X-linked Agammaglobulinaemia (XLA / Bruton’s Disease)

Notes

Immunodeficiency Disorders | Immunology | Paediatrics | Primary Immunodeficiency | Primary Immunodeficiency Disorders

Overview

X-linked agammaglobulinaemia (XLA) is a rare primary immunodeficiency caused by mutations in the Bruton’s tyrosine kinase (BTK) gene, leading to failure of B-cell maturation. It results in profound hypogammaglobulinaemia and susceptibility to recurrent bacterial infections, particularly with encapsulated organisms. It usually presents after 6 months of age (once maternal IgG wanes). Prevalence is ~1 in 200,000 live male births.

Triad “Bruton’s = Boys, B-cells, Bacteria.”

Definition

BTK (Bruton’s tyrosine kinase): Enzyme critical for B-cell maturation.
Hypogammaglobulinaemia: Low levels of immunoglobulins (IgG, IgA, IgM).
Encapsulated bacteria: Bacteria such as S. pneumoniae, H. influenzae that require opsonising antibodies for clearance.
Opsonisation: Process where antibodies coat bacteria to promote phagocytosis.

Anatomy & Physiology

Normal B-cell development: Pro-B cell → pre-B cell (BTK required) → immature B cell → plasma cell producing antibodies.
In XLA, mutation in BTK halts differentiation at the pre-B stage, leading to:
- Absent circulating B cells.
- Absent plasma cells.
Absent immunoglobulins (IgG, IgA, IgM, IgE).

“XLA = no B cells, no antibodies.”

Aetiology & Risk Factors

Aetiology

Genetics: Mutations in BTK gene (Xq21.3–Xq22).
Inheritance: X-linked recessive → almost exclusively affects boys.

Risk Factors

Family history of affected males.
Carrier mothers (asymptomatic).

Pathophysiology

BTK mutation → defective pre-B to mature B-cell transition.
Absent mature B cells and plasma cells.
Profound hypogammaglobulinaemia.
No antibody-mediated opsonisation → impaired clearance of encapsulated bacteria.
Recurrent bacterial infections from ~6 months of age (loss of maternal IgG).

Timing is key – healthy until 6 months, then recurrent infections.

Clinical Manifestations

Onset after 6 months of age.
Recurrent bacterial infections:
- Otitis media, sinusitis, pneumonia.
- Septicaemia, meningitis.
- Organisms: Streptococcus pneumoniae, Haemophilus influenzae, Enteroviruses (esp. polio, echovirus).
GI infections: Chronic diarrhoea from Giardia lamblia.
Absent lymphoid tissue: Very small or absent tonsils, adenoids, lymph nodes.
Chronic lung disease: Bronchiectasis if untreated.

“Boy with recurrent bacterial infections + absent tonsils” = XLA.

Diagnosis

CBC: Normal lymphocyte count.
Immunoglobulins: Profound ↓ IgG, IgA, IgM.
Flow cytometry: Absent/very low CD19+ B cells.
Genetic testing: BTK mutation.
Physical exam: Absent tonsils/lymph nodes.

Differential Diagnosis

Condition	Differentiating Feature
CVID	Later onset, some B cells present, not complete absence
Selective IgA deficiency	Only IgA absent, often asymptomatic
SCID	Severe infections earlier (<3 months), T- and B-cell defects
Secondary hypogammaglobulinaemia	Drug-induced (rituximab, steroids), protein loss

Treatment

Lifelong IVIG or SCIG replacement therapy.
Prompt antibiotic therapy for infections.
Prophylactic antibiotics may be used.
Avoid live vaccines (esp. oral polio)
Aggressive management of chronic lung disease (bronchiectasis).

Treatment is supportive (antibodies supplied), no curative therapy currently.

Complications & Prognosis

Recurrent severe infections → bronchiectasis, chronic lung disease.
Enteroviral meningoencephalitis.
Arthritis (from Mycoplasma or Ureaplasma).
Prognosis: excellent with immunoglobulin replacement and infection prevention.

Without treatment, most die in childhood; with Ig replacement, can live near-normal lifespan.

References

Bruton OC. Agammaglobulinemia. Pediatrics. 1952;9(6):722–728.
Conley ME, Dobbs AK, Quintana AM, et al. Genetic basis of X-linked agammaglobulinemia. N Engl J Med. 2009;360(7):676–81.
Winkelstein JA, Marino MC, Lederman HM, et al. X-linked agammaglobulinemia: report on a United States registry of 201 patients. Medicine (Baltimore). 2006;85(4):193–202.
Ochs HD, Smith CIE. X-linked agammaglobulinemia: a model primary immunodeficiency. J Allergy Clin Immunol. 1996;98(4):687–99.
Picard C, Al-Herz W, Bousfiha A, et al. Primary immunodeficiency diseases: 2015 IUIS classification. J Clin Immunol. 2015;35(8):696–726.