Diagnostic Dilemma on Novel Pathogenic Variant of Cytotoxic T-Lymphocyte Associated Protein 4 (CTLA-4) in a Family with Chronic ITP and Immune Dysregulation

Abstract

Inborn errors of immunity are increasingly linked to autoimmune cytopenias, especially in families with immunodeficiency and immune dysregulation. We present a large family study with several members presenting with chronic immune thrombocytopenia (ITP) and variable combinations of immune dysregulation and infections. The proband and kindred were diagnosed with a novel variant of unknown significance (VUS) in CTLA-4. Diagnostic approach to confirm the association between clinical phenotype and the pathogenicity of this novel variant is described. Retrospective chart review yielded demographic information, clinical history, immunological phenotype, genetic panel testing and treatment response. Functional testing included CTLA-4 expression and transendocytosis assay. Proband a 50-year-old female, presented with recurrent pneumonia, chronic diarrhea, hypothyroidism, granulomatous interstitial lung disease, and ITP. Immune phenotyping confirmed hypogammaglobulinemia requiring immunoglobulin replacement therapy. Proband, along with three other family members, had a novel CTLA4-VUS (c.173G>C p.Cys58Ser). Proband and her adult cousin had chronic ITP and hypogammaglobulinemia; however, two children with this VUS only had history of milk-induced colitis and asthma, respectively. Internalization of CD80/86 was impaired in CTLA-4 trans-endocytosis assay performed on T cells from proband’s cousin, revealing a functional impairment of CTLA-4. For the proband, abatacept (CTLA4-Ig) was initiated and resulted in marked improvement in respiratory and gastrointestinal symptoms along with decreased frequency of infections. The segregation of clinical phenotype within the family, functional testing, and response to abatacept support this CTLA-4 VUS as pathogenic variant. Our study highlights the importance of genetic testing and functional studies in patients with immune dysregulation and immunodeficiency.