Case Report: Aplastic anemia related to a novel CTLA4 variant.

A 20-year-old male patient with a history of celiac disease came to medical attention after developing profound fatigue and pancytopenia. Evaluation demonstrated pan-hypogammaglobulinemia. There was no history of significant clinical infections. Bone marrow biopsy confirmed hypocellular marrow consistent with aplastic anemia. Oncologic and hematologic evaluations were unremarkable for iron deficiency, paroxysmal nocturnal hemoglobinuria, myelodysplastic syndromes, T-cell clonality, and leukemia. A next generation genetic sequencing immunodeficiency panel revealed a heterozygous variant of uncertain significance in CTLA4 c.385T >A, p.Cys129Ser (C129S). Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is an inhibitory receptor important in maintaining immunologic homeostasis. To determine the functional significance of the C129S variant, additional testing was pursued to assess for diminished protein expression, as described in other pathogenic CTLA4 variants. The results demonstrated severely impaired CTLA-4 expression and CD80 transendocytosis, consistent with other variants causing CTLA-4 haploinsufficiency. He was initially treated with IVIG and cyclosporine, and became transfusion independent for few months, but relapsed. Treatment with CTLA-4 - Ig fusion protein (abatacept) was considered, however the patient opted for definitive therapy through reduced-intensity haploidentical hematopoietic stem cell transplant, which was curative.
Competing Interests: The authors disclose the following commercial and/or financial relationships which were not related to study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication. Dr. Mousallem received funding from Chiesi for a project entitled: A Single Arm, Open-Label, Multicenter, Registry Study of Revcovi Treatment in ADA-SCID Patients Requiring Enzyme Replacement Therapy. Dr. Mousallem is the Duke Site PI for PIDTC (NIAID-University of California, San Francisco U54 AI082973 Puck (PI) 09/2019-08/2024)- Prospective Study of SCID Infants who receive Hematopoietic Cell Therapy. Dr. Sleasman receives grant funding from Sumitomo Pharma America, Inc. Dr. G. Hall received funding from Thermo Fisher Scientific, Inc for the 2023 Prestige Award. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.
(© 2024 Hall, Markle, Maiarana, Martin, Rothman, Sleasman, Lederman, Azar, Brodsky and Mousallem.)