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A clinically variable form of isolated agammaglobulinemia, an inherited immunodeficiency disorder, characterized in affected males by recurrent bacterial infections during infancy.
ORPHA:47Classification level: Subtype of disorder
Estimated prevalence is 1/350,000 to 1/700,000. Annual incidence is not known. The disorder has been reported in various ethnic groups worldwide. Only males are affected and females are asymptomatic carriers.
Affected individuals are usually healthy in the first few months of life due to residual maternal immunoglobulins. The majority of patients develop recurrent or persistent bacterial infections, most commonly caused by S. pneumoniae and H. influenzae, within the first two years of life,: otitis media, conjunctivitis, sinusitis, respiratory infections, diarrhea and skin infections (impetigo, cellulitis, abscesses, and furuncles). Other severe infections may include empyema, meningitis, sepsis, or septic arthritis. Pyoderma or cellulitis (associated with neutropenia) and pseudomonas or staphylococcal sepsis are frequent presenting findings, particularly in patients less than 12 months of age. Lymph nodes, tonsils, and other lymphoid tissues are unusually small or absent. Rare patients are reported to have vitiligo, erythematous rash, or alopecia totalis. Infections tend to persist throughout adulthood. Affected patients are reported to have a higher susceptibility to severe and chronic enteroviral infections. Growth and development are usually normal. Some patients have a less severe clinical presentation and are not recognized as immunodeficient until 10 years of age or later. Complications of X-linked agammaglobulinemia (XLA) include progressive lung disease, chronic sinusitis, inflammatory bowel disease, arthritis , as well as neurological changes.
XLA is caused by mutations in the BTK gene (Xq21.33-q22) involved in B lymphocyte differentiation and maturation.
A diagnosis of XLA should be considered in patients with recurrent or persistent otitis media, pneumonia, sinusitis, and conjunctivitis starting before age five years or severe bacterial infections such as sepsis, meningitis, cellulitis, or empyema. A family history consistent with X-linked transmission also points to this diagnosis. Suspicion can be confirmed with blood tests showing low serum Ig and markedly reduced B lymphocyte counts. Molecular genetic testing can also be used to establish or confirm the diagnosis.
Differential diagnoses include autosomal recessive or dominant agammaglobulinemia, common variable immunodeficiency (CVID), hyper IgM syndrome and severe combined immunodeficiency (SCID) (see these terms).
Prenatal diagnosis is possible following identification of the disease-causing mutation in the family.
XLA, as the name indicates, follows an X-linked pattern of inheritance. Nearly 50% of cases are familial, while the remainder are thought to be related to de novo mutations. Genetic counseling should be provided to members of affected families.
Management and treatment
There is no curative treatment for XLA but good disease control can be achieved through consistent gammaglobulin therapy. This can be given intravenously (400-600 mg/kg every 3 to 4 weeks) or subcutaneously (100 mg/kg every week). Therapy should be started as early as possible. Some immunologists advocate chronic prophylactic antibiotics and treatment of acute infections should be prolonged and at maximal doses of antibiotics.
Most patients with XLA lead a normal life. Life expectancy may be reduced in some patients as a result of complications such as severe infections and chronic pulmonary damage. Early therapeutic measures and treatment compliance are major prognostic factors.
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