X-linked agammaglobulinaemia

Recurrent bacterial infections typically begin in the first two years of life. Affected males are usually well during the first few months due to transplacentally acquired maternal immunoglobulin, after which immunodeficiency manifests and most are recognised before age five years; approximately 10% remain unrecognised until after age ten years or into adulthood.

Recurrent otitis is the most common infection prior to diagnosis, with conjunctivitis, sinopulmonary infections, recurrent diarrhoea, and skin infections also frequently seen. In approximately 60% of individuals, immunodeficiency becomes apparent through a severe, life-threatening infection such as pneumonia, empyema, meningitis, sepsis, cellulitis, or septic arthritis. Late-onset complications include chronic pulmonary changes, gastrointestinal Helicobacter and Giardia infections, nodular regenerative hyperplasia of the liver, and rare chronic enteroviral meningoencephalitis.

Clinical expression is variable, and some affected males retain higher residual serum immunoglobulin concentrations than expected. Female carriers of a heterozygous pathogenic variant in BTK extremely rarely have clinical and laboratory findings of XLA.

The estimated prevalence is approximately 1/167,000-1/333,000 males.

X-linked agammaglobulinaemia is caused by germline pathogenic variants in BTK at Xq22.1. BTK encodes Bruton tyrosine kinase, which mediates signalling from the antigen-specific B-cell receptor; loss-of-function variants abolish downstream phospholipase Cγ2/NF-κB activation, arrest B-cell development at the pre-B-cell stage, and result in markedly reduced peripheral B-cell numbers with absent production of all major immunoglobulin isotypes.

X-linked agammaglobulinaemia is inherited in an X-linked recessive manner. The mother of an affected male carries a BTK pathogenic variant in approximately 80-85% of families. Carrier females have a 50% risk of transmitting the variant; male offspring inheriting it will be affected; female offspring will be carriers. Prenatal molecular testing is technically possible once the familial pathogenic variant has been identified.

The diagnosis is established by molecular testing and supported by characteristic immunological findings. Marked reduction of all serum immunoglobulin classes (IgG typically <200 mg/dL; IgM and IgA typically <20 mg/dL), markedly reduced peripheral B lymphocytes (CD19+ cells <1% of lymphocytes), and absent antibody responses to vaccine antigens are suggestive; identification of a hemizygous pathogenic variant in BTK in a male proband confirms the diagnosis. The diagnosis of XLA can also be established in a female proband with characteristic clinical and laboratory findings and a heterozygous pathogenic variant in BTK.

Main differential diagnoses include:

• caused by variants in other genes required for normal B cell development: indistinguishable from XLA on routine clinical or laboratory testing, differentiation by molecular genetic testing; should be considered in females with XLA-phenotype or males without a variant in BTK; CD79A, CD79B, BLNK, IGLL1, LRRC8A, PIK3R1.
• X-linked : low IgG and IgA with normal or elevated IgM and preserved peripheral B-cell numbers; CD40LG.

• A molecular genetic diagnosis confirms the clinical suspicion and provides the basis for accurate disease classification.
• Identification of the underlying pathogenic variant enables individualised surveillance and is a prerequisite for targeted medical care planned by the treating physicians in consultation with the affected individual.
• Identification of the familial pathogenic variant allows targeted testing of at-risk relatives, including predictive testing of asymptomatic male relatives and carrier testing of female relatives, with implications for family planning.

• Smith CIE, Berglöf A. X-linked agammaglobulinemia. 2024 Jun 27. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: PMID:20301626.
• El-Sayed ZA, Abramova I, Aldave JC, Al-Herz W, Bezrodnik L, Boukari R, et al. X-linked agammaglobulinemia (XLA): phenotype, diagnosis, and therapeutic challenges around the world. World Allergy Organ J. 2019;12(3):100018. doi:10.1016/j.waojou.2019.100018. PMID:; PMCID: PMC6439403.
• Cardenas-Morales M, Hernandez-Trujillo VP. Agammaglobulinemia: from X-linked to autosomal forms of disease. Clin Rev Allergy Immunol. 2022;63(1):22-35. doi:10.1007/s12016-021-08870-5. PMID:; PMCID: PMC8269404.