Pathogenic mechanisms and clinical implications of congenital neutropenia syndromes

Curr Opin Allergy Clin Immunol. 2013 Dec;13(6):596-606. doi: 10.1097/ACI.0000000000000014.


Purpose of review: The purpose of this review is to summarize pathogenic mechanisms and clinical implications of the most illustrative genetic entities of congenital neutropenia syndromes.

Recent findings: Congenital 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.

Summary: Advanced 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / immunology
  • Adaptor Proteins, Signal Transducing / metabolism
  • Biological Transport, Active / genetics
  • Biological Transport, Active / immunology
  • Congenital Bone Marrow Failure Syndromes
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / immunology
  • DNA-Binding Proteins / metabolism
  • Endoplasmic Reticulum Stress / genetics
  • Endoplasmic Reticulum Stress / immunology
  • Glucose-6-Phosphatase / genetics
  • Glucose-6-Phosphatase / immunology
  • Glucose-6-Phosphatase / metabolism
  • Humans
  • Membrane Potential, Mitochondrial / genetics
  • Membrane Potential, Mitochondrial / immunology
  • Neutropenia / congenital*
  • Neutropenia / genetics
  • Neutropenia / immunology
  • Neutropenia / metabolism
  • Neutropenia / pathology
  • Neutropenia / physiopathology
  • Neutrophils* / immunology
  • Neutrophils* / metabolism
  • Neutrophils* / pathology
  • Transcription Factors / genetics
  • Transcription Factors / immunology
  • Transcription Factors / metabolism
  • Unfolded Protein Response / genetics
  • Unfolded Protein Response / immunology
  • Vesicular Transport Proteins / genetics
  • Vesicular Transport Proteins / immunology
  • Vesicular Transport Proteins / metabolism


  • Adaptor Proteins, Signal Transducing
  • DNA-Binding Proteins
  • GFI1 protein, human
  • HAX1 protein, human
  • Transcription Factors
  • VPS45 protein, human
  • Vesicular Transport Proteins
  • Glucose-6-Phosphatase
  • G6PC3 protein, human

Supplementary concepts

  • Neutropenia, Severe Congenital, Autosomal Recessive 3