X-Linked Agammaglobulinaemia

X-linked agammaglobulinaemia is an inherited primary antibody deficiency due to mutations in the Bruton tyrosine kinase gene (BTK), which blocks B-cell development. Affected boys have absent or very low B cells and profound hypogammaglobulinaemia.

The incidence is about 1 in 100 000 to 200 000 male births. Infection begins after 3 to 6 months of age, once maternal IgG has waned, but diagnosis is often delayed to a median age of 2 to 3 years. Female carriers are asymptomatic.

Autosomal recessive agammaglobulinaemia (for example IGHM, CD79A, BLNK) has a similar presentation and occurs in girls and boys.

Pathophysiology.

BTK is essential for pre-B-cell receptor signalling. In its absence, B-cell precursors arrest in the bone marrow, so mature B cells and plasma cells are nearly absent, and all immunoglobulin classes are low.

T-cell and neutrophil function is largely normal, but antibody dependent defence against encapsulated bacteria and enteroviruses is lost.

• Recurrent sinopulmonary infections (otitis media, sinusitis, pneumonia, bronchitis) due to Streptococcus pneumoniae and Haemophilus influenzae.
• Chronic diarrhoea (Giardia lamblia, Campylobacter), skin and soft tissue infection, conjunctivitis, and septic arthritis (including Ureaplasma and Mycoplasma).
• Enteroviral meningoencephalitis and vaccine associated polio after live oral poliovirus vaccine.
• Absent or very small tonsils and lymph nodes, growth delay and neutropenia in early infection. Bronchiectasis in untreated or late treated disease.

Red flags.

• Meningoencephalitis, dermatomyositis like illness or chronic enterovirus infection.
• Recurrent pneumonia or bronchiectasis in a boy with a family history of immunodeficiency.
• Symptoms after oral polio vaccine, or severe infection with no tonsils.

• Serum immunoglobulins: IgG usually under 2 g/L with very low IgA and IgM. Interpret using age related reference ranges, and consider maternal IgG in infants under 6 months.
• Flow cytometry: CD19-positive B cells under 1% of lymphocytes, with normal T cells and natural killer cells.
• BTK protein expression by flow cytometry in monocytes, and genetic testing of BTK to confirm the diagnosis and test carriers.
• Chest imaging (CT for bronchiectasis), lung function, sinus imaging and screening for chronic infection.

Differential diagnosis. Common variable immunodeficiency, other agammaglobulinaemias, transient hypogammaglobulinaemia of infancy, hyper-IgM syndrome, severe combined immunodeficiency, secondary hypogammaglobulinaemia (protein loss, drugs) and haematological malignancy.

• Immunoglobulin replacement for life. Intravenous: 400 to 600 mg/kg every 3 to 4 weeks. Subcutaneous: 100 to 150 mg/kg weekly (or equivalent in frequent smaller doses). Adjust the dose to maintain trough IgG over 8 g/L, or higher if infections persist.
• Prompt treatment of infection with antibiotics for longer courses, and consider antibiotic prophylaxis (for example azithromycin 10 mg/kg 3 times each week) for recurrent infection or bronchiectasis.
• Avoid live vaccines (oral poliovirus, live typhoid). Inactivated vaccines give the patient no protective antibody response, but household contacts should be fully immunised.
• Airway clearance physiotherapy and treatment of bronchiectasis. Haematopoietic stem cell transplantation is not usually offered.
• Reaction monitoring: infusion reactions, thrombosis and renal impairment with immunoglobulin.

Monitoring. Trough IgG every 3 to 6 months, infection record, growth, lung function and high resolution CT every 1 to 3 years, and screening for autoimmunity and malignancy.

Referral and escalation. Refer to a paediatric immunology service at diagnosis, with genetic counselling for the family.