Abstract：Neutrophils, an important type of human immune cells, are involved in host defense against infections. Neutropenia refers to a group of diseases manifesting as a reduction in the absolute value of mature neutrophils and is often accompanied by an increased risk of bacterial infection. According to etiology and pathogenesis, neutropenia is classified into congenital and acquired neutropenia. This article reviews the current research status and advances in the etiology of neutropenia in children. A deep understanding of the etiology of neutropenia helps to improve the diagnosis and treatment of this disease.
Kruger P, Saffarzadeh M, Weber AN, et al. Neutrophils:Between host defence, immune modulation, and tissue injury[J]. PLoS Pathog, 2015, 11(3):e1004651.
Xia J, Bolyard AA, Rodger E, et al. Prevalence of mutations in ELANE, GFI1, HAX1, SBDS, WAS and G6PC3 in patients with severe congenital neutropenia[J]. Br J Haematol, 2009, 147(4):535-542.
[5]
Germeshausen M, Deerberg S, Peter Y, et al. The spectrum of ELANE mutations and their implications in severe congenital and cyclic neutropenia[J]. Hum Mutat, 2013, 34(6):905-914.
[6]
Massaad MJ, Ramesh N, Geha RS. Wiskott-Aldrich syndrome:a comprehensive review[J]. Ann N Y Acad Sci, 2013, 1285:26-43.
[7]
Donadieu J, Leblanc T, Bader Meunier B, 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[J]. Haematologica, 2005, 90(1):45-53.
[8]
Fioredda F, Lanza T, Gallicola F, et al. Long-term use of Pegfilgrastim in children with severe congenital neutropenia:clinical and pharmacokinetic data[J]. Blood, 2016, 128(17):2178-2181.
[9]
Rosenberg PS, Zeidler C, Bolyard AA, et al. Stable long-term risk of leukaemia in patients with severe congenital neutropenia maintained on G-CSF therapy[J]. Br J Haematol, 2010, 150(2):196-199.
[10]
Carlsson G, Fasth A, Berglöf E, et al. Incidence of severe congenital neutropenia in Sweden and risk of evolution to myelodysplastic syndrome/leukaemia[J]. Br J Haematol, 2012, 158(3):363-369.
[11]
Fioredda F, Calvillo M, Lanciotti M, et al. Lethal sepsis and malignant transformation in severe congenital neutropenia:report from the Italian Neutropenia Registry[J]. Pediatr Blood Cancer, 2015, 62(6):1110-1112.
[12]
Peffaultde Latour R, Peters C, Gibson B, et al. Recommendations on hematopoietic stem cell transplantation for inherited bone marrow failure syndromes[J]. Bone Marrow Transplant, 2015, 50(9):1168-1172.
[13]
Connelly JA, Choi SW, Levine JE. Hematopoietic stem cell transplantation for severe congenital neutropenia[J]. Curr Opin Hematol, 2012, 19(1):44-51.
[14]
Fioredda F, Iacobelli S, van Biezen A, et al. Stem cell transplantation in severe congenital neutropenia:an analysis from the European Society for Blood and Marrow Transplantation[J]. Blood, 2015, 126(16):1885-1892.
[15]
Celkan T, Koç BS. Approach to the patient with neutropenia in childhood[J]. Turk Pediatri Ars, 2015, 50(3):136-144.
[16]
Walkovich K, Boxer LA. How to approach neutropenia in childhood[J]. Pediatr Rev, 2013, 34(4):173-184.
[17]
Denic S, Showqi S, Klein C, et al. Prevalence, phenotype and inheritance of benign neutropenia in Arabs[J]. BMC Blood Disord, 2009, 9:3.
Nayak RC, Trump LR, Aronow BJ, et al. Pathogenesis of ELANE-mutant severe neutropenia revealed by induced pluripotent stem cells[J]. J Clin Invest, 2015, 125(8):3103-3116.
[20]
Klimiankou M, Mellor-Heineke S, Klimenkova O, et al. Two cases of cyclic neutropenia with acquired CSF3R mutations, with 1 developing AML[J]. Blood, 2016, 127(21):2638-2641.
[21]
Germeshausen M, Ballmaier M, Welte K. Incidence of CSF3R mutations in severe congenital neutropenia and relevance for leukemogenesis:Results of a long-term survey[J]. Blood, 2007, 109(1):93-99.
[22]
Touw IP. Game of clones:the genomic evolution of severe congenital neutropenia[J]. Hematology Am Soc Hematol Educ Program, 2015, 2015:1-7.
[23]
Horwitz MS, Duan Z, Korkmaz B, et al. Neutrophil elastase in cyclic and severe congenital neutropenia[J]. Blood, 2007, 109(5):1817-1824.
[24]
Dall'oca C, Bondi M, Merlini M, et al. Shwachman-Diamond syndrome[J]. Musculoskelet Surg, 2012, 96(2):81-88.
[25]
Myers KC, Davies SM, Shimamura A. Clinical and molecular pathophysiology of Shwachman-Diamond syndrome:an update[J]. Hematol Oncol Clin North Am, 2013, 27(1):117-128.
[26]
Boocock GR, Morrison JA, Popovic M, et al. Mutations in SBDS are associated with Shwachman-Diamond syndrome[J]. Nat Genet, 2003, 33(1):97-101.
[27]
Bezzerri V, Vella A, Calcaterra E, et al. New insights into the Shwachman-Diamond syndrome-related haematological disorder:hyper-activation of mTOR and STAT3 in leukocytes[J]. Sci Rep, 2016, 6:33165.
[28]
Beaussant Cohen S, Fenneteau O, Plouvier E, et al. Description and outcome of a cohort of 8 patients with WHIM syndrome from the French Severe Chronic Neutropenia Registry[J]. Orphanet J Rare Dis, 2012, 7:71.
[29]
Balabanian K, Brotin E, Biajoux V, et al. Proper desensitization of CXCR4 is required for lymphocyte development and peripheral compartmentalization in mice[J]. Blood, 2012, 119(24):5722-5730.
[30]
McDermott DH, Lopez J, Deng F, et al. AMD3100 is a potent antagonist at CXCR4(R334X), a hyperfunctional mutant chemokine receptor and cause of WHIM syndrome[J]. J Cell Mol Med, 2011, 15(10):2071-2081.
[31]
McDermott DH, Liu Q, Velez D, et al. A phase 1 clinical trial of long-term, low-dose treatment of WHIM syndrome with the CXCR4 antagonist plerixafor[J]. Blood, 2014, 123(15):2308-2316.
[32]
Lagresle-Peyrou C, Six EM, Picard C, et al. Human adenylate kinase 2 deficiency causes a profound hematopoietic defect associated with sensorineural deafness[J]. Nat Genet, 2009, 41(1):106-111.
[33]
Pannicke U, Hönig M, Hess I, et al. Reticular dysgenesis (aleukocytosis) is caused by mutations in the gene encoding mitochondrial adenylate kinase 2[J]. Nat Genet, 2009, 41(1):101-105.
[34]
Rissone A, Weinacht KG, la Marca G, et al. Reticular dysgenesis-associated AK2 protects hematopoietic stem and progenitor cell development from oxidative stress[J]. J Exp Med, 2015, 212(8):1185-1202.
[35]
Al-Zahrani D, Al-Ghonaium A, Al-Mousa H, et al. Skeletal abnormalities and successful hematopoietic stem cell transplantation in patients with reticular dysgenesis[J]. J Allergy Clin Immunol, 2013, 132(4):993-996.
[36]
Vulliamy TJ, Marrone A, Knight SW, et al. Mutations in dyskeratosis congenita:their impact on telomere length and the diversity of clinical presentation[J]. Blood, 2006, 107(7):2680-2685.
[37]
Guo Y, Kartawinata M, Li J, et al. Inherited bone marrow failure associated with germline mutation of ACD, the gene encoding telomere protein TPP1[J]. Blood, 2014, 124(18):2767-2774.
Tummala H, Walne A, Collopy L, et al. Poly(A)-specific ribonuclease deficiency impacts telomere biology and causes dyskeratosis congenita[J]. J Clin Invest, 2015, 125(5):2151-2160.
[40]
Khincha PP, Wentzensen IM, Giri N, et al. Response to androgen therapy in patients with dyskeratosis congenita[J]. Br J Haematol, 2014, 165(3):349-357.
[41]
Amarasinghe K, Dalley C, Dokal I, et al. Late death after unrelated-BMT for dyskeratosis congenita following conditioning with alemtuzumab, fludarabine and melphalan[J]. Bone Marrow Transplant, 2007, 40(9):913-914.
[42]
Husain EH, Mullah-Ali A, Al-Sharidah S, et al. Infectious etiologies of transient neutropenia in previously healthy children[J]. Pediatr Infect Dis J, 2012, 31(6):575-577.
[43]
Schwartzberg LS. Neutropenia:etiology and pathogenesis[J]. Clin Cornerstone, 2006, 8(Suppl 5):S5-S11.
[44]
Bhatt V, Saleem A. Review:Drug-induced neutropeniapathophysiology, clinical features, and management[J]. Ann Clin Lab Sci, 2004, 34(2):131-137.
[45]
Johnston A, Uetrecht J. Current understanding of the mechanisms of idiosyncratic drug-induced agranulocytosis[J]. Expert Opin Drug Metab Toxicol, 2015, 11(2):243-257.
Andrès, Federici L, Weitten T, et al. Recognition and management of drug-induced blood cytopenias:the example of drug-induced acute neutropenia and agranulocytosis[J]. Expert Opin Drug Saf, 2008, 7(4):481-489.
[48]
Watts RG. Neutropenia[M]//Greer JP, Foerster J, Lukens JN, et al. Wintrobe's Clinical Hematology. 11th ed. Philadelphia:Lippincott Williams & Wilkins, 2004:1777-1800.
[49]
Flesch BK, Curtis BR, de Haas M, et al. Update on the nomenclature of human neutrophil antigens and alleles[J]. Transfusion, 2016, 56(6):1477-1479.
[50]
Bux J, Behrens G, Jaeger G, et al. Diagnosis and clinical course of autoimmune neutropenia in infancy:analysis of 240 cases[J]. Blood, 1998, 91(1):181-186.
[51]
Shastri KA, Logue GL. Autoimmune neutropenia[J]. Blood, 1993, 81(8):1984-1995.
[52]
Audrain M, Martin J, Fromont P, et al. Autoimmune neutropenia in children:analysis of 116 cases[J]. Pediatr Allergy Immunol, 2011, 22(5):494-496.
[53]
Farruggia P, Fioredda F, Puccio G, et al. Autoimmune neutropenia of infancy:Data from the Italian neutropenia registry[J]. Am J Hematol, 2015, 90(12):E221-222.
[54]
Farruggia P, Dufour C. Diagnosis and management of primary autoimmune neutropenia in children:insights for clinicians[J]. Ther Adv Hematol, 2015, 6(1):15-24.
[55]
Autrel-Moignet A, Lamy T. Autoimmune neutropenia[J]. Presse Med, 2014, 43(4 Pt 2):e105-118.
[56]
Bruin MC, von dem Borne AE, Tamminga RY, et al. Neutrophil antibody specificity in different types of childhood autoimmune neutropenia[J]. Blood, 1999, 94(5):1797-1802.
[57]
Youinou P, Jamin C, Le Pottier L, et al. Diagnostic criteria for autoimmune neutropenia[J]. Autoimmun Rev, 2014, 13(4-5):574-576.
[58]
Bux J. Human neutrophil alloantigens[J]. Vox Sang, 2008, 94(4):277-285.
[59]
Curtis BR, Roman AS, Sullivan MJ, et al. Two cases of maternal alloimmunization against human neutrophil alloantigen-4b, one causing severe alloimmune neonatal neutropenia[J]. Transfusion, 2016, 56(1):101-106.
[60]
Mraz GA, Crighton GL, Christie DJ. Antibodies to human neutrophil antigen HNA-4b implicated in a case of neonatal alloimmune neutropenia[J]. Transfusion, 2016, 56(5):1161-1165.
[61]
Porcelijn L, Abbink F, Terraneo L, et al. Neonatal alloimmune neutropenia due to immunoglobulin G antibodies against human neutrophil antigen-5a[J]. Transfusion, 2011, 51(3):574-577.
