title: Severe congenital neutropenia: inheritance and pathophysiology.
abstract: OBJECTIVE
  Severe congenital neutropenia is a heterogeneous disorder of hematopoiesis characterized by a maturation arrest of granulopoiesis at the level of promyelocytes with peripheral blood absolute neutrophil counts below 0.5 x 10/l. In this review we summarize our current knowledge on inheritance and pathophysiolgy of congenital neutropenia.
  
  
  RESULTS
  There are two major subtypes of congenital neutropenia as judged by inheritance: autosomal dominant trait defined by neutrophil elastase mutations consisting of 60% of patients and autosomal recessive trait comprising approximately 30% of patients. This genetic heterogeneity suggests that several pathologic mechanisms may lead to the same phenotype due to downregulation of common myeloid transcription factors. Lymphoid enhancer-binding factor 1 is the most promising candidate, as its abrogation together with downregulation of lymphoid enhancer-binding factor 1 target genes is compatible with this phenotype. Congenital neutropenia is considered as a preleukemic syndrome, since after 10 years of observation the cumulative incidence for leukemia is 21%. Acquired granulocyte colony-stimulating factor receptor mutations are detected in approximately 80% of congenital neutropenia patients who developed acute myeloid leukemia.
  
  
  CONCLUSIONS
  Congenital neutropenia is a congenital disorder of hematopoiesis inherited by autosomal dominant or recessive traits. Downregulation of lymphoid enhancer-binding factor 1 is involved in the pathophysiology of all congenital neutropenia patients. Congenital neutropenia patients with acquired granulocyte colony-stimulating factor receptor mutations define a group with high risk for development of leukemia.
authors.affiliation: Department of Pediatric Hematology/Oncology, Medical University Hannover, Hannover, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Skokowa
authors.forename: Manuela
authors.initials: M
authors.lastname: Germeshausen
authors.forename: Cornelia
authors.initials: C
authors.lastname: Zeidler
authors.forename: Karl
authors.initials: K
authors.lastname: Welte
mesh_terms: D016179:Granulocyte Colony-Stimulating Factor / Q000627:therapeutic use; D006801:Humans; D040582:Inheritance Patterns; D019272:Leukocyte Elastase / Q000235:genetics; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000235:genetics; D009503:Neutropenia / Q000151:congenital* / Q000235:genetics / Q000503:physiopathology* / Q000628:therapy; D010641:Phenotype; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000235:genetics
chemical_list: D051821:Lymphoid Enhancer-Binding Factor 1; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D016179:Granulocyte Colony-Stimulating Factor; D019272:Leukocyte Elastase