Severe Hematologic Abnormality Associated with an Inborn Error of Immunity (IEI)

Abstract

Genetic sequencing improves our recognition of IEI's through genotype/phenotype correlations; however, variants of uncertain significance (VUSs) remain an obstacle. Functional assays provide avenues to identify variant pathogenicity but are infrequently commercially available, resulting in delayed diagnosis. We report the case of one such experience, and utilization of research-based functional testing to help characterize variant pathogenicity.A 20-year-old male patient with celiac disease came to medical attention after developing profound fatigue with pancytopenia: white blood cell count (4,400cells/mL), hemoglobin (8.4 g/dL), and platelets (18,000cells/mL). Evaluation included normal iron studies, folate, B12, copper levels, lactate dehydrogenase and haptoglobin, and low immunoglobulin levels (IgG 122 mg/dL; IgM 7 mg/dL; IgA 12 mg/dL). Infectious evaluation was negative including CMV, EBV, HHV-6, and Parvovirus. Bone marrow biopsy confirmed hypocellular marrow consistent with aplastic anemia. Hematologic testing was unremarkable (karyotype, myelodysplastic mutation sequencing, telomere length, leukemia flow cytometry immunophenotyping, and T-cell clonality).Lymphocyte flow cytometry showed severe lymphopenia: absolute lymphocyte count (268cells/mL), CD3+ (222cells/mL;83%), CD4+ (107cells/mL;40.1%), CD8+ (88cells/mL;32.9%), CD45RA+/CD4+/CD62L+ (15cells/mL;14.4%), and CD19+ (3cells/mL;1.3%). T-cell proliferation to phytohemagglutinin and tetanus was normal, and antibody titers were protective. Infection history was unremarkable. A primary immunodeficiency next generation sequencing panel uncovered a VUS in CTLA-4, c.385T> A (p.Cys129Ser) for the patient and his father (received biologic therapy for rheumatologic disease). Without commercially available transendocytosis assays, the patient and paternal samples were sent for research analysis. Testing demonstrated reduced CD4+ & CD8+ naïve T-cells with increased memory T-cells, and CD80-GFP transendocytosis assay showed reduced GFP uptake by C129S variant-expressing cells relative to wild-type CTLA-4. The clinical and immune phenotype were highly suggestive of CLTA-4 haploinsufficiency. Despite conventional immunomodulatory/immunosuppressive treatment with calcineurin inhibitors, corticosteroids and high-dose IVIG, only a partial response was achieved. Abatacept trial was considered, but haploidentical transplant was elected due to clinical severity, and he no longer requires repetitive transfusions. Our case outlines a novel CTLA-4 variant resulting in CLTA-4 haploinsufficiency presenting as aplastic anemia and hypogammaglobulinemia/CVID. The absence of easily accessible testing for CTLA-4 resulted in delayed functional evaluation, prolonging consideration for abatacept. Fortunately, the patient has benefited from hematopoietic stem cell transplant, which remains the mainstay curative therapy for severe disease. [Display omitted] [Display omitted]