X-Linked Agammaglobulinemia

Clinical characteristics: X-linked agammaglobulinemia (XLA) is characterized by recurrent bacterial infections in affected males in the first two years of life. Recurrent otitis is the most common infection prior to diagnosis. Conjunctivitis, sinopulmonary infections, diarrhea, and skin infections are also frequently seen. Approximately 60% of individuals with XLA are recognized as having immunodeficiency when they develop a severe, life-threatening infection such as pneumonia, empyema, meningitis, sepsis, cellulitis, or septic arthritis. S pneumoniae and H influenzae are the most common organisms found prior to diagnosis and may continue to cause sinusitis and otitis after diagnosis and the initiation of gammaglobulin substitution therapy. Severe, difficult-to-treat enteroviral infections (often manifest as dermatomyositis or chronic meningoencephalitis) can be prevented by this treatment. The prognosis for individuals with XLA has improved markedly in the last 25 years as a result of earlier diagnosis, the development of preparations of gammaglobulin that allow normal concentrations of serum IgG to be achieved, and more liberal use of antibiotics.

Diagnosis/testing: The diagnosis of XLA is suspected in males with early-onset bacterial infections, marked reduction in all classes of serum immunoglobulins, and absent B cells (CD19+ cells); the decrease in the number of B cells is the most consistent and distinctive feature. Adenoids and tonsils are frequently rudimentary and lymph nodes are reduced in size. Having a maternal uncle or male cousin with absent B cells makes the diagnosis almost certain. The diagnosis is established (or confirmed) in males who have a hemizygous BTK pathogenic variant and females who have a heterozygous BTK pathogenic variant.

Management: Treatment of manifestations: The mainstay of treatment is gammaglobulin substitution therapy (by weekly subcutaneous injection or intravenous infusion every 2-4 weeks) to prevent bacterial infections; some centers use chronic prophylactic antibiotics to prevent infections.

Prevention of secondary complications: The most common secondary complications of XLA are chronic sinusitis, chronic lung disease, inflammatory bowel disease, and enteroviral infection. Generous use of antibiotics can decrease the incidence of chronic sinusitis and lung disease. Diagnosis and treatment of bowel infections may decrease the risk of inflammatory bowel disease.

Agents/circumstances to avoid: Live viral vaccines, particularly oral polio vaccine; inactivated polio vaccine rather than live oral polio vaccine should be given to patients and their family contacts.

Evaluation of relatives at risk: Molecular genetic testing of at-risk male relatives as soon after birth as possible ensures that gammaglobulin substitution therapy is initiated as soon as possible in affected individuals.

Genetic counseling: XLA is inherited in an X-linked manner. The risk to the sibs depends on the carrier status of the mother: if the mother is heterozygous for a BTK pathogenic variant, there is a 50% chance of transmitting the BTK pathogenic variant in each pregnancy; males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be carriers. All daughters of a male proband will inherit the BTK pathogenic variant and will be carriers; sons are not affected. Once the BTK pathogenic variant has been identified in an affected family member, carrier testing for at-risk females is possible and prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible options.