X-Linked (Bruton) Agammaglobulinemia Clinical Presentation

Updated: Mar 26, 2021
  • Author: Robert A Schwartz, MD, MPH; Chief Editor: Dirk M Elston, MD  more...
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Recurrent infections begin in infancy and persist throughout adulthood.

The most common presentation of X-linked agammaglobulinemia (XLA), or Bruton agammaglobulinemia, is increased susceptibility to encapsulated pyogenic bacteria, such as Streptococcus pneumoniae, Haemophilus influenzae, and Pseudomonas species. [3] Skin infections in patients with XLA are mostly caused by group A streptococci and Staphylococcus aureus, and they can present as impetigo, cellulitis, abscesses, or furuncles.

A form of eczema that resembles atopic dermatitis may be evident, along with an increased incidence of pyoderma gangrenosum, vitiligo, alopecia totalis, and Stevens-Johnson syndrome (from increased use of medications). Other infections that commonly present with XLA include enteroviral infections, sepsis, meningitis, and bacterial diarrhea (often caused by common organisms, such as Campylobacter jejuni and Giardia species). [17] Individuals who are affected may have an increased incidence of autoimmune diseases leading to thrombocytopenia, neutropenia, hemolytic anemia, and rheumatoid arthritis. [18] Persistent enteroviral infections may rarely lead to fatal encephalitis or a dermatomyositis-meningoencephalitis syndrome. [19] In addition to the neurologic changes, clinical manifestations of this syndrome include edema, muscle wasting, and an erythematous rash over the extensor surfaces of the joints.

Males affected with XLA usually present when they are younger than 1 year with unusually severe and/or recurrent otitis media, sinopulmonary infections, and pneumonia. The most common pathogen is S pneumoniae, followed by H influenzae type b, staphylococcal species, Neisseria meningitidis, and Moraxella catarrhalis. Clinical suspicion of XLA should be followed up with a detailed family history. One third to one half of all patients with XLA have spontaneous mutations and no family history of immunodeficiency. Suspect disease when increased otitis media, sinusitis, chronic coughs, and pneumonias.

For children younger than 12 years, typical infections are caused by encapsulated bacteria. Common infections in this age group are recurrent pneumonia, sinusitis, and otitis media caused by S pneumoniae and H influenzae type b that are difficult to treat.

In adulthood, skin manifestations become more common, usually due to Staphylococcus and group A Streptococcus organisms. Otitis media is replaced by chronic sinusitis, and pulmonary disease becomes a constant recurring problem, in both the restrictive form and the obstructive form.

Both infants and adults can have autoimmune diseases associated with XLA. Typically, these disorders include arthritis, autoimmune hemolytic anemia, autoimmune thrombocytopenia, autoimmune neutropenia, infection enteritis, and inflammatory bowel disease. [20] Inflammatory bowel disease can be very difficult to control and often promotes chronic weight loss and malnutrition.

Diarrhea is common and is caused by Giardia or Campylobacter species.

Patients with XLA are prone to enteroviral infections, including poliovirus. They may develop extensive molluscum contagiosum. [21]

Ureaplasma and Mycoplasma infections may be more common than in the general population, as are bladder and joint infections.

Its diagnosis may be delayed due to insufficient awareness in a population with frequent infections in immunocompetent children. [22] Delayed diagnosis and atypical manifestations may also be related to mutation type and BTK expression. [23]


Physical Examination

Male infants with X-linked agammaglobulinemia (XLA), or Bruton agammaglobulinemia, may appear physically smaller than male infants without XLA because of delayed growth and development from recurrent infections. Rarely, XLA is associated with growth hormone deficiency, leading to significantly shorter stature in males with XLA than in males without XLA of the same age.

On examination, the lymph nodes, the tonsils, and other lymphoid tissues may be very small or absent.

The disease is diagnosed when the male infant repeatedly becomes ill with various sinopulmonary infections, otitis media, or staphylococcal skin infections and conjunctivitis that do not respond well to antibiotic therapy. These severe infections may be associated with neutropenia.

Diarrhea due to Giardia, C jejuni, Shigella, and Salmonella infections may be a clinical feature of XLA.

Pyoderma gangrenosum – like ulcers and cellulitis of the lower extremities may be seen with X-linked (Bruton) agammaglobulinemia. [24] They may occur with recurrent fever and be caused by Helicobacter bilis, an organism difficult recover in blood and wound cultures that can be identified using a novel application of gene amplification polymerase chain reaction and electrospray ionization time-of-flight mass spectrometry.



Complications for patients with XLA include chronic sinopulmonary infections, enteroviral infections of the central nervous system, increased occurrence of autoimmune diseases, and skin infections. XLA patients have an increased risk of lymphoma. [25]