Main Article Content

Ilaria Lazzareschi
Elena Rossi
Antonietta Curatola
Giovanna Capozio
Luca Benacquista
Ludovica Iezzi
Donato Rigante


Congenital neutropenia, cyclic neutropenia, myelopoiesis, neutrophil elastase, periodic fever, autoinflammation, PFAPA syndrome, innovative biotechnologies, granulocyte-colony stimulating factor, personalized medicine


A disparate group of rare hematological diseases characterized by impaired maturation of neutrophil granulocytes defines congenital neutropenias. Neutropenic patients are prone to recurrent infections beginning in the first months of life. Of interest is “cyclic neutropenia”, an ultra-rare disorder revealed by sinusoidal variations of the neutrophil count and periodically-recurring infections every 21 days. Diagnosis of these disorders is frequently obscured by the multiple causes of recurrent fevers in children. Aim of this overview is to outline the physical assessment of children presenting with early-onset symptomatic neutropenia, identify the disease between the many medical conditions and even emergencies which should enter in differential diagnosis, hint at the potential management with granulocyte-colony stimulating factor, define the risk of evolution to hematologic malignancy, and summarize inter-professional team strategies for improving care coordination and outcomes of such patients.


Download data is not yet available.
Abstract 158 | PDF Downloads 55 HTML Downloads 18


1. Badolato R, Fontana S, Notarangelo LD, et al. Congenital neutropenia: advances in diagnosis and treatment. Curr Opin Allergy Clin Immunol 2004;4:513-21. doi: 10.1097/00130832-200412000-00007 PMid 15640692
2. Segel GB, Halterman JS. Neutropenia in pediatric practice. Pediatr Rev 2008;29:12-23. doi: 10.1542/pir.29-1-12 PMid 18166617
3. Dale DC, Person RE, Bolyard AA, et al. Mutations in the gene encoding neutrophil elastase in congenital and cyclic neutropenia. Blood 2000;96:2317-22. PMid 11001877
4. Dale DC, Hammond WP. Cyclic neutropenia: a clinical review. Blood Rev 1988;2:178-85. doi: 10.1016/0268-960x(88)90023-9 PMid: 3052663
5. Horwitz M, Benson KF, Person RE, et al. Mutations in ELA2, encoding neutrophil elastase, define a 21-day biological clock in cyclic haematopoiesis. Nat Genet 1999;23:433-6. doi: 10.1038/70544 PMid 10581030
6. Rigante D. When, how, and why do fevers hold children hostage? J Evid Based Med 2020;13:85-8. doi: 10.1111/jebm.12377 PMid: 32086995
7. Kollner I, Sodeik B, Schreek S, et al. Mutations in neutrophil elastase causing congenital neutropenia lead to cytoplasmic protein accumulation and induction of the unfolded protein response. Blood 2006;108:493-500. doi: 10.1182/blood-2005-11-4689 PMid 16551967
8. Bellanne-Chantelot C, Clauin S, Leblanc T, et al. Mutations in the ELA2 gene correlate with more severe expression of neutropenia: a study of 81 patients from the French Neutropenia Register. Blood 2004;103:4119-25. doi: 10.1182/blood-2003-10-3518 PMid 14962902
9. Garwicz D, Lennartsson A, Jacobsen SE, et al. Biosynthetic profiles of neutrophil serine proteases in a human bone marrow-derived cellular myeloid differentiation model. Haematologica 2005;90:38-44. PMid: 15642667
10. Haurie C, Dale DC, Mackey MC. Cyclical neutropenia and other periodic hematological disorders: a review of mechanisms and mathematical models. Blood 1998;92:2629-40. PMid: PMID: 9763544
11. Mir P, Klimiankou M, Findik B, et al. New insights into the pathomechanism of cyclic neutropenia. Ann NY Acad Sci 2020;1466:83-92. doi: 10.1111/nyas.14309 PMid: 32083314
12. Makaryan V, Zeidler C, Bolyard AA, et al. The diversity of mutations and clinical outcomes for ELANE-associated neutropenia. Curr Opin Hematol 2015;22:3-11. doi: 10.1097/MOH.0000000000000105 PMid 25427142
13. Olofsen PA, Bosch DA, Roovers O, et al. PML-controlled responses in severe congenital neutropenia with ELANE-misfolding mutations. Blood Adv 2021;5:775-86. doi: 10.1182/bloodadvances.2020003214 PMid: 33560392
14. Boxer LA, Newburger PE. A molecular classification of congenital neutropenia syndromes. Pediatr Blood Cancer 2007;49:609-14. doi: 10.1002/pbc.21282 PMid 17584878
15. Ishikawa N, Okada S, Miki M, et al. Neurodevelopmental abnormalities associated with severe congenital neutropenia due to the R86X mutation in the HAX1 gene. J Med Genet 2008;45:802-7. doi: 10.1136/jmg.2008.058297 PMid: 18611981
16. Aprikyan AAG, Kutyavin T, Stein S, et al. Cellular and molecular abnormalities in severe congenital neutropenia predisposing to leukemia. Exp Hematol 2003;31:372-81. doi: 10.1016/s0301-472x(03)00048-1 PMid: 12763135
17. Newburger PE, Pindyck TN, Zhu Z, 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 2010;55:314-17. doi: 10.1002/pbc.22537 PMid: 20582973
18. Horwitz MS, Corey SJ, Grimes HL, et al. ELANE mutations in cyclic and severe congenital neutropenia: genetics and pathophysiology. Hematol Oncol Clin North Am 2013;27:19-41. doi: 10.1016/j.hoc.2012.10.004 PMid 23351986
19. Klein C, Grudzien M, Appaswamy G, et al. HAX1 deficiency causes autosomal recessive severe congenital neutropenia (Kostmann disease). Nature Genet 2007;39:86-92. doi: 10.1038/ng1940 PMid: 17187068
20. Bellanné-Chantelot C, Clauin S, Leblanc T, et al. Mutations in the ELA2 gene correlate with more severe expression of neutropenia: a study of 81 patients from the French Neutropenia Register. Blood 2004;103:4119-25. doi: 10.1182/blood-2003-10-3518 PMid: 14962902
21. Banka S, Newman WG, Özgül RK, et al. Mutations in the G6PC3 gene cause Dursun syndrome. Am J Med Genet A 2010;152A:2609-11. doi: 10.1002/ajmg.a.33615 PMid: 20799326
22. Devriendt K, Kim AS, Mathijs G, et al. Constitutively activating mutation in WASP causes X-linked severe congenital neutropenia. Nat Genet 2001;27:313-7. doi: 10.1038/85886 PMid: 11242115
23. Person RE, Li FQ, Duan Z, et al. Mutations in proto-oncogene GFI1 cause human neutropenia and target ELA2. Nat Genet 2003;34:308-12. doi: 10.1038/ng1170 PMid: 12778173
24. Thobakgale CF, Ndung'u T. Neutrophil counts in persons of African origin. Curr Opin Hematol 2014;21:50-7. doi: 10.1097/MOH.0000000000000007 PMid: 24257098
25. Guerry D, Dale DC, Omine M, et al. Periodic hematopoiesis in human cyclic neutropenia. J Clin Invest 1973;52:3220-30. doi: 10.1172/JCI107522 PMid 4750451
26. Germeshausen M, Deerberg S, Peter Y, et al. The spectrum of ELANE mutations and their implications in severe congenital and cyclic neutropenia. Hum Mutat 2013;34:905-14. doi: 10.1002/humu.22308 PMid 23463630
27. Wright DG, Dale DC, Fauci AS, et al. Human cyclic neutropenia: clinical review and long-term follow-up of patients. Medicine (Baltimore) 1981;60:1-13. doi: 10.1097/00005792-198101000-00001 PMid 7453561
28. Palmer SE, Stephens K, Dale DC. Genetics, phenotype, and natural history of autosomal dominant cyclic hematopoiesis. Am J Med Genet 1996;66:413-22. doi: 10.1002/(SICI)1096-8628(19961230)66:4<413::AID-AJMG5>3.0.CO;2-L PMid: 8989458
29. Rosenberg PS, Alter BP, Link DC, et al. Neutrophil elastase mutations and risk of leukaemia in severe congenital neutropenia. Br J Haematol 2008;140:210-3. doi: 10.1111/j.1365-2141.2007.06897.x PMid 18028488
30. Makaryan V, Zeidler C, Bolyard AA, et al. The diversity of mutations and clinical outcomes for ELANE associated neutropenia. Curr Opin Hematol 2015;22:3-11. doi: 10.1097/MOH.0000000000000105 PMid: 25427142
31. Barnes C, Gerstle JT, Freedman MH, et al. Clostridium septicum myonecrosis in congenital neutropenia. Pediatrics 2004;114:e757-60. doi: 10.1002/(SICI)1096-8628(19961230)66:4<413::AID-AJMG5>3.0.CO;2-L PMid: 8989458
32. Link DC. Mechanisms of leukemic transformation in congenital neutropenia. Curr Opin Hematol 2019;26:34-40. doi: 10.1097/MOH.0000000000000479 PMid: 30431463
33. Mercuri A, Cannata E, Perbellini O, et al. Immunophenotypic analysis of hematopoiesis in patients suffering from Shwachman-Bodian-Diamond Syndrome. Eur J Haematol 2015;95:308-15. doi: 10.1111/ejh.12490 PMid: 25402872
34. Dale DC, Welte K. Cyclic and chronic neutropenia. Cancer Treat Res 2011;157:97-108. doi: 10.1007/978-1-4419-7073-2_6 PMid: 21052952
35. 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. Br J Haematol 2010;150:196-9. doi: 10.1111/j.1365-2141.2010.08216.x PMid 20456363
36. 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. Haematologica 2005;90:45-53. PMid: 15642668
37. Zeidler C, Welte K. Kostmann syndrome and severe congenital neutropenia. Semin Hematol 2002;39:82-8. doi: 10.1053/shem.2002.31913 PMid: 11957189
38. Klimiankou M, Mellor-Heineke S, Klimenkova O, et al. Two cases of cyclic neutropenia with acquired CSF3R mutations, with 1 developing AML. Blood 2016;127:2638-41. doi: 10.1182/blood-2015-12-685784 PMid: 27030388
39. Rosenberg PS, Alter BP, Bolyard AA, et al. The incidence of leukemia and mortality from sepsis in patients with severe congenital neutropenia receiving long-term G-CSF therapy. Blood 2006; 107:4628-35. doi: 10.1182/blood-2005-11-4370 PMid: 16497969
40. Dale DC, Bolyard A, Marrero T, et al. Long-term effects of G-CSF therapy in cyclic neutropenia. N Engl J Med 2017;377:2290-2. doi: 10.1056/NEJMc1709258 PMid: 29211670
41. De Rose DU, Coppola M, Gallini F, Maggi L, Vento G, Rigante D. Overview of the rarest causes of fever in newborns: handy hints for the neonatologist. J Perinatol 2021;41:372-82. doi: 10.1038/s41372-020-0744-8 PMid: 32719496
42. Bux J, Behrens G, Jaeger G, et al. Diagnosis and clinical course of autoimmune neutropenia in infancy: analysis of 240 cases. Blood 1998;91:181-6. PMid: 9414283
43. Pernu HE, Pajari UH, Lanning M. The importance of regular dental treatment in patients with cyclic neutropenia. Follow-up of 2 cases. J Periodontol 1996;67:454-9. doi: 10.1902/jop.1996.67.4.454 PMid 8708974
44. Geelhoed GW, Kane MA, Dale DC, et al. Colon ulceration and perforation in cyclic neutropenia. J Pediatr Surg 1973;8:379-82. doi: 10.1016/0022-3468(73)90105-x PMid: 4715743
45. Horwitz MS, Duan Z, Korkmaz B, et al. Neutrophil elastase in cyclic and severe congenital neutropenia. Blood 2007;109:1817. doi: 10.1182/blood-2006-08-019166 PMid: 17053055
46. Dale DC, Cottle TE, Fier CJ, et al. Severe chronic neutropenia: treatment and follow-up of patients in the Severe Chronic Neutropenia International Registry. Am J Hematol 2003;72:82-93. doi: 10.1002/ajh.10255 PMid: 12555210
47. Hammond WP, Price TH, Souza LM, et al. Treatment of cyclic neutropenia with granulocyte colony-stimulating factor. N Engl J Med 1989;320:1306-11. doi: 10.1056/NEJM198905183202003 PMid: 2469956
48. Matarasso S, Daniele V, Iorio Siciliano V, et al. The effect of recombinant granulocyte colony-stimulating factor on oral and periodontal manifestations in a patient with cyclic neutropenia: a case report. Int J Dent 2009;2009:654239. doi: 10.1155/2009/654239 PMid: 20339570
49. Welte K, Zeidler C, Reiter A, et al. Differential effects of granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor in children with severe congenital neutropenia. Blood 1990; 75:1056-63. PMid: 1689595
50. Ishida Y, Higaki A, Tauchi H, et al. Disappearance of neutrophil fluctuations in a child with cyclic neutropenia by combination therapy of granulocyte colony-stimulating factor and high-dose immunoglobulin. Acta Paediatr Jpn 1995;37:388-90. doi: 10.1111/j.1442-200x.1995.tb03338.x PMid 7544058
51. Okada M, Kobayashi M, Hino T, et al. Clinical periodontal findings and microflora profiles in children with chronic neutropenia under supervised oral hygiene. J Periodontol 2001;72:945-52. doi: 10.1902/jop.2001.72.7.945 PMid: 11495144
52. Zeidler C, Reiter A, Yakisan E, et al. Long-term treatment with recombinant human granulocyte colony stimulating factor in patients with severe congenital neutropenia. Klin Padiatr 1993;205:264-71. doi: 10.1055/s-2007-1025236 PMid: 7690865
53. Shiohara M, Shigemura T, Saito S, et al. ELA2 mutations and clinical manifestations in familial congenital neutropenia. ELA2 mutations and clinical manifestations in familial congenital neutropenia. J Pediatr Hematol Oncol 2009;31:319-24. doi: 10.1097/MPH.0b013e3181984dbe PMid: 19415009
54. Krance RA, Spruce WE, Forman SJ, et al. Human cyclic neutropenia transferred by allogeneic bone marrow grafting. Blood 1982;60:1263-6. PMid 6753968
55. Rao S Yao Y, Soares de Brito J, et al. Dissecting ELANE neutropenia pathogenicity by human HSC gene editing. Cell Stem Cell 2021;28:833-45. doi: 10.1016/j.stem.2020.12.015 PMid 33513358
56. Rigante D. Autoinflammatory syndromes behind the scenes of recurrent fevers in children. Med Sci Monit 2009;15:RA179-87. PMid: 19644432
57. Donadieu J, Beaupain B, Fenneteau O, et al. Congenital neutropenia in the era of genomics: classification, diagnosis, and natural history. Br J Haematol 2017;179:557-74. doi: 10.1111/bjh.14887 PMid: 28875503
58. Marshall GS. Prolonged and recurrent fevers in children. J Infect 2014;68 Suppl 1:S83-93. doi: 10.1016/j.jinf.2013.09.017 PMid: 24120354
59. Rigante D. Phenotype variability of autoinflammatory disorders in the pediatric patient: a pictorial overview. J Evid Based Med 2020;13:227-45. doi: 10.1111/jebm.12406 PMid: 32627322
60. Rigante D. New mosaic tiles in childhood hereditary autoinflammatory disorders. Immunol Lett 2018;193:67-76. doi: 10.1016/j.imlet.2017.11.013 PMid: 29198619
61. Rigante D, Frediani B, Galeazzi M, et al. From the Mediterranean to the sea of Japan: the transcontinental odyssey of autoinflammatory diseases. Biomed Res Int 2013;2013:485103. doi: 10.1155/2013/485103 PMid: 23971037
62. Manna R, Rigante D. Familial Mediterranean fever: assessing the overall clinical impact and formulating treatment plans. Mediterr J Hematol Infect Dis 2019;11:e2019027. doi: 10.4084/MJHID.2019.027 PMid: 31205631
63. Esposito S, Ascolese B, Senatore L, et al. Current advances in the understanding and treatment of mevalonate kinase deficiency. Int J Immunopathol Pharmacol 2014;27:491-8. doi: 10.1177/039463201402700404 PMid: 25572728
64. Rigante D, Lopalco G, Vitale A, et al. Key facts and hot spots on tumor necrosis factor receptor-associated periodic syndrome. Clin Rheumatol 2014;33:1197-207. doi: 10.1007/s10067-014-2722-z PMid: 24935411
65. Rigante D. The broad-ranging panorama of systemic autoinflammatory disorders with specific focus on acute painful symptoms and hematologic manifestations in children. Mediterr J Hematol Infect Dis 2018;10:e2018067 doi: 10.4084/MJHID.2018.067 PMid: 30416699
66. Rigante D. A systematic approach to autoinflammatory syndromes: a spelling booklet for the beginner. Expert Rev Clin Immunol 2017;13:571-97. doi: 10.1080/1744666X.2017.1280396 PMid: 28064547
67. Ter Haar NM, Annink KV, Al-Mayouf SM, et al. Development of the autoinflammatory disease damage index (ADDI). Ann Rheum Dis 2017;76:821-30. doi: 10.1136/annrheumdis-2016-210092 PMid: 27811147
68. Esposito S, Bianchini S, Fattizzo M, et al. The enigma of periodic fever, aphthous stomatitis, pharyngitis and adenitis syndrome. Pediatr Infect Dis J 2014;33:650-2. doi: 10.1097/INF.0000000000000346 PMid: 24642520
69. Rigante D. The protean visage of systemic autoinflammatory syndromes: a challenge for inter-professional collaboration. Eur Rev Med Pharmacol Sci 2010;14:1-18. PMid: 20184084
70. Manna R, Rigante D. The everchanging framework of autoinflammation. Intern Emerg Med 2021 May 17 - Epub ahead of print - doi: 10.1007/s11739-021-02751-7 PMid: 33999387
71. Yazgan H, Keleş E, Yazgan Z, et al. C-reactive protein and procalcitonin during febril attacks in PFAPA syndrome. Int J Pediatr Otorhinolaryngol 2012;76:1145-7. doi: 10.1016/j.ijporl.2012.04.022 PMid: 22658448
72. Rigante D, Corina L. Periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome: a debate about diagnosis and treatment in children continues. Int J Pediatr Otorhinolaryngol 2020;130:109830. doi: 10.1016/j.ijporl.2019.109830 PMid: 31866107
73. Sicignano LL, Rigante D, Moccaldi B, et al. Children and adults with PFAPA syndrome: similarities and divergences in a real-life clinical setting. Adv Ther 2021;38:1078-93. doi: 10.1007/s12325-020-01576-8 PMid: 33315168
74. Rigante D, Vitale A, Natale MF, et al. A comprehensive comparison between pediatric and adult patients with periodic fever, aphthous stomatitis, pharyngitis, and cervical adenopathy (PFAPA) syndrome. Clin Rheumatol 2017;36:463-8. doi: 10.1007/s10067-016-3317-7 PMid: 27251674
75. Gentileschi S, Vitale A, Frediani B, et al. Challenges and new horizons in the periodic fever, aphthous stomatitis, pharingitis and adenitis (PFAPA) syndrome. Expert Opin Orphan Drugs 2017;5:165-71. doi: 10.1080/21678707.2017.1279049
76. Rigante D. A developing portrait of hereditary periodic fevers in childhood. Expert Opin Orphan Drugs 2018;6:47-55. doi: 10.1080/21678707.2018.1406797

Most read articles by the same author(s)