X-linked agammaglobulinemia (XLA) is caused by pathogenic variants in Bruton tyrosine kinase (BTK), causing arrest of B cell development and immunoglobulin production. Patients typically present in infancy or early childhood with recurrent infections, notably bacterial sinopulmonary and gastrointestinal infections. Older presentations are infrequently described, and their cause remains unclear.
We describe two unrelated patients who presented with late-onset XLA and unusual manifestations, both harboring the same variant in the kinase domain.
Patient 1 was diagnosed at age 17 after experiencing multiple sinopulmonary infections. He subsequently developed several difficult-to-treat autoimmune/inflammatory complications, including recurrent fevers with adenopathy, seronegative tenosynovitis, immune thrombocytopenic purpura, liver nodular regenerative hyperplasia (NRH), portal hypertension, and widespread granuloma annular-like lesions. After failing multiple immunosuppressive medications, he experienced some improvement on tofacitinib. Patient 2 was diagnosed at age 54, following a less extensive infectious history, including a pneumonia (age 8) requiring intravenous antibiotics and bacteremia secondary to trauma (age 38). He also has a likely NRH, pending biopsy.
Patient 1 had absent B cells and complete agammaglobulinemia with residual IgM. Patient 2 had near-absent B cells, with surprisingly normal total IgG and IgA and low IgM. He mounted an abnormally low pneumococcal titer despite boosting. Both patients underwent extensive genetic testing, revealing only the pathogenic BTK variant: c.1574G>A (p.Arg525Gln).
Adult-onset XLA is rare and can present clinically as “CVID.” Interestingly, most late cases described to date had absent B cells, suggesting a likely decline in B cells over time. Our patients both harbored a known variant affecting Arg525 of the kinase domain. This variant has been previously reported in classical, early onset XLA. However, it has also been described in patients presenting later with CVID. This variant is expected to abrogate the catalytic kinase activity due to loss of substrate recognition. It is unclear if phenotypic variability relates to the variant itself or to a polygenic effect. We suggest clinicians maintain suspicion for XLA in patients presenting with absent B cells at any age, while the best management strategies for autoimmune/inflammatory manifestations remain to be determined.
