ASSESSMENT OF CONGENITAL NEUTROPENIA IN CHILDREN: COMMON CLINICAL SCENERIES AND CLUES FOR MANAGEMENT Assessment of congenital neutropenia in children
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Keywords
Congenital neutropenia, cyclic neutropenia, myelopoiesis, neutrophil elastase, periodic fever, autoinflammation, PFAPA syndrome, innovative biotechnologies, granulocyte-colony stimulating factor, personalized medicine
Abstract
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.
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References
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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
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Jan 1, 2022
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Lazzareschi, I. (2022) “ ASSESSMENT OF CONGENITAL NEUTROPENIA IN CHILDREN: COMMON CLINICAL SCENERIES AND CLUES FOR MANAGEMENT: Assessment of congenital neutropenia in children”, Mediterranean Journal of Hematology and Infectious Diseases, 14(1), p. e2022008. doi: 10.4084/MJHID.2022.008.
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