Heterozygous mutations in cytotoxic T-lymphocyte-associated-antigen4 (CTLA-4) gene is often associated to immune dysregulation syndrome characterized by increased cancer susceptibility. We describe 3 CTLA4 mutation carriers identified among a cohort of 17 CID/CVID patients.
Immunophenotypical, functional and molecular studies
Two mutation carriers (Pt1 and Pt2) were affected presenting decreased naïve-CD4+ T-, Treg-, NK-, memory B -cells with increased CD21low B cells, Tfh-, effector-memory CD8+ T –cells and a chronic EBV viremia. Pt1 was admitted to our Hospital for a gastric cancer with a previous history of IBD, diabetes mellitus, polyarthritis. Pt2, currently 35y has hypogammaglobulinemia and thrombocytopenia treated with high doses of Ig and corticosteroids at the age of 13y. She developed melanoma and uterine myofibromas in adult age. Parents with the same mutations, developed milder clinical manisfestations in older age (Pt1-father autoimmune thyroiditis and Pt2-mother’ ndd-cholangitis).NGS revealed two heterozygous mutations in CTLA4 gene. Marked and mild decrease of CTLA4 upregulation assessed on activated memory Treg cells were observed in Pt1-2. Finally, Pt3 carries p.T17A polymorphism that has been reported associated to nephrotic disease. He was admitted at 16y to our Hospital for lymphoadenopathies, hypogammaglobulinemia, persistent fever, and chronic EBV-viremia. At 10y he had nephrotic syndrome treated with Mabthera.
Early genetic diagnosis could change clinical history and management of CTLA4 patients conditioning the choice of a proper-targeted therapy. As reported in a large study cohort (Grimbacher et al) chronic EBV viremia and lymphoproliferation frequencies in these patients, should be carefully monitored to avoid a worsening of the disease and cancer onset