Delayed Diagnosis in X-Linked Agammaglobulinemia and Its Relationship to the Occurrence of Mutations in the Bruton Tyrosine Kinase Catalytic Domain

Background Bruton tyrosine kinase (BTK) is a protein-coding gene crucial for B cell development. It is found on Xq21.3-Xq22 of the long arm of the X chromosome and belongs to the Tec family of cytoplasmic protein tyrosine kinases consisting of 5 structural domains: PH, TH, Src3, Src2, and TK. Pathogenic variants in the BTK gene can fully or partially block B cell development. BTK has been linked to various antibody deficiencies beyond agammaglobulinemia, including CVID. In hypomorphic BTK variants, there are detectable B cells in the periphery that may result in variable levels of serum immunoglobulins and clinical phenotype. Objective Investigate the impact of a missense pathogenic hypomorphic BTK variant (p.Arg525Gln) observed in a large kindred. Results We plan to assess by flow cytometry BTK protein expression in specific B cell subsets in hypomorphic XLA patients in this kindred. The flow cytometry revealed a uniformly reduced BTK expression in B cells (B cells evaluation is limited by low cell counts). BTK expression was decreased with an unexpected bimodal distribution in monocytes. Since both patients were male, XXY syndrome was initially considered but deemed less likely. The unexpected monocyte expression pattern in the current patient suggests possible somatic mosaicism or other genetic factors, or the two peaks are related to BTK protein degradation, and this may differ in specific cellular compartments or change with age, warranting further investigation. Conclusions This highlights the challenges of diagnosing hypomorphic XLA, especially in patients with detectable B cell counts and atypical BTK expression. Flow cytometric analysis of two patients with BTK mutations identified bimodal mosaic patterns of BTK expression in monocytes. This bimodal expression pattern may reflect cellular mosaicism like in mothers who are obligate carriers of XLA. BTK biology with hypomorphic variants remains incompletely understood, particularly how these variants affect B cell development and result in milder antibody deficiency phenotypes, warranting further investigation. This emphasizes the importance of genetic screening in kindreds with XLA and the need for increased awareness of partial XLA among healthcare providers to ensure timely diagnosis and treatment.