X-linked Agammaglobulinemia

X-linked agammaglobulinemia, also known as Bruton’s agammaglobulinemia or Bruton’s disease, is a rare, recessive genetic disorder characterized by the improper development of B cells, leading to a lack of mature B cells capable of responding to stimulation by cell-mediated immune responses or certain antigen-presenting cells. X-linked agammaglobulinemia is more likely to be found in males than females and is due to mutations in the Bruton’s tyrosine kinase gene on the X chromosome. The result of this mutation is a complete or near-complete lack of all antibodies. Presentation includes recurrent bacterial infections after the first few months of life. Management consists of IV immunoglobulins and prophylactic use of antibiotics.

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Epidemiology and Pathophysiology

Epidemiology

  • 1:200,000 live births 
  • 1:100,000 male newborns
  • Occurs more commonly in boys due to X-linked recessive inheritance pattern
  • No ethnic predisposition

Etiology

  • The most common X-linked recessive disorder found in males; females are usually asymptomatic carriers
    • Males have an XY karyotype and only possess 1 X chromosome, while females would require 2 affected X chromosomes to develop the disease.
  • Caused by a mutation in the Bruton’s tyrosine kinase (Btk) gene (this mutation inhibits B cell maturation into pre-B cells)
  • 30%50% of cases are due to familial genetic inheritance.
  • 50%70% of cases are due to spontaneous mutations.
X-linked recessive inheritance

The pattern of inheritance of X-linked agammaglobulinemia. Note that the mother must contribute the defective X gene to the male child in order for him to express this phenotype.

Image by Lecturio.

Pathophysiology

  • Mutations in the Btk gene prevent normal B cell maturation from pro-B into pre-B lymphocytes.
  • Mature B cells do not form, and immunoglobulin light chains cannot be produced, although free heavy chains can be found in the cytoplasm. 
  • Results in an almost complete absence of immunogammaglobulin (Ig)
  • Humoral immunity response is non-functional (with normal T-cell–mediated immunity).
  • Patients are prone to develop serious and even fatal infections during early childhood, especially from encapsulated bacteria.
X-linked agammaglobulinemia

The absence or defect of the Btk enzyme inhibits the normal development of pro-B cells into pre-B cells.

Image by Lecturio.

Clinical Presentation

  • Children are asymptomatic until 69 months of age when maternal immune protection (IgG) previously supplied via the placenta falls.
  • Presents as recurrent infections such as:
    • Pneumonia
    • Otitis media
    • Cellulitis
    • Conjunctivitis
    • Pharyngitis
    • Bronchitis
    • Sinusitis
  • Patients are at especially increased risk for recurrent infections by:
    • Encapsulated bacteria, such as Streptococcus pneumoniae, Haemophilus influenzae, and Mycoplasma pneumoniae
    • Viruses, such as hepatitis viruses and enterovirus
    • Parasitic infections, such as Giardia lamblia
  • Examination shows lymphoid hypoplasia, or rudimentary lymph nodes, tonsils, Peyer’s patches, and appendix.

Diagnosis and Management

Diagnosis

  • Suspicion is based on a history of recurrent infections during childhood, mostly in the respiratory tract.
  • Flow cytometry shows:
    • Complete lack or significant reduction of circulating B cells determined by the B-cell markers CD19 and CD20
    • Absence of plasma cells throughout the body
    • Low levels of all antibody classes, including IgG, IgA, IgM, IgE, and IgD
    • Normal-to-high levels of T cells
  • Genetic testing is used to confirm the diagnosis and identify the specific Btk mutation.

Management

  • There is no cure, but management can increase the patient’s lifespan and quality of life.
  • Mainly consists of lifelong weekly or monthly immunoglobulin replacement therapy (IVIG)
  • Prophylactic antibiotics are administered to prevent infections.
  • Live vaccines are contraindicated (increased risk of vaccine-related polio)

Differential Diagnosis

The following conditions are differential diagnoses for X-linked agammaglobulinemia.

  • Autosomal recessive or dominant agammaglobulinemia: a rare form of primary immunodeficiency disease characterized by a complete or near-complete absence of immunoglobulins, which leads to variable immune dysfunction and frequent/recurrent bacterial infections. Molecular genetic testing is required to determine the causative genetic defect.
  • Common variable immunodeficiency (CVID): a type of primary immunodeficiency characterized by reduced serum levels of immunoglobulins IgG, IgA, and IgM. The underlying causes of CVID are largely unknown. Patients with this condition are prone to infections in the gastrointestinal tract and the upper and lower respiratory tracts and have a higher risk of developing autoimmune, granulomatous, and neoplastic diseases.
  • Hyper IgM syndrome: a disorder caused by an X-linked mutation in the CD40 ligand gene that results in abnormal signaling between B and T lymphocytes. Presentation is mild and often only presents in later life as opportunistic infections and immune dysregulation of IgE eosinophils, B cells, NK cells, and CD8+ T cell proliferation and activation.
  • Severe combined immunodeficiency (SCID): the most severe form of primary immunodeficiency, SCID is a genetic disorder that involves defective antibody response due to either direct involvement with B lymphocytes or through improper B-lymphocyte activation due to non-functional T-helper cells. Presents as severe and recurrent opportunistic infections and is diagnosed through quantitative PCR and flow cytometry
  • Ataxia telangiectasia: a rare, autosomal recessive disorder characterized by the association of severe combined immunodeficiency, tumor development, and neurological abnormalities. Presents as gait ataxia, apraxia, abnormal movements, telangiectasia, recurrent pulmonary infections, and a higher risk of lymphoma, leukemia, and gastric carcinoma

References

  1. Le, T., & Bhushan, V. (2020). First Aid for the USMLE Step 1 (30th anniversary edition) (P. 116). New York: McGraw-Hill Medical.
  2. Kumar, V., Abbas, A. K., Aster, J. C., & Robbins, S. L. (2013). Robbins basic pathology (P. 140, 141). Philadelphia, PA: Elsevier/Saunders.
  3. U.S. National Library of Medicine. (Reviewed 2015, published 2020). X-linked agammaglobulinemia. https://ghr.nlm.nih.gov/condition/x-linked-agammaglobulinemia#genes
  4. Genetic and Rare Diseases Information Center. X-linked agammaglobulinemia. National Center for Advancing Translational Sciences; rarediseases.info.nih. Retrieved August 17, 2020, from https://rarediseases.info.nih.gov/diseases/1033/x-linked-agammaglobulinemia

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