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Severe congenital neutropenia: genetics and pathogenesis.

ABSTRACT: Severe congenital neutropenia (SCN) is a rare hematological disease characterized by a selective decrease in circulating neutrophils, bone marrow maturation arrest at the promyelocyte stage, and occurrence of infections. Studies of SCN patients revealed impaired proliferative characteristics and accelerated apoptosis of bone marrow progenitor cells. Sequencing analysis indicated a heterozygous deletion or substitution mutations in the neutrophil elastase (NE gene) in many patients. Expression of NE mutants but not normal NE accelerated apoptosis of human HL-60 progenitor cells similar to that seen with actual patient cells. Our data indicate that impaired survival of bone marrow myeloid progenitor cells arises from expression of mutant NE which contributes to neutropenia in SCN. In an unusual clinical set of studies during which SCN developed in five children from four families impregnated by the same sperm donor, we identified the responsible donor by employing genomic DNA studies.

SUBMITTER: Boxer LA

PROVIDER: S-EPMC1500938 | biostudies-literature | 2006

REPOSITORIES: biostudies-literature

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Severe congenital neutropenia: genetics and pathogenesis.

Boxer Laurence A LA

Transactions of the American Clinical and Climatological Association 20060101

Severe congenital neutropenia (SCN) is a rare hematological disease characterized by a selective decrease in circulating neutrophils, bone marrow maturation arrest at the promyelocyte stage, and occurrence of infections. Studies of SCN patients revealed impaired proliferative characteristics and accelerated apoptosis of bone marrow progenitor cells. Sequencing analysis indicated a heterozygous deletion or substitution mutations in the neutrophil elastase (NE gene) in many patients. Expression of ...[more]

PMID: 18528462

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Project description:Objectives: Severe congenital neutropenia (SCN) is a primary immunodeficiency disease characterized by the early onset of recurrent infections and persistent severe neutropenia, with or without genetic defect. We aimed to study the different clinical features and hematological and bone marrow characteristics of patients with SCN and the non-congenital form of severe neutropenia (SN) with unknown etiology. Methods: Thirty-nine Chinese children with severe neutropenia for longer than 6 months unrelated to virus infection or autoimmune diseases were enrolled in the study to analyse the clinical, laboratory, and molecular characteristics. They were followed clinically to observe their remission status. Results: Seven patients were found to have SCN mutations, including ELANE and G6PC3. Among 26 patients with close follow-up, one died for an unknown reason, and 10 resolved spontaneously with a median neutropenia duration of 14.5 months; these patients were designated as having recovered SN. The demographic characteristics of both groups were similar, with a median infection rate of 5 times/year. SCN patients had more frequent infection than recovered SN patients (4 times/year, P = 0.039). The median absolute neutrophil count (ANC) was 0.40 × 109/L in SCN patients, which was significantly higher than 0.2 × 109/L in SN with unknown etiology and 0.21 × 109/L in recovered SN patients (P = 0.021, P = 0.017). The median monocyte count was 1.60 × 109/L in SCN patients, which was also significantly higher than 0.57 × 109/L in SN of unknown etiology and 0.55 × 109/L in recovered SN patients (P = 0.018, P = 0.001). Bone marrow examinations demonstrated myeloid maturation arrest at the myelocyte-metamyelocyte stage in SCN patients and normal findings in SN with unknown etiology and recovered SN patients. Conclusions: Patients with severe neutropenia due to gene mutations demonstrate more serious symptoms than patients with unknown etiology. Patients with relatively higher ANC and monocyte counts are more likely to have known gene mutations. Future studies should focus on more detailed laboratory investigation, prolonged follow-up and advanced molecular biology tools to facilitate accurate diagnosis and effective treatment.

Dataset Information

Severe congenital neutropenia: genetics and pathogenesis.

Publications

Severe congenital neutropenia: genetics and pathogenesis.

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