Atypical X-linked agammaglobulinemia diagnosed in adulthood with arthritis caused by a hypomorphic BTK splice-site variant: a case report and literature review.

X-linked agammaglobulinemia (XLA) is an inborn error of immunity (IEI) caused by loss-of-function variants in the Bruton tyrosine kinase (BTK) gene, classically presenting in early childhood with recurrent bacterial infections. Here, we report an atypical case of XLA diagnosed in adulthood during evaluation of inflammatory arthritis. A 42-year-old man with no history of severe or recurrent infections initially presented with monoarticular inflammation of the right elbow joint and later developed Doppler-positive synovitis and tenosynovitis of the hands, together with a methicillin-sensitive Staphylococcus aureus lung abscess and a subsequent deep gluteal abscess. Immunological evaluation showed profound hypogammaglobulinemia with markedly reduced circulating B cells. Genetic testing revealed a BTK splice-site variant, c.1103-2A>G (NM_000061.3). Functional analyses demonstrated abnormal splicing at the exon 12-13 junction, reduced BTK mRNA expression, and reduced but detectable BTK protein expression in monocytes, supporting residual protein expression consistent with a hypomorphic or leaky phenotype. Although XLA is generally considered to show limited genotype-phenotype correlation, residual BTK expression in this case could have contributed, at least in part, to the relatively mild early infectious phenotype. In addition, the patient's longstanding social withdrawal, with presumably limited exposure to infectious sources, may also have contributed to delayed clinical recognition until adulthood. Importantly, immunoglobulin replacement therapy was followed by sustained prevention of further deep infections and gradual improvement of synovitis, tenosynovitis, and skin manifestations. This case highlights that common rheumatologic presentations in adults, such as arthritis, may mask an underlying IEI. Early recognition of IEI can enable timely immunoglobulin replacement therapy, which may restore humoral immune protection, prevent further severe infections, and improve rheumatologic manifestations. It also underscores the importance of integrating immunological and genetic evaluation with protein- and transcript-level analyses when interpreting atypical presentations and splice-site variants.