X-linked Agammaglobulinemia

Mendelian MONDO:0010421 Pathograph 8 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.
18
Phenotypes
8
Pathograph
1
Genes
4
Medical Actions
3
Differentials
1
References
🏷

Classifications

Harrison's Part
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 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Precursor B cell (CL:0000817). CL:0000817 is a cell type from the Cell Ontology. B cell CL:0000236 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves B cell (CL:0000236). CL:0000236 is a cell type from the Cell Ontology.
B Cell Receptor Signaling GO:0050853 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves B Cell Receptor Signaling, annotated with B cell receptor signaling pathway (GO:0050853). GO:0050853 is a biological process from the Gene Ontology.
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 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Precursor B cell (CL:0000817). CL:0000817 is a cell type from the Cell Ontology. B cell CL:0000236 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves B cell (CL:0000236). CL:0000236 is a cell type from the Cell Ontology.
B Cell Differentiation GO:0030183 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves B Cell Differentiation (GO:0030183). GO:0030183 is a biological process from the Gene Ontology.
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 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Plasma cell (CL:0000786). CL:0000786 is a cell type from the Cell Ontology. B cell CL:0000236 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves B cell (CL:0000236). CL:0000236 is a cell type from the Cell Ontology.
Immunoglobulin Production GO:0002377 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Immunoglobulin Production (GO:0002377). GO:0002377 is a biological process from the Gene Ontology. Humoral Immune Response GO:0006959 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Humoral Immune Response (GO:0006959). GO:0006959 is a biological process from the Gene Ontology.
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 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves Immunoglobulin Mediated Immune Response (GO:0016064). GO:0016064 is a biological process from the Gene Ontology.
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.
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Phenotypes

18
Blood 6
Panhypogammaglobulinemia VERY_FREQUENT Decreased circulating immunoglobulin concentration HP:0004313 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Panhypogammaglobulinemia, annotated with Decreased circulating immunoglobulin concentration (HP:0004313). HP:0004313 is a phenotype from the Human Phenotype Ontology.
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 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased Circulating IgG, annotated with Decreased circulating IgG concentration (HP:0004315). HP:0004315 is a phenotype from the Human Phenotype Ontology.
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 in XLA is panhypogammaglobulinemia affecting IgG, IgA, and IgM. The source establishes the global immunoglobulin deficit but does not report IgG levels separately, so this isotype-specific record is only partially supported.
Decreased Circulating IgA VERY_FREQUENT Decreased circulating IgA concentration HP:0002720 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased Circulating IgA, annotated with Decreased circulating IgA concentration (HP:0002720). HP:0002720 is a phenotype from the Human Phenotype Ontology.
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 in XLA is panhypogammaglobulinemia affecting IgG, IgA, and IgM. The source establishes the global immunoglobulin deficit but does not report IgA levels separately, so this isotype-specific record is only partially supported.
Decreased Total B Cell Count VERY_FREQUENT HP:0010976 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased Total B Cell Count (HP:0010976). HP:0010976 is a phenotype from the Human Phenotype Ontology.
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).
Neutropenia OCCASIONAL Decreased total neutrophil count HP:0001875 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Neutropenia, annotated with Decreased total neutrophil count (HP:0001875). HP:0001875 is a phenotype from the Human Phenotype Ontology.
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).
Decreased Circulating IgM VERY_FREQUENT Decreased circulating total IgM HP:0002850 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased Circulating IgM, annotated with Decreased circulating total IgM (HP:0002850). HP:0002850 is a phenotype from the Human Phenotype Ontology.
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 in XLA is panhypogammaglobulinemia affecting IgG, IgA, and IgM. The source establishes the global immunoglobulin deficit but does not report IgM levels separately, so this isotype-specific record is only partially supported.
Cardiovascular 1
Conjunctivitis OCCASIONAL HP:0000509 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Conjunctivitis (HP:0000509). HP:0000509 is a phenotype from the Human Phenotype Ontology.
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 2
Chronic Diarrhea OCCASIONAL HP:0002028 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Chronic Diarrhea (HP:0002028). HP:0002028 is a phenotype from the Human Phenotype Ontology.
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).
Hepatitis OCCASIONAL HP:0012115 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hepatitis (HP:0012115). HP:0012115 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:16862044 SUPPORT Human Clinical
"6% at least 1 episode of hepatitis"
6% of registry patients had at least one episode of hepatitis (OCCASIONAL band).
Ear 1
Recurrent Otitis Media FREQUENT HP:0000403 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent Otitis Media (HP:0000403). HP:0000403 is a phenotype from the Human Phenotype Ontology.
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.
Head and Neck 1
Recurrent Sinusitis FREQUENT HP:0011108 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent Sinusitis (HP:0011108). HP:0011108 is a phenotype from the Human Phenotype Ontology.
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).
Immune 5
Recurrent Infections VERY_FREQUENT HP:0002719 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent Infections (HP:0002719). HP:0002719 is a phenotype from the Human Phenotype Ontology.
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 HP:0006532 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent Pneumonia (HP:0006532). HP:0006532 is a phenotype from the Human Phenotype Ontology.
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 HP:0001287 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Meningitis (HP:0001287). HP:0001287 is a phenotype from the Human Phenotype Ontology.
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 HP:0100806 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sepsis (HP:0100806). HP:0100806 is a phenotype from the Human Phenotype Ontology.
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).
Osteomyelitis VERY_RARE HP:0002754 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Osteomyelitis (HP:0002754). HP:0002754 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:16862044 SUPPORT Human Clinical
"3% at least 1 episode of osteomyelitis"
3% of registry patients had at least one episode of osteomyelitis (VERY_RARE band, under 5%).
Musculoskeletal 2
Pyoderma and Cellulitis OCCASIONAL HP:0100658 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pyoderma and cellulitis, annotated with Cellulitis (HP:0100658). HP:0100658 is a phenotype from the Human Phenotype Ontology.
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).
Septic Arthritis OCCASIONAL HP:0003095 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Septic arthritis (HP:0003095). HP:0003095 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:16862044 SUPPORT Human Clinical
"8% at least 1 episode of septic arthritis"
8% of registry patients had at least one episode of septic arthritis (OCCASIONAL band).
PMID:20301626 SUPPORT Human Clinical
"they develop a severe, life-threatening infection such as pneumonia, empyema, meningitis, sepsis, cellulitis, or septic arthritis"
The XLA GeneReviews lists septic arthritis among the severe, life-threatening infections through which XLA is often first recognised.
🧬

Genetic Associations

1
BTK (Causative)
Gene: BTK hgnc:1133 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is BTK (hgnc:1133). hgnc:1133 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (5 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.
+ 2 more references
💊

Medical Actions

4
Immunoglobulin Replacement Therapy
Action: immunoglobulin replacement therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is immunoglobulin replacement therapy, annotated with Immunoglobulin Therapy (NCIT:C62710). NCIT:C62710 is a clinical intervention from the NCI Thesaurus. Ontology label: Immunoglobulin Therapy NCIT:C62710
Platform: Protein replacement
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. Per GeneReviews it is given by weekly subcutaneous injection or intravenous infusion every two to four weeks, and it prevents the severe enteroviral complications (dermatomyositis, chronic meningoencephalitis) of untreated disease.
Mechanism Target:
BYPASSES Panhypogammaglobulinemia from Absent Plasma Cells — Passive polyclonal IgG substitutes for the antibody the absent plasma-cell compartment cannot make; it bypasses rather than corrects the upstream B-cell developmental block.
Show evidence (3 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.
PMID:20301626 SUPPORT Human Clinical
"(by weekly subcutaneous injection or intravenous infusion every two to four weeks) to prevent bacterial infections"
GeneReviews specifies the dosing routes and intervals and the preventive goal of gammaglobulin substitution described here.
Antibiotic Therapy and Prophylaxis
Action: antibiotic therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is antibiotic therapy (NCIT:C15620). NCIT:C15620 is a clinical intervention from the NCI Thesaurus. Ontology label: Antibiotic Therapy NCIT:C15620
Platform: Small molecule
Therapeutic and prophylactic antibiotics are used to treat and prevent the recurrent bacterial sinopulmonary infections that characterize XLA; generous antibiotic use reduces the incidence of chronic sinusitis and chronic lung disease.
Show evidence (2 references)
PMID:20301626 SUPPORT Human Clinical
"Generous use of antibiotics can decrease the incidence of chronic sinusitis and lung disease."
GeneReviews supports generous therapeutic antibiotic use to prevent chronic sinus and lung disease in XLA.
PMID:20301626 SUPPORT Human Clinical
"Prophylactic antibiotics can be considered to prevent infections."
GeneReviews supports the prophylactic-antibiotic arm of this treatment.
Avoidance of Live Attenuated Vaccines (Agents to Avoid)
Action: Preventive InterventionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Preventive Intervention (NCIT:C15843). NCIT:C15843 is a clinical intervention from the NCI Thesaurus. NCIT:C15843
Platform: Behavioral / lifestyle
Live viral vaccines — above all oral poliovirus vaccine — are contraindicated because the replicating vaccine strain cannot be neutralised in the absence of antibody. Inactivated poliovirus vaccine should be substituted, for affected individuals and for their family contacts; non-live vaccines are otherwise recommended to prevent infection.
Show evidence (3 references)
PMID:20301626 SUPPORT Human Clinical
"Agents/circumstances to avoid: Live viral vaccines, particularly oral polio vaccine."
The GeneReviews Agents/Circumstances to Avoid recommendation for XLA.
PMID:20301626 SUPPORT Human Clinical
"Inactivated polio vaccine (as opposed to live oral polio vaccine) should be given to affected individuals and their family contacts."
Specifies substituting inactivated for oral poliovirus vaccine, including for household contacts.
PMID:20301626 SUPPORT Human Clinical
"Vaccines, apart from live vaccines, are recommended to prevent infection."
GeneReviews recommends non-live vaccines while excluding live vaccines.
Allogeneic Hematopoietic Cell Transplantation
Action: hematopoietic cell transplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is hematopoietic cell transplantation (NCIT:C15431). NCIT:C15431 is a clinical intervention from the NCI Thesaurus. Ontology label: Hematopoietic Cell Transplantation NCIT:C15431
Platform: Cell therapy
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. In the international survey of 22 transplanted XLA patients, 2-year overall survival was 86% and event-free survival 77%, and immunoglobulin replacement could be discontinued in 89% at one year; the authors advise performing HCT, when indicated, before organ damage develops.
Mechanism Target:
INHIBITS Arrest of B-Cell Development at the Pre-B Stage — Donor haematopoiesis supplies BTK-competent B-cell progenitors that can traverse the pre-B checkpoint, replacing the arrested host B lineage.
Show evidence (4 references)
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.
PMID:37454339 SUPPORT Human Clinical
"In all patients, 2-year overall survival (OS) and event-free survival (EFS) were 86% and 77%, respectively."
Quantifies the transplant outcome (2-year OS 86%, EFS 77%) across the 22 surveyed XLA transplants.
PMID:37454339 SUPPORT Human Clinical
"the 1-year discontinuation rate of IgRT was 89%"
Demonstrates that successful HCT allows most patients to stop immunoglobulin replacement within a year.
+ 1 more reference
🔬

Diagnosis

3
Quantitative serum immunoglobulins and B-cell flow cytometry
The characteristic laboratory findings are profound panhypogammaglobulinemia (IgG, IgA and IgM all severely reduced) with a severe deficit of circulating CD19+ B cells against normal T-cell numbers. These findings raise the diagnosis, which is then established molecularly.
diagnostic procedure NCIT:C18020 NCI Thesaurus (NCIT)
Markers: Serum IgG, IgA and IgM; CD19+ B cell percentage
Results: Profound panhypogammaglobulinemia with near-absent circulating B cells
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"
States the defining laboratory pattern this work-up demonstrates.
Molecular genetic testing for a BTK pathogenic variant
Identification of a hemizygous BTK pathogenic variant in a male proband with compatible clinical and laboratory findings establishes the diagnosis; a heterozygous BTK pathogenic variant can establish it in the extremely rare symptomatic female. Testing at-risk male relatives as soon after birth as possible allows immunoglobulin replacement to begin before infection and live vaccines to be avoided.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Results: Hemizygous BTK pathogenic variant identified
Show evidence (2 references)
PMID:20301626 SUPPORT Human Clinical
"The diagnosis of XLA is established in a male proband with characteristic clinical and laboratory findings and a hemizygous BTK pathogenic variant identified by molecular genetic testing."
The GeneReviews diagnostic criterion for XLA.
PMID:20301626 SUPPORT Human Clinical
"Molecular genetic testing of at-risk male relatives as soon after birth as possible ensures that gammaglobulin substitution therapy is initiated as soon as possible in affected individuals and administration of live viral vaccines can be avoided."
Supports newborn testing of at-risk male relatives as part of the diagnostic pathway.
Clinical recognition and diagnostic delay
Diagnosis is usually prompted by recurrent infection. In the US registry, a positive family history lowered the mean age at diagnosis from 5.37 to 2.59 years, yet only about a third of boys with a family history known at birth were diagnosed before symptoms — a persistent missed opportunity for pre-symptomatic diagnosis. Emerging screening measurements (KREC levels, serum BCMA) may allow earlier identification.
diagnostic procedure NCIT:C18020 NCI Thesaurus (NCIT)
Show evidence (4 references)
PMID:16862044 SUPPORT Human Clinical
"the average age of diagnosis was younger in patients with a positive family history (mean, 2.59 yr) than in patients with a negative family history (mean, 5.37 yr)"
Registry quantification of the effect of family history on age at diagnosis.
PMID:16862044 SUPPORT Human Clinical
"only 34.5% of patients with a positive family history at the time of their birth were diagnosed before clinical symptoms developed"
Quantifies the missed opportunity for pre-symptomatic diagnosis from family history alone.
PMID:34241796 SUPPORT Human Clinical
"The diagnosis of XLA is often delayed, and can be missed if patient has a mild phenotype."
Review confirmation that XLA diagnosis is often delayed, particularly with mild phenotypes.
+ 1 more reference
📈

Progression

2
Onset in infancy after maternal IgG wanes
Age: First two years of life
Recurrent bacterial infection begins in affected males in the first two years of life, once transplacental maternal IgG has been catabolised. About 60% of individuals are recognised only when a severe, life-threatening infection occurs.
Show evidence (2 references)
PMID:20301626 SUPPORT Human Clinical
"X-linked agammaglobulinemia (XLA) is characterized by recurrent bacterial infections in affected males in the first two years of life."
GeneReviews places disease onset in the first two years of life.
PMID:20301626 SUPPORT Human Clinical
"Approximately 60% of individuals with XLA are recognized as having immunodeficiency when they develop a severe, life-threatening infection"
Quantifies how often recognition awaits a severe infection.
Long-term course on immunoglobulin replacement
On adequate immunoglobulin replacement, severe enteroviral complications are largely prevented and prognosis has improved markedly over recent decades with earlier diagnosis, gammaglobulin preparations achieving normal serum IgG concentrations, and liberal antibiotic use. S pneumoniae and H influenzae may nonetheless continue to cause sinusitis and otitis after treatment is established.
Show evidence (2 references)
PMID:20301626 SUPPORT Human Clinical
"The prognosis for individuals with XLA has improved markedly in the last 25 years as a result of earlier diagnosis, the development of preparations of gammaglobulin that allow normal concentrations of serum immunoglobulin G to be achieved, and more liberal use of antibiotics."
GeneReviews statement of the markedly improved modern prognosis and its drivers.
PMID:20301626 SUPPORT Human Clinical
"S pneumoniae and H influenzae are the most common organisms found prior to diagnosis and may continue to cause sinusitis and otitis after diagnosis and the initiation of gammaglobulin substitution therapy."
Documents the residual sinopulmonary infection burden on treatment.
📊

Prevalence

1
United States (all live births, 1988-1997)
Birth Prevalence 0.26 per 100,000 1–9 per 1,000,000 (births)
The US XLA registry estimated a birth rate of 1/379,000 for 1988-1997, i.e. 0.26 per 100,000 live births. Note this denominator is ALL live births; because XLA manifests in hemizygous males, the male-specific birth prevalence is roughly twice this (on the order of 1/190,000 males). As a voluntary physician-reported registry it is a minimum estimate.
Show evidence (1 reference)
PMID:16862044 SUPPORT Human Clinical
"The estimated birth rate for the 10-year period of 1988-1997 was 1/379,000."
The US XLA registry provides the birth-rate estimate for XLA.
⚖️

Clinical Burden

High
Lifelong immunoglobulin replacement with ongoing infection surveillance is required, and the disorder retained measurable mortality in the modern US registry era: 6.9% of registered patients had died at entry, and 3.75% of prospectively followed living patients died during roughly four years of follow-up, with disseminated enterovirus infection and pulmonary insufficiency the leading causes of death. Prognosis is nonetheless much better than historically, given earlier diagnosis and adequate immunoglobulin dosing.
Show evidence (3 references)
PMID:16862044 SUPPORT Human Clinical
"Fourteen of 201 (6.9%) patients were dead at the time they were entered in the Registry."
Registry mortality at enrolment.
PMID:16862044 SUPPORT Human Clinical
"Causes of death included disseminated enterovirus infection (n = 6), pulmonary insufficiency (n = 5), adenovirus infection (n = 1), sepsis (n = 1)"
Enumerates the leading registry causes of death, dominated by disseminated enterovirus infection and pulmonary insufficiency.
PMID:20301626 SUPPORT Human Clinical
"The prognosis for individuals with XLA has improved markedly in the last 25 years"
Balances the burden assessment: mortality and morbidity have fallen substantially in the modern treatment era.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from X-linked Agammaglobulinemia:

Autosomal agammaglobulinemia MONDO:0011096
Overlapping Features The autosomal recessive and dominant forms of congenital agammaglobulinemia (IGHM, IGLL1, CD79A, CD79B, BLNK and other loci) reproduce the same pre-B developmental block, absent B cells and panhypogammaglobulinemia without involving BTK; they account for the roughly 15% of congenital agammaglobulinemia that is not XLA. Curated separately in dismech as Autosomal_Agammaglobulinemia.
Distinguishing Features
  • Affects females as well as males; consanguinity is common in the recessive forms
  • No BTK pathogenic variant; biallelic (or de novo dominant) variants in pre-BCR or B-lymphopoiesis genes instead
  • Earlier onset and typically more severe clinical features than XLA
Show evidence (2 references)
PMID:34241796 SUPPORT Human Clinical
"While the most common cause of congenital agammaglobulinemia is X-linked agammaglobulinemia (XLA), accounting for approximately 85% of cases, other genetic forms of agammaglobulinemia have been identified."
Quantifies the XLA share of congenital agammaglobulinemia and names the autosomal forms as the alternative diagnoses.
PMID:34241796 SUPPORT Human Clinical
"In contrast, while less common, autosomal recessive forms of agammaglobulinemia present at younger ages and with typically more severe clinical features resulting in an earlier diagnosis."
The clinical discriminator: the autosomal recessive forms present earlier and more severely than XLA.
Common variable immunodeficiency MONDO:0015517
Overlapping Features The commonest symptomatic antibody deficiency. Shares hypogammaglobulinemia and recurrent sinopulmonary infection, but B cells are made and circulate — the lesion is in terminal differentiation rather than early B-cell development. Curated separately in dismech as Common_Variable_Immunodeficiency.
Distinguishing Features
  • CD19+ B cells are present, usually in normal numbers; XLA has under 1-2%
  • Onset typically in the second to fourth decade rather than infancy
  • Affects both sexes; no BTK variant, and BTK protein expression is normal
  • Prominent autoimmunity, lymphoproliferation and granulomatous disease, which XLA lacks
Transient hypogammaglobulinemia of infancy Not Yet Curated MONDO:0015698
Overlapping Features A self-limited exaggeration of the physiological IgG nadir after maternal IgG is catabolised. It is the benign mimic to exclude in an infant with low immunoglobulins.
Distinguishing Features
  • B cells are present in normal numbers
  • IgG is low but detectable and vaccine responses are usually intact
  • Immunoglobulin levels normalise spontaneously, typically by 2-4 years of age
{ }

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).
    - reference: PMID:35748970
      reference_title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "agammaglobulinemia (XLA) BTK XL 300300"
      explanation: >-
        The XLA row of IUIS 2022 Table 3 (predominantly antibody
        deficiencies), section 1 (agammaglobulinemia). The row label spans two
        printed lines ("BTK deficiency, X-linked / agammaglobulinemia (XLA)");
        the quote is the second line, which carries the gene, inheritance, and
        OMIM columns.
prevalence:
- population: United States (all live births, 1988-1997)
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_9_PER_1000000
  rate_per_100000: 0.26
  notes: >-
    The US XLA registry estimated a birth rate of 1/379,000 for 1988-1997,
    i.e. 0.26 per 100,000 live births. Note this denominator is ALL live
    births; because XLA manifests in hemizygous males, the male-specific birth
    prevalence is roughly twice this (on the order of 1/190,000 males). As a
    voluntary physician-reported registry it is a minimum estimate.
  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: The estimated birth rate for the 10-year period of 1988-1997 was 1/379,000.
    explanation: The US XLA registry provides the birth-rate estimate for 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
  conforms_to: "germinal_center_reaction#Durable Protective Humoral Immunity"
  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
    modifier: DECREASED
  - preferred_term: Humoral Immune Response
    term:
      id: GO:0006959
      label: humoral immune response
    modifier: DECREASED
  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
  conforms_to: "germinal_center_reaction#Clinical Susceptibility to 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
  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 in XLA is panhypogammaglobulinemia
      affecting IgG, IgA, and IgM. The source establishes the global
      immunoglobulin deficit but does not report IgG levels separately, so this
      isotype-specific record is only partially supported.
- 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
  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 in XLA is panhypogammaglobulinemia
      affecting IgG, IgA, and IgM. The source establishes the global
      immunoglobulin deficit but does not report IgA levels separately, so this
      isotype-specific record is only partially supported.
- 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
  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 in XLA is panhypogammaglobulinemia
      affecting IgG, IgA, and IgM. The source establishes the global
      immunoglobulin deficit but does not report IgM levels separately, so this
      isotype-specific record is only partially supported.
- 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).
- name: Septic Arthritis
  category: Musculoskeletal
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Septic arthritis
    term:
      id: HP:0003095
      label: Septic arthritis
  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: >-
      8% at least 1 episode of septic arthritis
    explanation: >-
      8% of registry patients had at least one episode of septic arthritis
      (OCCASIONAL band).
  - reference: PMID:20301626
    reference_title: "X-Linked Agammaglobulinemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      they develop a severe, life-threatening infection such as pneumonia, empyema,
      meningitis, sepsis, cellulitis, or septic arthritis
    explanation: >-
      The XLA GeneReviews lists septic arthritis among the severe,
      life-threatening infections through which XLA is often first recognised.
- name: Hepatitis
  category: Gastrointestinal
  frequency: OCCASIONAL
  description: >-
    Hepatitis in XLA is usually infectious; it appeared both among registry
    morbidity (6% of patients) and among registry causes of death.
  phenotype_term:
    preferred_term: Hepatitis
    term:
      id: HP:0012115
      label: Hepatitis
  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: >-
      6% at least 1 episode of hepatitis
    explanation: >-
      6% of registry patients had at least one episode of hepatitis
      (OCCASIONAL band).
- name: Osteomyelitis
  category: Musculoskeletal
  frequency: VERY_RARE
  phenotype_term:
    preferred_term: Osteomyelitis
    term:
      id: HP:0002754
      label: Osteomyelitis
  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: >-
      3% at least 1 episode of osteomyelitis
    explanation: >-
      3% of registry patients had at least one episode of osteomyelitis
      (VERY_RARE band, under 5%).
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.
  - reference: PMID:34241796
    reference_title: "Agammaglobulinemia: from X-linked to Autosomal Forms of Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The lack of correlation between phenotype and genotype in this condition
      makes management and predicting outcomes quite difficult.
    explanation: >-
      Supports the genotype-phenotype claim recorded in notes: overall clinical
      severity in XLA cannot be predicted from the specific BTK genotype.
  - reference: PMID:30240888
    reference_title: "Comparison of Common Monogenic Defects in a Large Predominantly Antibody Deficiency Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We found a genotype-phenotype correlation among patients with BTK mutations
      regarding clinical manifestation of meningitis and chronic diarrhea.
    explanation: >-
      A 550-patient predominantly-antibody-deficiency cohort reports a
      manifestation-specific exception (meningitis, chronic diarrhea) to the
      general absence of BTK genotype-phenotype correlation.
  notes: >-
    Genotype-phenotype correlation in XLA is weak: review evidence states that
    overall phenotype severity does not track the specific BTK genotype, which
    complicates management and outcome prediction, although one large cohort
    reported a genotype-phenotype correlation restricted to the specific
    manifestations of meningitis and chronic diarrhea. Some BTK alleles are
    hypomorphic and permit residual, leaky B-cell output with a milder, later
    presentation that can delay or evade diagnosis.
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. Per
    GeneReviews it is given by weekly subcutaneous injection or intravenous
    infusion every two to four weeks, and it prevents the severe enteroviral
    complications (dermatomyositis, chronic meningoencephalitis) of untreated
    disease.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: immunoglobulin replacement therapy
    term:
      id: NCIT:C62710
      label: Immunoglobulin Therapy
  target_mechanisms:
  - target: Panhypogammaglobulinemia from Absent Plasma Cells
    treatment_effect: BYPASSES
    description: >-
      Passive polyclonal IgG substitutes for the antibody the absent plasma-cell
      compartment cannot make; it bypasses rather than corrects the upstream
      B-cell developmental block.
  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.
  - reference: PMID:20301626
    reference_title: "X-Linked Agammaglobulinemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      (by weekly subcutaneous injection or intravenous infusion
      every two to four weeks) to prevent bacterial infections
    explanation: >-
      GeneReviews specifies the dosing routes and intervals and the preventive
      goal of gammaglobulin substitution described here.
- name: Antibiotic Therapy and Prophylaxis
  description: >-
    Therapeutic and prophylactic antibiotics are used to treat and prevent the
    recurrent bacterial sinopulmonary infections that characterize XLA;
    generous antibiotic use reduces the incidence of chronic sinusitis and
    chronic lung disease.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: antibiotic therapy
    term:
      id: NCIT:C15620
      label: Antibiotic Therapy
  evidence:
  - reference: PMID:20301626
    reference_title: "X-Linked Agammaglobulinemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Generous use of antibiotics can decrease the incidence of chronic sinusitis
      and lung disease.
    explanation: >-
      GeneReviews supports generous therapeutic antibiotic use to prevent
      chronic sinus and lung disease in XLA.
  - reference: PMID:20301626
    reference_title: "X-Linked Agammaglobulinemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Prophylactic antibiotics can be considered
      to prevent infections.
    explanation: >-
      GeneReviews supports the prophylactic-antibiotic arm of this treatment.
- name: Avoidance of Live Attenuated Vaccines (Agents to Avoid)
  description: >-
    Live viral vaccines — above all oral poliovirus vaccine — are
    contraindicated because the replicating vaccine strain cannot be
    neutralised in the absence of antibody. Inactivated poliovirus vaccine
    should be substituted, for affected individuals and for their family
    contacts; non-live vaccines are otherwise recommended to prevent
    infection.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Preventive Intervention
    term:
      id: NCIT:C15843
      label: Preventive Intervention
  evidence:
  - reference: PMID:20301626
    reference_title: "X-Linked Agammaglobulinemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Agents/circumstances to avoid: Live viral
      vaccines, particularly oral polio vaccine.
    explanation: >-
      The GeneReviews Agents/Circumstances to Avoid recommendation for XLA.
  - reference: PMID:20301626
    reference_title: "X-Linked Agammaglobulinemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Inactivated polio vaccine (as opposed to live oral polio vaccine) should be
      given to affected individuals and their family contacts.
    explanation: >-
      Specifies substituting inactivated for oral poliovirus vaccine, including
      for household contacts.
  - reference: PMID:20301626
    reference_title: "X-Linked Agammaglobulinemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Vaccines, apart from live vaccines, are recommended to prevent infection.
    explanation: >-
      GeneReviews recommends non-live vaccines while excluding live vaccines.
- 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. In the international
    survey of 22 transplanted XLA patients, 2-year overall survival was 86% and
    event-free survival 77%, and immunoglobulin replacement could be
    discontinued in 89% at one year; the authors advise performing HCT, when
    indicated, before organ damage develops.
  therapeutic_modality: CELL_THERAPY
  treatment_term:
    preferred_term: hematopoietic cell transplantation
    term:
      id: NCIT:C15431
      label: Hematopoietic Cell Transplantation
  target_mechanisms:
  - target: Arrest of B-Cell Development at the Pre-B Stage
    treatment_effect: INHIBITS
    description: >-
      Donor haematopoiesis supplies BTK-competent B-cell progenitors that can
      traverse the pre-B checkpoint, replacing the arrested host B lineage.
  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.
  - reference: PMID:37454339
    reference_title: "An International Survey of Allogeneic Hematopoietic Cell Transplantation for X-Linked Agammaglobulinemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In all patients, 2-year overall survival (OS) and event-free survival (EFS) were
      86% and 77%, respectively.
    explanation: >-
      Quantifies the transplant outcome (2-year OS 86%, EFS 77%) across the 22
      surveyed XLA transplants.
  - reference: PMID:37454339
    reference_title: "An International Survey of Allogeneic Hematopoietic Cell Transplantation for X-Linked Agammaglobulinemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the 1-year discontinuation rate of IgRT was 89%
    explanation: >-
      Demonstrates that successful HCT allows most patients to stop
      immunoglobulin replacement within a year.
  - reference: PMID:37454339
    reference_title: "An International Survey of Allogeneic Hematopoietic Cell Transplantation for X-Linked Agammaglobulinemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It is ideal to
      perform HCT in XLA patients for whom transplantation is indicated before they
      develop organ damage.
    explanation: >-
      Supports the timing recommendation carried in the description.
diagnosis:
- name: Quantitative serum immunoglobulins and B-cell flow cytometry
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  description: >-
    The characteristic laboratory findings are profound
    panhypogammaglobulinemia (IgG, IgA and IgM all severely reduced) with a
    severe deficit of circulating CD19+ B cells against normal T-cell numbers.
    These findings raise the diagnosis, which is then established molecularly.
  markers: Serum IgG, IgA and IgM; CD19+ B cell percentage
  results: Profound panhypogammaglobulinemia with near-absent circulating B cells
  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: >-
      States the defining laboratory pattern this work-up demonstrates.
- name: Molecular genetic testing for a BTK pathogenic variant
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  description: >-
    Identification of a hemizygous BTK pathogenic variant in a male proband
    with compatible clinical and laboratory findings establishes the
    diagnosis; a heterozygous BTK pathogenic variant can establish it in the
    extremely rare symptomatic female. Testing at-risk male relatives as soon
    after birth as possible allows immunoglobulin replacement to begin before
    infection and live vaccines to be avoided.
  results: Hemizygous BTK pathogenic variant identified
  evidence:
  - reference: PMID:20301626
    reference_title: "X-Linked Agammaglobulinemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of XLA is established in a male proband with
      characteristic clinical and laboratory findings and a hemizygous BTK pathogenic
      variant identified by molecular genetic testing.
    explanation: >-
      The GeneReviews diagnostic criterion for XLA.
  - reference: PMID:20301626
    reference_title: "X-Linked Agammaglobulinemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Molecular genetic testing of at-risk male relatives as soon after birth as
      possible ensures that gammaglobulin substitution therapy is initiated as soon as
      possible in affected individuals and administration of live viral vaccines can
      be avoided.
    explanation: >-
      Supports newborn testing of at-risk male relatives as part of the
      diagnostic pathway.
- name: Clinical recognition and diagnostic delay
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  description: >-
    Diagnosis is usually prompted by recurrent infection. In the US registry,
    a positive family history lowered the mean age at diagnosis from 5.37 to
    2.59 years, yet only about a third of boys with a family history known at
    birth were diagnosed before symptoms — a persistent missed opportunity for
    pre-symptomatic diagnosis. Emerging screening measurements (KREC levels,
    serum BCMA) may allow earlier identification.
  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: >-
      the average age of diagnosis was younger in patients with a positive family
      history (mean, 2.59 yr) than in patients with a negative family history (mean,
      5.37 yr)
    explanation: >-
      Registry quantification of the effect of family history on age at
      diagnosis.
  - reference: PMID:16862044
    reference_title: "X-linked agammaglobulinemia: report on a United States registry of 201 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      only 34.5% of patients with a positive family history at the time
      of their birth were diagnosed before clinical symptoms developed
    explanation: >-
      Quantifies the missed opportunity for pre-symptomatic diagnosis from
      family history alone.
  - reference: PMID:34241796
    reference_title: "Agammaglobulinemia: from X-linked to Autosomal Forms of Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of
      XLA is often delayed, and can be missed if patient has a mild phenotype.
    explanation: >-
      Review confirmation that XLA diagnosis is often delayed, particularly
      with mild phenotypes.
  - reference: PMID:34241796
    reference_title: "Agammaglobulinemia: from X-linked to Autosomal Forms of Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Some diagnostic innovations, such as KREC level measurements and
      serum BCMA measurements, may aid in facilitating an earlier identification of
      agammaglobulinemia leading to prompt treatment.
    explanation: >-
      Supports the KREC/BCMA screening claim in the description.
progression:
- phase: Onset in infancy after maternal IgG wanes
  age_range: First two years of life
  notes: >-
    Recurrent bacterial infection begins in affected males in the first two
    years of life, once transplacental maternal IgG has been catabolised.
    About 60% of individuals are recognised only when a severe,
    life-threatening infection occurs.
  evidence:
  - reference: PMID:20301626
    reference_title: "X-Linked Agammaglobulinemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      X-linked agammaglobulinemia (XLA) is characterized by
      recurrent bacterial infections in affected males in the first two years of life.
    explanation: >-
      GeneReviews places disease onset in the first two years of life.
  - reference: PMID:20301626
    reference_title: "X-Linked Agammaglobulinemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Approximately 60% of individuals with XLA are recognized as
      having immunodeficiency when they develop a severe, life-threatening infection
    explanation: >-
      Quantifies how often recognition awaits a severe infection.
- phase: Long-term course on immunoglobulin replacement
  notes: >-
    On adequate immunoglobulin replacement, severe enteroviral complications
    are largely prevented and prognosis has improved markedly over recent
    decades with earlier diagnosis, gammaglobulin preparations achieving
    normal serum IgG concentrations, and liberal antibiotic use. S pneumoniae
    and H influenzae may nonetheless continue to cause sinusitis and otitis
    after treatment is established.
  evidence:
  - reference: PMID:20301626
    reference_title: "X-Linked Agammaglobulinemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The prognosis for
      individuals with XLA has improved markedly in the last 25 years as a result of
      earlier diagnosis, the development of preparations of gammaglobulin that allow
      normal concentrations of serum immunoglobulin G to be achieved, and more liberal
      use of antibiotics.
    explanation: >-
      GeneReviews statement of the markedly improved modern prognosis and its
      drivers.
  - reference: PMID:20301626
    reference_title: "X-Linked Agammaglobulinemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      S pneumoniae and H influenzae are the most common organisms found prior to
      diagnosis and may continue to cause sinusitis and otitis after diagnosis and the
      initiation of gammaglobulin substitution therapy.
    explanation: >-
      Documents the residual sinopulmonary infection burden on treatment.
clinical_burden:
  burden_level: HIGH
  rationale: >-
    Lifelong immunoglobulin replacement with ongoing infection surveillance is
    required, and the disorder retained measurable mortality in the modern US
    registry era: 6.9% of registered patients had died at entry, and 3.75% of
    prospectively followed living patients died during roughly four years of
    follow-up, with disseminated enterovirus infection and pulmonary
    insufficiency the leading causes of death. Prognosis is nonetheless much
    better than historically, given earlier diagnosis and adequate
    immunoglobulin dosing.
  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: >-
      Fourteen of 201 (6.9%)
      patients were dead at the time they were entered in the Registry.
    explanation: >-
      Registry mortality at enrolment.
  - 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),
      pulmonary insufficiency (n = 5), adenovirus infection (n = 1), sepsis (n = 1)
    explanation: >-
      Enumerates the leading registry causes of death, dominated by
      disseminated enterovirus infection and pulmonary insufficiency.
  - reference: PMID:20301626
    reference_title: "X-Linked Agammaglobulinemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The prognosis for
      individuals with XLA has improved markedly in the last 25 years
    explanation: >-
      Balances the burden assessment: mortality and morbidity have fallen
      substantially in the modern treatment era.
differential_diagnoses:
- name: Autosomal agammaglobulinemia
  description: >-
    The autosomal recessive and dominant forms of congenital
    agammaglobulinemia (IGHM, IGLL1, CD79A, CD79B, BLNK and other loci)
    reproduce the same pre-B developmental block, absent B cells and
    panhypogammaglobulinemia without involving BTK; they account for the
    roughly 15% of congenital agammaglobulinemia that is not XLA. Curated
    separately in dismech as Autosomal_Agammaglobulinemia.
  disease_term:
    preferred_term: autosomal agammaglobulinemia
    term:
      id: MONDO:0011096
      label: autosomal agammaglobulinemia
  distinguishing_features:
  - Affects females as well as males; consanguinity is common in the recessive forms
  - No BTK pathogenic variant; biallelic (or de novo dominant) variants in pre-BCR or B-lymphopoiesis genes instead
  - Earlier onset and typically more severe clinical features than XLA
  evidence:
  - reference: PMID:34241796
    reference_title: "Agammaglobulinemia: from X-linked to Autosomal Forms of Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      While the most common cause of congenital
      agammaglobulinemia is X-linked agammaglobulinemia (XLA), accounting for
      approximately 85% of cases, other genetic forms of agammaglobulinemia have been
      identified.
    explanation: >-
      Quantifies the XLA share of congenital agammaglobulinemia and names the
      autosomal forms as the alternative diagnoses.
  - reference: PMID:34241796
    reference_title: "Agammaglobulinemia: from X-linked to Autosomal Forms of Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In contrast, while less common, autosomal recessive forms of
      agammaglobulinemia present at younger ages and with typically more severe
      clinical features resulting in an earlier diagnosis.
    explanation: >-
      The clinical discriminator: the autosomal recessive forms present
      earlier and more severely than XLA.
- name: Common variable immunodeficiency
  description: >-
    The commonest symptomatic antibody deficiency. Shares
    hypogammaglobulinemia and recurrent sinopulmonary infection, but B cells
    are made and circulate — the lesion is in terminal differentiation rather
    than early B-cell development. Curated separately in dismech as
    Common_Variable_Immunodeficiency.
  disease_term:
    preferred_term: common variable immunodeficiency
    term:
      id: MONDO:0015517
      label: common variable immunodeficiency
  distinguishing_features:
  - CD19+ B cells are present, usually in normal numbers; XLA has under 1-2%
  - Onset typically in the second to fourth decade rather than infancy
  - Affects both sexes; no BTK variant, and BTK protein expression is normal
  - Prominent autoimmunity, lymphoproliferation and granulomatous disease, which XLA lacks
- name: Transient hypogammaglobulinemia of infancy
  description: >-
    A self-limited exaggeration of the physiological IgG nadir after maternal
    IgG is catabolised. It is the benign mimic to exclude in an infant with
    low immunoglobulins.
  disease_term:
    preferred_term: transient hypogammaglobulinemia of infancy
    term:
      id: MONDO:0015698
      label: transient hypogammaglobulinemia of infancy
  distinguishing_features:
  - B cells are present in normal numbers
  - IgG is low but detectable and vaccine responses are usually intact
  - Immunoglobulin levels normalise spontaneously, typically by 2-4 years of age
references:
- reference: PMID:20301626
  title: "X-Linked Agammaglobulinemia."
  tags:
  - GeneReviews
  findings: []
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References & Deep Research

References

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