X-linked agammaglobulinemia (XLA) (incidence approximately 1:100,000) is a primary humoral immunodeficiency syndrome based on a B cell maturation disturbance. The clinical symptoms begin between the 4th and 12th month of life with severe bacterial infections (such as otitis media, pneumonia, meningitis and sepsis) caused especially by encapsulated germs. One of the most common infections is chronic sinusitis. Although the defense against viral infections is generally not impaired, patients are susceptible to enterovirus infections. Some of those affected develop chronic infections such as dermatomyositis or meningoencephalitis, and about 20% develop arthritis.
The B cell maturation disturbance shows itself through massively reduced B cell counts and an almost complete absence of plasma cells and immunoglobulins of all isotypes. T lymphocyte numbers and functions are normal. Despite the frequent infections small or missing tonsils, adenoids and lymph nodes are noticed during clinical examination. The therapy consists of the administration of immunoglobulins and antibiotics according to the pathogen. Complications include chronic lung disease and an increased risk of colon cancer and lymphoreticular malignancies.
XLA is caused by pathogenic variants in the BTK gene, which is located on the X chromosome. Pathogenic variants in the BTK gene are identifiable in about 90% of patients with suspected XLA. Pathogenic variants in other genes essential for normal B cell maturation are detectable in the majority of cases in males without detectable variants in the BTK gene and in female patients with an XLA-like phenotype (see hereditary agammaglobulinemia,). Obligate female carriers show a "non-random" X inactivation in their B cells.
Smith et al. 2016, GeneReviews® [Internet], https://www.ncbi.nlm.nih.gov/books/NBK1453/ / El-Sayed et al. 2019, World Allergy Organ J 12:100018 / Chen et al. 2016, Medicine (Baltimore) 95:e4544 / Lee et al. 2010, J Clin Immunol 30:121 / XLA in: Stiehm, Ochs, Winkelstein: Immunologic conditions in infants and children 5th Edition