Severe congenital neutropenia: inheritance and pathophysiology

Abstract

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. 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. 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.