Neutropenia, cyclic / Neutropenia, severe congenital 1

Heterozygous pathogenic variants in the ELANE gene, coding for neutrophil elastase, are causative for cyclic neutropenia (CyN) and for about 40-80% of severe congenital neutropenia (SCN). The exact pathomechanism by which ELANE variants lead to a lack of mature neutrophil granulocytes in the peripheral blood is not known. A direct role of neutrophil elastase in granulopoiesis has not yet been established. There is no clear genotype-phenotype correlation; some pathogenic variants have been identified in both CyN and SCN patients.

Cyclic neutropenia occurs every 2-3 weeks for approximately 1 week and is detected by regular monitoring of the neutrophil count over 2 months. In patients with well-documented cyclic neutropenia and known affected family members, the detection rate of pathogenic variants in the ELANE gene is 90-100%. CyN shows variable symptoms depending on the duration and severity of the neutropenia: severe bacterial infections, pneumonia, abscesses, lymphadenitis, stomatitis, skin and mucous membrane ulcerations, or only fever episodes, can occur.

SCN is characterized by a permanently severely reduced absolute number of neutrophil granulocytes in the peripheral blood, which leads to severe infections, pneumonia, otitis, stomatitis, abscesses, skin and mucous membrane ulcerations as early as the first year of life. The treatment of choice is the administration of G-CSF, a growth factor that stimulates the maturation of neutrophil granulocytes. The only causal treatment for the disease is blood stem cell transplantation.

The most common genetic cause of congenital neutropenia is pathogenic variants in the ELANE gene. In rarer cases, pathogenic variants are present in other SCN-associated genes. NGS panel analysis can be used to test other genes that are causally linked to neutropenia.

References

Spoor et al. 2019, Crit Rev Oncol Hematol 133:149 / Shearer et al. 2014, J Allergy Clin Immunol 133:1092 / Buckley et al. 1997, J Pediatr 130:378 / Puck et al. 1997, Blood 89:1968 / Puck et al. 1993, Hum Mol Genet 2:1099