Novel CTLA4 Haploinsufficiency with Pure Red Cell Aplasia as the Core Manifestation: Insights from a Sibling Pair with Divergent Tumorigenic Outcomes

Abstract

Cytotoxic T‑lymphocyte antigen‑4 (CTLA4) is a key immune checkpoint molecule, and its haploinsufficiency can lead to a highly heterogeneous immune dysregulation syndrome; however, its association with pure red cell aplasia (PRCA) remains to be systematically characterized. Here we report two adult‑onset siblings carrying an identical novel germline missense mutation in CTLA4 (c.394G>A; p.Glu132Lys), both presenting with PRCA as the initial and core manifestation, with involvement of the stomach, spleen, thyroid, and other organs. Although their genetic backgrounds are similar, the disease trajectories of the two patients exhibited noteworthy differences: the proband (elder sister) had persistent Epstein–Barr virus (EBV) infection, responded initially to long‑term cyclosporine combined with androgen therapy, then gradually developed splenomegaly, and eventually relapsed with EBV‑associated poorly differentiated gastric adenocarcinoma; the younger sister, in contrast, was EBV‑negative, but concurrently developed T‑cell large granular lymphocytic leukemia (T‑LGLL), atrophic gastritis, and splenomegaly, and her PRCA responded to cyclosporine treatment. The phenotypic divergence between the two cases (solid tumor vs. hematologic malignancy) highlights the complexity and heterogeneity of tumorigenesis in the context of immune dysregulation. Based on these observations, we propose a speculative but testable working framework that regards immune dysregulation as the common pathophysiological foundation, and suggests that different types of “second‑hit” events—such as chronic viral‑driven immune inflammation or autoreactive T‑cell clonal expansion resulting from thymic selection abnormalities—may steer the disease toward distinct neoplastic endpoints. This is the first report to describe the comorbidity of T‑LGLL in a germline CTLA4 mutation carrier. These findings expand the disease spectrum of CTLA4 haploinsufficiency and provide a reference for risk stratification and individualized management of such patients.