Clinical Information

X-linked agammaglobulinemia (XLA) is a humoral primary immunodeficiency affecting male patients in approximately 1 in 200,000 live births. XLA is caused by variants in the Bruton tyrosine kinase gene (BTK), which results in a profound block in B-cell development within the bone marrow and a significant reduction, or complete absence, of mature B cells in peripheral blood.(1,2)

Approximately 85% of male patients with defects in early B-cell development have XLA. Due to the lack of mature B cells, XLA patients have markedly reduced levels of all major classes of immunoglobulins in the serum and are, therefore, susceptible to severe and recurrent bacterial infections.(2) Pneumonia, otitis media, enteritis, and recurrent sinopulmonary infections are among the key diagnostic clinical characteristics of the disease. The spectrum of infectious complications also includes enteroviral meningitis, septic arthritis, cellulitis, and empyema, among others. XLA typically manifests in male infants.(2) However, other patients present with milder phenotypes, resulting in diagnosis later in childhood or in adulthood. Delayed diagnoses can be partly explained by the variable severity of XLA, even within families in which the same variant is present. X-inactivation of this gene is not typical, and XLA in female patients has rarely been reported.(3) Therefore, female patients with clinical features that are identical to XLA should be first evaluated for autosomal recessive agammaglobulinemia and for XLA if their biological father is affected with the disease.

A diagnosis of XLA should be suspected in male patients with early-onset bacterial infections, marked reduction in all classes of serum immunoglobulins, and absent B cells (CD19+ cells). The decrease in numbers of peripheral B cells is a key feature, although this can also be seen in a small subset of patients with common variable immunodeficiency. Conversely, some BTK variants can preserve small numbers of circulating B cells and, therefore, all 3 of the criteria mentioned above need to be evaluated.(2)

The preferred approach for confirming a diagnosis of XLA in male patients and identifying female carriers requires testing for the BTK protein expression on B cells by flow cytometry and genetic testing for a BTK variant. Patients can be screened for the presence of BTK protein by flow cytometry (BTK / Bruton Tyrosine Kinase [BTK], Protein Expression, Flow Cytometry, Blood); however, normal results by flow cytometry do not rule out the presence of a BTK variant with normal protein expression but aberrant protein function. The diagnosis is confirmed only in those individuals with appropriate clinical history who have a disease-causing variant identified within BTK by gene sequencing or who have male family members with hypogammaglobulinemia with absent or low B cells.