Conclusion and discussion:
The proband and the family members in our cohort harbors CTLA-4 splice site mutation, c.458-1G>C, in the region of intron 2. As described above, the patients presented with variable degree of immune dysregulation and autoimmunity. The mutation has been previously shown to disrupt the acceptor site of second CTLA-4 intron, and cause defective transcription of third exon.12 The common manifestations in the majority of the patients described by previous reports have lymphoproliferation, lymphocytic infiltration of non-lymphoid organs, autoimmune cytopenias and hypogammaglobinemia.8,12 Mutations described in total of 18 patients in those reports spanned across the CTLA-4 gene, including non-sense mutations such as c.151C>t (p.R51X), c.105C>A (p.C35*), c.208C>T (p.R70W), c.371A>C (p.T124P), c.223C>T (p.R75W) and c.2T>C (p.?), splice site mutations such as c110 + 1G>T in intron 1, c.458-1G>C in intron 2, c.567+5G>C in intron 3, and frameshift deletion c.75delG> p.L28Fs*44.8,12 Although the nature and the location of these mutations were heterogeneous, all of these mutations led to decreased CTLA-4 expression in Treg cells compared to healthy controls. Furthermore, the reduction was more pronounced on T cell activation for unclear reason. The Treg cells’ CTLA-4 dependent suppressive function, ligand binding and transendocytosis of CD80 were uniformly impaired.
One patient reported by Kuehn et al harbored c.458-1G>C mutation, as in our cohort, and presented with diffuse lymphadenopathy, splenomegaly, AIHA, ITP, ALE and childhood onset EBV positive HL.12 The severity and expressivity of immune dysregulation in our cohort appears somewhat more penetrant in male gender. Gastrointestinal manifestations especially ALE appear more common and may pose management challenges. The role of abatacept in the management of these patients may need to be studied further, alone or in conjunction with tacrolimus and/or sirolimus. Two patients in our cohort presented with lymphoma (two episodes of EBV driven cHL of different histologies in one patient and one case of atypical marginal zone non-Hodgkin lymphoma). An earlier published worldwide cohort of 184 patients with CTLA-4 mutations, has reported various malignancies in these patients, such as lymphoma, gastric cancers, multiple myeloma and metastatic melanoma.9
In conclusion, heterozygous CTLA-4 mutation and the associated immune dysregulation is a complex entity which is both phenotypically as well as genotypically heterogeneous. Although the previous studies have extensively investigated the essential role of CTLA-4 in T and B cell homeostasis, our understanding of the molecular, genetic and epigenetic regulation of its penetrance and expressivity remains limited, and merits further investigation. Defining the genotypic and phenotypic correlates may help refine the management options for this intriguing disorder.