Cytotoxic T Lymphocyte Antigen 4 Haploinsufficiency Presenting As Refractory Celiac-Like Disease: Case Report

Abstract

Primary immunodeficiency may present with treatment-refractory enteropathy. We present two patients with celiac/celiac-like disease diagnosed in early childhood and refractory to the gluten-free diet. One patient had features of multi-system autoimmunity, whereas the other had celiac-like disease as an isolated clinical finding. Both patients underwent genetic testing given disease refractoriness and were ultimately diagnosed with cytotoxic T lymphocyte antigen 4 (CTLA4) haploinsufficiency. They are both now in complete clinical and endoscopic remission on abatacept. CTLA4 haploinsufficiency has incomplete penetrance and significant phenotypic heterogeneity but should be considered in the differential diagnosis of refractory celiac/celiac-like disease, as treatment implications are significant.

Keywords: CTLA4 deficiency; CTLA4 haploinsufficiency; abatacept; autoimmunity; case report; celiac disease; primary immunodeficencies (PID); refractory celiac disease.

Figure 1

Laboratory trend in patient 1. 6MP, 6-mercaptopurine; ADA, adalimumab; GFD, gluten-free diet; IVIg, intravenous immunoglobulin; MTX, methotrexate.

Figure 2

Histopathology findings in patient 1. (A) Duodenal mucosa with total villous atrophy, crypt hyperplasia, and patchy intraepithelial lymphocytosis, suggestive of celiac disease. (B) Normal duodenal mucosa, two years into treatment with abatacept.

Figure 3

Reduced CTLA4 expression in unstimulated memory regulatory T cells (T_regs) in patients 1 and 2 compared to healthy controls. Flow cytometry data gated on live/CD4⁺/Foxp3⁺. Representative expression of total CTLA4 in T_regs in patient 1 compared to healthy control (A) and patient 2 compared to healthy control (B). Percentages shown in quadrants, with percentage CD45RA⁻ (memory) T_regs expressing CTLA4 highlighted in red.