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.

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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.

References

  1. 1

    Welte, K., Zeidler, C. & Dale, D. C. Severe congenital neutropenia. Semin. Hematol. 43, 189–195 (2006).

    CAS  Google Scholar 

  2. 2

    Skokowa, J., Germeshausen, M., Zeidler, C. & Welte, K. Severe congenital neutropenia: inheritance and pathophysiology. Curr. Opin. Hematol. 14, 22–28 (2007).

    Google Scholar 

  3. 3

    Donadieu, J., Beaupain, B., Mahlaoui, N. & Bellanne-Chantelot, C. Epidemiology of congenital neutropenia. Hematol. Oncol. Clin. North Am. 27, 1–17 (2013).

    Google Scholar 

  4. 4

    Carlsson, G. et al. Incidence of severe congenital neutropenia in Sweden and risk of evolution to myelodysplastic syndrome/leukaemia. Br. J. Haematol. 158, 363–369 (2012).

    Google Scholar 

  5. 5

    Lebel, A. et al. Genetic analysis and clinical picture of severe congenital neutropenia in Israel. Pediatr. Blood Cancer 62, 103–108 (2015).

    CAS  Google Scholar 

  6. 6

    Grann, V. R. et al. Duffy (Fy), DARC, and neutropenia among women from the United States, Europe and the Caribbean. Br. J. Haematol. 143, 288–293 (2008).

    CAS  Google Scholar 

  7. 7

    Denic, S. et al. Prevalence of neutropenia in children by nationality. BMC Hematol. 16, 15 (2016).

    Google Scholar 

  8. 8

    Chown, G. & Gelfand, A. S. Agranulocytosis. Can. Med. Assoc. J. 29, 128–134 (1933).

    CAS  Google Scholar 

  9. 9

    Gilman, P. A., Jackson, D. P. & Guild, H. G. Congenital agranulocytosis: prolonged survival and terminal acute leukemia. Blood 36, 576–585 (1970).

    CAS  Google Scholar 

  10. 10

    Souza, L. M. et al. Recombinant human granulocyte colony-stimulating factor: effects on normal and leukemic myeloid cells. Science 232, 61–65 (1986). This paper describes the cloning and production of recombinant G-CSF for potential clinical use for patients with congenital neutropenia.

    CAS  Google Scholar 

  11. 11

    Bonilla, M. A. et al. Effects of recombinant human granulocyte colony-stimulating factor on neutropenia in patients with congenital agranulocytosis. N. Engl. J. Med. 320, 1574–1580 (1989). This study reports the first successful treatment of patients with congenital neutropenia with G-CSF, who achieved neutrophil counts of >1,000 cells per μl of blood.

    CAS  Google Scholar 

  12. 12

    Hammond, W. P., Price, T. H., Souza, L. M. & Dale, D. C. Treatment of cyclic neutropenia with granulocyte colony-stimulating factor. N. Engl. J. Med. 320, 1306–1311 (1989). This study reports the first successful treatment of patients with cyclic neutropenia with G-CSF, who achieved increases in the median neutrophil counts.

    Google Scholar 

  13. 13

    Welte, K. et al. Differential effects of granulocyte–macrophage colony-stimulating factor and granulocyte colony-stimulating factor in children with severe congenital neutropenia. Blood 75, 1056–1063 (1990).

    CAS  Google Scholar 

  14. 14

    Dale, D. C. et al. A randomized controlled phase III trial of recombinant human granulocyte colony-stimulating factor (filgrastim) for treatment of severe chronic neutropenia. Blood 81, 2496–2502 (1993).

    CAS  Google Scholar 

  15. 15

    Donadieu, J., Fenneteau, O., Beaupain, B., Mahlaoui, N. & Chantelot, C. B. Congenital neutropenia: diagnosis, molecular bases and patient management. Orphanet J. Rare Dis. 6, 26 (2011).

    Google Scholar 

  16. 16

    Rosenberg, P. S. et al. Stable long-term risk of leukaemia in patients with severe congenital neutropenia maintained on G-CSF therapy. Br. J. Haematol. 150, 196–199 (2010).

    CAS  Google Scholar 

  17. 17

    Rosenberg, P. S. et al. The incidence of leukemia and mortality from sepsis in patients with severe congenital neutropenia receiving long-term G-CSF therapy. Blood 107, 4628–4635 (2006).

    CAS  Google Scholar 

  18. 18

    Rigaud, C. et al. Natural history of Barth syndrome: a national cohort study of 22 patients. Orphanet J. Rare Dis. 8, 70 (2013).

    Google Scholar 

  19. 19

    Donadieu, J. et al. Analysis of risk factors for myelodysplasias, leukemias and death from infection among patients with congenital neutropenia. Experience of the French Severe Chronic Neutropenia Study Group. Haematologica 90, 45–53 (2005).

    Google Scholar 

  20. 20

    Horwitz, M., Benson, K. F., Person, R. E., Aprikyan, A. G. & Dale, D. C. Mutations in ELA2, encoding neutrophil elastase, define a 21-day biological clock in cyclic haematopoiesis. Nat. Genet. 23, 433–436 (1999). This is the first description of ELANE mutations as a cause for cyclic neutropenia.

    CAS  Google Scholar 

  21. 21

    Dale, D. C. et al. Mutations in the gene encoding neutrophil elastase in congenital and cyclic neutropenia. Blood 96, 2317–2322 (2000). This paper reports on the detection of autosomal dominant inheritance of ELANE mutations as a cause for cyclic neutropenia.

    CAS  Google Scholar 

  22. 22

    Horwitz, M. S. et al. Neutrophil elastase in cyclic and severe congenital neutropenia. Blood 109, 1817–1824 (2007).

    CAS  Google Scholar 

  23. 23

    Makaryan, V. et al. The diversity of mutations and clinical outcomes for ELANE-associated neutropenia. Curr. Opin. Hematol. 22, 3–11 (2015).

    CAS  Google Scholar 

  24. 24

    Germeshausen, M. et al. The spectrum of ELANE mutations and their implications in severe congenital and cyclic neutropenia. Hum. Mutat. 34, 905–914 (2013).

    CAS  Google Scholar 

  25. 25

    Newburger, P. E. et al. Cyclic neutropenia and severe congenital neutropenia in patients with a shared ELANE mutation and paternal haplotype: evidence for phenotype determination by modifying genes. Pediatr. Blood Cancer 55, 314–317 (2010).

    Google Scholar 

  26. 26

    Boxer, L. A., Stein, S., Buckley, D., Bolyard, A. A. & Dale, D. C. Strong evidence for autosomal dominant inheritance of severe congenital neutropenia associated with ELA2 mutations. J. Pediatr. 148, 633–636 (2006).

    CAS  Google Scholar 

  27. 27

    Germeshausen, M., Schulze, H., Ballmaier, M., Zeidler, C. & Welte, K. Mutations in the gene encoding neutrophil elastase (ELA2) are not sufficient to cause the phenotype of congenital neutropenia. Br. J. Haematol. 115, 222–224 (2001).

    CAS  Google Scholar 

  28. 28

    Benson, K. F. & Horwitz, M. Possibility of somatic mosaicism of ELA2 mutation overlooked in an asymptomatic father transmitting severe congenital neutropenia to two offspring. Br. J. Haematol. 118, 923 (2002).

    Google Scholar 

  29. 29

    Kostmann, R. Infantile genetic agranulocytosis; agranulocytosis infantilis hereditaria. Acta Paediatr. Suppl. 45 (Suppl. 105), 1–78 (1956). A seminal description of inheritance of congenital neutropenia, which led to the term Kostmann syndrome.

    CAS  Google Scholar 

  30. 30

    Klein, C. et al. HAX1 deficiency causes autosomal recessive severe congenital neutropenia (Kostmann disease). Nat. Genet. 39, 86–92 (2007). This is the first description of autosomal recessive inheritance of congenital neutropenia-causing HAX1 mutations, including in patients with so-called Kostmann syndrome.

    CAS  Google Scholar 

  31. 31

    Germeshausen, M. et al. Novel HAX1 mutations in patients with severe congenital neutropenia reveal isoform-dependent genotype–phenotype associations. Blood 111, 4954–4957 (2008).

    CAS  Google Scholar 

  32. 32

    Matsubara, K. et al. Severe developmental delay and epilepsy in a Japanese patient with severe congenital neutropenia due to HAX1 deficiency. Haematologica 92, e123–e125 (2007).

    CAS  Google Scholar 

  33. 33

    Skokowa, J. et al. Interactions among HCLS1, HAX1 and LEF-1 proteins are essential for G-CSF-triggered granulopoiesis. Nat. Med. 18, 1550–1559 (2012).

    CAS  Google Scholar 

  34. 34

    Skokowa, J. & Welte, K. Defective G-CSFR signaling pathways in congenital neutropenia. Hematol. Oncol. Clin. North Am. 27, 75–88 (2013).

    Google Scholar 

  35. 35

    Boztug, K. et al. A syndrome with congenital neutropenia and mutations in G6PC3. N. Engl. J. Med. 360, 32–43 (2009).

    CAS  Google Scholar 

  36. 36

    Bione, S. et al. A novel X-linked gene, G4.5. is responsible for Barth syndrome. Nat. Genet. 12, 385–389 (1996).

    CAS  Google Scholar 

  37. 37

    Boocock, G. R. et al. Mutations in SBDS are associated with Shwachman–Diamond syndrome. Nat. Genet. 33, 97–101 (2003).

    CAS  Google Scholar 

  38. 38

    Bohn, G. et al. A novel human primary immunodeficiency syndrome caused by deficiency of the endosomal adaptor protein p14. Nat. Med. 13, 38–45 (2007).

    CAS  Google Scholar 

  39. 39

    Menasche, G. et al. Mutations in RAB27A cause Griscelli syndrome associated with haemophagocytic syndrome. Nat. Genet. 25, 173–176 (2000).

    CAS  Google Scholar 

  40. 40

    Marcolongo, P. et al. Structure and mutation analysis of the glycogen storage disease type 1b gene. FEBS Lett. 436, 247–250 (1998).

    CAS  Google Scholar 

  41. 41

    Veiga-da-Cunha, M. et al. A gene on chromosome 11q23 coding for a putative glucose- 6-phosphate translocase is mutated in glycogen-storage disease types Ib and Ic. Am. J. Hum. Genet. 63, 976–983 (1998).

    CAS  Google Scholar 

  42. 42

    Germeshausen, M. et al. Digenic mutations in severe congenital neutropenia. Haematologica 95, 1207–1210 (2010).

    CAS  Google Scholar 

  43. 43

    Klimiankou, M. et al. GM-CSF stimulates granulopoiesis in a congenital neutropenia patient with loss-of-function biallelic heterozygous CSF3R mutations. Blood 126, 1865–1867 (2015).

    CAS  Google Scholar 

  44. 44

    Ward, A. C. et al. Novel point mutation in the extracellular domain of the granulocyte colony-stimulating factor (G-CSF) receptor in a case of severe congenital neutropenia hyporesponsive to G-CSF treatment. J. Exp. Med. 190, 497–507 (1999).

    CAS  Google Scholar 

  45. 45

    Triot, A. et al. Inherited biallelic CSF3R mutations in severe congenital neutropenia. Blood 123, 3811–3817 (2014).

    CAS  Google Scholar 

  46. 46

    Li, F. Q. & Horwitz, M. Characterization of mutant neutrophil elastase in severe congenital neutropenia. J. Biol. Chem. 276, 14230–14241 (2001).

    CAS  Google Scholar 

  47. 47

    Aprikyan, A. A. et al. Cellular and molecular abnormalities in severe congenital neutropenia predisposing to leukemia. Exp. Hematol. 31, 372–381 (2003).

    CAS  Google Scholar 

  48. 48

    Tidwell, T. et al. Neutropenia-associated ELANE mutations disrupting translation initiation produce novel neutrophil elastase isoforms. Blood 123, 562–569 (2014).

    CAS  Google Scholar 

  49. 49

    Grenda, D. S. et al. Mutations of the ELA2 gene found in patients with severe congenital neutropenia induce the unfolded protein response and cellular apoptosis. Blood 110, 4179–4187 (2007).

    CAS  Google Scholar 

  50. 50

    Nanua, S. et al. Activation of the unfolded protein response is associated with impaired granulopoiesis in transgenic mice expressing mutant Elane. Blood 117, 3539–3547 (2011).

    CAS  Google Scholar 

  51. 51

    Kollner, I. et al. Mutations in neutrophil elastase causing congenital neutropenia lead to cytoplasmic protein accumulation and induction of the unfolded protein response. Blood 108, 493–500 (2006).

    Google Scholar 

  52. 52

    Nustede, R. et al. ELANE mutant-specific activation of different UPR pathways in congenital neutropenia. Br. J. Haematol. 172, 219–227 (2016).

    CAS  Google Scholar 

  53. 53

    Skokowa, J., Fobiwe, J. P., Dan, L., Thakur, B. K. & Welte, K. Neutrophil elastase is severely down-regulated in severe congenital neutropenia independent of ELA2 or HAX1 mutations but dependent on LEF-1. Blood 114, 3044–3051 (2009).

    CAS  Google Scholar 

  54. 54

    Kawaguchi, H. et al. Dysregulation of transcriptions in primary granule constituents during myeloid proliferation and differentiation in patients with severe congenital neutropenia. J. Leukoc. Biol. 73, 225–234 (2003).

    CAS  Google Scholar 

  55. 55

    Klimenkova, O. et al. A lack of secretory leukocyte protease inhibitor (SLPI) causes defects in granulocytic differentiation. Blood 123, 1239–1249 (2014).

    CAS  Google Scholar 

  56. 56

    Carlsson, G. et al. Kostmann syndrome: severe congenital neutropenia associated with defective expression of Bcl-2, constitutive mitochondrial release of cytochrome c, and excessive apoptosis of myeloid progenitor cells. Blood 103, 3355–3361 (2004).

    CAS  Google Scholar 

  57. 57

    Cario, G. et al. Heterogeneous expression pattern of pro- and anti-apoptotic factors in myeloid progenitor cells of patients with severe congenital neutropenia treated with granulocyte colony-stimulating factor. Br. J. Haematol. 129, 275–278 (2005).

    Google Scholar 

  58. 58

    Carlsson, G. et al. Survivin expression in the bone marrow of patients with severe congenital neutropenia. Leukemia 23, 622–625 (2009).

    CAS  Google Scholar 

  59. 59

    Boztug, K. et al. JAGN1 deficiency causes aberrant myeloid cell homeostasis and congenital neutropenia. Nat. Genet. 46, 1021–1027 (2014).

    CAS  Google Scholar 

  60. 60

    Hayee, B. et al. G6PC3 mutations are associated with a major defect of glycosylation: a novel mechanism for neutrophil dysfunction. Glycobiology 21, 914–924 (2011).

    CAS  Google Scholar 

  61. 61

    Bonilla, M. A. et al. Long-term safety of treatment with recombinant human granulocyte colony-stimulating factor (r-metHuG-CSF) in patients with severe congenital neutropenias. Br. J. Haematol. 88, 723–730 (1994).

    CAS  Google Scholar 

  62. 62

    Radomska, H. S. et al. CCAAT/enhancer binding protein alpha is a regulatory switch sufficient for induction of granulocytic development from bipotential myeloid progenitors. Mol. Cell. Biol. 18, 4301–4314 (1998).

    CAS  Google Scholar 

  63. 63

    Rosenbauer, F. & Tenen, D. G. Transcription factors in myeloid development: balancing differentiation with transformation. Nat. Rev. Immunol. 7, 105–117 (2007).

    CAS  Google Scholar 

  64. 64

    Skokowa, J. et al. LEF-1 is crucial for neutrophil granulocytopoiesis and its expression is severely reduced in congenital neutropenia. Nat. Med. 12, 1191–1197 (2006).

    CAS  Google Scholar 

  65. 65

    Skokowa, J. & Welte, K. Dysregulation of myeloid-specific transcription factors in congenital neutropenia. Ann. NY Acad. Sci. 1176, 94–100 (2009).

    CAS  Google Scholar 

  66. 66

    Buitenhuis, M. et al. Differential regulation of granulopoiesis by the basic helix-loop-helix transcriptional inhibitors Id1 and Id2. Blood 105, 4272–4281 (2005).

    CAS  Google Scholar 

  67. 67

    Mempel, K., Pietsch, T., Menzel, T., Zeidler, C. & Welte, K. Increased serum levels of granulocyte colony-stimulating factor in patients with severe congenital neutropenia. Blood 77, 1919–1922 (1991).

    CAS  Google Scholar 

  68. 68

    Kyas, U., Pietsch, T. & Welte, K. Expression of receptors for granulocyte colony-stimulating factor on neutrophils from patients with severe congenital neutropenia and cyclic neutropenia. Blood 79, 1144–1147 (1992).

    CAS  Google Scholar 

  69. 69

    Rauprich, P., Kasper, B., Tidow, N. & Welte, K. The protein tyrosine kinase JAK2 is activated in neutrophils from patients with severe congenital neutropenia. Blood 86, 4500–4505 (1995).

    CAS  Google Scholar 

  70. 70

    Gupta, K. et al. Bortezomib inhibits STAT5-dependent degradation of LEF-1, inducing granulocytic differentiation in congenital neutropenia CD34+ cells. Blood 123, 2550–2561 (2014).

    CAS  Google Scholar 

  71. 71

    Futami, M. et al. G-CSF receptor activation of the Src kinase Lyn is mediated by Gab2 recruitment of the Shp2 phosphatase. Blood 118, 1077–1086 (2011).

    CAS  Google Scholar 

  72. 72

    Zhu, Q. S., Robinson, L. J., Roginskaya, V. & Corey, S. J. G-CSF-induced tyrosine phosphorylation of Gab2 is Lyn kinase dependent and associated with enhanced Akt and differentiative, not proliferative, responses. Blood 103, 3305–3312 (2004).

    CAS  Google Scholar 

  73. 73

    Tidow, N., Kasper, B. & Welte, K. SH2-containing protein tyrosine phosphatases SHP-1 and SHP-2 are dramatically increased at the protein level in neutrophils from patients with severe congenital neutropenia (Kostmann's syndrome). Exp. Hematol. 27, 1038–1045 (1999).

    CAS  Google Scholar 

  74. 74

    Hirai, H. et al. C/EBPβ is required for ‘emergency’ granulopoiesis. Nat. Immunol. 7, 732–739 (2006).

    CAS  Google Scholar 

  75. 75

    Skokowa, J. et al. NAMPT is essential for the G-CSF-induced myeloid differentiation via a NAD+–sirtuin-1-dependent pathway. Nat. Med. 15, 151–158 (2009). This is the first description of an alternative pathway of G-CSF-induced neutrophilic granulopoiesis in congenital neutropenia via NAMPT and the C/EBPβ emergency pathway.

    CAS  Google Scholar 

  76. 76

    Freedman, M. H. Safety of long-term administration of granulocyte colony-stimulating factor for severe chronic neutropenia. Curr. Opin. Hematol. 4, 217–224 (1997).

    CAS  Google Scholar 

  77. 77

    Welte, K. & Dale, D. Pathophysiology and treatment of severe chronic neutropenia. Ann. Hematol. 72, 158–165 (1996).

    CAS  Google Scholar 

  78. 78

    Germeshausen, M., Ballmaier, M. & Welte, K. Incidence of CSF3R mutations in severe congenital neutropenia and relevance for leukemogenesis: results of a long-term survey. Blood 109, 93–99 (2007).

    CAS  Google Scholar 

  79. 79

    Ancliff, P. J., Gale, R. E., Liesner, R., Hann, I. & Linch, D. C. Long-term follow-up of granulocyte colony-stimulating factor receptor mutations in patients with severe congenital neutropenia: implications for leukaemogenesis and therapy. Br. J. Haematol. 120, 685–690 (2003).

    CAS  Google Scholar 

  80. 80

    Carlsson, G. et al. Neutrophil elastase and granulocyte colony-stimulating factor receptor mutation analyses and leukemia evolution in severe congenital neutropenia patients belonging to the original Kostmann family in northern Sweden. Haematologica 91, 589–595 (2006).

    CAS  Google Scholar 

  81. 81

    Germeshausen, M. et al. Granulocyte colony-stimulating factor receptor mutations in a patient with acute lymphoblastic leukemia secondary to severe congenital neutropenia. Blood 97, 829–830 (2001).

    CAS  Google Scholar 

  82. 82

    Germeshausen, M. et al. An acquired G-CSF receptor mutation results in increased proliferation of CMML cells from a patient with severe congenital neutropenia. Leukemia 19, 611–617 (2005).

    CAS  Google Scholar 

  83. 83

    [No authors listed.] The Severe Chronic Neutropenia International Registry — European branch. Severe Chronic Neutropeniawww.severe-chronic-neutropenia.org (2013).

  84. 84

    Klimiankou, M. et al. Two cases of cyclic neutropenia with acquired CSF3R mutations, with 1 developing AML. Blood 127, 2638–2641 (2016).

    CAS  Google Scholar 

  85. 85

    Dong, F. et al. Distinct cytoplasmic regions of the human granulocyte colony-stimulating factor receptor involved in induction of proliferation and maturation. Mol. Cell. Biol. 13, 7774–7781 (1993).

    CAS  Google Scholar 

  86. 86

    Fukunaga, R., Ishizaka-Ikeda, E. & Nagata, S. Growth and differentiation signals mediated by different regions in the cytoplasmic domain of granulocyte colony-stimulating factor receptor. Cell 74, 1079–1087 (1993).

    CAS  Google Scholar 

  87. 87

    Ziegler, S. F. et al. Distinct regions of the human granulocyte-colony-stimulating factor receptor cytoplasmic domain are required for proliferation and gene induction. Mol. Cell. Biol. 13, 2384–2390 (1993).

    CAS  Google Scholar 

  88. 88

    Palande, K., Meenhuis, A., Jevdjovic, T. & Touw, I. P. Scratching the surface: signaling and routing dynamics of the CSF3 receptor. Front. Biosci. (Landmark Ed). 18, 91–105 (2013).

    CAS  Google Scholar 

  89. 89

    Touw, I. P. & van de Geijn, G. J. Granulocyte colony-stimulating factor and its receptor in normal myeloid cell development, leukemia and related blood cell disorders. Front. Biosci. 12, 800–815 (2007).

    CAS  Google Scholar 

  90. 90

    Dong, F. et al. Mutations in the gene for the granulocyte colony-stimulating-factor receptor in patients with acute myeloid leukemia preceded by severe congenital neutropenia. N. Engl. J. Med. 333, 487–493 (1995). This is the first description of acquired CSF3R mutations as an initial step in leukaemogenesis.

    CAS  Google Scholar 

  91. 91

    Hermans, M. H. et al. Sustained receptor activation and hyperproliferation in response to granulocyte colony-stimulating factor (G-CSF) in mice with a severe congenital neutropenia/acute myeloid leukemia-derived mutation in the G-CSF receptor gene. J. Exp. Med. 189, 683–692 (1999).

    CAS  Google Scholar 

  92. 92

    Zhu, Q. S. et al. G-CSF induced reactive oxygen species involves Lyn–-PI3-kinase–Akt and contributes to myeloid cell growth. Blood 107, 1847–1856 (2006).

    CAS  Google Scholar 

  93. 93

    Liu, F. et al. Csf3r mutations in mice confer a strong clonal HSC advantage via activation of Stat5. J. Clin. Invest. 118, 946–955 (2008).

    CAS  Google Scholar 

  94. 94

    Dong, F. et al. Mutations in the granulocyte colony-stimulating factor receptor gene in patients with severe congenital neutropenia. Leukemia 11, 120–125 (1997).

    CAS  Google Scholar 

  95. 95

    Germeshausen, M., Skokowa, J., Ballmaier, M., Zeidler, C. & Welte, K. G-CSF receptor mutations in patients with congenital neutropenia. Curr. Opin. Hematol. 15, 332–337 (2008).

    CAS  Google Scholar 

  96. 96

    Tidow, N. et al. Clinical relevance of point mutations in the cytoplasmic domain of the granulocyte colony-stimulating factor receptor gene in patients with severe congenital neutropenia. Blood 89, 2369–2375 (1997).

    CAS  Google Scholar 

  97. 97

    Beekman, R. et al. Sequential gain of mutations in severe congenital neutropenia progressing to acute myeloid leukemia. Blood 119, 5071–5077 (2012).

    CAS  Google Scholar 

  98. 98

    Skokowa, J. et al. Cooperativity of RUNX1 and CSF3R mutations in severe congenital neutropenia: a unique pathway in myeloid leukemogenesis. Blood 123, 2229–2237 (2014). A seminal paper on the role of CSF3R mutations and subsequent RUNX1 mutations in leukaemogenesis in the majority of patients with congenital neutropenia.

    CAS  Google Scholar 

  99. 99

    Klimiankou, M., Mellor-Heineke, S., Zeidler, C., Welte, K. & Skokowa, J. Role of CSF3R mutations in the pathomechanism of congenital neutropenia and secondary acute myeloid leukemia. Ann. NY Acad. Sci. 1370, 119–125 (2016).

    CAS  Google Scholar 

  100. 100

    Tschan, C. A., Pilz, C., Zeidler, C., Welte, K. & Germeshausen, M. Time course of increasing numbers of mutations in the granulocyte colony-stimulating factor receptor gene in a patient with congenital neutropenia who developed leukemia. Blood 97, 1882–1884 (2001).

    CAS  Google Scholar 

  101. 101

    Zeidler, C. et al. Management of Kostmann syndrome in the G-CSF era. Br. J. Haematol. 109, 490–495 (2000).

    CAS  Google Scholar 

  102. 102

    Bux, J., Behrens, G., Jaeger, G. & Welte, K. Diagnosis and clinical course of autoimmune neutropenia in infancy: analysis of 240 cases. Blood 91, 181–186 (1998).

    CAS  Google Scholar 

  103. 103

    Farruggia, P. et al. Autoimmune neutropenia of infancy: data from the Italian Neutropenia Registry. Am. J. Hematol. 90, E221–E222 (2015).

    Google Scholar 

  104. 104

    Myers, K. C. et al. Variable clinical presentation of Shwachman–Diamond syndrome: update from the North-American Shwachman–Diamond Syndrome Registry. J. Pediatr. 164, 866–870 (2014).

    Google Scholar 

  105. 105

    Ghemlas, I. et al. Improving diagnostic precision, care and syndrome definitions using comprehensive next-generation sequencing for the inherited bone marrow failure syndromes. J. Med. Genet. 52, 575–584 (2015).

    CAS  Google Scholar 

  106. 106

    Ancliff, P. J. et al. Two novel activating mutations in the Wiskott–Aldrich syndrome protein result in congenital neutropenia. Blood 108, 2182–2189 (2006).

    CAS  Google Scholar 

  107. 107

    Gauthier-Vasserot, A. et al. Application of whole-exome sequencing to unravel the molecular basis of undiagnosed syndromic congenital neutropenia with intellectual disability. Am. J. Med. Genet. A 173, 62–71 (2017).

    CAS  Google Scholar 

  108. 108

    Boxer, L. A. et al. Is there a role for anti-neutrophil antibody testing in predicting spontaneous resolution of neutropenia in young children. Blood 126, 2211 (2015).

    Google Scholar 

  109. 109

    Lee, W. I. et al. Identifying patients with neutrophil elastase (ELANE) mutations from patients with a presumptive diagnosis of autoimmune neutropenia. Immunobiology 218, 828–833 (2013).

    CAS  Google Scholar 

  110. 110

    Zeidler, C., Germeshausen, M., Klein, C. & Welte, K. Clinical implications of ELA2-, HAX1-, and G-CSF-receptor (CSF3R) mutations in severe congenital neutropenia. Br. J. Haematol. 144, 459–467 (2008).

    Google Scholar 

  111. 111

    [No authors listed.] The Severe Chronic Neutropenia International Registry. Washington.eduwww.depts.washington.edu/registry (1994). References 83 and 111 show websites in which the reader can obtain handbooks for patients and their families in English and other languages.

  112. 112

    Elsner, J., Roesler, J., Emmendorffer, A., Lohmann-Matthes, M. L. & Welte, K. Abnormal regulation in the signal transduction in neutrophils from patients with severe congenital neutropenia: relation of impaired mobilization of cytosolic free calcium to altered chemotaxis, superoxide anion generation and F-actin content. Exp. Hematol. 21, 38–46 (1993).

    CAS  Google Scholar 

  113. 113

    Koch, C. et al. GM-CSF treatment is not effective in congenital neutropenia patients due to its inability to activate NAMPT signaling. Ann. Hematol. 96, 345–353 (2017).

    CAS  Google Scholar 

  114. 114

    Donini, M. et al. G-CSF treatment of severe congenital neutropenia reverses neutropenia but does not correct the underlying functional deficiency of the neutrophil in defending against microorganisms. Blood 109, 4716–4723 (2007).

    CAS  Google Scholar 

  115. 115

    Karlsson, J. et al. Low plasma levels of the protein pro-LL-37 as an early indication of severe disease in patients with chronic neutropenia. Br. J. Haematol. 137, 166–169 (2007).

    CAS  Google Scholar 

  116. 116

    Pütsep, K., Carlsson, G., Boman, H. G. & Andersson, M. Deficiency of antibacterial peptides in patients with morbus Kostmann: an observation study. Lancet 360, 1144–1149 (2002).

    Google Scholar 

  117. 117

    Ye, Y. et al. The antimicrobial propeptide hCAP-18 plasma levels in neutropenia of various aetiologies: a prospective study. Sci. Rep. 5, 11685 (2015).

    CAS  Google Scholar 

  118. 118

    Allen, R. C., Stevens, P. R., Price, T. H., Chatta, G. S. & Dale, D. C. In vivo effects of recombinant human granulocyte colony-stimulating factor on neutrophil oxidative functions in normal human volunteers. J. Infect. Dis. 175, 1184–1192 (1997).

    CAS  Google Scholar 

  119. 119

    Yakisan, E. et al. High incidence of significant bone loss in patients with severe congenital neutropenia (Kostmann's syndrome). J. Pediatr. 131, 592–597 (1997).

    CAS  Google Scholar 

  120. 120

    Zeidler, C. et al. Stem cell transplantation in patients with severe congenital neutropenia without evidence of leukemic transformation. Blood 95, 1195–1198 (2000).

    CAS  Google Scholar 

  121. 121

    Fioredda, F. et al. Stem cell transplantation in severe congenital neutropenia: an analysis from the European Society for Blood and Marrow Transplantation. Blood 126, 1885–1892 (2015).

    CAS  Google Scholar 

  122. 122

    Oshima, K. et al. Hematopoietic stem cell transplantation in patients with severe congenital neutropenia: an analysis of 18 Japanese cases. Pediatr. Transplant. 14, 657–663 (2010).

    CAS  Google Scholar 

  123. 123

    Ferry, C. et al. Hematopoietic stem cell transplantation in severe congenital neutropenia: experience of the French SCN register. Bone Marrow Transplant. 35, 45–50 (2005).

    CAS  Google Scholar 

  124. 124

    Zeidler, C., Nickel, A., Sykora, K. W. & Welte, K. Improved outcome of stem cell transplantation for severe chronic neutropenia with or without secondary leukemia: a long-term analysis of European data for more than 25 years by the SCNIR. Blood 122, 3347 (2013).

    Google Scholar 

  125. 125

    Zeidler, C. et al. Outcome and management of pregnancies in severe chronic neutropenia patients by the European Branch of the Severe Chronic Neutropenia International Registry. Haematologica 99, 1395–1402 (2014).

    Google Scholar 

  126. 126

    Boxer, L. A. et al. Use of granulocyte colony-stimulating factor during pregnancy in women with chronic neutropenia. Obstet. Gynecol. 125, 197–203 (2015).

    CAS  Google Scholar 

  127. 127

    Jones, E., Bolyard, A. A. & Dale, D. C. Quality of life in patients receiving granulocyte colony stimulating factor for treatment of severe chronic neutropenia. JAMA 270, 1132–1133 (1993).

    CAS  Google Scholar 

  128. 128

    Touw, I. P. Game of clones: the genomic evolution of severe congenital neutropenia. Hematology Am. Soc. Hematol. Educ. Program 2015, 1–7 (2015).

    Google Scholar 

  129. 129

    Nayak, R. C. et al. Pathogenesis of ELANE-mutant severe neutropenia revealed by induced pluripotent stem cells. J. Clin. Invest. 125, 3103–3116 (2015).

    Google Scholar 

  130. 130

    Morishima, T. et al. Genetic correction of HAX1 in induced pluripotent stem cells from a patient with severe congenital neutropenia improves defective granulopoiesis. Haematologica 99, 19–27 (2014).

    CAS  Google Scholar 

  131. 131

    Hiramoto, T. et al. Wnt3a stimulates maturation of impaired neutrophils developed from severe congenital neutropenia patient-derived pluripotent stem cells. Proc. Natl Acad. Sci. USA 110, 3023–3028 (2013).

    CAS  Google Scholar 

  132. 132

    Morishima, T. et al. Neutrophil differentiation from human-induced pluripotent stem cells. J. Cell. Physiol. 226, 1283–1291 (2011).

    CAS  Google Scholar 

  133. 133

    Lachmann, N. et al. Large-scale hematopoietic differentiation of human induced pluripotent stem cells provides granulocytes or macrophages for cell replacement therapies. Stem Cell Rep. 4, 282–296 (2015).

    CAS  Google Scholar 

  134. 134

    Dale, D. C. & Welte, K. Cyclic and chronic neutropenia. Cancer Treat. Res. 157, 97–108 (2011).

    CAS  Google Scholar 

  135. 135

    Engelhard, D. et al. Cycling of peripheral blood and marrow lymphocytes in cyclic neutropenia. Proc. Natl Acad. Sci. USA 80, 5734–5738 (1983).

    CAS  Google Scholar 

  136. 136

    Leale, M. Reccurent furunculosis in an infant showing an unusual blood picture. JAMA 23, 1845–1855 (1910).

    Google Scholar 

  137. 137

    Reimann, H. A. Periodic disease; a probable syndrome including periodic fever, benign paroxysmal peritonitis, cyclic neutropenia and intermittent arthralgia. JAMA 136, 6 (1948).

    Google Scholar 

  138. 138

    Palmer, S. E., Stephens, K. & Dale, D. C. Genetics, phenotype, and natural history of autosomal dominant cyclic hematopoiesis. Am. J. Med. Genet. 66, 413–422 (1996).

    CAS  Google Scholar 

  139. 139

    Dingli, D., Antal, T., Traulsen, A. & Pacheco, J. M. Progenitor cell self-renewal and cyclic neutropenia. Cell Prolif. 42, 330–338 (2009).

    CAS  Google Scholar 

  140. 140

    Schmitz, S., Franke, H., Wichmann, H. E. & Diehl, V. The effect of continuous G-CSF application in human cyclic neutropenia: a model analysis. Br. J. Haematol. 90, 41–47 (1995).

    CAS  Google Scholar 

  141. 141

    Schmitz, S., Franke, H., Loeffler, M., Wichmann, H. E. & Diehl, V. Model analysis of the contrasting effects of GM-CSF and G-CSF treatment on peripheral blood neutrophils observed in three patients with childhood-onset cyclic neutropenia. Br. J. Haematol. 95, 616–625 (1996).

    CAS  Google Scholar 

  142. 142

    Østby, I. & Winther, R. Stability of a model of human granulopoiesis using continuous maturation. J. Math. Biol. 49, 501–536 (2004).

    Google Scholar 

  143. 143

    Lei, J. & Mackey, M. C. Multistability in an age-structured model of hematopoiesis: cyclical neutropenia. J. Theor. Biol. 270, 143–153 (2011).

    Google Scholar 

  144. 144

    Lei, J. & Mackey, M. C. Understanding and treating cytopenia through mathematical modeling. Adv. Exp. Med. Biol. 844, 279–302 (2014).

    Google Scholar 

  145. 145

    Dale, D. C. & Mackey, M. C. Understanding, treating and avoiding hematological disease: better medicine through mathematics? Bull. Math. Biol. 77, 739–757 (2015).

    Google Scholar 

  146. 146

    Schultz, W. Gangräneszierende prozesse und defekt des granulozytensystems [German]. Dtsch. Med. Wochenschr. 48, 1495–1496 (1922).

    Google Scholar 

  147. 147

    Friedemann, U. Agranulocytic angina. Med. Klin. 19, 1357 (1923).

    Google Scholar 

  148. 148

    Prendergast, D. A. Case of agranulocytic angina. Can. Med. Assoc. J. 17, 446–447 (1927).

    CAS  Google Scholar 

  149. 149

    Hitzig, W. H. Familial neutropenia with dominant hereditary factor and hypergammaglobulinemia [German]. Helv. Med. Acta 26, 779–784 (1959).

    CAS  Google Scholar 

  150. 150

    Person, R. E. et al. Mutations in proto-oncogene GFI1 cause human neutropenia and target ELA2. Nat. Genet. 34, 308–312 (2003).

    CAS  Google Scholar 

  151. 151

    Hernandez, P. A. et al. Mutations in the chemokine receptor gene CXCR4 are associated with WHIM syndrome, a combined immunodeficiency disease. Nat. Genet. 34, 70–74 (2003).

    CAS  Google Scholar 

  152. 152

    Makaryan, V. et al. TCIRG1-associated congenital neutropenia. Hum. Mutat. 35, 824–827 (2014).

    CAS  Google Scholar 

  153. 153

    Dong, F. et al. Identification of a nonsense mutation in the granulocyte-colony-stimulating factor receptor in severe congenital neutropenia. Proc. Natl Acad. Sci. USA 91, 4480–4484 (1994).

    CAS  Google Scholar 

  154. 154

    Ward, A. C., van Aesch, Y. M., Schelen, A. M. & Touw, I. P. Defective internalization and sustained activation of truncated granulocyte colony-stimulating factor receptor found in severe congenital neutropenia/acute myeloid leukemia. Blood 93, 447–458 (1999).

    CAS  Google Scholar 

  155. 155

    Carlsson, G. et al. Periodontal disease in patients from the original Kostmann family with severe congenital neutropenia. J. Periodontol. 77, 744–751 (2006).

    Google Scholar 

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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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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.).

Corresponding author

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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