Dual Heterozygous LRBA Variants in an Adult with Combined Immunodeficiency: A Diagnostic Challenge

Autosomal recessive forms of CVID are rare in the Western world, with LRBA deficiency being a key example. Caused by biallelic mutations in the LRBA gene, it leads to a spectrum of immune dysfunctions, including combined immunodeficiency (CID). We present the case of a 34-year-old female whose late-onset symptoms and dual heterozygous LRBA gene variants at distinct loci challenge the conventional understanding of this condition. The patient experienced recurrent respiratory infections over two years, chronic sinusitis, arthralgia, and severe diarrhea, later diagnosed as microscopic colitis. Initial immune evaluation revealed hypogammaglobulinemia, low specific antibody titers, and significantly reduced T and B cell subsets. Family history includes a sister with severe refractory Evans syndrome, requiring hematopoietic stem cell transplantation. Treatment with weekly subcutaneous immunoglobulin replacement therapy (IgRT) resulted in decreased infection frequency. Though meeting CVID criteria, her lymphopenia and strong family history prompted consideration of a monogenic CID. Genetic testing identified pathogenic heterozygous LRBA variants—c.2836_2839del (p.Glu946*) and c.7480C>T (p.Gln2494*)—without determination of compound heterozygosity. Flow cytometry findings include low naïve CD4+ T cells (10% of CD4+ T cells), immune dysregulation evident by expansion of T follicular helper (Tfh) cells (32% of CD4+ T cells) and increased CD19 high CD21lo B cells (26% of naïve B cell compartment), and absence of transitional B cells. LRBA deficiency is strongly suspected due to immunophenotypic and clinical features consistent with previously reported cases, along with the presence of two heterozygous pathogenic LRBA variants. Interestingly, her late-onset presentation raises the possibility that heterozygous LRBA variants may delay disease onset compared with the early presentation (preschool years) typically seen in biallelic LRBA deficiency. Ongoing studies aim to elucidate shared genetic factors and CTLA4 expression. Despite current IgRT, the patient's immune dysregulation, arthralgias, mild cytopenias, and thyroid antibodies suggest immunomodulation with CTLA4-Ig may benefit her management. This case emphasizes the diagnostic challenges of primary immunodeficiencies with atypical, late-onset presentations and highlights the role of heterozygous LRBA variants in influencing disease progression. Identifying monogenic causes in adult “CVID” cases can expedite targeted therapies, improve outcomes, and aid early management of at-risk family members.