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.