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Query: UMLS:C0027947 (neutropenia)
 17,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent advances in our understanding of the molecular basis of inherited neutrophil disorders and complementary studies in transgenic mouse models have provided new insights into the normal mechanisms regulating myelopoiesis and the functional responses of mature neutrophils. Neutrophil specific granule deficiency is a rare disorder of neutrophil function characterized by a lack of neutrophil secondary granule proteins and associated with recurrent bacterial infections. The CCAAT/enhancer binding protein (C/EBP) epsilon, a leucine zipper transcription factor expressed primarily in myeloid cells, and C/EBPepsilon-deficient mice generated by gene targeting lack specific granules and have impaired host defense are discussed by Dr. Lekstrom-Himes in Section I. The similarity between these phenotypes led to the identification of a loss of function mutation in the C/EBPepsilon gene in a subset of patients with specific granule deficiency. Dr. Dale reviews the clinical features and management of congenital neutropenia and cyclic hematopoiesis in Section II. Inherited mutations in the neutrophil elastase gene have recently been identified in both disorders. Specific mutations identified in cyclic and congenital neutropenia are described along with possible mechanisms for regulation of hematopoiesis by neutrophil elastase. In Section III, Dr. Dinauer reviews the molecular genetics of chronic granulomatous disease and studies in knockout mouse models. This work has revealed important features of the regulation of the respiratory burst oxidase and its role in host defense and inflammation. Results from preclinical studies and phase 1 clinical trials for gene therapy for CGD are summarized, in addition to alternative approaches using allogeneic bone marrow transplantation with nonmyeloablative conditioning.
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PMID:Inherited Neutrophil Disorders: Molecular Basis and New Therapies. 1170 48

Mutations in the ELA2 gene encoding human neutrophil elastase have been reported recently to be involved in the aetiology of both, cyclic (CyN) and congenital neutropenia (CN). We analysed the correlation between the occurrence of ELA2 mutations and the neutropenic phenotype in a family with two children affected with CN. The two children harboured the same heterozygous mutation in the ELA2 gene that was inherited from their unaffected father. We conclude that ELA2 mutations are not the single cause of CN although they might be a necessary prerequisite for the expression of the neutropenic phenotype in a subgroup of CN patients.
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PMID:Mutations in the gene encoding neutrophil elastase (ELA2) are not sufficient to cause the phenotype of congenital neutropenia. 1218 Oct 69

Recently, some of the mechanisms and consequences in the severe chronic neutropenias (e.g. the neutrophil elastase gene mutations and the risk to progress to myelodysplasia and acute leukaemia) and in drug-induced agranulocytosis (e.g. the apoptosis-inducing ability of metabolites of clozapine) have been elucidated, and new aspects of autoimmune and the large granular lymphocyte syndrome were described (e.g. aberrant elaboration of Fas-ligand causing neutrophil apoptosis). Investigations of the mild to moderate chronic neutropenias have shown the significance of interactions between the myeloid development and the immune network (e.g. relations to immunoglobulin aberrations). Granulocyte-colony stimulation factor (G-CSF) is widely used in patients with severe chronic neutropenia, however, its use in other conditions is mostly based on anecdotal evidence. In addition, immune modulating regimens, such as metothrexate, ciclosporine and monoclonal antibodies, are increasingly employed for the autoimmune neutropenias.
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PMID:Acute and chronic neutropenias. What is new? 1190 16

Congenital neutropenia (CN) includes hematologic disorders characterized by severe neutropenia with an absolute neutrophil count (ANC) below 0.5 x 10(9)/L associated with severe systemic bacterial infections from early infancy. One subtype of CN, Kostmann syndrome, was originally described as an autosomal-recessive disorder, characterized by early-stage maturation arrest of myelopoiesis. Autosomal-dominant and sporadic cases have also been reported. Recent studies on the genetic bases of CN have detected different inherited or spontaneous point mutations in the neutrophil elastase gene. Development of additional genetic defects during the course of disease, such as granulocyte colony-stimulating factor (G-CSF)-receptor gene mutations and cytogenetic aberrations, indicates an underlying genetic instability. Data on more than 300 patients with CN collected by the Severe Chronic Neutropenia International Registry (SCNIR) since 1994 demonstrate that, independent of the CN subtype, more than 90% of patients respond to recombinant human (rHu)G-CSF with ANCs that can be maintained at approximately 1.0 x 10(9)/L. Adverse events include mild splenomegaly, moderate thrombocytopenia, osteoporosis, and malignant transformation into myelodysplasia (MDS)/leukemia. If and how rHuG-CSF treatment impacts on these adverse events remains unclear since there are no historical controls for comparison. Hematopoietic stem cell transplantation (HSCT) is still the only available treatment for patients refractory to rHuG-CSF treatment.
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PMID:Kostmann syndrome and severe congenital neutropenia. 1195 89

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.
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PMID:Cyclic neutropenia. 1195 90

Heterozygous mutations in neutrophil elastase have been detected in many sporadic cases of congenital neutropenia. However, a convincing pathogenetic mechanism has not been established, and it is unclear whether the effects of the mutant enzyme occur within the cell of production or are paracrine in nature. The healthy father of a patient was demonstrated to be mosaic for his daughter's Cys42Arg elastase mutation. Using semiquantitative polymerase chain reaction, approximately half of his T cells were shown to carry the mutation in contrast to less than 10% of neutrophils. Individual hematopoietic colonies grown from peripheral blood were heterozygous for the mutation or were homozygous wild type. These results demonstrate that precursors containing the mutation are selectively lost during myelopoiesis or fail to develop into neutrophils. This is the first in vivo confirmation of the pathogenic nature of elastase mutations in humans. The normal neutrophil count in the father suggests that the mutant elastase does not have paracrine effects.
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PMID:Paternal mosaicism proves the pathogenic nature of mutations in neutrophil elastase in severe congenital neutropenia. 1209 71

In this review, we present the most recent discoveries at the molecular level in white blood cell defects, and explain how their identification helped us to understand the underlying pathophysiology and directed our approach in clinical management. These lately discovered genes, relevant to immune disorders of mononuclear phagocytes and neutrophils, include defects in the interferon gamma (IFNg)/interleukin 12 (IL-12) pathway, such as IFNg receptor (IFNgR) defects, IL-12 defect, IL-12 receptor (IL-12R) defect, and signal transducer and activator of transcription 1 (STAT-1) defect. We have also included NF-kappaB essential modifier (NEMO) defects, which lead to X-linked ectodermal dysplasia, with or without lymphedema and osteopetrosis, and a wide range of involvement of the immune system, which can mimic the hyper-IgM phenotype. Neutrophil-specific granule deficiency and neutrophil elastase deficiency are discussed, the latter being the molecular defect in both cyclic neutropenia and in some sporadic cases of severe congenital neutropenia.
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PMID:White blood cell defects: molecular discoveries and clinical management. 1216 4

Severe congenital neutropenia (SCN) is a syndrome characterized by an isolated block in granulocytic differentiation and an increased risk of developing acute myeloid leukemia (AML). Recent studies have demonstrated that the majority of patients with SCN and cyclic neutropenia, a related disorder characterized by periodic oscillations in the number of circulating neutrophils, have heterozygous germline mutations in the ELA2 gene encoding neutrophil elastase (NE). To test the hypothesis that these mutations are causative for SCN, we generated transgenic mice carrying a targeted mutation of their Ela2 gene ("V72M") reproducing a mutation found in 2 unrelated patients with SCN, one of whom developed AML. Expression of mutant NE mRNA and enzymatically active protein was confirmed. Mice heterozygous and homozygous for the V72M allele have normal numbers of circulating neutrophils, and no accumulation of myeloid precursors in the bone marrow was observed. Serial blood analysis found no evidence of cycling in any of the major hematopoietic lineages. Rates of apoptosis following cytokine deprivation were similar in wild-type and mutant neutrophils, as were the frequency and cytokine responsiveness of myeloid progenitors. The stress granulopoiesis response, as measured by neutrophil recovery after cyclophosphamide-induced myelosuppression, was normal. To define the leukemogenic potential of V72M NE, a tumor watch was established. To date, no cases of leukemia have been detected. Collectively, these data suggest that expression of V72M NE is not sufficient to induce an SCN phenotype or leukemia in mice.
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PMID:Mice expressing a neutrophil elastase mutation derived from patients with severe congenital neutropenia have normal granulopoiesis. 1238 20

There is evidence that neutrophil production is a balance between the proliferative action of granulocyte-colony-stimulating factor (G-CSF) and a negative feedback from mature neutrophils (the chalone). Two neutrophil serine proteases have been implicated in granulopoietic regulation: pro-proteinase 3 inhibits granulocyte macrophage-colony-forming unit (CFU-GM) growth, and elastase mutations cause cyclic and congenital neutropenia. We further studied the action of the neutrophil serine proteases (proteinase 3, elastase, azurocidin, and cathepsin G) on granulopoiesis in vitro. Elastase inhibited CFU-GM in methylcellulose culture. In serum-free suspension cultures of CD34+ cells, elastase completely abrogated the proliferation induced by G-CSF but not that of GM-CSF or stem cell factor (SCF). The blocking effect of elastase was prevented by inhibition of its enzymatic activity with phenylmethylsulfonyl fluoride (PMSF) or heat treatment. When exposed to enzymatically active elastase, G-CSF, but not GM-CSF or SCF, was rapidly cleaved and rendered inactive. These results support a role for neutrophil elastase in providing negative feedback to granulopoiesis by direct antagonism of G-CSF.
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PMID:Neutrophil elastase enzymatically antagonizes the in vitro action of G-CSF: implications for the regulation of granulopoiesis. 1239 22

There are several common themes that are emerging from our expanding knowledge about the inherited bone marrow failure syndromes. Patients have a spectrum of birth defects, which are relatively characteristic for each syndrome. but overlap in features such as poor growth. radial ray anomalies, and involvement of skin, eyes, renal, cardiac, skeletal, and other organs. Within each syndrome the composition and severity of the physical phenotype varies widely, and it may require the astute observer to make the correct diagnoses in the milder cases. There is also a wide spectrum to the hematologic picture. These range from single cytopenias such as DBA, SCN, and TAR, which do not develop pancytopenia, to SD and Amega patients who begin with deficiency of a specific single lineage, but evolve to aplastic anemia, to patients with FA or DC, who may present with a deficiency of any one of the cell lines, but almost inevitably end up with full-blown aplastic anemia. Acute myeloid leukemia has been observed in FA, DBA, DC, SD, SCN, and Amega, although not yet in TAR patients. MDS has also been reported in all of the same disorders as AML, although whether it is a preleukemic condition or an independent bone marrow dyspoiesis is not yet clear. Solid tumors are also now appearing in patients whose underlying disease involves hematopoiesis and physical development. These tumors occur at much younger ages than in the general population, in patients who do not appear to have the usual risk factors, and have patterns that are characteristic to the syndrome, such as head and neck and gynecologic cancers in FA and DC, and osteogenic sarcomas in DBA. The other syndromes have not yet been reported to have a propensity for solid tumors. Several genes have been identified that are mutant in some of the syndromes, although the pathophysiology is still not entirely clear. The inheritance patterns include X-linked recessive, autosomal dominant, autosomal recessive, and even mitochondrial. The FA gene products appear to cooperate, and are important in the pathways involved in response to DNA damage. However, the role of this pathway in developmental defects, hematopoietic failure, and the specific malignancies in FA is not fully elucidated. The DC gene products are important for maintenance of telomere length, which may have relevance to development of aplastic anemia and malignancies, but the relation to the physical phenotype is less apparent. The role of mutations in c-mpl in Amega is more straightforward. since the gene codes for the receptor for thrombopoietin. which is the hormone required for megakaryocyte and platelet development; patients with mutant c-mpl do not have birth defects. The role of mutations in RPS19 in erythropoiesis or developmental defects in DBA patients is not obvious, and the increased frequency of osteogenic sarcomas suggests that at least that subset of patients may have a mutant tumor suppressor gene (such as p53, the mutant gene in Li-Fraumeni syndrome) [68]. Although patients with SCN have mutations in neutrophil elastase, patients with similar mutations may have relatively benign cyclic neutropenia, or may even have normal neutrophil levels [69,70]. The mitochondrial gene deletions in Pearson's Syndrome result in variable degrees of acidosis, and varied organ involvement due to heteroplasmy. Thus, the disorders included under the rubric "inherited bone marrow failure syndromes" have clinical. hematologic, oncologic, and genetic diversity.
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PMID:Bone marrow failure syndromes in children. 1243 Jun 21


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