Late-diagnosed severe congenital neutropenia due to an ELANE splice-site mutation

Dear Editor,

Severe congenital neutropenia (SCN), also known as Kostmann syndrome, is a rare inherited disorder characterised by profound and persistent neutropenia, predisposing affected children to recurrent, potentially life-threatening infections from early life. We report a case of SCN diagnosed in late childhood, highlighting the importance of considering congenital causes of neutropenia even beyond infancy and emphasising the role of genetic testing in establishing the diagnosis.

A 10-year-old boy, born of a third-degree consanguineous marriage (fourth birth order), presented with a 1-month history of recurrent pyogenic infections, including pneumonia requiring three hospitalisations, intermittent fever, stomatitis with dysphagia, trismus and bilateral cervical lymphadenopathy. There was also a remote history of recurrent skin abscesses since childhood, but no history of seizures or developmental delay. Notably, similar recurrent infections were reported in the mother and elder sister, all of which strongly raised the suspicion of a familial disorder.

On examination, the child was thriving well with stable vital parameters. There was bilateral tender cervical lymphadenopathy, with the largest node measuring 2 × 3 cm in the right submandibular region. No hepatosplenomegaly was detected. Laboratory evaluation revealed marked neutropenia (neutrophils 8%, absolute neutrophil count (ANC) 416/µL) with monocytosis (26%, absolute monocyte count 1352/µL), while haemoglobin and platelet counts were normal. Cardiac evaluation and immunodeficiency work-up were unremarkable. Bone marrow examination demonstrated reactive marrow without evidence of malignant infiltration or dysplasia, thereby ruling out haematological malignancy. No maturation arrest of neutrophils was observed, likely because neutropenia in SCN is cyclical and can return to near-normal levels every 21–28 days. We therefore believe that the bone marrow biopsy appeared normal at that particular time.^[1] The child was managed symptomatically and advised close follow-up.

Serial blood counts over subsequent visits demonstrated fluctuating but persistently low neutrophil counts, with ANC ranging from as low as 53/µL to a maximum of 840/µL [Figure 1]. Given the chronicity, family history, and infection burden, whole-exome sequencing was performed, which identified a heterozygous likely pathogenic 5' splice-site variant in intron 4 of the ELANE gene (c.597+5G>A; autosomal dominant), previously reported in patients with SCN (OMIM #202700), thereby confirming the molecular diagnosis in correlation with the clinical phenotype. The child was managed with infection-directed antimicrobial therapy and initiated on granulocyte colony-stimulating factor (G-CSF) with close haematological monitoring, resulting in clinical stabilisation.

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Figure 1: Trends in total leucocyte count, ANC, and neutrophil percentage over time. (TLC: Total leukocyte count; ANC: Absolute neutrophil count)

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SCN is most commonly associated with mutations in ELANE, accounting for approximately 40–55% of cases.^[2] The ELANE gene encodes neutrophil elastase, a serine protease essential for neutrophil maturation and function. Mutant neutrophil elastase leads to misfolded protein accumulation, endoplasmic reticulum stress, and maturation arrest at the promyelocyte stage, resulting in severe neutropenia with compensatory monocytosis.^[3,4] Clinical manifestations include recurrent bacterial and fungal infections, oral ulcers, and deep-seated infections. Importantly, ELANE-related neutropenia carries a recognised risk of progression to myelodysplastic syndrome or acute myeloid leukaemia, particularly with long-term high-dose G-CSF therapy.

This case underscores several key learning points. First, congenital neutropenia should be considered in children with recurrent infections and persistent neutropenia, even when the diagnosis is delayed beyond infancy. Second, serial ANC monitoring is essential, as single measurements may be misleading. Third, genetic testing plays a pivotal role in confirming the diagnosis, guiding prognosis, family counselling, and long-term surveillance. Early recognition and proper management, including infection prevention, judicious use of G-CSF, and genetic counselling, are critical to improving outcomes and quality of life in affected children.