenia , Sistema de Registros , Feminino , Humanos , Masculino , Neutropenia/diagnóstico , Neutropenia/epidemiologia , Neutropenia/terapia
6.
Curr Opin Hematol ; 26(1): 16-21, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30451720

RESUMO

PURPOSE OF REVIEW: Glycogen storage disease Ib (GSD Ib) is characterized by hepatomegaly, hypoglycemia, neutropenia, enterocolitis and recurrent bacterial infections. It is attributable to mutations in G6PT1, the gene for the glucose-6-phosphate transporter responsible for transport of glucose into the endoplasmic reticulum. Neutropenia in GSD Ib is now frequently treated with granulocyte colony-stimulating factor (G-CSF). We formed a cooperative group to review outcomes of the long-term treatment of GSD Ib patients treated with G-CSF. RECENT FINDINGS: The study enrolled 103 patients (48 men and 55 women), including 47 currently adult patients. All of these patients were treated with G-CSF, starting at a median age of 3.8 years (range 0.04-33.9 years) with a median dose of 3.0 mcg/kg/day (range 0.01-93.1 mcg/kg/day) for a median of 10.3 years (range 0.01-29.3 years). Neutrophils increased in response to G-CSF in all patients (median values before G-CSF 0.2 × 10/l, on G-CSF 1.20 x 10/l). Treatment increased spleen size (before G-CSF, 47%, on treatment on G-CSF 76%), and splenomegaly was the dose-limiting adverse effect of treatment (pain and early satiety). Clinical observations and records attest to reduce frequency of infectious events and the severity of inflammatory bowel symptoms, but fever and recurrent infections remain a significant problem. In the cohort of patients followed carefully through the Severe Chronic Neutropenia International Registry, four patients have developed myelodysplasia or acute myeloid leukemia and we are aware of four other cases, (altogether seven on G-CSF, one never treated with G-CSF). Liver transplantation in five patients did not correct neutropenia. Four patients had hematopoietic stem cell transplantation; two adults and two children were transplanted; one adult and one child survived. SUMMARY: GSD Ib is a complex disorder of glucose metabolism causing severe chronic neutropenia. G-CSF is effective to raise blood neutrophil counts and reduce fevers and infections in most patients. In conjunction with other therapies (salicylates, mesalamine sulfasalazine and prednisone), G-CSF ameliorates inflammatory bowel symptoms, but doses must be limited because it increases spleen size associated with abdominal pain.


Assuntos
Doença de Depósito de Glicogênio Tipo I/tratamento farmacológico , Doença de Depósito de Glicogênio Tipo I/mortalidade , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Neutropenia/tratamento farmacológico , Neutropenia/mortalidade , Sistema de Registros , Adolescente , Adulto , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Doença de Depósito de Glicogênio Tipo I/sangue , Doença de Depósito de Glicogênio Tipo I/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Neutropenia/sangue , Neutropenia/patologia , Neutrófilos/metabolismo , Neutrófilos/patologia , Taxa de Sobrevida
8.
Curr Opin Hematol ; 22(1): 3-11, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25427142

RESUMO

PURPOSE OF REVIEW: Mutations in the gene for neutrophil elastase, ELANE, cause cyclic neutropenia (CyN) and severe congenital neutropenia (SCN). This study summarized data from the Severe Chronic Neutropenia International Registry (SCNIR) on genotype-phenotype relationships of ELANE mutations to important clinical outcomes. We also summarize findings for ELANE mutations not observed in SCNIR patients. RECENT FINDINGS: There were 307 SCNIR patients with 104 distinctive ELANE mutations who were followed longitudinally for up to 27 years. The ELANE mutations were diverse; there were 65 single amino acid substitutions; 61 of these mutations (94%) were 'probably' or 'possibly damaging' by PolyPhen-2 analysis, and one of the 'benign' mutations was associated with two cases of acute myeloid leukemia (AML). All frame-shift mutations (19/19) were associated with the SCN. The pattern of mutations in the SCN versus CyN was significantly different (P < 10), but some mutations were observed in both groups (overlapping mutations). The cumulative incidence of severe adverse events, that is, myelodysplasia, AML, stem cell transplantation, or deaths was significantly greater for patients with SCN versus those with CyN or overlapping mutations. Specific mutations (i.e. G214R or C151Y) had a high risk for evolution to AML. SUMMARY: Sequencing is useful for predicting outcomes of ELANE-associated neutropenia.


Assuntos
Doenças Genéticas Inatas/genética , Elastase de Leucócito/genética , Mutação , Neutropenia/genética , Animais , Doenças Genéticas Inatas/enzimologia , Humanos , Leucemia Mieloide Aguda/enzimologia , Leucemia Mieloide Aguda/genética , Elastase de Leucócito/metabolismo , Neutropenia/enzimologia
9.
Hum Mutat ; 35(7): 824-7, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24753205

RESUMO

Severe congenital neutropenia (SCN) is a rare hematopoietic disorder, with estimated incidence of 1 in 200,000 individuals of European descent, many cases of which are inherited in an autosomal dominant pattern. Despite the fact that several causal genes have been identified, the genetic basis for >30% of cases remains unknown. We report a five-generation family segregating a novel single nucleotide variant (SNV) in TCIRG1. There is perfect cosegregation of the SNV with congenital neutropenia in this family; all 11 affected, but none of the unaffected, individuals carry this novel SNV. Western blot analysis show reduced levels of TCIRG1 protein in affected individuals, compared to healthy controls. Two unrelated patients with SCN, identified by independent investigators, are heterozygous for different, rare, highly conserved, coding variants in TCIRG1.


Assuntos
Neutropenia/congênito , ATPases Vacuolares Próton-Translocadoras/genética , Síndrome Congênita de Insuficiência da Medula Óssea , Análise Mutacional de DNA , Heterozigoto , Humanos , Mutação , Neutropenia/diagnóstico , Neutropenia/genética , Neutropenia/metabolismo , Linhagem , ATPases Vacuolares Próton-Translocadoras/metabolismo
10.
J Pediatr ; 164(4): 866-70, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24388329

RESUMO

OBJECTIVES: To investigate the range of clinical presentations for Shwachman-Diamond syndrome (SDS) with the long-term goal of improving diagnosis. STUDY DESIGN: We reviewed the North American Shwachman-Diamond Syndrome Registry. Genetic reports of biallelic Shwachman-Bodian-Diamond syndrome mutations confirming the diagnosis of SDS were available for 37 patients. RESULTS: Neutropenia was the most common hematologic abnormality at presentation (30/37, 81%); however, only 51% (19/37) of patients presented with the classic combination of neutropenia and steatorrhea. Absence of pancreatic lipomatosis on ultrasound or computed tomography scan, normal fecal elastase levels, and normal skeletal survey do not rule out the diagnosis of SDS. SDS was diagnosed in 2 asymptomatic siblings of SDS probands. Twenty-four of 37 patients (65%) had congenital anomalies. CONCLUSION: Our cohort reveals a broad range of clinical presentation for SDS. Clues to the underlying diagnosis of SDS included cytopenias with a hypocellular marrow, congenital anomalies, family history, and myelodysplasia with clonal abnormalities frequently found in SDS. Reliance on classic clinical criteria for SDS would miss or delay diagnosis of a significant subset of patients with SDS.


Assuntos
Doenças da Medula Óssea/diagnóstico , Insuficiência Pancreática Exócrina/diagnóstico , Lipomatose/diagnóstico , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , América do Norte , Sistema de Registros , Estudos Retrospectivos , Síndrome de Shwachman-Diamond
11.
Blood ; 118(18): 4963-6, 2011 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-21835955

RESUMO

Mutations in CXCR4 cause severe leukopenia in myelokathexis or WHIM syndrome. Plerixafor inhibits binding of CXCR4 to its ligand CXCL12. We investigated the effects of plerixafor (0.04 to 0.24 mg/kg) administered at 2-4 day intervals in 6 patients. Outcome measures were the patients' complete blood cell counts, CD34(+) cell counts and lymphocyte subtypes compared with 5 normal subjects similarly treated with plerixafor. All patients showed prompt leukocytosis with maximum blood neutrophils and lymphocytes at 6-12 hours. Blood neutrophils peaked at 6-12 hours, increasing from a mean baseline of 0.4 ± 0.1 × 109/L, to mean peak of 4.5 ± 0.78 × 109/L. Lymphocytes also increased; the greatest increase was in B cells (CD19(+) cells), a > 40-fold increase over baseline at the 0.08 mg/kg dose. None of the patients experienced any significant adverse effects. Plerixafor is a promising therapy for this condition.


Assuntos
Células Precursoras de Granulócitos/efeitos dos fármacos , Compostos Heterocíclicos/uso terapêutico , Síndromes de Imunodeficiência/tratamento farmacológico , Verrugas/tratamento farmacológico , Adulto , Idoso , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/uso terapêutico , Benzilaminas , Doenças da Medula Óssea/tratamento farmacológico , Doenças da Medula Óssea/patologia , Ciclamos , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Células Precursoras de Granulócitos/patologia , Compostos Heterocíclicos/administração & dosagem , Compostos Heterocíclicos/efeitos adversos , Compostos Heterocíclicos/farmacocinética , Humanos , Síndromes de Imunodeficiência/sangue , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/patologia , Leucopenia/complicações , Leucopenia/tratamento farmacológico , Leucopenia/patologia , Masculino , Pessoa de Meia-Idade , Doenças da Imunodeficiência Primária , Receptores CXCR4/antagonistas & inibidores , Receptores CXCR4/genética , Verrugas/sangue , Verrugas/genética , Verrugas/patologia
12.
Expert Rev Hematol ; 16(12): 1025-1033, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37978893

RESUMO

INTRODUCTION: Severe chronic neutropenia, i.e. absolute neutrophil count (ANC) less than 0.5 × 109/L, is a serious health problem because it predisposes patients to recurrent bacterial infections. Management radically changed with the discovery that granulocyte colony-stimulating factor (G-CSF) could be used to effectively treat most patients; therapy required regular subcutaneous injections. In the early days of G-CSF therapy, there were concerns that it might somehow overstimulate the bone marrow and cause myelodysplasia (MDS) or acute myeloid leukemia (AML). Detailed research records from the Severe Chronic Neutropenia International Registry (SCNIR) indicate that this is a relatively low-risk event. The research records suggest that certain patient groups are primarily at risk. Presently, allogeneic hematopoietic stem cell therapy serves as an alternate form of therapy. AREAS COVERED: Due to these concerns and the desire for an easy-to-take oral alternative, several new treatments are under investigation. These treatments include neutrophil elastase inhibitors, SGLT-2 inhibitors, mavorixafor - an oral CXCR4 inhibitor, gene therapy, and gene editing. EXPERT OPINION: All of these alternatives to G-CSF are promising. The risks, relative benefits, and costs are yet to be determined.


Assuntos
Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Neutropenia , Humanos , Neutropenia/terapia , Neutropenia/induzido quimicamente , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Leucemia Mieloide Aguda/genética , Síndromes Mielodisplásicas/etiologia
13.
Blood Adv ; 6(13): 3861-3869, 2022 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-35476051

RESUMO

Severe chronic neutropenia (SCN), defined as blood neutrophils <0.5 × 109/L for >3 months, is an uncommon hematological condition associated with recurrent and severe bacterial infections. After short-term clinical trials showed the benefits of granulocyte colony-stimulating factor (G-CSF) treatment for SCN, SCNIR (Severe Chronic Neutropenia International Registry) opened to determine the long-term benefits and safety of this treatment. This report summarizes findings from more than 16 000 patient-years of prospective observations for patients with congenital and acquired SCN. We observed that adverse outcomes depend on the underlying etiology. Myelodysplasia (MDS) and acute myeloid leukemia (AML) occur infrequently and largely in patients with congenital neutropenias. Having cyclic or chronic autoimmune/ idiopathic neutropenia portends a favorable prognosis. A few patients with idiopathic neutropenia evolve to develop lymphoid malignancies, but they do not appear to be at increased risk of myeloid malignancies, even with very long-term G-CSF therapy. Progression to systemic autoimmune diseases, bone marrow (BM) failure, aplastic anemia, or nonmyeloid malignancies are not expected consequences of SCN or treatment with G-CSF.


Assuntos
Fator Estimulador de Colônias de Granulócitos , Síndromes Mielodisplásicas , Neutropenia , Doença Crônica , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Humanos , Síndromes Mielodisplásicas/tratamento farmacológico , Neutropenia/tratamento farmacológico , Estudos Prospectivos
14.
Pediatr Blood Cancer ; 55(2): 314-7, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20582973

RESUMO

BACKGROUND: Cyclic neutropenia (CN) and severe congenital neutropenia (SCN) are disorders of neutrophil production that differ markedly in disease severity. Mutations of the ELANE gene (the symbol recently replacing ELA2) are considered largely responsible for most cases of CN and SCN, but specific mutations are typically associated with one or the other. PROCEDURE: We performed ELANE genotyping on all individuals and paternal sperm in an SCN kindred with eight SCN progeny of a sperm donor and six different mothers. RESULTS: One patient with CN had the same S97L ELANE mutation as seven patients with the SCN phenotype. The mutant allele was detected in the donor's spermatozoa, representing 18% of the ELANE gene pool, but not in DNA from his lymphocytes, neutrophils, or buccal mucosa, indicating gonadal mosaicism. CONCLUSIONS: The coexistence of CN and SCN phenotypes in this kindred with a shared paternal haplotype strongly suggests both a role for modifying genes in determination of congenital neutropenia disease phenotypes, and the classification of CN and SCN within a spectrum of phenotypes expressing varying degrees of the same disease process.


Assuntos
Haplótipos , Padrões de Herança/genética , Elastase de Leucócito/genética , Mutação , Neutropenia/genética , Sequência de Bases , Criança , Pré-Escolar , Pai , Predisposição Genética para Doença , Humanos , Lactente , Masculino , Neutropenia/congênito , Linhagem , Fenótipo , Espermatozoides/enzimologia
15.
J Leukoc Biol ; 102(4): 1143-1151, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28754797

RESUMO

Mutations in ELANE, the gene for neutrophil elastase (NE), a protease expressed early in neutrophil development, are the most frequent cause of cyclic (CyN) and severe congenital neutropenia (SCN). We hypothesized that inhibitors of NE, acting either by directly inhibiting enzymatic activity or as chaperones for the mutant protein, might be effective as therapy for CyN and SCN. We investigated ß-lactam-based inhibitors of human NE (Merck Research Laboratories, Kenilworth, NJ, USA), focusing on 1 inhibitor called MK0339, a potent, orally absorbed agent that had been tested in clinical trials and shown to have a favorable safety profile. Because fresh, primary bone marrow cells are rarely available in sufficient quantities for research studies, we used 3 cellular models: patient-derived, induced pluripotent stem cells (iPSCs); HL60 cells transiently expressing mutant NE; and HL60 cells with regulated expression of the mutant enzyme. In all 3 models, the cells expressing the mutant enzyme had reduced survival as measured with annexin V and FACS. Coincubation with the inhibitors, particularly MK0339, promoted cell survival and increased formation of mature neutrophils. These studies suggest that cell-permeable inhibitors of neutrophil elastase show promise as novel therapies for ELANE-associated neutropenia.


Assuntos
Inibidores Enzimáticos/farmacologia , Elastase de Leucócito , Mutação , Neutropenia/congênito , Sobrevivência Celular , Síndrome Congênita de Insuficiência da Medula Óssea , Feminino , Células HL-60 , Humanos , Elastase de Leucócito/antagonistas & inibidores , Elastase de Leucócito/genética , Elastase de Leucócito/metabolismo , Masculino , Neutropenia/tratamento farmacológico , Neutropenia/enzimologia , Neutropenia/genética
16.
Obstet Gynecol ; 125(1): 197-203, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25560125

RESUMO

OBJECTIVE: To report outcomes associated with the administration of granulocyte colony-stimulating factor (G-CSF) to women with chronic neutropenia during pregnancy. METHODS: We conducted an observational study of women of childbearing potential with congenital, cyclic, idiopathic, or autoimmune neutropenia enrolled in the Severe Chronic Neutropenia International Registry to determine outcomes of pregnancies, without and with chronic G-CSF therapy, 1999-2014. Treatment decisions were made by the patients' personal physicians. A research nurse conducted telephone interviews of all enrolled U.S. women of childbearing potential using a standard questionnaire. Comparisons used Fisher's exact test analysis and Student's t test. RESULTS: One hundred seven women reported 224 pregnancies, 124 without G-CSF therapy and 100 on chronic G-CSF therapy (median dose 1.0 micrograms/kg per day, range 0.02-8.6 micrograms/kg per day). There were no significant differences in adverse events between the groups considering all pregnancies or individual mothers, for example, spontaneous terminations (all pregnancies: no G-CSF in 27/124, G-CSF in 13/100; P=.11, Fisher's exact test), preterm labors (all pregnancies, no G-CSF in 9/124, G-CSF in 2/100, P=.12). A study with at least 300 per group would be needed to detect a difference in these events with 80% statistical power (α=0.05). Four newborns of mothers with idiopathic or autoimmune neutropenia not on G-CSF (4/101) had life-threatening infections, whereas there were no similar events (0/90) in the treated group, but this difference was also not statistically significant (P=.124). Adverse events in the neonates were similar for the two groups. CONCLUSION: This observational study showed no significant adverse effects of administration of G-CSF to women with severe chronic neutropenia during pregnancy. LEVEL OF EVIDENCE: III.


Assuntos
Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Neutropenia/tratamento farmacológico , Neutrófilos , Complicações Hematológicas na Gravidez/tratamento farmacológico , Aborto Espontâneo/epidemiologia , Adolescente , Adulto , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Infecções/epidemiologia , Contagem de Leucócitos , Nascido Vivo , Neutropenia/sangue , Trabalho de Parto Prematuro/epidemiologia , Gravidez , Complicações Hematológicas na Gravidez/sangue , Adulto Jovem
17.
Semin Hematol ; 39(2): 89-94, 2002 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-11957190

RESUMO

Cyclic neutropenia is a rare hematologic disorder, characterized by repetitive episodes of fever, mouth ulcers, and infections attributable to recurrent severe neutropenia. Fluctuations in blood cells are due to oscillatory production of cells by the bone marrow. Recent genetic, molecular, and cellular studies have shown that autosomal-dominant cyclic neutropenia and sporadic cases of this disease are due to a mutation in the gene for neutrophil elastase (ELA2), located at 19p13.3. This enzyme is synthesized in neutrophil precursors early in the process of primary granule formation. It is currently presumed that the mutant neutrophil elastase functions aberrantly within the cells to accelerate apoptosis of the precursors, resulting in effective and oscillatory production. Cyclic neutropenia is effectively treated with granulocyte colony-stimulating factor (G-CSF), usually at doses of 1 to 5 microg/kg/d (median dose, 2.5 microg/kg/d). Long-term, daily, or alternate-day administration reduces fever, mouth ulcers, and other inflammatory events associated with this disorder. Leukemic transformation is not a recognized risk for cyclic neutropenia, with or without treatment with G-CSF.


Assuntos
Neutropenia/enzimologia , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Humanos , Elastase de Leucócito/genética , Mutação , Neutropenia/tratamento farmacológico , Neutropenia/etiologia , Periodicidade , Recidiva
18.
Blood ; 110(5): 1648-55, 2007 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-17494858

RESUMO

Severe congenital neutropenia (SCN) is an inborn disorder of granulopoiesis. Like most other bone marrow failure syndromes, it is associated with a marked propensity to transform into a myelodysplastic syndrome (MDS) or acute leukemia, with a cumulative rate of transformation to MDS/leukemia that exceeds 20%. The genetic (and/or epigenetic) changes that contribute to malignant transformation in SCN are largely unknown. In this study, we performed mutational profiling of 14 genes previously implicated in leukemogenesis using 14 MDS/leukemia samples from patients with SCN. We used high-throughput exon-based resequencing of whole-genome-amplified genomic DNA with a semiautomated method to detect mutations. The sensitivity and specificity of the sequencing pipeline was validated by determining the frequency of mutations in these 14 genes using 188 de novo AML samples. As expected, mutations of tyrosine kinase genes (FLT3, KIT, and JAK2) were common in de novo AML, with a cumulative frequency of 30%. In contrast, no mutations in these genes were detected in the SCN samples; instead, mutations of CSF3R, encoding the G-CSF receptor, were common. These data support the hypothesis that mutations of CSF3R may provide the "activated tyrosine kinase signal" that is thought to be important for leukemogenesis.


Assuntos
Doenças Genéticas Inatas/genética , Leucemia Mieloide Aguda/genética , Proteínas de Neoplasias/genética , Neutropenia/genética , Proteínas Tirosina Quinases/genética , Receptores de Fator Estimulador de Colônias/genética , Adulto , Análise Mutacional de DNA , Ativação Enzimática/genética , Epigênese Genética , Doenças Genéticas Inatas/complicações , Genoma Humano/genética , Humanos , Leucemia Mieloide Aguda/etiologia , Síndromes Mielodisplásicas/etiologia , Síndromes Mielodisplásicas/genética , Neutropenia/complicações , Neutropenia/congênito
19.
J Pediatr ; 148(5): 633-6, 2006 May.
Artigo em Inglês | MEDLINE | ID: mdl-16737875

RESUMO

OBJECTIVE: To investigate cases of severe congenital neutropenia (SCN) to ascertain SCN inheritance after determining that the same sperm donor was used by 4 different families to impregnate mothers. STUDY DESIGN: Because the donor sperm was not available, alternative methods were used to determine whether the sperm donor transmitted SCN. DNA isolated from leukocytes was used to sequence the ELA2 gene in the affected children and their mothers. ELA2 was amplified by polymerase chain reaction (PCR), and the product was sequenced. PCR was also performed with genomic DNA from the mothers and affected children using a set of 22 microsatellite PCR primers on chromosomes 14 and 19 to establish linkage to the paternal allele. RESULTS: None of the mothers had a mutation in ELA2, but all 5 affected children had the same mutation affecting the fourth exon at site S97L. Linkage mapping analysis confirmed that all affected children had the same paternal allele on chromosome 19, which contains ELA2. CONCLUSIONS: Our findings indicate that the father provided consistent haplotypes leading to the expression of SCN in all affected children, supporting an autosomal dominant inheritance in which ELA2 mutations occur.


Assuntos
Genes Dominantes/genética , Elastase de Leucócito/genética , Mutação , Neutropenia/congênito , Neutropenia/genética , Criança , Feminino , Fertilização in vitro , Heterozigoto , Humanos , Inseminação Artificial Heteróloga , Masculino , Repetições de Microssatélites/genética , Linhagem
20.
Support Cancer Ther ; 3(4): 220-31, 2006 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-18632498

RESUMO

BACKGROUND: The Severe Chronic Neutropenia International Registry (SCNIR) was organized 10 years ago to improve understanding and treatment of the group of rare hematologic disorders causing blood neutrophil counts to be < 500/muL for months or years. PATIENTS AND METHODS: Patients now enrolled include those with severe congenital neutropenia (n = 526), cyclic neutropenia (n = 205), idiopathic neutropenia (n = 349), autoimmune neutropenia (n = 68), and other (n = 15). More than 90% (1053 of 1163) of patients in the SCNIR have been treated with granulocyte colony-stimulating factor (G-CSF), median dose 3.33 mug/kg per day. RESULTS: Granulocyte colony-stimulating factor has reduced the occurrence of infection, hospitalization, and antibiotics and improved patients' quality of life. Most patients have noted few adverse effects with G-CSF treatment. Osteoporosis/osteopenia has been reported in 14% of all patients, and myelodysplastic syndrome and acute myelocytic leukemia have occurred in 57 patients, including severe congenital neutropenia (11.8%; 50 of 422), Shwachman-Diamond syndrome (8.1%; 3 of 37), and 4 others. The SCNIR is an important resource for studies on the genetic and molecular basis for the disorders causing chronic neutropenia. CONCLUSION: The findings of mutations in the gene for neutrophil elastase as causing cyclic and congenital neutropenia, the role of mutations in the gene for the G-CSF receptor in the evolution of severe congenital neutropenia to acute myelocytic leukemia, and the importance of apoptosis as the cellular mechanism for several diseases causing severe chronic neutropenia have come from studies on these patients.

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