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Cytotoxic T-lymphocyte-associated antigen-4 (CTLA4) haploinsufficiency is an autosomal dominant primary immune dysregulation syndrome characterized by early‐onset lymphoproliferation, hypogammaglobulinemia and multiorgan autoimmunity (PMID:32499327). CTLA4 functions as a coinhibitory receptor on regulatory T cells (Treg) and activated T cells, maintaining self‐tolerance by outcompeting CD28 for CD80/CD86 binding.
Genetic evidence includes over 70 unrelated patients harboring heterozygous CTLA4 loss‐of‐function alleles—comprising 12 large 2q33 deletions (26 kb–7.1 Mb) encompassing CTLA4 (PMID:39578275) and truncating variants such as c.151C>T (p.Arg51Ter) (PMID:32499327). Segregation in multiple kindreds, including three affected individuals from two families, supports autosomal dominant inheritance with variable penetrance (PMID:32499327).
Clinical series from the French CEREDIH registry describe 70 patients, of whom 13 (21%) developed neurologic involvement—headaches, focal deficits, seizures (HP:0001250) and tumefactive white‐matter lesions on MRI (PMID:37487754). Other manifestations include benign lymphadenopathy, recurrent infections and autoimmunity affecting the gut, lung and endocrine organs.
Functional assays demonstrate decreased CTLA4 surface expression on Treg cells upon stimulation and impaired ligand uptake. Targeted therapy with abatacept (CTLA4-Ig) restored clinical and radiologic remission in 90–100% of treated patients across studies, confirming haploinsufficiency as the pathogenic mechanism and validating therapeutic targeting of CTLA4 pathways (PMID:34291137; PMID:37487754).
No studies have yet refuted the CTLA4–autoimmune lymphoproliferative syndrome association. Additional modifiers, such as LRBA mutations, phenocopy CTLA4 deficiency but are distinguishable by lysosomal trafficking assays.
In summary, CTLA4 haploinsufficiency is a definitive autosomal dominant immune dysregulation syndrome with strong genetic and functional evidence. Early genetic testing enables precision therapy with abatacept, improving outcomes in affected individuals.
Gene–Disease AssociationDefinitiveOver 70 probands across >12 unrelated kindreds, segregation in multiple families, and functional rescue with abatacept Genetic EvidenceStrong70 unrelated patients with heterozygous CTLA4 LOF variants including 12 large deletions and truncating c.151C>T segregating in 2 families Functional EvidenceStrongReduced CTLA4 expression and ligand uptake in Treg cells; abatacept therapy induced remission in >90% of treated patients |