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.