Intrafamilial clinical variability of CTLA-4 insufficiency hindering early diagnosis

İntroduction

Cytotoxic T lymphocyte antigen-4 (CTLA-4), also known as (CD152), is a member of the CD28:B7 immunoglobulin superfamily, acting as an important immune checkpoint protein, which is constitutively expressed on fork-head box P3 (FOXP3)⁺ regulatory T (Treg) cells and induced upon activation of conventional T cells [Kuehn HS et al., 2014;345:1623, Schubert D et al., 2014;20:1410]. The immune suppression via CTLA-4 has competition with signal activation molecule CD28 for B7 binding. The higher affinity of CTLA-4 to B7, when compared to CD28, regulates the immune system by keeping it from over-activation [Gibney GT et., 2016;17:5513]. Recently, monoallelic CTLA4 mutations associated with immunodysregulation have been reported in patients originally diagnosed as common variable immunodeficiency (CVID) and characterized by over-active T-cells driving the lymphoproliferation and autoimmunity [Kuehn HS et al., 2014;345:1623, Schubert D et al., 2014; 20:1410, Tangye SG et al., 2022;42:1473]. Previously, incomplete penetrance was defined in CTLA4-deficient patients [Schwab C et al., 2018;142:1932]. The exact mechanism underpinning the variable clinical presentation is still elusive and needs more investigation. Presenting families with variable phenotypes in CTLA-4 insufficiency will evoke attention to the disorder and can be helpful for early diagnosis and, thus, better outcomes.

Herein, we report a family with heterozygous c.436 G>A; p.G146R mutation in CTLA4 demonstrating a variable clinical and immunological penetrance in three consecutive generations. The index of the family was referred with chronic immune thrombocytopenia (ITP) and frequent infections rate. Similar complaints were noticed in his father; however, CTLA4-mutant grandfather was asymptomatic for the disease. One uniform mutation in the same gene can appear with variable penetrance that results in multifaceted clinical presentation and brings to mind epigenetic and environmental factors that may determine the disease’s clinical course. This study provides valuable insight into the incomplete penetrance in CTLA-4 insufficiency and can be helpful for early diagnosis.

Publication History

Article published online:
21 November 2023