Severe congenital neutropenia (SCN) or Kostmann syndrome was originally reported to be an autosomal recessive disease of neutrophil production causing recurrent, life-threatening infections. Mutations in the neutrophil elastase gene (ELA-2) have previously been identified in patients with sporadic or autosomal dominant SCN.We studied 14 individuals (four patients with SCN and ten close relatives) belonging to the original Kostmann family in northern Sweden for mutations in the ELA-2 and the granulocyte colony-stimulating factor (G-CSF) receptor genes.One patient belonging to the original Kostmann family harbored a novel heterozygous ELA-2 mutation (g.2310T-->A;Leu92His) that was not inherited from her parents. The mutation was identified in DNA isolated from both whole blood and skin fibroblasts, suggesting a sporadic de novo mutation. As a young adult this patient sequentially acquired two mutations in the gene for the G-CSF receptor (G-CSFR) and therefore recently received a hematopoietic stem cell transplant, due to the risk of evolution to leukemia. Moreover, another patient developed acute leukemia and was treated with transplantation. No pathogenic ELA-2 or G-CSFR gene mutations were found in this patient or the other two patients, nor in any healthy relative.Our data are the first to document leukemia evolution and G-CSFR gene mutations in the original Kostmann kindred. In addition, our findings indicate that ELA-2 mutations are not the primary cause of SCN in the Swedish Kostmann family.
Abstract. Using data on the fraction of post‐mitotic neutrophil precursors (CD15 + cells) displaying positive markers for apoptosis in 12 normal humans, and a simple mathematical model, we have estimated the apoptotic rate to be about 0.28/day in this compartment. This implies that the influx of myelocytes into the post‐mitotic compartment exceeds twice the granulocyte turnover rate (GTR), and that about 55% of the cells entering this compartment die before being released into the blood. The normal half life of apoptotic post‐mitotic neutrophil precursors is calculated to be 10.4 h. Comparable calculations for patients indicate apoptosis rates in the post‐mitotic compartment of about 17 times normal for one myelokathexis patient and rates of about 13 times normal for the one cyclical neutropenic patient and two severe congenital neutropenic patients. The estimated half life for apoptotic post‐mitotic neutrophil precursors in the myelokathexis patient was about 0.4 h, 1.4 h in the cyclical neutropenia patient, and about 0.6 h in the severe congenital neutropenic patients.
This report presents the case of a 15-year-old male with severe chronic neutropenia, leukopenia, and persistent tetraploid mosaicism in the bone marrow and peripheral blood. His father had mild neutropenia and bone marrow tetraploidy. Flow cytometric analysis of DNA content peripheral blood showed tetraploidy in 20% of granulocytes and 15% of monocytes. Sequence analysis of the ELA2 gene was normal, but the GFI1 gene exhibited transient appearance of single base changes the coding region and promoter. We speculate that an underlying genetic defect, inherited in an autosomal dominant pattern, leads to both disordered mitosis and neutropenia in this kindred.
Severe congenital neutropenia (SCN) is a heterogeneous bone marrow failure syndrome predisposing to myelodysplastic syndrome and acute myeloid leukaemia (MDS/AML). We studied 82 North American and Australian SCN patients enrolled in the Severe Chronic Neutropenia International Registry who were on long-term treatment with granulocyte colony-stimulating factor and for whom the neutrophil elastase (ELA2) gene was sequenced. There was no significant difference in the risk of MDS/AML in patients with mutant versus wild-type ELA2: the respective cumulative incidences at 15 years were 36% and 25% (P = 0.96). Patients with either mutant or wild-type ELA2 should be followed closely for leukaemic transformation.
Severe neutropenia is characterized by maturation arrest of myeloid cells at the promyelocyte stage of hematopoiesis. We reported that accelerated apoptosis of bone marrow myeloid progenitor cells was observed in both cyclic (CN) and severe congenital neutropenia (SCN). Short and long-term cultures of bone marrow CD34+ cells revealed reduced production of multipotent progenitors in SCN. In contrast, production of these cells was slightly elevated in CN compared with CD34+ cells from healthy volunteers. Production of myeloid-committed progenitor cells was significantly reduced in both CN and SCN. FACS analysis of CD34+ cells revealed G0/G1 cell cycle arrest in SCN but not in CN. All CN patients and more than 90% of SCN patients have mutation in the neutrophil elastase (NE) gene. Molecular modeling of NE tertiary structure indicates that mutations observed in SCN are primarily located around the glycosylation sites, whereas CN mutations affect predominantly the active site. Transient expression of CN- or SCN-specific mutant NE cDNA results in impaired survival of human myeloid progenitor cells compared with control cells transfected with intact NE cDNA. We hypothesize that abnormal processing and subcellular localization of mutant NE might predetermine the etiology of cyclic or severe congenital neutropenia.
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