X-linked agammaglobulinaemia (BTK gene): infections, inheritance and treatment

Antibodies, also called immunoglobulins, are proteins that help the body fight germs. They are made by white blood cells called B-cells. Immunodeficiency UK explains that in XLA genetic changes in the BTK gene block the development of normal mature B-cells, so people with XLA have very few mature B-cells and cannot make the antibodies needed to protect against infections.

XLA belongs to a group of conditions known as primary antibody deficiencies. It is also known as Bruton's agammaglobulinaemia. The charity gives about 5 to 10 people in a million as affected, and a charity FAQ page gives about 1 in 100,000.

Most viral infections can be coped with. Immunodeficiency UK notes that people with XLA are usually able to cope with most viral infections, including measles and chickenpox, and that in rare cases enteroviruses can cause serious infection, though this is uncommon for those on adequate replacement therapy.

The NHS Genomics Education Programme explains that XLA is an X-linked recessive condition caused by pathogenic variants in the BTK gene, which codes for a tyrosine kinase that is critical in B-cell development. Affected individuals are almost all male. Either they inherited the variant from their mother, who is a carrier, or it arose newly in the child, which the programme says accounts for 15 to 20 per cent of cases.

Immunodeficiency UK says more than 600 different changes in the BTK gene have been found to cause XLA. For every boy conceived to a carrier mother there is a 50 per cent chance that he will have XLA, and each daughter has a 50 per cent chance of being a carrier. Affected fathers have carrier daughters but their sons are not affected and are not carriers.

Female carriers are typically unaffected, although a small number have been reported to have symptoms because of skewed X-inactivation. Occasional cases of girls with XLA have been described for the same reason.

Because of these patterns, mothers, maternal aunts and sisters may be carriers, and the charity says they should receive genetic counselling. Prenatal genetic diagnosis is available for families in which XLA has already been diagnosed.

The NHS Genomics Education Programme says affected boys typically present in the first two years with recurrent bacterial infections such as ear infections and pneumonia. Conjunctivitis, sinusitis, diarrhoea and skin infections are also frequent, and the first presentation may be a severe, life-threatening infection such as pneumonia, meningitis or sepsis.

Immunodeficiency UK lists common features: sinus infections, ear infections, throat and chest infections, stomach and intestinal infections including giardiasis, skin abscesses, eye infections, urinary infections, meningitis, joint infections and septicaemia. Very small or absent tonsils and lymph glands in the neck may be a physical sign, because B-cells normally gather there.

Longer-term complications can include bronchiectasis, chronic sinus disease, arthritis, bowel inflammation and temporary neutropenia, usually in people not receiving immunoglobulin replacement.

Antibody deficiency is considered in people with repeated, severe or persistent infections, and a clinical immunologist usually makes the diagnosis. Immunodeficiency UK describes blood tests for immunoglobulin levels, antibody function after test immunisations, and counts of lymphocytes including B-cells. In XLA mature B-cells are absent from blood while T-cell levels are normal.

The NHS Genomics Education Programme says that, using the European Society for Immunodeficiencies criteria, a diagnosis is considered in a male with less than 2 per cent B-cells, onset of recurrent bacterial infections in the first five years of life, and low immunoglobulins, with other causes excluded. A definite diagnosis comes from finding a variant in the BTK gene, and in males molecular investigation of suspected agammaglobulinaemia starts with BTK analysis.

The programme also notes that XLA may occasionally be identified before symptoms begin, for example through the Generation Study of newborn genome sequencing, and that management of those children may differ from that of children presenting with symptoms. Diagnosis requires referral to clinical immunology.

The mainstay of treatment is immunoglobulin replacement, made from donated plasma. It can be given into a vein or under the skin. Immunodeficiency UK says subcutaneous therapy is usually needed every day or every week and intravenous therapy every 2 to 4 weeks, with blood tests typically every 3 to 6 months to check IgG levels and watch for complications.

Antibiotics are needed for breakthrough infections, and a few people take them daily. Physiotherapy helps clear the airways if bronchiectasis has developed. The charity says children with XLA should take part in regular school activities, including exercise, and do not need to be limited in what they can do, though the school should be aware of the diagnosis.

Not all vaccines are safe for people with XLA, so recommended vaccinations should be discussed with the clinical immunology team first.

Because the first presentation can be a serious infection, a fever or feeling very unwell in a child or adult known to have XLA should be treated seriously and the immunology team contacted promptly. If there is difficulty breathing, a stiff neck, severe drowsiness or confusion, call 999 or go to A&E and say that the person has an antibody deficiency.