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Case Reports
. 2024 Aug 16:12:1434076.
doi: 10.3389/fped.2024.1434076. eCollection 2024.

Case Report: Aplastic anemia related to a novel CTLA4 variant

Geoffrey Hall  1 , Janet G Markle  2 , James Maiarana  2 , Paul L Martin  3 , Jennifer A Rothman  4 , John W Sleasman  1 , Howard Lederman  5 , Antoine E Azar  6 , Robert A Brodsky  7 , Talal Mousallem  1
Affiliations
Case Reports

Case Report: Aplastic anemia related to a novel CTLA4 variant

Geoffrey Hall et al. Front Pediatr. .

Abstract

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.

Keywords: Aplastic anemia; CTLA-4; haploinsufficiency; hematopoietic stem cell transplantation (HSCT); inborn error of immunity (IEI); novel variant.

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Conflict of interest statement

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.

Figures

Figure 1
Figure 1
T-cell stimulation and regulation. (A) Co-stimulatory signaling through CD80/86-CD28 interaction resulting in T-cell activation and proliferation. (B) Co-inhibition through CD80/86-CTLA-4 interaction resulting T-cell regulation due to transendocytosis of CD80/86-CTLA-4 complex. Figure created with Biorender.com.
Figure 2
Figure 2
The C129S missense mutation dramatically impairs CTLA-4 expression resulting in decreased transendocytosis. (A) Representative example of CD80GFP transendocytosis assay results. These plots show cells previously gated on forward and side scatter profile, and negative for Cell Trace Violet. GFP signal represents percent transendocytosis of CD80. (B) Summary results from n = 3 independent experiments, performed as in A. (C) Percent CTLA-4+ CHO cells after transfection with WT or mutant CTLA-4 plasmids (n = 3),**p < 0.01, unpaired t-tests. (D) Flow cytometry analysis of peripheral blood mononuclear cells (PBMCs) to identify CD4 + FoxP3 + regulatory T-cells (T¬¬regs) and CD4 + CD3- cells. (E) Analysis of CTLA-4 protein expression by Tregs (upper row) and CD4 + FoxP3 + cells (lower row), gated as shown in (D). (F) Mean fluorescence intensity for CTLA-4 on Tregs from two healthy donors, and the patient and his father with the C129S variant.
See this image and copyright information in PMC

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