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Internal Medicine

X-linked (Bruton) agammaglobulinemia (XLA)

Primary immunodeficiency of B-lymphocytes due to an arrest in B-lymphocyte development, is caused by mutations in the gene encoding Btk (Bruton tyrosine kinase).

Introduction

X-linked agammaglobulinemia (XLA) is an X-linked recessive genetic condition where B cells aren’t able to fully mature, resulting in a lack of immunoglobulins (antibodies) in the blood.

Primary immunodeficiency of B-lymphocytes due to an arrest in B-lymphocyte development, is caused by mutations in the gene encoding Btk (Bruton tyrosine kinase).

  • X-linked recessive inheritance
  • Accounts for 6-11% of primary immunodeficiency (PID)
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History:

In 1952, Ogden Bruton, a paediatrician at the Walter Reed Army Hospital in Washington, DC, reported the first case of congenital agammaglobulinemia in an 8-year-old boy who suffered from recurrent pneumococcal sepsis. Protein electrophoresis revealed lack of the serum globulin fraction in this first patient and in a subsequent series of patients analyzed in collaboration with Charles Janeway. Immunoglobulin (Ig) replacement therapy was subsequently demonstrated to be effective in preventing infections and became central to the foundation of the discipline of clinical immunology.3,4 Today, this primary immunologic deficiency (PID) is called X-linked agammaglobulinemia (XLA) or Bruton’s agammaglobulinemia, and its estimated incidence is approximately 1:250,000.3 After Bruton’s and Janeway’s discoveries in the 1950s, it was approximately four decades until the genetic basis of XLA was identified5,6 (Fig 2). In 1993, two laboratories cloned BTK independently,7,8 and deciphered the coding sequence and Bruton’s tyrosine kinase (BTK) mutations.7 Before that, the gene locus for XLA in the Xq22 region was already narrowed down with DNA probes,13,14 which served as the basis for the cloning strategy. Because of its involvement in XLA, this kinase was named after Bruton. With these groundbreaking discoveries, XLA became the first example of mutations in a tyrosine kinase that cause a PID.

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Milestones in Bruton’s tyrosine kinase (BTK) research. CLL, chronic lymphocytic leukemia; FDA, US Food and Drug Administration; MCL, mantle-cell lymphoma; xid, X-linked immunodeficiency; XLA, X-linked agammaglobulinemia. | Ponader, S., & Burger, J. A. (2014). Bruton’s tyrosine kinase: from X-linked agammaglobulinemia toward targeted therapy for B-cell malignancies. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology, 32(17), 1830–1839. https://doi.org/10.1200/JCO.2013.53.1046

Aetiology

Bruton’s tyrosine kinase (Btk) gene mutation:

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Early stages of B-cell differentiation can be identified by the status of the immunoglobulin genes and by the cell surface markers CD34, CD19, and surface immunoglobulin (sIg). | Conley ME. Genes required for B cell development. J Clin Invest. 2003;112: 1636-8. American Society for Clinical Investigation via Copyright Clearance Center.

Associated conditions:

  • Autoimmune conditions (35%): Arthritis and dermatomyositis

Pathophysiology

Mutation occurs at the Bruton’s tyrosine kinase (Btk) gene → severe block in B cell development (at the pre-B cell to immature B cell stage) → reduced immunoglobulin production

x-linked-agammaglobulinemia
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Clinical features

Presents in early childhood.

  • Humoral immunodeficiencyRecurrent infections
    • Streptococcus pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae, hepatitis virus, and enterovirus CNS infections.
  • Lymphoid hypoplasia: Tonsils and adenoids are atrophied
  • No splenomegaly or lymphadenopathy
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Distribution of the age of disease onset and diagnosis in patients with XLA. | Chen, X.-F., Wang, W.-F., Zhang, Y.-D., Zhao, W., Wu, J., & Chen, T.-X. (2016). Clinical characteristics and genetic profiles of 174 patients with X-linked agammaglobulinemia: Report from Shanghai, China (2000-2015). Medicine, 95(32), e4544–e4544. https://doi.org/10.1097/MD.0000000000004544

Diagnosis

  • Complete lack of circulating B cells (determined by the B cell marker CD19 and/or CD20)
  • Low levels of all antibody classes (IgG, IgA, IgM, IgE and IgD)
  • Western Blot test
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Relative frequencies of different stages of B-lineage cells among BM lymphoid cells in XLA patients and in infant, children, and adult controls. | Nomura, K., Kanegane, H., Karasuyama, H., Tsukada, S., Agematsu, K., Murakami, G., … Miyawaki, T. (2000). Genetic defect in human X-linked agammaglobulinemia impedes a maturational evolution of pro-B cells into a later stage of pre-B cells in the B-cell differentiation pathway. Blood, 96(2), 610 LP-617. Retrieved from http://www.bloodjournal.org/content/96/2/610.abstract

Differential diagnosis:

Other primary immunodeficiencies (PID)
  • Autosomal recessive agammaglobulinemia (ARA)
  • Common variable immunodeficiency disease (CVID)
    • No splenomegaly or lymphadenopathy
    • Presents in late childhood
  • Transient hypogammaglobulinemia of infancy (THI)
  • X-linked hyper IgM syndrome (Hyper-IgM)
  • X-linked lymphoproliferative disease (X-LPD)
  • Severe combined immunodeficiency disease (SCID)

Management

  • IV immunoglobulin (IV-Ig) every 3–4 weeks, for life
  • If adverse reactions shown, Subcutaneous treatment (SCIg) given

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