Genetics · MU Sofia

26. Congenital Immunodeficiencies: Humoral and Immune Regulation Defects

Covers the two conditions in this topic: X-linked agammaglobulinaemia (Bruton's disease), explained through BTK gene function, B-cell maturation arrest, pathophysiology, clinical features, diagnosis and treatment, and Chediak-Higashi syndrome, covering the LYST gene, phagolysosomal fusion defect, albinism, bleeding, accelerated phase and transplant. A classification table of congenital immunodeficiencies and a side-by-side comparison table of the two disorders are included.

Inside: 17 sections · 7 labelled pictures · 4 tables · 15 flashcards · 5 min

Topic 26 of 65 in the MU Sofia syllabus for Genetics (Medicine, Year 3). The free AceMed note covers it in 12 sections, about 526 words (5 min of reading), with 15 flashcards.

In this note

  1. Congenital Immunodeficiencies: Humoral and Immune Regulation Defects
  2. General Characteristics
  3. Classification of Congenital Immunodeficiencies
  4. I. Deficiency of Humoral Immunity: X-linked Agammaglobulinemia (XLA)
  5. Genetic and Molecular Basis
  6. Pathophysiology
  7. Clinical Features
  8. Diagnosis
  9. Treatment
  10. II. Deficiency of Immune Regulation: Chediak–Higashi Syndrome (CHS)
  11. Definition
  12. Comparison

Congenital Immunodeficiencies: Humoral and Immune Regulation Defects

Congenital (Primary) Immunodeficiencies are inherited disorders that impair the development or function of specific immune components.

They can involve antibody production (B-cell defects), cell-mediated immunity (T cells), or immune regulation and phagocytosis.

This topic focuses on:

  1. 1. Deficiency of humoral immunity – X-linked Agammaglobulinemia (XLA).
  2. 2. Deficiency of immune regulation / phagocyte function – Chediak–Higashi Syndrome (CHS).

General Characteristics

  • Appear early in life (infancy or childhood).
  • Present with recurrent, severe, and often unusual infections.
  • Strong association with genetic mutations affecting lymphocyte differentiation or immune cell function.
  • Some may have autoimmune or malignant complications due to immune dysregulation.

I. Deficiency of Humoral Immunity: X-linked Agammaglobulinemia (XLA)

X-linked Agammaglobulinemia (Bruton’s Disease) is a primary B-cell immunodeficiency characterized by failure of B-cell maturation and severe reduction or absence of antibodies in the blood.

It leads to recurrent bacterial infections, especially of the respiratory and gastrointestinal tract.

Genetic and Molecular Basis

  • Gene involved: BTK (Bruton Tyrosine Kinase) gene on Xq21.3–Xq22.
  • Inheritance: X-linked recessive (affects only males; females are carriers).
  • Normal function of BTK:
  • Mediates B-cell receptor (BCR) signaling → required for pre-B to mature B-cell transition in bone marrow.
  • Mutation effect:
  • Arrests B-cell development at pre-B stage → no mature B cells in circulation.
  • As a result → absence of all immunoglobulin classes (IgG, IgA, IgM, IgE, IgD).

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