Diagnostic guidance for hereditary neutropenia in children: Narrative literature review


Zakaria Kasmi
Jalila El Bakkouri
Fatima Ailal
Bouchra Oukkache
Jean Donadieu
Ahmed Aziz Bousfiha


In the era of genomics, orientation in the face of hereditary neutropenia still requires, first and foremost, a good clinical and cytological analysis. The thirty responsible genes now explain 60% of congenital neutropenia. These are rare since they are only found in 1‰ of all congenital neutropenia, estimated at 1% of the population. The clinical examination looks for phenotypes associated with syndromic hereditary neutropenia and cytology will guide this etiological research thanks to the data collected from blood count and bone marrow analysis.

The objective of this narrative literature review is to provide an overview of the most recent literature regarding acquired and congenital chronic neutropenia and will provide a decision tree to guide towards aetiology. This will allow a better discussion with geneticists even if the genotype-phenotype correlation is not very strong.


Congenital neutropenia, chronic neutropenia, hereditary neutropenia



  1. Bousfiha A, Jeddane L, Picard C, Ailal F, Bobby Gaspar H, Al-Herz W, et al. The 2017 IUIS Phenotypic Classification for Primary Immunodeficiencies. J Clin Immunol 2018;38:129‑43.
  2. Schwartzberg LS. Neutropenia: etiology and pathogenesis. Clin Cornerstone 2006;8(5 Suppl):5-11.
  3. Donadieu J, Beaupain B, Fenneteau O, Bellanné-Chantelot C. Congenital neutropenia in the era of genomics: classification, diagnosis, and natural history. Br J Haematol 2017;179:557–74.
  4. Hsieh MM, Everhart JE, Byrd-Holt DD, Tisdale JF, Rodgers GP. Prevalence of neutropenia in the U.S. population: age, sex, smoking status, and ethnic differences. Ann Intern Med 2007;146:486–92.
  5. Palmblad JEW, von dem Borne AEGK. Idiopathic, immune, infectious, and idiosyncratic neutropenias. Semin Hematol 2002;39:113–20.
  6. Kyle RA, Linman JW. Chronic idiopathic neutropenia. A newly recognized entity? N Engl J Med 1968;279:1015–9.
  7. Forbes WH, Johnson RE, Consolazio F. Leukopenia in Negro workmen. The American Journal of the Medical Sciences. 201st ed. 1941;407–12.
  8. Bejjani N, Beaupain B, Bertrand Y, Bellanne-Chantelot C, Donadieu J. How to differentiate congenital from noncongenital chronic neutropenia at the first medical examination? Proposal of score: A pilot study from the French Severe Chronic Neutropenia registry. Pediatr Blood Cancer 2017;64.
  9. Palmblad J, Dufour C, Papadaki HA. How we diagnose neutropenia in the adult and elderly patient. Haematologica 2014;99:1130–3.
  10. Donadieu J, Fenneteau O, Beaupain B, Mahlaoui N, Chantelot CB. Congenital neutropenia: diagnosis, molecular bases and patient management. Orphanet J Rare Dis 2011;6:26.
  11. Fata F, Myers P, Addeo J, Grinberg M, Nawabi I, Cappell MS. Cyclic neutropenia in Crohn’s ileocolitis: efficacy of granulocyte colony-stimulating factor. J Clin Gastroenterol 1997;24:253 6.
  12. Schmutz N, Henry E, Jopling J, Christensen RD. Expected ranges for blood neutrophil concentrations of neonates: the Manroe and Mouzinho charts revisited. J Perinatol Off J Calif Perinat Assoc 2008;28:275–81.
  13. Klein C. Congenital neutropenia. In: Sullivan KE, Stiehm ER, eds. Stiehm’s Immune Deficiencies. Second Edition. Academic Press, 2020:797–812.
  14. Donadieu J, Leblanc T, Bader Meunier B, Barkaoui M, Fenneteau O, Bertrand Y, 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.
  15. Haapaniemi EM, Fogarty CL, Keskitalo S, Katayama S, Vihinen H, Ilander M, et al. Combined immunodeficiency and hypoglycemia associated with mutations in hypoxia upregulated 1. J Allergy Clin Immunol 2017;139:1391-1393.
  16. Kuhns DB, Fink DL, Choi U, Sweeney C, Lau K, Priel DL, et al. Cytoskeletal abnormalities and neutrophil dysfunction in WDR1 deficiency. Blood 2016;128:2135‑43.
  17. Walkovich K, Connelly JA. Congenital Neutropenia and Rare Functional Phagocyte Disorders in Children. Hematol Oncol Clin North Am 2019;33:533–51.
  18. Skokowa J, Dale DC, Touw IP, Zeidler C, Welte K. Severe congenital neutropenias. Nat Rev Dis Primer 2017;3:17032.
  19. Segel GB, Halterman JS. Neutropenia in Pediatric Practice. Pediatr Rev 2008;29:12–24.
  20. Horwitz MS, Duan Z, Korkmaz B, Lee HH, Mealiffe ME, Salipante SJ. Neutrophil elastase in cyclic and severe congenital neutropenia. Blood 2007;109:1817–24.
  21. Armistead PM, Wieder E, Akande O, Alatrash G, Quintanilla K, Liang S, Molldrem J. Cyclic neutropenia associated with T cell immunity to granulocyte proteases and a double de novo mutation in GFI1, a transcriptional regulator of ELANE. Br J Haematol 2010;150:716–9.
  22. Auer PL, Teumer A, Schick U, O’Shaughnessy A, Lo KS, Chami N, et al. Rare and low-frequency coding variants in CXCR2 and other genes are associated with hematological traits. Nat Genet 2014;46:629‑34.
  23. Spoor J, Farajifard H, Rezaei N. Congenital neutropenia and primary immunodeficiency diseases. Crit Rev Oncol Hematol 2019;133:149–62.
  24. Thomas AE. Investigating neutropenia. Paediatr Child Health 2007;17:328–32.
  25. Fioredda F, Calvillo M, Bonanomi S, Coliva T, Tucci F, Farruggia P, et al. Congenital and acquired neutropenia consensus guidelines on diagnosis from the Neutropenia Committee of the Marrow Failure Syndrome Group of the AIEOP (Associazione Italiana Emato-Oncologia Pediatrica). Pediatr Blood Cancer 2011;57:10‑7.