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Pathogenic mechanisms and clinical implications of congenital neutropenia syndromes

Hauck, Fabian; Klein, Christoph

Current Opinion in Allergy and Clinical Immunology: December 2013 - Volume 13 - Issue 6 - p 596–606
doi: 10.1097/ACI.0000000000000014
PRIMARY IMMUNE DEFICIENCY DISEASE: Edited by Ramsay L. Fuleihan and Bruce D. Mazer

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.

Dr von Hauner Children's Hospital, Ludwig-Maximilians-University Munich, Munich, Germany

Correspondence to Christoph Klein, Dr von Hauner University Children's Hospital, Lindwurmstrasse 4, 80337 Munich, Germany. Tel: +49 89 5160 7700; fax: +49 89 5160 7702; e-mail:

Copyright © 2013 Wolters Kluwer Health, Inc. All rights reserved.