D3.404 - From CVID to CTLA-4 Haploinsufficiency: The Impact of Genetic Diagnosis on Targeted Therapy

Background:CTLA-4 insufficiency was initially described in 2014, as a form of immune dysregulation inherited in an autosomal dominant manner with incomplete penetrance. Historically, patients with CTLA-4 insufficiency were labeled as having common variable immune deficiency (CVID) but genetic testing permits a more specific diagnosis and points to targeted therapy.

Case description:We report a 50-year-old male referred to suspect CVID treated with immunoglobulin replacement for 5 years. Patient had an history of classical Hodgkin lymphoma (at 20 years old and relapse 10 years later) treated with chemotherapy and autologous stem cell transplantation, who developed progressive hypogammaglobulinemia, recurrent respiratory infections and chronic diarrhea, in the following 10 years. Immunologic assessment revealed defective antibody responses and a marked reduction of switched memory B cells (fulfilling CVID criteria), elevated CD21low subpopulation but also T cells impairment. Clinically, the patient developed bronchiectasis, chronic lymphoplasmacytic colitis, recurrent Clostridioides difficile infection, persistent norovirus GI/GII infection refractory to ribavirin and recurrent viral reactivations were also observed, including Epstein–Barr virus (EBV). Further genetic analysis identified a heterozygous pathogenic variant in CTLA4 (c.95del; p.Pro32Leufs*40), confirming CTLA-4 haploinsufficiency.

Targeted immunomodulatory therapy with abatacept was initiated in a multidisciplinary setting. Following treatment, gastrointestinal inflammation improved significantly, with normalization of fecal calprotectin and complete resolution of chronic diarrhea, despite persistent norovirus PCR positivity. Despite optimized immunoglobulin replacement therapy, from November 2025 the patient developed persistent fever, progressive lymphopenia, hepatosplenomegaly and increasing EBV viral load. Antiviral therapy with was ineffective, and rituximab was subsequently initiated with actual response. Patient is now waiting to stem cell transplantation. 

Discussion and Conclusion: This case illustrates the broad spectrum and complexity of CTLA-4 haploinsufficiency, including combined immunodeficiency, immune-mediated gastrointestinal disease, chronic viral infections and lymphoproliferation. Clinical improvement following abatacept highlights the central role of CTLA-4 dysfunction in immune dysregulation and supports precision-based immunomodulatory therapy in selected patients. Early genetic diagnosis is essential to guide individualized treatment and multidisciplinary management in CVID labeled patients(specially in the presence of immune dysregulation).