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Agammaglobulinemia (X-Linked)

X-linked agammaglobulinemia (XLA) is a condition that affects the immune system (our body’s system for fighting infections). XLA is caused by mutations in the BTK gene on the X chromosome. The BTK gene is important in allowing for the maturation of B cells, a special type of cell in the immune system that normally create antibodies (immunoglobulins) against infections. Because patients with XLA have a defective BTK gene, they have low levels of B cells and antibodies. As a result, these patients are highly susceptible to infections, are not protected by most vaccines, and can get much more sick from an infection than other people1.

Nearly all patients with XLA are male (see below). Males with XLA generally begin developing frequent bacterial infections around 6 months of life, including lung infections (pneumonia and bronchitis), ear infections, eye infections (conjunctivitis), sinus infections, skin infections, and infections causing chronic diarrhea. Patients are usually healthy in the first few months of life because they still have antibodies in their blood that were passed to them from their biological mother through the placenta during pregnancy. These maternal antibodies protect the child from infections for some time at the beginning of life, then they clear away and the child’s own immune system becomes responsible for creating more.

 

Females with XLA

Females are almost never affected by XLA. Those with a BTK mutation on one of their X chromosomes (heterozygotes) are highly likely to be asymptomatic carriers of XLA. These females are especially protected from developing the disease because of a selective survival advantage that occurs among B cells that carry the normal BTK gene, described below:

Early in the development of female embryos, X-inactivation occurs, where one of the two X chromosomes is randomly inactivated in each cell. Because this process is random, it usually results in ~50:50 ratio of expression of each X chromosome across all cells. In a female carrier of XLA, this means that roughly half of her B-cell precursors (cells that are destined to mature into B cells) will have the normal X active and half will have the mutant X (i.e. the one with a BTK mutation) active. However, the precursors that have the mutant X active cannot mature into B cells, because a functioning BTK gene is needed for that.  So, those cells will instead die off, leaving only precursors with the normal X. Those precursors can and will successfully mature into functional B cells. The result of this is that 100% of a carrier’s mature B cells will express the normal X chromosome, while her other cells in the body (where the BTK gene is not essential) show the expected random ~50:50 X-inactivation pattern2. This phenomenon of B-cell-lineage-specific skewing is so reliable across nearly all females with XLA that it is used as a diagnostic test for carrier detection2.

Therefore, for a female to develop the clinical effects of XLA, none of her B cell precursors should have a normal X chromosome active. This would happen in females who are homozygous for XLA, meaning they inherit a BTK mutation from both their mother and their father (and thus both of their X chromosomes have a mutation), which is so rare that no cases have ever been reported in the medical literature. Or, this could happen in females who have such extreme skewage of their X-inactivation during development that none of their B cell precursors have the normal X chromosome. This is considered exceedingly rare, but has been reported in one case of a girl who developed signs and symptoms of XLA disease equal in severity to males with XLA3.

This page was last updated in July, 2026. Please note that research into females with this condition is limited. Decisions regarding your own health should be made in consultation with your medical provider.

  1. X-linked agammaglobulinemia: MedlinePlus Genetics. Accessed July 21, 2026. https://medlineplus.gov/genetics/condition/x-linked-agammaglobulinemia/
  2. Allen RC, Nachtman RG, Rosenblatt HM, Belmont JW. Application of carrier testing to genetic counseling for X-linked agammaglobulinemia. Am J Hum Genet. 1994;54(1):25-35.
  3. Takada H, Kanegane H, Nomura A, et al. Female agammaglobulinemia due to the Bruton tyrosine kinase deficiency caused by extremely skewed X-chromosome inactivation. Blood. 2004;103(1):185-187. doi:10.1182/blood-2003-06-1964