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Severe congenital neutropenias

Nature Reviews Disease Primers volume 3, Article number: 17032 (2017) Cite this article

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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.

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Figure 1: Maturation arrest of granulopoiesis in patients with severe congenital neutropenia.
Figure 2: Milestones of the history of severe congenital neutropenia.
Figure 3: Genes with germline mutations associated with severe congenital neutropenia.
Figure 4: Main cellular localization of proteins mutated in patients with congenital neutropenia.
Figure 5: Granulocyte colony-stimulating factor receptor downstream signalling pathways.
Figure 6: Dominant action of granulocyte colony-stimulating factor receptor truncation mutants leads to sustained proliferation and survival signalling.
Figure 7: Model of leukaemogenesis in severe congenital neutropenia.
Figure 8: Severe gingivitis and periodontitis in patients with severe congenital neutropenia.
Figure 9: Algorithm for the management of patients with severe congenital neutropenia based on response to granulocyte colony-stimulating factor therapy.

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Acknowledgements

This manuscript is dedicated to the late Dr L. Boxer, a pioneer of neutropenia research. The work was supported by grants from the US National Institutes of Health, the Deutsche Forschungsgemeinschaft (DFG), the Bundesministerium für Bildung und Forschung (BMBF), the Deutsche Jose-Carreras Leukämie-Stiftung e.V., the Excellence Initiative of the Tuebingen University, Volkswagen foundation, Madeleine Schickedanz-KinderKrebs-Stiftung and the Amgen Foundation.

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Authors and Affiliations

  1. Department of Hematology, Oncology, Clinical Immunology, University of Tübingen, Tübingen, Germany

    Julia Skokowa

  2. Department of Medicine, University of Washington, Seattle, Washington, USA

    David C. Dale

  3. Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands

    Ivo P. Touw

  4. Department of Hematology and Oncology, Medical School Hannover, Hannover, Germany

    Cornelia Zeidler

  5. Department of General Pediatrics and Pediatric Hematology and Oncology, University Children's Hospital, Hoppe-Seyler-Str. 1, Tübingen, 72076, Germany

    Karl Welte

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  1. Julia Skokowa
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  2. David C. Dale
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  3. Ivo P. Touw
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  4. Cornelia Zeidler
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  5. Karl Welte
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Contributions

Introduction (K.W. and D.C.D.); Epidemiology (D.C.D. and J.S.); Mechanisms/pathophysiology (J.S., I.P.T. and K.W.); Diagnosis, screening and prevention (D.C.D., K.W. and J.S.); Management (C.Z., K.W. and J.S.); Quality of life (C.Z. and K.W.); Outlook (K.W. and J.S.); Overview of the Primer (K.W.).

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Correspondence to Karl Welte.

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Competing interests

D.C.D. is a consultant and receives research support from Amgen, a manufacturer of granulocyte colony-stimulating factor (G-CSF) used to treat neutropenia. All other authors declare no competing interests.

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Skokowa, J., Dale, D., Touw, I. et al. Severe congenital neutropenias. Nat Rev Dis Primers 3, 17032 (2017). https://doi.org/10.1038/nrdp.2017.32

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