X-Linked Agammaglobulinemia

Excerpt

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 manifesting 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 immunoglobulin G to be achieved, and more liberal use of antibiotics.

Diagnosis/testing: The diagnosis of XLA is established in a male proband with characteristic clinical and laboratory findings and a hemizygous BTK pathogenic variant identified by molecular genetic testing. The diagnosis of XLA can be established in a female proband with characteristic clinical and laboratory findings and a heterozygous pathogenic variant in BTK identified by molecular genetic testing. Females with a heterozygous pathogenic variant in BTK extremely rarely have clinical and laboratory findings of XLA.

Management: Targeted therapy: The mainstay of treatment is gammaglobulin substitution therapy (by weekly subcutaneous injection or intravenous infusion every two to four weeks) to prevent bacterial infections.

Treatment of manifestations: Generous use of antibiotics can decrease the incidence of chronic sinusitis and lung disease. Prophylactic antibiotics can be considered to prevent infections. Vaccines, apart from live vaccines, are recommended to prevent infection. Inactivated polio vaccine (as opposed to live oral polio vaccine) should be given to affected individuals and their family contacts.

Surveillance: Complete blood count with differential and quantitative serum immunoglobulins at least annually; chest and sinus imaging as needed to assess for chronic lung and/or sinus disease.

Agents/circumstances to avoid: Live viral vaccines, particularly oral polio vaccine.

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 and administration of live viral vaccines can be avoided.

Genetic counseling: By definition, XLA is inherited in an X-linked manner. The risk to sibs of a male proband depends on the genetic status of the mother: if the mother has a BTK pathogenic variant, the chance of transmitting the BTK pathogenic variant in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be carriers and are highly unlikely to be affected. Affected males transmit the BTK pathogenic variant to all of their daughters and none of their sons. Once the BTK pathogenic variant has been identified in an affected family member, carrier testing for at-risk female relatives, prenatal testing, and preimplantation genetic testing are possible.