X-linked Agammaglobulinemia

Mendelian MONDO:0010421 Pathograph 6 Show in embeddings browser Primary Immunodeficiency Antibody Deficiency Disorder X-linked disease

X-linked agammaglobulinemia (XLA), or Bruton agammaglobulinemia, is a prototypical primary antibody-deficiency disorder caused by loss-of-function variants in BTK, the gene encoding Bruton tyrosine kinase. BTK is a cytoplasmic (Tec-family) tyrosine kinase that transduces pre-B-cell-receptor and B-cell-receptor signals required for B-lineage maturation. In affected males, defective BTK signaling arrests B-cell development at the pre-B stage in the bone marrow, producing a severe deficit of circulating B cells and plasma cells and profound panhypogammaglobulinemia (low IgG, IgA, and IgM). The resulting loss of humoral immunity causes recurrent encapsulated-bacterial sinopulmonary infections beginning in infancy and a characteristic susceptibility to disseminated enteroviral infection. Lifelong immunoglobulin replacement therapy is the cornerstone of management.

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1
Inheritance
4
Pathophys.
15
Phenotypes
6
Pathograph
1
Genes
3
Medical Actions
1
References
🏷

Classifications

Harrison's Chapter
IMMUNE_RHEUMATOLOGIC
IUIS Category
predominantly antibody deficiency
👪

Inheritance

1
X-linked inheritance HP:0001417
XLA is inherited as an X-linked recessive trait; BTK maps to the X chromosome and the disorder manifests in hemizygous males.
X-linked inheritance
Show evidence (1 reference)
PMID:16862044 SUPPORT Human Clinical
"X-linked agammaglobulinemia (XLA) is a primary immunodeficiency caused by mutations in the gene for Bruton tyrosine kinase (BTK) that result in the deficient development of B lymphocytes and hypogammaglobulinemia."
The US registry describes XLA as an X-linked primary immunodeficiency caused by BTK mutations.
⚙

Pathophysiology

4
BTK Loss of Function Impairs B-Cell Receptor Signaling
BTK (Bruton tyrosine kinase) is a cytoplasmic tyrosine kinase expressed throughout the B lineage that transduces signals from the pre-B-cell and mature B-cell receptors. Loss-of-function BTK variants reduce or abolish kinase expression and activity, disabling the signaling pathways required for B-cell expansion and maturation.
Precursor B cell CL:0000817 B cell CL:0000236
B Cell Receptor Signaling GO:0050853
Downstream
Arrest of B-Cell Development at the Pre-B Stage Defective BTK signaling blocks progression of B-lineage precursors, arresting development at the pre-B stage.
Show evidence (2 references)
PMID:8425221 SUPPORT Human Clinical
"Reduction in or the absence of BPK mRNA, protein expression, and kinase activity was observed in XLA pre-B and B cell lines."
The landmark study identifying BTK (then BPK) in XLA shows that XLA pre-B and B cells have reduced or absent kinase expression and activity.
PMID:8332901 SUPPORT Model Organism
"Loss of kinase activity results in the human immunodeficiency, X-linked agammaglobulinemia, characterized by a failure to produce B cells."
The murine Xid model links BTK kinase function to B-cell development and confirms that loss of kinase activity underlies XLA.
Arrest of B-Cell Development at the Pre-B Stage
The central lesion of XLA is failure of pre-B cells in the bone marrow to develop into circulating mature B cells. This developmental block produces a severe deficit of peripheral B cells.
Precursor B cell CL:0000817 B cell CL:0000236
B Cell Differentiation GO:0030183
Downstream
Decreased Total B Cell Count The pre-B developmental block leaves very few mature B cells in the circulation.
Panhypogammaglobulinemia from Absent Plasma Cells Absence of mature B cells and plasma cells prevents immunoglobulin production, producing panhypogammaglobulinemia.
Show evidence (1 reference)
PMID:8380905 SUPPORT Human Clinical
"failure of pre-B cells in the bone marrow to develop into circulating mature B cells"
The gene-identification study defines XLA as a failure of pre-B cells to develop into circulating mature B cells.
Panhypogammaglobulinemia from Absent Plasma Cells
Without mature B cells to differentiate into antibody-secreting plasma cells, immunoglobulin production fails across all isotypes, producing profound hypogammaglobulinemia (markedly reduced IgG, IgA, and IgM).
Plasma cell CL:0000786 B cell CL:0000236
Immunoglobulin Production GO:0002377
Downstream
Recurrent Infections Loss of protective antibody predisposes to recurrent infection with encapsulated bacteria.
Susceptibility to Disseminated Enteroviral Infection Loss of neutralizing antibody leaves XLA patients unable to control enteroviral infection, predisposing to severe disseminated enteroviral disease.
Show evidence (1 reference)
PMID:34241796 SUPPORT Human Clinical
"Interruptions or alterations in the B cell development pathway can lead to primary B cell immunodeficiency with resultant absence or diminished immunoglobulin production"
The review confirms that the B-cell developmental defect results in absent or diminished immunoglobulin production.
Susceptibility to Disseminated Enteroviral Infection
Beyond pyogenic bacterial infection, the absence of neutralizing antibody gives XLA patients a characteristic vulnerability to severe and disseminated enteroviral disease (including chronic meningoencephalitis), historically a leading cause of mortality.
Immunoglobulin Mediated Immune Response GO:0016064
Show evidence (2 references)
PMID:16862044 SUPPORT Human Clinical
"Causes of death included disseminated enterovirus infection (n = 6)"
Disseminated enteroviral infection was the leading cause of death in the XLA registry, reflecting loss of antibody-mediated neutralization.
PMID:20301626 SUPPORT Human Clinical
"Severe, difficult-to-treat enteroviral infections (often manifesting as dermatomyositis or chronic meningoencephalitis) can be prevented by this treatment."
The XLA GeneReviews confirms the characteristic susceptibility to severe enteroviral infection (dermatomyositis, chronic meningoencephalitis) that immunoglobulin replacement can prevent.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for X-linked Agammaglobulinemia Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

15
Blood 4
Panhypogammaglobulinemia VERY_FREQUENT Decreased circulating immunoglobulin concentration HP:0004313
Show evidence (1 reference)
PMID:8425221 SUPPORT Human Clinical
"an inherited immunodeficiency characterized by a severe deficit of B and plasma cells and profound hypogammaglobulinemia"
Profound hypogammaglobulinemia is a defining feature of XLA (VERY_FREQUENT).
Decreased Circulating IgG VERY_FREQUENT Decreased circulating IgG concentration HP:0004315
Decreased Circulating IgA VERY_FREQUENT Decreased circulating IgA concentration HP:0002720
Neutropenia OCCASIONAL Decreased total neutrophil count HP:0001875
Show evidence (1 reference)
PMID:16862044 SUPPORT Human Clinical
"followed by a positive family history (41%) and neutropenia (11%)"
Neutropenia was present at initial presentation in 11% of registry patients (OCCASIONAL band).
Cardiovascular 1
Conjunctivitis OCCASIONAL Conjunctivitis HP:0000509
Show evidence (2 references)
PMID:16862044 SUPPORT Human Clinical
"21% at least 1 episode of conjunctivitis"
21% of registry patients had at least one episode of conjunctivitis (OCCASIONAL band).
PMID:20301626 SUPPORT Human Clinical
"Conjunctivitis, sinopulmonary infections, diarrhea, and skin infections are also frequently seen."
The XLA GeneReviews lists conjunctivitis among the infections frequently seen in XLA.
Digestive 1
Chronic Diarrhea OCCASIONAL Chronic diarrhea HP:0002028
Show evidence (1 reference)
PMID:16862044 SUPPORT Human Clinical
"23% at least 1 episode of chronic/recurrent diarrhea"
23% of registry patients had at least one episode of chronic/recurrent diarrhea (OCCASIONAL band).
Ear 1
Recurrent Otitis Media FREQUENT Recurrent otitis media HP:0000403
Show evidence (2 references)
PMID:16862044 SUPPORT Human Clinical
"Seventy percent of patients had at least 1 episode of otitis"
70% of registry patients had at least one episode of otitis (FREQUENT band).
PMID:20301626 SUPPORT Human Clinical
"Recurrent otitis is the most common infection prior to diagnosis."
The XLA GeneReviews identifies recurrent otitis as the most common infection prior to diagnosis.
Immune 4
Recurrent Infections VERY_FREQUENT Recurrent infections HP:0002719
Show evidence (1 reference)
PMID:16862044 SUPPORT Human Clinical
"Infection was the most common initial clinical presentation (85%), followed by a positive family history (41%) and neutropenia (11%)."
Infection was the initial presentation in 85% of registry patients, supporting recurrent infection as the cardinal feature (VERY_FREQUENT band).
Recurrent Pneumonia FREQUENT Recurrent pneumonia HP:0006532
Show evidence (1 reference)
PMID:16862044 SUPPORT Human Clinical
"62% at least 1 episode of pneumonia"
62% of registry patients had at least one episode of pneumonia (FREQUENT band).
Meningitis OCCASIONAL Meningitis HP:0001287
Show evidence (1 reference)
PMID:16862044 SUPPORT Human Clinical
"11% at least 1 episode of meningitis/encephalitis"
11% of registry patients had at least one episode of meningitis/encephalitis (OCCASIONAL band).
Sepsis OCCASIONAL Sepsis HP:0100806
Show evidence (1 reference)
PMID:16862044 SUPPORT Human Clinical
"10% at least 1 episode of sepsis"
10% of registry patients had at least one episode of sepsis (OCCASIONAL band).
Other 4
Decreased Total B Cell Count VERY_FREQUENT Decreased total B cell count HP:0010976
Show evidence (1 reference)
PMID:8425221 SUPPORT Human Clinical
"an inherited immunodeficiency characterized by a severe deficit of B and plasma cells and profound hypogammaglobulinemia"
The severe deficit of circulating B cells is a defining laboratory hallmark of XLA (VERY_FREQUENT).
Recurrent Sinusitis FREQUENT Recurrent sinusitis HP:0011108
Show evidence (1 reference)
PMID:16862044 SUPPORT Human Clinical
"60% at least 1 episode of sinusitis"
60% of registry patients had at least one episode of sinusitis (FREQUENT band).
Decreased Circulating IgM VERY_FREQUENT Decreased circulating total IgM HP:0002850
Pyoderma and Cellulitis OCCASIONAL Cellulitis HP:0100658
Show evidence (1 reference)
PMID:16862044 SUPPORT Human Clinical
"18% at least 1 episode of pyoderma and/or cellulitis"
18% of registry patients had at least one episode of pyoderma and/or cellulitis (OCCASIONAL band).
🧬

Genetic Associations

1
BTK (Causative)
Gene: BTK hgnc:1133
Show evidence (3 references)
PMID:8380905 SUPPORT Human Clinical
"A novel gene has been isolated which maps to the XLA locus, is expressed in B cells, and shows mutations in families with the disorder."
The gene-identification study mapped BTK to the XLA locus and found disease-segregating mutations in affected families.
PMID:8425221 SUPPORT Human Clinical
"BPK is likely the XLA gene and functions in pathways critical to B cell expansion."
The companion study independently identified BTK (BPK) as the XLA gene.
PMID:16862044 SUPPORT Human Clinical
"X-linked agammaglobulinemia (XLA) is a primary immunodeficiency caused by mutations in the gene for Bruton tyrosine kinase (BTK) that result in the deficient development of B lymphocytes and hypogammaglobulinemia."
The US registry confirms BTK mutations as the cause of XLA.
💊

Medical Actions

3
Immunoglobulin Replacement Therapy
Action: immunoglobulin replacement therapy Ontology label: Pharmacotherapy NCIT:C15986
Lifelong intravenous (IVIG) or subcutaneous (SCIG) immunoglobulin replacement is the cornerstone of XLA management, replacing the missing antibody and reducing the frequency and severity of infections.
Show evidence (2 references)
PMID:37454339 SUPPORT Human Clinical
"XLA patients require lifelong immunoglobulin replacement therapy (IgRT)."
Confirms lifelong immunoglobulin replacement therapy as the standard of care for XLA.
PMID:20301626 SUPPORT Human Clinical
"The mainstay of treatment is gammaglobulin substitution therapy"
The XLA GeneReviews states that gammaglobulin substitution therapy is the mainstay of treatment.
Antibiotic Therapy and Prophylaxis
Action: antibiotic therapy Ontology label: Antibiotic Therapy NCIT:C15620
Therapeutic and prophylactic antibiotics are used to treat and prevent the recurrent bacterial sinopulmonary infections that characterize XLA.
Allogeneic Hematopoietic Cell Transplantation
Action: hematopoietic cell transplantation Ontology label: Hematopoietic Cell Transplantation NCIT:C15431
Allogeneic hematopoietic cell transplantation is a potentially curative option reserved for selected XLA patients with severe complications such as recurrent or life-threatening infection or malignancy.
Show evidence (1 reference)
PMID:37454339 SUPPORT Human Clinical
"Only few XLA patients are indicated for allogeneic hematopoietic cell transplantation (HCT) because of severe complications."
Allogeneic HCT is reserved for selected XLA patients with severe complications.
{ }

Source YAML

click to show 
name: X-linked Agammaglobulinemia
creation_date: "2026-06-30T00:00:00Z"
category: Mendelian
synonyms:
- XLA
- Bruton agammaglobulinemia
- Bruton-type agammaglobulinemia
- BTK deficiency
- Agammaglobulinemia, X-linked
description: >-
  X-linked agammaglobulinemia (XLA), or Bruton agammaglobulinemia, is a
  prototypical primary antibody-deficiency disorder caused by loss-of-function
  variants in BTK, the gene encoding Bruton tyrosine kinase. BTK is a
  cytoplasmic (Tec-family) tyrosine kinase that transduces pre-B-cell-receptor
  and B-cell-receptor signals required for B-lineage maturation. In affected
  males, defective BTK signaling arrests B-cell development at the pre-B stage
  in the bone marrow, producing a severe deficit of circulating B cells and
  plasma cells and profound panhypogammaglobulinemia (low IgG, IgA, and IgM).
  The resulting loss of humoral immunity causes recurrent encapsulated-bacterial
  sinopulmonary infections beginning in infancy and a characteristic
  susceptibility to disseminated enteroviral infection. Lifelong immunoglobulin
  replacement therapy is the cornerstone of management.
disease_term:
  preferred_term: X-linked Agammaglobulinemia
  term:
    id: MONDO:0010421
    label: Bruton-type agammaglobulinemia
parents:
- Primary Immunodeficiency
- Antibody Deficiency Disorder
- X-linked disease
inheritance:
- name: X-linked inheritance
  description: >-
    XLA is inherited as an X-linked recessive trait; BTK maps to the X
    chromosome and the disorder manifests in hemizygous males.
  inheritance_term:
    preferred_term: X-linked inheritance
    term:
      id: HP:0001417
      label: X-linked inheritance
  evidence:
  - reference: PMID:16862044
    reference_title: "X-linked agammaglobulinemia: report on a United States registry of 201 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      X-linked agammaglobulinemia (XLA) is a primary immunodeficiency caused by
      mutations in the gene for Bruton tyrosine kinase (BTK) that result in the
      deficient development of B lymphocytes and hypogammaglobulinemia.
    explanation: >-
      The US registry describes XLA as an X-linked primary immunodeficiency
      caused by BTK mutations.
classifications:
  harrisons_chapter:
  - classification_value: IMMUNE_RHEUMATOLOGIC
    evidence:
    - reference: PMID:16862044
      reference_title: "X-linked agammaglobulinemia: report on a United States registry of 201 patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        X-linked agammaglobulinemia (XLA) is a primary immunodeficiency caused by
        mutations in the gene for Bruton tyrosine kinase (BTK) that result in the
        deficient development of B lymphocytes and hypogammaglobulinemia.
      explanation: >-
        XLA is a primary immunodeficiency, supporting placement in Harrison's
        immune/rheumatologic Part.
  iuis_category:
    classification_value: predominantly antibody deficiency
    evidence:
    - reference: PMID:16862044
      reference_title: "X-linked agammaglobulinemia: report on a United States registry of 201 patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        X-linked agammaglobulinemia (XLA) is a primary immunodeficiency caused by
        mutations in the gene for Bruton tyrosine kinase (BTK) that result in the
        deficient development of B lymphocytes and hypogammaglobulinemia.
      explanation: >-
        Deficient B-lymphocyte development with hypogammaglobulinemia places XLA
        in IUIS Table 3, predominantly antibody deficiencies (which explicitly
        lists XLA).
pathophysiology:
- name: BTK Loss of Function Impairs B-Cell Receptor Signaling
  description: >-
    BTK (Bruton tyrosine kinase) is a cytoplasmic tyrosine kinase expressed
    throughout the B lineage that transduces signals from the pre-B-cell and
    mature B-cell receptors. Loss-of-function BTK variants reduce or abolish
    kinase expression and activity, disabling the signaling pathways required
    for B-cell expansion and maturation.
  cell_types:
  - preferred_term: Precursor B cell
    term:
      id: CL:0000817
      label: precursor B cell
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  biological_processes:
  - preferred_term: B Cell Receptor Signaling
    term:
      id: GO:0050853
      label: B cell receptor signaling pathway
  evidence:
  - reference: PMID:8425221
    reference_title: "Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Reduction in or the absence of BPK mRNA, protein expression, and kinase
      activity was observed in XLA pre-B and B cell lines.
    explanation: >-
      The landmark study identifying BTK (then BPK) in XLA shows that XLA
      pre-B and B cells have reduced or absent kinase expression and activity.
  - reference: PMID:8332901
    reference_title: "Mutation of unique region of Bruton's tyrosine kinase in immunodeficient XID mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Loss of kinase activity results in the human immunodeficiency, X-linked
      agammaglobulinemia, characterized by a failure to produce B cells.
    explanation: >-
      The murine Xid model links BTK kinase function to B-cell development and
      confirms that loss of kinase activity underlies XLA.
  downstream:
  - target: Arrest of B-Cell Development at the Pre-B Stage
    causal_link_type: DIRECT
    description: >-
      Defective BTK signaling blocks progression of B-lineage precursors,
      arresting development at the pre-B stage.
    evidence:
    - reference: PMID:8425221
      reference_title: "Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        BPK is likely the XLA gene and functions in pathways critical to B cell
        expansion.
      explanation: >-
        BTK function is critical to B-cell expansion, so its loss arrests
        B-cell development.
- name: Arrest of B-Cell Development at the Pre-B Stage
  description: >-
    The central lesion of XLA is failure of pre-B cells in the bone marrow to
    develop into circulating mature B cells. This developmental block produces
    a severe deficit of peripheral B cells.
  cell_types:
  - preferred_term: Precursor B cell
    term:
      id: CL:0000817
      label: precursor B cell
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  biological_processes:
  - preferred_term: B Cell Differentiation
    term:
      id: GO:0030183
      label: B cell differentiation
  evidence:
  - reference: PMID:8380905
    reference_title: "The gene involved in X-linked agammaglobulinaemia is a member of the src family of protein-tyrosine kinases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      failure of pre-B cells in the bone marrow to develop into circulating
      mature B cells
    explanation: >-
      The gene-identification study defines XLA as a failure of pre-B cells to
      develop into circulating mature B cells.
  downstream:
  - target: Decreased Total B Cell Count
    causal_link_type: DIRECT
    description: >-
      The pre-B developmental block leaves very few mature B cells in the
      circulation.
    evidence:
    - reference: PMID:8425221
      reference_title: "Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        an inherited immunodeficiency characterized by a severe deficit of B
        and plasma cells and profound hypogammaglobulinemia
      explanation: >-
        XLA is characterized by a severe deficit of B cells, reflecting the
        developmental arrest.
  - target: Panhypogammaglobulinemia from Absent Plasma Cells
    causal_link_type: DIRECT
    description: >-
      Absence of mature B cells and plasma cells prevents immunoglobulin
      production, producing panhypogammaglobulinemia.
    evidence:
    - reference: PMID:8425221
      reference_title: "Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        an inherited immunodeficiency characterized by a severe deficit of B
        and plasma cells and profound hypogammaglobulinemia
      explanation: >-
        The severe deficit of B and plasma cells directly produces profound
        hypogammaglobulinemia.
- name: Panhypogammaglobulinemia from Absent Plasma Cells
  description: >-
    Without mature B cells to differentiate into antibody-secreting plasma
    cells, immunoglobulin production fails across all isotypes, producing
    profound hypogammaglobulinemia (markedly reduced IgG, IgA, and IgM).
  cell_types:
  - preferred_term: Plasma cell
    term:
      id: CL:0000786
      label: plasma cell
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  biological_processes:
  - preferred_term: Immunoglobulin Production
    term:
      id: GO:0002377
      label: immunoglobulin production
  evidence:
  - reference: PMID:34241796
    reference_title: "Agammaglobulinemia: from X-linked to Autosomal Forms of Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Interruptions or alterations in the B cell development pathway can lead to
      primary B cell immunodeficiency with resultant absence or diminished
      immunoglobulin production
    explanation: >-
      The review confirms that the B-cell developmental defect results in
      absent or diminished immunoglobulin production.
  downstream:
  - target: Recurrent Infections
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Absent antibody removes humoral protection against encapsulated bacteria.
    description: >-
      Loss of protective antibody predisposes to recurrent infection with
      encapsulated bacteria.
    evidence:
    - reference: PMID:16862044
      reference_title: "X-linked agammaglobulinemia: report on a United States registry of 201 patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Infection was the most common initial clinical presentation (85%),
        followed by a positive family history (41%) and neutropenia (11%).
      explanation: >-
        Infection is the most common presenting feature of XLA, reflecting the
        loss of humoral immunity.
  - target: Susceptibility to Disseminated Enteroviral Infection
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Absent neutralizing antibody removes humoral control of enteroviruses.
    description: >-
      Loss of neutralizing antibody leaves XLA patients unable to control
      enteroviral infection, predisposing to severe disseminated enteroviral
      disease.
    evidence:
    - reference: PMID:16862044
      reference_title: "X-linked agammaglobulinemia: report on a United States registry of 201 patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Causes of death included disseminated enterovirus infection (n = 6)
      explanation: >-
        Disseminated enteroviral infection was a leading cause of death in the
        XLA registry, reflecting loss of antibody-mediated neutralization that
        follows panhypogammaglobulinemia.
- name: Susceptibility to Disseminated Enteroviral Infection
  description: >-
    Beyond pyogenic bacterial infection, the absence of neutralizing antibody
    gives XLA patients a characteristic vulnerability to severe and
    disseminated enteroviral disease (including chronic meningoencephalitis),
    historically a leading cause of mortality.
  biological_processes:
  - preferred_term: Immunoglobulin Mediated Immune Response
    term:
      id: GO:0016064
      label: immunoglobulin mediated immune response
  evidence:
  - reference: PMID:16862044
    reference_title: "X-linked agammaglobulinemia: report on a United States registry of 201 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Causes of death included disseminated enterovirus infection (n = 6)
    explanation: >-
      Disseminated enteroviral infection was the leading cause of death in the
      XLA registry, reflecting loss of antibody-mediated neutralization.
  - reference: PMID:20301626
    reference_title: "X-Linked Agammaglobulinemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Severe, difficult-to-treat enteroviral infections (often manifesting as
      dermatomyositis or chronic meningoencephalitis) can be prevented by this
      treatment.
    explanation: >-
      The XLA GeneReviews confirms the characteristic susceptibility to severe
      enteroviral infection (dermatomyositis, chronic meningoencephalitis) that
      immunoglobulin replacement can prevent.
phenotypes:
- name: Recurrent Infections
  category: Immunologic
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Recurrent Infections
    term:
      id: HP:0002719
      label: Recurrent infections
  evidence:
  - reference: PMID:16862044
    reference_title: "X-linked agammaglobulinemia: report on a United States registry of 201 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Infection was the most common initial clinical presentation (85%),
      followed by a positive family history (41%) and neutropenia (11%).
    explanation: >-
      Infection was the initial presentation in 85% of registry patients,
      supporting recurrent infection as the cardinal feature (VERY_FREQUENT band).
- name: Panhypogammaglobulinemia
  category: Immunologic
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Panhypogammaglobulinemia
    term:
      id: HP:0004313
      label: Decreased circulating immunoglobulin concentration
  evidence:
  - reference: PMID:8425221
    reference_title: "Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      an inherited immunodeficiency characterized by a severe deficit of B and
      plasma cells and profound hypogammaglobulinemia
    explanation: >-
      Profound hypogammaglobulinemia is a defining feature of XLA (VERY_FREQUENT).
- name: Decreased Circulating IgG
  category: Immunologic
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Decreased Circulating IgG
    term:
      id: HP:0004315
      label: Decreased circulating IgG concentration
- name: Decreased Circulating IgA
  category: Immunologic
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Decreased Circulating IgA
    term:
      id: HP:0002720
      label: Decreased circulating IgA concentration
- name: Decreased Total B Cell Count
  category: Immunologic
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Decreased Total B Cell Count
    term:
      id: HP:0010976
      label: Decreased total B cell count
  evidence:
  - reference: PMID:8425221
    reference_title: "Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      an inherited immunodeficiency characterized by a severe deficit of B and
      plasma cells and profound hypogammaglobulinemia
    explanation: >-
      The severe deficit of circulating B cells is a defining laboratory
      hallmark of XLA (VERY_FREQUENT).
- name: Recurrent Otitis Media
  category: Otolaryngologic
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Recurrent Otitis Media
    term:
      id: HP:0000403
      label: Recurrent otitis media
  evidence:
  - reference: PMID:16862044
    reference_title: "X-linked agammaglobulinemia: report on a United States registry of 201 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Seventy percent of patients had at least 1 episode of otitis
    explanation: >-
      70% of registry patients had at least one episode of otitis (FREQUENT band).
  - reference: PMID:20301626
    reference_title: "X-Linked Agammaglobulinemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Recurrent otitis is the most common infection prior to diagnosis.
    explanation: >-
      The XLA GeneReviews identifies recurrent otitis as the most common
      infection prior to diagnosis.
- name: Recurrent Pneumonia
  category: Respiratory
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Recurrent Pneumonia
    term:
      id: HP:0006532
      label: Recurrent pneumonia
  evidence:
  - reference: PMID:16862044
    reference_title: "X-linked agammaglobulinemia: report on a United States registry of 201 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      62% at least 1 episode of pneumonia
    explanation: >-
      62% of registry patients had at least one episode of pneumonia (FREQUENT band).
- name: Recurrent Sinusitis
  category: Otolaryngologic
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Recurrent Sinusitis
    term:
      id: HP:0011108
      label: Recurrent sinusitis
  evidence:
  - reference: PMID:16862044
    reference_title: "X-linked agammaglobulinemia: report on a United States registry of 201 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      60% at least 1 episode of sinusitis
    explanation: >-
      60% of registry patients had at least one episode of sinusitis (FREQUENT band).
- name: Chronic Diarrhea
  category: Gastrointestinal
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Chronic Diarrhea
    term:
      id: HP:0002028
      label: Chronic diarrhea
  evidence:
  - reference: PMID:16862044
    reference_title: "X-linked agammaglobulinemia: report on a United States registry of 201 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      23% at least 1 episode of chronic/recurrent diarrhea
    explanation: >-
      23% of registry patients had at least one episode of chronic/recurrent
      diarrhea (OCCASIONAL band).
- name: Meningitis
  category: Neurologic
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Meningitis
    term:
      id: HP:0001287
      label: Meningitis
  evidence:
  - reference: PMID:16862044
    reference_title: "X-linked agammaglobulinemia: report on a United States registry of 201 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      11% at least 1 episode of meningitis/encephalitis
    explanation: >-
      11% of registry patients had at least one episode of
      meningitis/encephalitis (OCCASIONAL band).
- name: Sepsis
  category: Immunologic
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Sepsis
    term:
      id: HP:0100806
      label: Sepsis
  evidence:
  - reference: PMID:16862044
    reference_title: "X-linked agammaglobulinemia: report on a United States registry of 201 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      10% at least 1 episode of sepsis
    explanation: >-
      10% of registry patients had at least one episode of sepsis (OCCASIONAL band).
- name: Neutropenia
  category: Hematologic
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Neutropenia
    term:
      id: HP:0001875
      label: Decreased total neutrophil count
  evidence:
  - reference: PMID:16862044
    reference_title: "X-linked agammaglobulinemia: report on a United States registry of 201 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      followed by a positive family history (41%) and neutropenia (11%)
    explanation: >-
      Neutropenia was present at initial presentation in 11% of registry
      patients (OCCASIONAL band).
- name: Decreased Circulating IgM
  category: Immunologic
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Decreased Circulating IgM
    term:
      id: HP:0002850
      label: Decreased circulating total IgM
- name: Conjunctivitis
  category: Ophthalmologic
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Conjunctivitis
    term:
      id: HP:0000509
      label: Conjunctivitis
  evidence:
  - reference: PMID:16862044
    reference_title: "X-linked agammaglobulinemia: report on a United States registry of 201 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      21% at least 1 episode of conjunctivitis
    explanation: >-
      21% of registry patients had at least one episode of conjunctivitis
      (OCCASIONAL band).
  - reference: PMID:20301626
    reference_title: "X-Linked Agammaglobulinemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Conjunctivitis, sinopulmonary infections, diarrhea, and skin infections
      are also frequently seen.
    explanation: >-
      The XLA GeneReviews lists conjunctivitis among the infections frequently
      seen in XLA.
- name: Pyoderma and Cellulitis
  category: Dermatologic
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Pyoderma and cellulitis
    term:
      id: HP:0100658
      label: Cellulitis
  evidence:
  - reference: PMID:16862044
    reference_title: "X-linked agammaglobulinemia: report on a United States registry of 201 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      18% at least 1 episode of pyoderma and/or cellulitis
    explanation: >-
      18% of registry patients had at least one episode of pyoderma and/or
      cellulitis (OCCASIONAL band).
genetic:
- name: BTK
  gene_term:
    preferred_term: BTK
    term:
      id: hgnc:1133
      label: BTK
  association: Causative
  evidence:
  - reference: PMID:8380905
    reference_title: "The gene involved in X-linked agammaglobulinaemia is a member of the src family of protein-tyrosine kinases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A novel gene has been isolated which maps to the XLA locus, is expressed
      in B cells, and shows mutations in families with the disorder.
    explanation: >-
      The gene-identification study mapped BTK to the XLA locus and found
      disease-segregating mutations in affected families.
  - reference: PMID:8425221
    reference_title: "Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      BPK is likely the XLA gene and functions in pathways critical to B cell
      expansion.
    explanation: >-
      The companion study independently identified BTK (BPK) as the XLA gene.
  - reference: PMID:16862044
    reference_title: "X-linked agammaglobulinemia: report on a United States registry of 201 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      X-linked agammaglobulinemia (XLA) is a primary immunodeficiency caused by
      mutations in the gene for Bruton tyrosine kinase (BTK) that result in the
      deficient development of B lymphocytes and hypogammaglobulinemia.
    explanation: >-
      The US registry confirms BTK mutations as the cause of XLA.
treatments:
- name: Immunoglobulin Replacement Therapy
  description: >-
    Lifelong intravenous (IVIG) or subcutaneous (SCIG) immunoglobulin
    replacement is the cornerstone of XLA management, replacing the missing
    antibody and reducing the frequency and severity of infections.
  treatment_term:
    preferred_term: immunoglobulin replacement therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:37454339
    reference_title: "An International Survey of Allogeneic Hematopoietic Cell Transplantation for X-Linked Agammaglobulinemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      XLA patients require lifelong immunoglobulin replacement therapy (IgRT).
    explanation: >-
      Confirms lifelong immunoglobulin replacement therapy as the standard of
      care for XLA.
  - reference: PMID:20301626
    reference_title: "X-Linked Agammaglobulinemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The mainstay of treatment is gammaglobulin substitution therapy
    explanation: >-
      The XLA GeneReviews states that gammaglobulin substitution therapy is the
      mainstay of treatment.
- name: Antibiotic Therapy and Prophylaxis
  description: >-
    Therapeutic and prophylactic antibiotics are used to treat and prevent the
    recurrent bacterial sinopulmonary infections that characterize XLA.
  treatment_term:
    preferred_term: antibiotic therapy
    term:
      id: NCIT:C15620
      label: Antibiotic Therapy
- name: Allogeneic Hematopoietic Cell Transplantation
  description: >-
    Allogeneic hematopoietic cell transplantation is a potentially curative
    option reserved for selected XLA patients with severe complications such as
    recurrent or life-threatening infection or malignancy.
  treatment_term:
    preferred_term: hematopoietic cell transplantation
    term:
      id: NCIT:C15431
      label: Hematopoietic Cell Transplantation
  evidence:
  - reference: PMID:37454339
    reference_title: "An International Survey of Allogeneic Hematopoietic Cell Transplantation for X-Linked Agammaglobulinemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Only few XLA patients are indicated for allogeneic hematopoietic cell
      transplantation (HCT) because of severe complications.
    explanation: >-
      Allogeneic HCT is reserved for selected XLA patients with severe
      complications.
references:
- reference: PMID:20301626
  title: "X-Linked Agammaglobulinemia."
  tags:
  - GeneReviews
  findings: []
📚

References & Deep Research

References

1
PMID:20301626
X-Linked Agammaglobulinemia.
No top-level findings curated for this source.