Neutrophil elastase and granulocyte colony-stimulating factor receptor mutation analyses and leukemia evolution in severe congenital neutropenia patients belonging to the original Kostmann family in northern Sweden

• Published in: Haematologica (Roma) 2006-05, Vol.91 (5), p.589-595
• Main Authors: Carlsson, G, Aprikyan, AA, Ericson, KG, Stein, S, Makaryan, V, Dale, DC, Nordenskjold, M, Fadeel, B, Palmblad, J, Hentera, JI
• Format: Article
• Language: English
• Subjects: Adult; Amino Acid Substitution; Biological and medical sciences; Cell Differentiation - genetics; Child; Disease Progression; DNA Mutational Analysis; DNA-Binding Proteins - genetics; Female; Genes, Recessive; Hematologic and hematopoietic diseases; Hematopoietic Stem Cell Transplantation; Humans; Karyotyping; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Leukocyte Elastase - genetics; Male; Medical sciences; Mutation, Missense; Neoplasm Proteins - genetics; Neutropenia - congenital; Neutropenia - epidemiology; Neutropenia - genetics; Neutropenia - surgery; Other diseases. Hematologic involvement in other diseases; Pedigree; Point Mutation; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - etiology; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - genetics; Preleukemia - epidemiology; Preleukemia - genetics; Protein Structure, Tertiary; Receptors, Granulocyte Colony-Stimulating Factor - genetics; Sequence Analysis, DNA; Sweden - epidemiology; Syndrome; Transcription Factors - genetics; Wiskott-Aldrich Syndrome Protein - genetics
• ISSN: 0390-6078; 1592-8721

Department of Woman and Child Health, Karolinska University Hospital Solna, Stockholm, Sweden. BACKGROUND AND OBJECTIVES: 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. DESIGN AND METHODS: 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. RESULTS: 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. INTERPRETATION AND CONCLUSIONS: 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.