Letter to the EditorAuthors: Renato Cerqueira¹; Josefina Aparecida Pellegrini Braga¹; Elyse Moritz¹; João Bosco Pesquero¹; José Orlando Bordin¹Institution : 1 - Universidade Federal de São PauloTitle: A Novel ELANE Variant Causing Severe Congenital Neutropenia Diagnosed in Adulthood.Dear Editor,Severe congenital neutropenia (SCN) has been associated with approximately 30 genes, with ELANE accounting for 45-55% of cases. ELANE is an autosomal dominant gene with over 200 described variants.1, 2,3-5 Predominantly affecting childhood, SCN is characterized by a life-threatening bone marrow failure syndrome. Before the introduction of granulocyte colony-stimulating factor (G-CSF), the mortality rate exceeded 80% due to bacterial infections, even with the use of antibiotics. The advent of G-CSF significantly reduced mortality, but the cumulative incidence of death from sepsis remains at 10% after 15 years of treatment.1We report the case of a 29-year-old woman admitted to the hospital with a tonsillar abscess and severe neutropenia. She had a lifelong history of neutropenia, with recurrent oral ulcers, gastroenterocolitis, urinary tract infections, pneumonia, and skin abscesses. Notably, she had no history of using G-CSF either prophylactically or during infections, having only received briefly for six months around the age of 10. Additionally, she lost her lower central incisor teeth at the age of 23 due to severe periodontitis.Physical examinations consistently revealed painful oral ulcers and skin abscesses. Serial blood counts, performed approximately twice a week over a ten-week period, were not compatible with cyclic neutropenia (Figure 1). Bone marrow aspirate revealed granulocytic series hypocellularity with maturation arrest at the promyelocyte stage, and bone marrow trephine confirmed global hypocellularity (~40%). Immunophenotyping showed no clonal cell populations, and a normal karyotype G band was observed in 20 metaphases. Whole exome sequencing identified a novel ELANE variant (ELANE :c.47T>G:p.[Leu16Arg]) confirmed by Sanger sequencing. This specific ELANE variant results in a leucine to arginine substitution at position 16 of the protein. Leucine is a hydrophobic amino acid, while arginine is hydrophilic and positively charged, which can cause significant changes in the structure or stability of the protein, possibly interfering with its function. Mutations in the ELANE gene are typically associated with defects in the processing of neutrophil elastase, leading to the accumulation of misfolded proteins in the endoplasmic reticulum of granulopoiesis precursor cells. This accumulation can trigger cellular stress, programmed cell death (apoptosis) and, consequently, failure in the maturation of neutrophils, which is characteristic of SCN.6Her parents were non-consanguineous, and her father, who died at the age of 68 from a stroke, was reportedly neutropenic but asymptomatic, though no blood count records were available. Her mother had normal blood counts and no history of recurrent infections, nor did she carryELANE variants. The patient’s only sister, aged 34, had a history of chronic neutropenia with recurrent skin abscesses, pneumonia, tooth loss at the age of 24 due to severe periodontitis, and had been using G-CSF since the age of 2. Blood samples revealed that this sibling is also heterozygous for the ELANE (c.47T>G) variant.To our knowledge, there have been no recorded cases of SCN diagnosed as late as 29 years of age, particularly when associated with ELANE mutations. This case reinforces the importance of considering genetic testing for neutropenia in selected adult patients, especially when clinical manifestations suggest SCN. Additionally, this novelELANE variant may be associated with a milder clinical phenotype, potentially explaining the delayed diagnosis in this patient.