Revisiting X-linked agammaglobulinemia

Discovered >70 years ago by Ogden Bruton, X-linked agammaglobulinemia (XLA), characterized by recurrent bacterial infections, hypo/agammaglobulinemia, and peripheral blood B-cell deficiency, is among the best-established inborn errors of immunity (IEIs) and one of the most well-documented single types of IEIs, the incidence of which is estimated to be between 1:100,000 and 1:200,000. However, although the pathogenesis of XLA is well understood, several issues remain open for discussion. In this review, we describe several unresolved issues, including noncoding BTK variants, contiguous deletion syndrome, Helicobacter infection, noninfectious neurodegeneration, renal involvement, and malignancies. The primary treatment for XLA, immunoglobulin replacement therapy, administered either intravenously or subcutaneously, has remained unchanged since its discovery. Allogeneic hematopoietic cell transplantation has been successful in some XLA patients, but there are still few reports. However, it may be considered as a treatment option in the future. Given that XLA is one of the most common types of IEIs, resolving these issues is a priority.