Hereditary agammaglobulinaemia

Hereditary agammaglobulinaemia (congenital agammaglobulinaemia) is a humoral primary immunodeficiency in which affected individuals are usually well during the first months of life owing to transplacentally acquired maternal immunoglobulin. Recurrent bacterial infections typically develop within the first years of life. Recurrent otitis is the most common presenting infection, followed by conjunctivitis, sinopulmonary infections, chronic diarrhoea, and skin infections. About 60% of individuals first come to attention with a severe, life-threatening infection such as pneumonia, empyema, meningitis, sepsis, cellulitis, or septic arthritis. Affected individuals are not susceptible to most viral infections but show particular vulnerability to severe and chronic enteroviral disease, occasionally manifesting as dermatomyositis-like syndrome or chronic meningoencephalitis. With adequate immunoglobulin substitution, most individuals lead a largely normal life, although chronic pulmonary changes and persistent infections occur in a subset.

The estimated prevalence of X-linked agammaglobulinaemia is 1/170,000-1/330,000 males. X-linked agammaglobulinaemia accounts for approximately 85% of hereditary agammaglobulinaemia with absent B cells; autosomal recessive and autosomal dominant forms together account for the remaining ~15% and are individually very rare.

Hereditary agammaglobulinaemia is associated with germline pathogenic variants in genes encoding components of the pre-B-cell and B-cell receptor signalling pathway required for B-cell maturation. Loss-of-function variants in BTK (Xq22.1), encoding Bruton tyrosine kinase, account for ~85% of cases and underlie the X-linked form. Rare autosomal recessive forms and very rare autosomal dominant forms involve other genes that are associated with B cell development and can be targeted by multigene panel testing. Across all genetic forms, the disrupted signalling arrests B-cell development at the pre-B-cell stage, producing profoundly reduced circulating mature B cells and a clinically indistinguishable phenotype.

The X-linked form (BTK) is inherited in an X-linked recessive manner, with affected males and largely asymptomatic female carriers; the remaining genetic forms follow autosomal recessive or, more rarely, autosomal dominant inheritance. For X-linked agammaglobulinaemia, female carriers have a 50% risk of transmitting the pathogenic variant per pregnancy, with affected sons and carrier daughters. Carrier testing of at-risk female relatives clarifies reproductive risk. Prenatal molecular testing is technically possible once the familial pathogenic variant has been identified.

The immunological hallmark is a marked reduction in all serum immunoglobulin classes (typically IgG <200 mg/dL; IgM and IgA <20 mg/dL) combined with markedly reduced CD19+ B lymphocytes (<1% of peripheral lymphocytes) and absent antibody responses to vaccine antigens. As no established clinical consensus criteria define the condition, the diagnosis is confirmed by molecular genetic testing, which identifies the specific genetic form and informs inheritance counselling.

Main differential diagnoses include:

• : a heterogenous group of conditions with reduced but not absent serum levels of IgG, IgA, and/or IgM, insufficient antibody production and recurrent infections, which are typically not as severe as in agammaglobulinaemia.
• X-linked (CD40 ligand deficiency): low serum IgG and IgA with normal or elevated IgM and preserved B-cell numbers, distinguishing it from agammaglobulinaemia where B cells are markedly reduced; CD40LG
• : combined T- and B-cell defect presenting earlier and more severely, with B-cell numbers usually normal or elevated rather than absent; IL2RG
• : dysregulated immune response to Epstein-Barr virus with hypogammaglobulinaemia but relatively preserved B-cell numbers; SH2D1A, XIAP

• Establishing the diagnosis through identification of the underlying pathogenic variant.
• Specific and individualised surveillance, including quantitative serum immunoglobulin monitoring and assessment for chronic pulmonary disease, is a prerequisite for targeted medical care; the choice and timing of measures are determined by the treating physicians in consultation with the affected individual.
• Identification of the familial pathogenic variant enables predictive and carrier testing of at-risk relatives and informs reproductive decisions.

• 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.
• 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