X-linked Agammaglobulinaemia
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Direct answer
X-linked agammaglobulinaemia is an inherited B cell defect caused by mutations in the Bruton tyrosine kinase gene, leading to absent mature B cells and very low immunoglobulins of all classes. Affected boys usually present after about six months of age, when maternal IgG wanes, with recurrent bacterial infections of the sinuses, chest and gut. Monthly immunoglobulin replacement and early antibiotic treatment of infections are the mainstays of care.
What you must remember
- Gene and inheritance: BTK on the X chromosome; B cell maturation stops at the pre-B cell stage, so circulating CD19 positive B cells are almost absent.
- Immunoglobulins: IgG, IgA and IgM are all very low, and the tonsils and lymph nodes are small or absent.
- Timing of onset: after about six months, once transplacental maternal IgG declines.
- Organisms: Streptococcus pneumoniae, Haemophilus influenzae and Pseudomonas, plus enteroviral meningoencephalitis and Giardia intestinalis.
- Diagnosis: very low immunoglobulins with absent B cells, confirmed by BTK mutation analysis, with affected male relatives in the family history.
- Replacement dose: monthly intravenous or subcutaneous immunoglobulin, commonly about 0.4 to 0.5 g/kg per dose, given long-term.
- Carrier clue: most mothers are carriers (about a third of cases are new mutations), and female relatives can be offered carrier testing for genetic counselling.
- Key differential: hyper IgM syndrome, where IgM is normal or raised while IgG and IgA are low.
Where the exam tests this disorder
Questions focus on the gene, the age of onset and the replacement therapy. These traps are common.
- Trap: choosing hyper IgM for a child with low IgM and absent B cells. Correct: absent B cells with low IgM point to X-linked agammaglobulinaemia, whereas hyper IgM has normal or raised IgM.
- Trap: expecting large tonsils and lymph nodes on examination. Correct: they are small or absent in X-linked agammaglobulinaemia, a useful bedside clue.
- Trap: stopping immunoglobulin replacement once the child is well. Correct: the defect is permanent, so replacement continues, with dose adjusted to trough IgG levels.
Frequently asked questions
What is the gene defect in X-linked agammaglobulinaemia?
X-linked agammaglobulinaemia is caused by mutations in the BTK gene, which encodes Bruton tyrosine kinase needed for B cell development. Mutations block B cell maturation at the pre-B cell stage.
Why do boys with X-linked agammaglobulinaemia present after six months of age?
Boys with X-linked agammaglobulinaemia present after about six months because transplacental maternal IgG protects them until it declines. Recurrent infections then emerge, since the child cannot make his own immunoglobulins.
What is the treatment of X-linked agammaglobulinaemia?
Monthly immunoglobulin replacement is the mainstay of treatment for X-linked agammaglobulinaemia, commonly given at about 0.4 to 0.5 g/kg per dose. Early and aggressive antibiotic treatment of infections is also needed, and replacement continues long-term.
Which organism causes chronic diarrhoea in X-linked agammaglobulinaemia?
Giardia intestinalis is a recognised cause of chronic diarrhoea in X-linked agammaglobulinaemia, because secretory IgA is absent from the gut. Stool examination and specific antiprotozoal treatment are used when this is suspected.