Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027947 (neutropenia)
 17,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Germ-line GATA2 gene mutations, leading to haploinsufficiency, have been identified in patients with familial myelodysplastic syndrome/acute myeloid leukemia, monocytopenia and mycobacterial infections, Emberger syndrome, and dendritic cell, monocyte, B-, and NK-cell deficiency. GATA2 mutations have also been reported in a minority of patients with congenital neutropenia and aplastic anemia (AA). The bone marrow (BM) from patients with GATA2 deficiency is typically hypocellular, with varying degrees of dysplasia. Distinguishing GATA2 patients from those with AA is critical for selecting appropriate therapy. We compared the BM flow cytometric, morphologic, and cytogenetic features of 28 GATA2 patients with those of 32 patients being evaluated for idiopathic AA. The marrow of GATA2 patients had severely reduced monocytes, B cells, and NK cells; absent hematogones; and inverted CD4:CD8 ratios. Atypical megakaryocytes and abnormal cytogenetics were more common in GATA2 marrows. CD34(+) cells were comparably reduced in GATA2 and AA. Using these criteria, we prospectively identified 4 of 32 patients with suspected AA who had features suspicious for GATA2 mutations, later confirmed by DNA sequencing. Our results show that routine BM flow cytometry, morphology, and cytogenetics in patients who present with cytopenia(s) can identify patients for whom GATA2 sequencing is indicated.
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PMID:GATA2 deficiency-associated bone marrow disorder differs from idiopathic aplastic anemia. 2535 90

GATA2 deficiency-formerly described as MonoMAC syndrome; dendritic cells, monocytes, B cells, and natural killer cell deficiency; familial myelodysplastic syndrome/acute myeloid leukemia; or Emberger syndrome-encompasses a range of hematologic and nonhematologic anomalies, mainly characterized by monocytopenia, B lymphopenia, natural killer cell cytopenia, neutropenia, immunodeficiency, and a high risk of developing acute myeloid leukemia. Herein, we present 7 patients with GATA2 deficiency recruited into the French Severe Chronic Neutropenia Registry, which enrolls patients with all kinds of congenital neutropenia. We performed extended immunophenotyping of their whole blood lymphocyte populations, together with the analysis of their chemotactic responses. Lymphopenia was recorded for B and CD4(+) T cells in 6 patients. Although only 3 patients displayed natural killer cell cytopenia, the CD56(bright) natural killer subpopulation was nearly absent in all 7 patients. Natural killer cells from 6 patients showed decreased CXCL12/CXCR4-dependent chemotaxis, whereas other lymphocytes, and most significantly B lymphocytes, displayed enhanced CXCL12-induced chemotaxis compared with healthy volunteers. Surface expression of CXCR4 was significantly diminished in the patients' natural killer cells, although the total expression of the receptor was found to be equivalent to that of natural killer cells from healthy individual controls. Together, these data reveal that GATA2 deficiency is associated with impaired membrane expression and chemotactic dysfunctions of CXCR4. These dysfunctions may contribute to the physiopathology of this deficiency by affecting the normal distribution of lymphocytes and thus potentially affecting the susceptibility of patients to associated infections.
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PMID:Altered chemotactic response to CXCL12 in patients carrying GATA2 mutations. 2671 Jul 99

WHIM syndrome is a condition in which affected persons have chronic peripheral neutropenia, lymphopenia, abnormal susceptibility to human papilloma virus infection, and myelokathexis. Myelokathexis refers to the retention of mature neutrophils in the bone marrow (BM), which accounts for degenerative changes and hypersegmentation. Most patients present heterozygous autosomal dominant mutations of the gene encoding CXCR4. Consequently, aberrant CXCL12/CXCR4 signaling impairs the receptor downregulation causing hyperactivation (gain-of-function) that affects BM homing for myelopoiesis and lymphopoiesis and the release of neutrophils in the bloodstream. We report the case of a 26-year-old female with severe foot and hand cutaneous warts since childhood, recalcitrant genital condylomatas, bacterial infections, and intraepithelial cervical neoplasia. Laboratory tests revealed severe B lymphopenia and HPV high and low risk types. HIV testing was negative. Not only CXCR4 but also GATA2, NEMO, and CD40L gene mutations were excluded. BM smears revealed, in the presence of a normal cellularity, hyperplasia of myeloid cells (MPO positive) and karyorrhexis, especially in neutrophils and eosinophils. Of note, neutrophils with altered lobation of nuclei connected by long thin chromatin filaments were observed. Our patient presented a clinical and histological picture reminiscent of WHIM in the presence of normal peripheral neutrophil counts and wild-type CXCR4 gene. Although the BM did not reveal a classical pattern of myelokathexis, the observation of consistent signs of neutrophil dysplasia has fuelled the hypothesis of a novel WHIM variant or a novel immunodeficiency. We speculate that abnormalities that affect CXCR4/CXCL12 pair, including GRK levels or activity, might be responsible for this WHIM-like disorder.
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PMID:Dysplasia of Granulocytes in a Patient with HPV Disease, Recurrent Infections, and B Lymphopenia: A Novel Variant of WHIM Syndrome? 2851 28

Pediatric myelodysplastic syndromes (MDSs) are a heterogeneous group of clonal disorders with an annual incidence of 1 to 4 cases per million, accounting for less than 5% of childhood hematologic malignancies. MDSs in children often occur in the context of inherited bone marrow failure syndromes, which represent a peculiarity of myelodysplasia diagnosed in pediatric patients. Moreover, germ line syndromes predisposing individuals to develop MDS or acute myeloid leukemia have recently been identified, such as those caused by mutations in GATA2, ETV6, SRP72, and SAMD9/SAMD9-L Refractory cytopenia of childhood (RCC) is the most frequent pediatric MDS variant, and it has specific histopathologic features. Allogeneic hematopoietic stem cell transplantation (HSCT) is the treatment of choice for many children with MDSs and is routinely offered to all patients with MDS with excess of blasts, to those with MDS secondary to previously administered chemoradiotherapy, and to those with RCC associated with monosomy 7, complex karyotype, severe neutropenia, or transfusion dependence. Immune-suppressive therapy may be a treatment option for RCC patients with hypocellular bone marrow and the absence of monosomy 7 or a complex karyotype, although the response rate is lower than that observed in severe aplastic anemia, and a relevant proportion of these patients will subsequently need HSCT for either nonresponse or relapse.
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PMID:How I treat myelodysplastic syndromes of childhood. 2943 60