Pathogenic mechanisms and clinical implications of congenital neutropenia syndromes

Purpose of reviewThe purpose of this review is to summarize
pathogenic mechanisms and clinical implications of the most
illustrative genetic entities of congenital neutropenia
syndromes.Recent findingsCongenital neutropenia comprise
monogenetic entities with or without additional immunologic and
extrahaematopoietic syndromatic features. Continuous careful
explorations of known entities such as ELANE, GFI1, HAX1, G6PC3
deficiency and XLN help to define principles controlling
differentiation and function of neutrophil granulocytes.
Furthermore, the identification of novel genetic defects associated
with congenital neutropenia, such as VPS45 deficiency, broadens our
understanding of neutrophil biology. Pathogenic mechanisms imply
protein and vesicle mistrafficking, endoplasmic reticulum stress,
the unfolded protein response, destabilization of the mitochondrial
membrane potential, disturbed energy metabolism, dysglycosylation
and deregulated actin polymerization.SummaryAdvanced genetic and
biochemical techniques have helped to expand our knowledge of
congenital neutropenia syndromes. Known and novel genetic entities
shed light on fundamental biological processes important for the
homeostatis and functioning not only of the neutrophil granulocyte
but as well of the entire haematopoietic system. Furthermore,
treatment decisions become more tailored and might pave the road
towards personalized molecular medicine.