Beyond Recurrent Infections: Immune Dysregulation Manifestations, Genotype–phenotype Heterogeneity, and Three Novel BTK Variants in X-linked Agammaglobulinemia

Abstract

X-linked agammaglobulinemia (XLA) is an inborn error of immunity caused by BTK gene mutations, characterized by hypogammaglobulinemia and recurrent infections. This study evaluates a long-term pediatric cohort to assess clinical spectrum, therapeutic outcomes, and molecular findings.

We retrospectively reviewed clinical, immunological, treatment, and genetic data for 11 male XLA patients followed over 20 years at our center.

Median age at symptom onset was 12.7 months (range: 3–60), while median age at diagnosis was 4.5 years (range: 1–10), revealing marked diagnostic delays in patients without family history. Severe complications included bronchiectasis, septic arthritis, and immune dysregulation (e.g., juvenile idiopathic arthritis, autoimmune hepatitis, pancytopenia, celiac disease). Immunoglobulin replacement and antibiotic prophylaxis significantly reduced median annual infections from 16.9 to 2.09. Six distinct BTK variants were identified, including three novel mutations: c.90del, c.1922_1924delGTC, and c.1589dup. Inter-sibling phenotypic heterogeneity was notable. In the absence of functional expression studies, pathogenic contributions of novel variants remain exploratory.

XLA extends beyond recurrent infections to encompass significant immune dysregulation and phenotypic variability. Early diagnosis, family screening, genetic testing, and tailored immunoglobulin therapy are vital to improve long-term outcomes. Larger multicenter cohorts with functional testing are needed to validate genotype–phenotype associations.