A Presentation of X-Linked Agammaglobulinemia with Normal Immunoglobulin Levels

Introduction X-linked agammaglobulinemia (XLA) is an inborn error of immunity caused by loss-of-function variants in Bruton’s tyrosine kinase (BTK) on the X chromosome. This defect disrupts B cell development, resulting in low or undetectable immunoglobulin levels. Rarely, patients may present with atypical features, including normal immunoglobulin levels. We report a case of XLA with normal immunoglobulin levels. Case Description A 12-year-old male with a history of asthma and a maternal half-brother with XLA was admitted to the hospital for an asthma exacerbation in the setting of pneumonia. He had recently been hospitalized within the past month for similar symptoms and was treated with antibiotics for pneumonia. His infection history was unremarkable until the age of 12, when he began to experience frequent upper respiratory infections in the months leading up to his presenting illness. An immunologic evaluation was performed that revealed the following immunoglobulin (Ig) levels: lgG 572 mg/dL, IgA 184 mg/dL, and IgM 50 mg/dL. Lymphocyte subsets were performed showing a CD3 count of 1,041 cells/μL (93%), a CD4 count of 688 cells/μL (59%), a CD8 count of 359 (31%), CD16 and CD56 counts of 58 cells/μL (5%), and a CD19 count of 3 cells/μL (0%). Specific antibodies to streptococcus pneumoniae, measles, mumps, and varicella were not protective. His antibody levels to diphtheria and tetanus were equivocal, but antibodies to rubella were protective. After resolution of his acute infection, examination in clinic was notable for presence of tonsillar tissue and small palpable submandibular and cervical lymphadenopathy. Repeat immunoglobulins revealed an IgG 802 mg/dL, IgA 271 mg/dL, and IgM 44 mg/dL. Next-generation sequencing revealed a hemizygous pathogenic mutation in BTK (c.82C>T and pArg28Cys). Discussion XLA typically manifests with severe hypogammaglobulinemia and absent mature B cells in peripheral blood. However, this case highlights an atypical presentation with normal total immunoglobulin levels. A review of the existing literature reveals that atypical presentations are rare but have been increasingly described as a manifestation of this disease. Clinicians should recognize the significant phenotypic and immunologic variability with XLA and consider the diagnosis in patients with recurrent infections, poor specific antibodies, but normal total immunoglobulin levels.