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Severe congenital neutropenias.

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.
PMID
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Authors

Mayor MeshTerms

Mutation

Keywords
Journal Title nature reviews. disease primers
Publication Year Start




PMID- 28593997
OWN - NLM
STAT- MEDLINE
DA  - 20170608
DCOM- 20170712
LR  - 20170713
IS  - 2056-676X (Electronic)
IS  - 2056-676X (Linking)
VI  - 3
DP  - 2017 Jun 08
TI  - Severe congenital neutropenias.
PG  - 17032
LID - 10.1038/nrdp.2017.32 [doi]
AB  - 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.
FAU - Skokowa, Julia
AU  - Skokowa J
AD  - Department of Hematology, Oncology, Clinical Immunology, University of Tubingen, 
      Tubingen, Germany.
FAU - Dale, David C
AU  - Dale DC
AD  - Department of Medicine, University of Washington, Seattle, Washington, USA.
FAU - Touw, Ivo P
AU  - Touw IP
AD  - Department of Hematology, Erasmus University Medical Center, Rotterdam, The
      Netherlands.
FAU - Zeidler, Cornelia
AU  - Zeidler C
AD  - Department of Hematology and Oncology, Medical School Hannover, Hannover,
      Germany.
FAU - Welte, Karl
AU  - Welte K
AD  - University Children's Hospital, Department of General Pediatrics and Pediatric
      Hematology and Oncology, Hoppe-Seyler-Str. 1, Tubingen 72076, Germany.
LA  - eng
PT  - Journal Article
PT  - Review
DEP - 20170608
PL  - England
TA  - Nat Rev Dis Primers
JT  - Nature reviews. Disease primers
JID - 101672103
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (CSF3R protein, human)
RN  - 0 (Core Binding Factor Alpha 2 Subunit)
RN  - 0 (HAX1 protein, human)
RN  - 0 (RUNX1 protein, human)
RN  - 0 (Receptors, Colony-Stimulating Factor)
RN  - 143011-72-7 (Granulocyte Colony-Stimulating Factor)
RN  - EC 3.4.21.37 (Leukocyte Elastase)
RN  - Neutropenia, Severe Congenital, Autosomal Recessive 3
SB  - IM
MH  - Adaptor Proteins, Signal Transducing/genetics
MH  - Blood Cell Count
MH  - Core Binding Factor Alpha 2 Subunit/genetics
MH  - Granulocyte Colony-Stimulating Factor/administration & dosage/therapeutic use
MH  - Hematopoietic Stem Cell Transplantation
MH  - Humans
MH  - Leukemia, Myeloid, Acute/genetics
MH  - Leukocyte Elastase/genetics
MH  - *Mutation
MH  - Myelodysplastic Syndromes/genetics
MH  - Neutropenia/complications/*congenital/diagnosis/genetics/therapy
MH  - Quality of Life
MH  - Receptors, Colony-Stimulating Factor/genetics
EDAT- 2017/06/09 06:00
MHDA- 2017/07/14 06:00
CRDT- 2017/06/09 06:00
AID - nrdp201732 [pii]
AID - 10.1038/nrdp.2017.32 [doi]
PST - epublish
SO  - Nat Rev Dis Primers. 2017 Jun 8;3:17032. doi: 10.1038/nrdp.2017.32.