Clinical Courses of IKAROS and CTLA4 Deficiencies: A Systematic Literature Review and Retrospective Longitudinal Study

Abstract

IKAROS and CTLA4 deficiencies are inborn errors of immunity and show similar clinical phenotypes, including hypogammaglobulinemia and autoimmune diseases (ADs). However, the differences in clinical features and pathogenesis of these are not fully understood. Therefore, we performed systematic literature reviews for IKAROS and CTLA4 deficiencies. The reviews suggested that patients with IKAROS deficiency develop AD earlier than hypogammaglobulinemia. However, no study assessed the detailed changes in clinical manifestations over time; this was likely due to the cross-sectional nature of the studies. Therefore, we conducted a retrospective longitudinal study on IKAROS and CTLA4 deficiencies in our cohort to evaluate the clinical course over time. In patients with IKAROS deficiency, AD and hypogammaglobulinemia often develop in that order, and AD often resolves before the onset of hypogammaglobulinemia; these observations were not found in patients with CTLA4 deficiency. Understanding this difference in the clinical course helps in the clinical management of both. Furthermore, our results suggest B- and T-cell-mediated ADs in patients with IKAROS and CTLA4 deficiencies, respectively.

Impact of age at diagnosis, sex, and immunopathological manifestations in 886 patients with pediatric chronic immune thrombocytopenia

“…Therefore, we cannot exclude the possibility that some patients had undiagnosed monogenic PID. Some PIDs can have variable expressivity and remain paucisymptomatic, such as shown in ALPS, CTLA4 haploinsufficiency, and LRBA deficiency 25–27 . Comprehensive genetic studies are required to definitively conclude whether an underlying PID is present.…”

Monogenic Inborn Errors of Immunity with impaired IgG response to polysaccharide antigens but normal IgG levels and normal IgG response to protein antigens

“…Clinical manifestations encompass lymphoproliferation, autoimmune conditions (predominantly cytopenia or gastrointestinal involvement), increased susceptibility to infections, particularly of the respiratory tract [viral (EBV, CMV, HSV), bacterial ( H. influenzae , S. pneumoniae , Salmonella enteritidis , S. aureus ) and fungal (Candida species, Aspergillus species)], as well as gastrointestinal and neurological features. Additionally, patients face an increased risk of malignancies such as lymphoma and gastric cancer, often associated with EBV ( 87 ).…”

Autoimmune lymphoproliferative immunodeficiencies (ALPID) in childhood: breakdown of immune homeostasis and immune dysregulation

“…In a review of published CTLA-4 haploinsufficiency cases, autoimmunity and hypogammaglobulinemia preceded the development of malignancy, with a cumulative incidence of disease manifestations increasing up to 70% at age 40 [ 72 ]. In a cohort of 131 patients, 12.9% developed malignancy with a median onset between 32 and 34 years of age, most commonly lymphoma or gastric cancer, with EBV viremia posing a significant risk factor [ 73 ].…”