Severe congenital neutropenias

Nat Rev Dis Primers. 2017 Jun 8;3:17032. doi: 10.1038/nrdp.2017.32.

Abstract

Severe congenital neutropenias are a heterogeneous group of rare haematological diseases characterized by impaired maturation of neutrophil granulocytes. Patients with severe congenital neutropenia are prone to recurrent, often life-threatening infections beginning in their first months of life. The most frequent pathogenic defects are autosomal dominant mutations in ELANE, which encodes neutrophil elastase, and autosomal recessive mutations in HAX1, whose product contributes to the activation of the granulocyte colony-stimulating factor (G-CSF) signalling pathway. The pathophysiological mechanisms of these conditions are the object of extensive research and are not fully understood. Furthermore, severe congenital neutropenias may predispose to myelodysplastic syndromes or acute myeloid leukaemia. Molecular events in the malignant progression include acquired mutations in CSF3R (encoding G-CSF receptor) and subsequently in other leukaemia-associated genes (such as RUNX1) in a majority of patients. Diagnosis is based on clinical manifestations, blood neutrophil count, bone marrow examination and genetic and immunological analyses. Daily subcutaneous G-CSF administration is the treatment of choice and leads to a substantial increase in blood neutrophil count, reduction of infections and drastic improvement of quality of life. Haematopoietic stem cell transplantation is the alternative treatment. Regular clinical assessments (including yearly bone marrow examinations) to monitor treatment course and detect chromosomal abnormalities (for example, monosomy 7 and trisomy 21) as well as somatic pre-leukaemic mutations are recommended.

Publication types

  • Review

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Blood Cell Count
  • Congenital Bone Marrow Failure Syndromes
  • Core Binding Factor Alpha 2 Subunit / genetics
  • Granulocyte Colony-Stimulating Factor / administration & dosage
  • Granulocyte Colony-Stimulating Factor / therapeutic use
  • Hematopoietic Stem Cell Transplantation
  • Humans
  • Leukemia, Myeloid, Acute / genetics
  • Leukocyte Elastase / genetics
  • Mutation*
  • Myelodysplastic Syndromes / genetics
  • Neutropenia / complications
  • Neutropenia / congenital*
  • Neutropenia / diagnosis
  • Neutropenia / genetics
  • Neutropenia / therapy
  • Quality of Life
  • Receptors, Colony-Stimulating Factor / genetics

Substances

  • Adaptor Proteins, Signal Transducing
  • CSF3R protein, human
  • Core Binding Factor Alpha 2 Subunit
  • HAX1 protein, human
  • RUNX1 protein, human
  • Receptors, Colony-Stimulating Factor
  • Granulocyte Colony-Stimulating Factor
  • Leukocyte Elastase

Supplementary concepts

  • Neutropenia, Severe Congenital, Autosomal Recessive 3