Cyclic neutropenia / severe congenital neutropenia 1

ELANE-related neutropenia presents as a clinical continuum ranging from cyclic neutropenia to severe congenital neutropenia, with intermediate phenotypes. Affected individuals develop recurrent fever and skin and oropharyngeal inflammation, including mouth ulcers, gingivitis, sinusitis, pharyngitis, and cervical adenopathy. In severe congenital neutropenia, diarrhoea, pneumonia, and deep abscesses of the liver, lung, and subcutaneous tissues are common, and omphalitis in the neonatal period may be the first sign. Cyclic neutropenia is typically recognised soon after birth or within the first year of life, with regular three-week oscillations of the absolute neutrophil count and nadir values below 0.2×10⁹/L. Chronic gingivitis, recurrent tooth abscesses, and alveolar bone loss frequently lead to permanent tooth loss in adolescence or young adulthood. Inter- and intra-familial variability is well documented, with the same pathogenic variant producing differing clinical severity.

The estimated prevalence is 1/1,000,000 for cyclic neutropenia. ELANE-related neutropenia is the most common cause of chronic neutropenia in children, although the precise prevalence is not established.

ELANE-related neutropenia is caused by heterozygous germline pathogenic variants in ELANE (19p13.3), which encodes neutrophil elastase, a serine protease packaged into the primary granules of developing neutrophils. It is hypothesized that the abnormal enzyme is inadequately inhibited and misfolded, triggering accelerated apoptosis of neutrophil precursors through the unfolded-protein response and Bcl-2-mediated pathways. The resulting maturation arrest at the promyelocyte and myelocyte stage produces the characteristic peripheral neutropenia.

ELANE-related neutropenia is inherited in an autosomal dominant manner. Each child of an affected individual has a 50% risk of inheriting the pathogenic variant. Apparent absence of family history may reflect undiagnosed mild disease in a parent or parental somatic mosaicism. Prenatal molecular testing is technically possible once the familial pathogenic variant has been identified.

Diagnosis rests on documented neutropenia together with molecular confirmation. Severe congenital neutropenia is supported by at least three absolute neutrophil counts below 0.5×10⁹/L (typically <0.2×10⁹/L) obtained beyond three months of age, while cyclic neutropenia is defined by serial complete blood counts showing regular three-week oscillations with nadirs below 0.2×10⁹/L for three to five days. Bone marrow aspirate typically shows maturation arrest at the promyelocyte or myelocyte stage, and baseline cytogenetic analysis supports surveillance for clonal evolution. Molecular genetic testing of ELANE establishes the diagnosis.

Main differential diagnoses include:

• Kostmann disease / HAX1-related severe congenital neutropenia: autosomal recessive severe congenital neutropenia, sometimes accompanied by neurodevelopmental features; HAX1
• G6PC3 deficiency: autosomal recessive nonsyndromic severe congenital neutropenia frequently associated with prominent superficial venous markings and cardiac or urogenital anomalies; G6PC3
• : syndromic congenital neutropenia with exocrine pancreatic insufficiency, skeletal abnormalities and elevated risk of MDS/AML; SBDS

• Establishing the molecular diagnosis confirms the clinical suspicion and distinguishes the condition from clinically overlapping disorders.
• Identification of the causative variant enables specific and individualised surveillance and clinical management, including monitoring for malignant transformation to myelodysplastic syndrome or acute myeloid leukaemia in severe congenital neutropenia; the resulting decisions remain with the treating physicians in consultation with the affected individual.
• Once the familial pathogenic variant is known, predictive testing of at-risk relatives is technically possible and may identify previously unrecognised mild or moderately affected family members.

• Dale DC, Makaryan V. ELANE-related neutropenia. 2018 Aug 23. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: PMID:20301705.
• Dale DC, Bolyard AA, Shannon JA, Connelly JA, Link DC, Bonilla MA, et al. Outcomes for patients with severe chronic neutropenia treated with granulocyte colony-stimulating factor. Blood Adv. 2022;6(13):3861-9. doi:10.1182/bloodadvances.2021005684. PMID:; PMCID: PMC9278291.
• Fioredda F, Spanoudakis M, Skokowa J, Tamary H, Farruggia P, Almeida A, et al. European guidelines on treatment and supportive measures in chronic neutropenias: a consensus between the European Hematology Association and the EuNet-INNOCHRON COST Action based on a systematic evidence review. HemaSphere. 2025;9(4). doi:10.1002/hem3.70113. PMID:; PMCID: PMC12001981.
• Xiao Y, Wang N, Jin X, Liu A, Zhang Z. Clinical relevance of SCN and CyN induced by ELANE mutations: a systematic review. Front Immunol. 2024;15:1349919. doi:10.3389/fimmu.2024.1349919. PMID:; PMCID:PMC11150597.