A novel missense variant in CTLA4 associated with immune dysregulation

Background: Cytotoxic T lymphocyte-associated antigen-4 (CTLA4) haploinsufficiency is a primary immunoregulatory disorder characterized by a broad clinical spectrum including combined immunodeficiency, autoimmunity, enteropathy, lymphoproliferation, and malignancy. Aim: We aim to broaden the recognized phenotypic and genetic spectrum of patients with variants in CTLA4. Methods: We report the case of a patient with persistent bicytopenia and an episode of soft tissue infection and associated bacteremia. Targeted genetic sequencing was performed using next-generation sequencing on the Illumina platform with Sanger sequencing for low-coverage regions through Cincinnati Children’s Hospital in addition to immune evaluation. Results: The proband presented at 14 years of age with cellulitis, and was found to have Bacillus cereus bacteremia, along with neutropenia and thrombocytopenia that persisted following infection resolution. Immune evaluation revealed T cell lymphopenia with preserved humoral immunity, and subsequently NK cell lymphopenia. A targeted ALPS genetic panel identified a novel heterozygous variant in the CTLA4 NM_005214.5(CTLA4):c.160G>T (p.Ala54Ser). Conclusion: A novel heterozygous CTLA4 variant caused immune dysregulation and immunodeficiency, in keeping with the described features of CTLA4 haploinsufficiency. Statement of novelty: We describe a previously unreported missense variant in CTLA4 leading to immune dysregulation and cytopenias, successfully managed with targeted abatacept therapy.