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 B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells, leading to a lack of mature B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. 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 Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations is a complete or near-complete lack of all antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins. Presentation includes recurrent bacterial infections after the first few months of life. Management consists of IV immunoglobulins Immunoglobulins Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. 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 Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in the Bruton’s tyrosine kinase (Btk) gene (this mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations inhibits B cell maturation into pre- B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. 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 B lymphocytes B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells.
  • Mature B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. 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 Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview.
X-linked agammaglobulinemia

The absence or defect of the Btk enzyme inhibits the normal development of pro- B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells into pre- B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. 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 Placenta The placenta consists of a fetal side and a maternal side, and it provides a vascular communication between the mother and the fetus. This communication allows the mother to provide nutrients to the fetus and allows for removal of waste products from fetal blood. Placenta, Umbilical Cord, and Amniotic Cavity falls.
  • Presents as recurrent infections such as:
    • Pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia
    • Otitis media
    • Cellulitis Cellulitis Cellulitis is a common infection caused by bacteria that affects the dermis and subcutaneous tissue of the skin. It is frequently caused by Staphylococcus aureus and Streptococcus pyogenes. The skin infection presents as an erythematous and edematous area with warmth and tenderness. Cellulitis
    • Conjunctivitis Conjunctivitis Conjunctivitis is a common inflammation of the bulbar and/or palpebral conjunctiva. It can be classified into infectious (mostly viral) and noninfectious conjunctivitis, which includes allergic causes. Patients commonly present with red eyes, increased tearing, burning, foreign body sensation, and photophobia. Conjunctivitis
    • Pharyngitis Pharyngitis Pharyngitis is an inflammation of the back of the throat (pharynx). Pharyngitis is usually caused by an upper respiratory tract infection, which is viral in most cases. It typically results in a sore throat and fever. Other symptoms may include a runny nose, cough, headache, and hoarseness. Pharyngitis
    • Bronchitis
    • Sinusitis Sinusitis Sinusitis refers to inflammation of the mucosal lining of the paranasal sinuses. The condition usually occurs concurrently with inflammation of the nasal mucosa (rhinitis), a condition known as rhinosinusitis. Acute sinusitis is due to an upper respiratory infection caused by a viral, bacterial, or fungal agent. Sinusitis
  • Patients are at especially increased risk for recurrent infections by:
    • Encapsulated bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview, such as Streptococcus Streptococcus Streptococcus is one of the two medically important genera of gram-positive cocci, the other being Staphylococcus. Streptococci are identified as different species on blood agar on the basis of their hemolytic pattern and sensitivity to optochin and bacitracin. There are many pathogenic species of streptococci, including S. pyogenes, S. agalactiae, S. pneumoniae, and the viridans streptococci. Streptococcus pneumoniae, Haemophilus Haemophilus Haemophilus is a genus of Gram-negative coccobacilli, all of whose strains require at least 1 of 2 factors for growth (factor V [NAD] and factor X [heme]); therefore, it is most often isolated on chocolate agar, which can supply both factors. The pathogenic species are H. influenzae and H. ducreyi. Haemophilus influenzae, and Mycoplasma Mycoplasma Mycoplasma is a species of pleomorphic bacteria that lack a cell wall, which makes them difficult to target with conventional antibiotics and causes them to not gram stain well. Mycoplasma bacteria commonly target the respiratory and urogenital epithelium. Mycoplasma pneumoniae (M. pneumoniae), the causative agent of atypical or "walking" pneumonia. Mycoplasma pneumoniae
    • Viruses, such as hepatitis viruses and enterovirus
    • Parasitic infections, such as Giardia lamblia Giardia lamblia Giardiasis is caused by Giardia lamblia (G. lamblia), a flagellated protozoan that can infect the intestinal tract. Giardia transmission occurs most commonly through consumption of cysts in contaminated water or through the fecal-oral route. Excystation occurs in the gastrointestinal (GI) tract, and trophozoites attach to the intestinal wall villi and cause malabsorption. Giardia/Giardiasis
  • 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 B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. 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 T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells
  • Genetic testing is used to confirm the diagnosis and identify the specific Btk mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations.

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 Vaccine A vaccine is usually an antigenic, non-virulent form of a normally virulent microorganism. Vaccinations are a form of primary prevention and are the most effective form due to their safety, efficacy, low cost, and easy access. Vaccination-related polio)

Differential Diagnosis

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

  • Autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritanceor dominant agammaglobulinemia: a rare form of primary immunodeficiency disease characterized by a complete or near-complete absence of immunoglobulins Immunoglobulins Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins, which leads to variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables immune dysfunction and frequent/recurrent bacterial infections. Molecular genetic testing is required to determine the causative genetic defect.
  • Common variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables immunodeficiency (CVID): a type of primary immunodeficiency characterized by reduced serum levels of immunoglobulins Immunoglobulins Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. 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 Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in the CD40 ligand gene that results in abnormal signaling between B and T lymphocytes T lymphocytes T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells. Presentation is mild and often only presents in later life as opportunistic infections and immune dysregulation of IgE eosinophils, B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells, NK cells, and CD8+ T cell proliferation and activation.
  • Severe combined immunodeficiency Severe Combined Immunodeficiency Severe combined immunodeficiency (SCID), also called "bubble boy disease," is a rare genetic disorder in which the development of functional B and T cells is disturbed due to several genetic mutations that result in reduced or absent immune function. 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 B lymphocytes B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells 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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