Chronic Granulomatous Disease

Mendelian MONDO:0018305 Pathograph 13 Show in embeddings browser Primary Immunodeficiency

Chronic granulomatous disease (CGD) is an inherited primary immunodeficiency of phagocytes (neutrophils, monocytes, macrophages, and eosinophils) caused by defects in the phagocyte NADPH oxidase (NOX2) complex. Loss of a functional oxidase abolishes the respiratory (oxidative) burst and the production of superoxide and downstream reactive oxygen species that phagocytes use to kill ingested catalase-positive bacteria and fungi. The result is a dual phenotype: recurrent, severe bacterial and fungal infections (classically Staphylococcus aureus, Serratia marcescens, Burkholderia cepacia, Nocardia, and Aspergillus) affecting the lung, lymph nodes, liver, skin, and bone, together with a dysregulated hyperinflammatory response that produces exuberant granulomas (obstructing the gastrointestinal and genitourinary tracts) and inflammatory bowel-disease-like colitis. CGD is genetically heterogeneous: X-linked disease from CYBB (gp91phox) accounts for roughly two-thirds of cases, and autosomal recessive disease arises from biallelic variants in CYBA (p22phox), NCF1 (p47phox), NCF2 (p67phox), NCF4 (p40phox), or CYBC1/EROS (a gp91phox chaperone). Diagnosis rests on demonstrating an absent oxidative burst by dihydrorhodamine (DHR) flow cytometry or the nitroblue tetrazolium (NBT) test, followed by molecular confirmation. Management combines lifelong antibacterial (trimethoprim-sulfamethoxazole) and antifungal (itraconazole) prophylaxis, interferon-gamma prophylaxis, aggressive treatment of infections, and corticosteroids for granulomatous/inflammatory complications; allogeneic hematopoietic stem cell transplantation is curative and gene therapy is emerging.

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2
Inheritance
4
Pathophys.
11
Phenotypes
13
Pathograph
6
Genes
8
Medical Actions
6
Subtypes
2
Differentials
1
References
1
Deep Research
🏷

Classifications

Harrison's Chapter
IMMUNE_RHEUMATOLOGIC GENETICS_ENVIRONMENT_DISEASE
IUIS Category
phagocyte defect
👪

Inheritance

2
X-linked (CYBB)
CGD due to a CYBB pathogenic variant is inherited in an X-linked manner; a heterozygous mother has a 50% chance of transmitting the variant in each pregnancy, and males who inherit it are affected.
Show evidence (1 reference)
PMID:22876374 SUPPORT Other
"CGD associated with a pathogenic variant in CYBB is inherited in an X-linked manner"
GeneReviews states CYBB-associated CGD is X-linked.
Autosomal recessive (CYBA/CYBC1/NCF1/NCF2/NCF4)
CGD due to biallelic variants in CYBA, CYBC1, NCF1, NCF2, or NCF4 is inherited in an autosomal recessive manner; each sib of an affected individual has a 25% chance of being affected.
Show evidence (1 reference)
PMID:22876374 SUPPORT Other
"CGD associated with biallelic pathogenic variants in CYBA, CYBC1, NCF1, NCF2, or NCF4 is inherited in an autosomal recessive manner"
GeneReviews states CYBA/CYBC1/NCF1/NCF2/NCF4-associated CGD is autosomal recessive.
◆

Subtypes

6
X-linked CGD (CYBB / gp91phox)
The most common form (about two-thirds of cases), caused by hemizygous pathogenic variants in CYBB encoding gp91phox (NOX2), the catalytic membrane subunit. Typically the most severe form with earliest onset. A contiguous-gene deletion at Xp21.1 can additionally produce McLeod neuroacanthocytosis syndrome. OMIM phenotype: 306400 (no distinct MONDO subtype term is available; MONDO models CGD only at the parent level).
Autosomal recessive CGD (NCF1 / p47phox)
The most common autosomal recessive form, caused by biallelic NCF1 variants (most often the recurrent GT deletion). Generally a milder clinical course with later presentation and better survival than X-linked CGD. OMIM phenotype: 233700 (no distinct MONDO subtype term is available).
Autosomal recessive CGD (CYBA / p22phox)
Autosomal recessive CGD from biallelic CYBA variants encoding p22phox, the membrane partner of gp91phox in flavocytochrome b558. OMIM phenotype: 233690 (no distinct MONDO subtype term is available).
Autosomal recessive CGD (NCF2 / p67phox)
Autosomal recessive CGD from biallelic NCF2 variants encoding the p67phox cytosolic activator subunit. OMIM phenotype: 233710 (no distinct MONDO subtype term is available).
Autosomal recessive CGD (NCF4 / p40phox)
A rare autosomal recessive form from biallelic NCF4 variants encoding p40phox, often with a distinctive predominantly inflammatory/colitis phenotype and comparatively preserved antimicrobial oxidase activity. OMIM phenotype: 613960 (no distinct MONDO subtype term is available).
Autosomal recessive CGD (CYBC1 / EROS)
Autosomal recessive CGD from biallelic CYBC1 (EROS) variants; CYBC1 encodes an endoplasmic reticulum chaperone required for gp91phox-p22phox stability, so its loss produces a functional NADPH oxidase deficiency. OMIM phenotype: 618935 (no distinct MONDO subtype term is available).
⚙

Pathophysiology

4
NADPH oxidase (NOX2) complex assembly failure
Pathogenic variants in any one of the NOX2 complex subunits (membrane gp91phox/CYBB and p22phox/CYBA forming flavocytochrome b558; cytosolic p47phox/NCF1, p67phox/NCF2, and p40phox/NCF4; and the CYBC1/EROS chaperone that stabilizes gp91phox) prevent assembly of a functional phagocyte NADPH oxidase on the phagosomal and plasma membranes. Without a functional oxidase, electrons cannot be transferred from cytosolic NADPH across the membrane to molecular oxygen.
neutrophil CL:0000775 monocyte CL:0000576 macrophage CL:0000235 eosinophil CL:0000771
CYBB hgnc:2578 NCF1 hgnc:7660
superoxide anion generation GO:0042554 ↓ DECREASED
Downstream
Failed respiratory burst and ROS deficiency A non-functional NADPH oxidase cannot generate superoxide, abolishing the respiratory burst and downstream reactive oxygen species.
Show evidence (1 reference)
PMID:22876374 SUPPORT Other
"identification of pathogenic variant(s) in one of six genes that encode or permit assembly of the subunits of phagocyte NADPH oxidase"
Establishes that CGD results from defects in the six NADPH oxidase subunit/assembly genes.
Failed respiratory burst and ROS deficiency
The assembled NADPH oxidase normally catalyzes the respiratory (oxidative) burst, reducing molecular oxygen to superoxide, which is dismutated and converted to hydrogen peroxide, hypohalous acids, and other reactive oxygen species within the phagosome. In CGD this burst is absent or markedly reduced, so phagocytes ingest microbes but fail to generate the oxidants required for efficient microbicidal activity.
neutrophil CL:0000775
respiratory burst GO:0045730 ↓ DECREASED reactive oxygen species metabolic process GO:0072593 ↓ DECREASED
Downstream
Impaired microbial killing and recurrent infection Loss of oxidant-dependent killing leaves phagocytes unable to clear catalase-positive bacteria and fungi, producing recurrent severe infection.
Dysregulated inflammation and granuloma formation Loss of ROS-dependent signaling impairs resolution of inflammation and drives exuberant granuloma formation and colitis.
Show evidence (1 reference)
PMID:22876374 SUPPORT Other
"resulting from impaired killing of bacteria and fungi"
The oxidase defect produces impaired phagocyte killing of bacteria and fungi via loss of the oxidative burst.
Impaired microbial killing and recurrent infection
Because oxidant-dependent killing is lost, phagocytes cannot efficiently clear catalase-positive organisms (which detoxify their own hydrogen peroxide) such as Staphylococcus aureus, Serratia marcescens, Burkholderia cepacia, Nocardia, and Aspergillus, producing the characteristic recurrent and severe pneumonias, abscesses, lymphadenitis, and osteomyelitis.
neutrophil CL:0000775
defense response to bacterium GO:0042742 ↓ DECREASED defense response to fungus GO:0050832 ↓ DECREASED
Show evidence (1 reference)
PMID:22876374 SUPPORT Other
"characterized by severe recurrent bacterial and fungal infections"
The killing defect produces the hallmark severe recurrent bacterial and fungal infections of CGD.
Dysregulated inflammation and granuloma formation
Independent of infection, NADPH oxidase deficiency dysregulates innate immune signaling and impairs the resolution of inflammation, driving persistent macrophage activation, exuberant granuloma formation that can obstruct hollow viscera (gastrointestinal and genitourinary tracts), and an inflammatory-bowel-disease-like colitis.
macrophage CL:0000235
granuloma formation GO:0002432 ↑ INCREASED inflammatory response GO:0006954 ↑ INCREASED
Show evidence (1 reference)
PMID:22876374 SUPPORT Other
"dysregulated inflammatory responses resulting in granuloma formation and other inflammatory disorders such as colitis"
Establishes the dysregulated-inflammation arm of CGD producing granulomas and colitis.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Chronic Granulomatous Disease 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

11
Blood 1
Granulomatous inflammation VERY_FREQUENT Granulomatosis HP:0002955
Show evidence (1 reference)
PMID:22876374 SUPPORT Other
"dysregulated inflammatory responses resulting in granuloma formation"
GeneReviews establishes granuloma formation as a defining feature of CGD.
Digestive 2
Liver abscess OCCASIONAL Liver abscess HP:0100523
Show evidence (2 references)
PMID:22876374 SUPPORT Other
"liver (abscess)"
GeneReviews lists liver abscess as a typical infection site in CGD.
PMID:10844935 SUPPORT Human Clinical
"liver abscess (27% of patients;"
The US registry documents liver abscess in 27% of patients, supporting the OCCASIONAL frequency band.
Colitis FREQUENT Colitis HP:0002583
Show evidence (1 reference)
PMID:22876374 SUPPORT Other
"other inflammatory disorders such as colitis"
GeneReviews lists colitis among the dysregulated inflammatory disorders of CGD.
Immune 4
Pneumonia FREQUENT Pneumonia HP:0002090
Show evidence (2 references)
PMID:22876374 SUPPORT Other
"Infections typically involve the lung (pneumonia)"
GeneReviews lists pneumonia as a typical infection site in CGD.
PMID:10844935 SUPPORT Human Clinical
"Pneumonia was the most prevalent infection (79% of patients; Aspergillus most prevalent cause)"
The US registry documents pneumonia in 79% of patients, supporting the FREQUENT frequency band.
Osteomyelitis OCCASIONAL Osteomyelitis HP:0002754
Show evidence (1 reference)
PMID:22876374 SUPPORT Other
"bone (osteomyelitis)"
GeneReviews lists osteomyelitis as a typical infection site in CGD.
Recurrent skin abscesses FREQUENT Recurrent abscess formation HP:0002722
Show evidence (1 reference)
PMID:22876374 SUPPORT Other
"skin (abscesses or cellulitis)"
GeneReviews lists skin abscesses/cellulitis as a typical infection site in CGD.
Sepsis OCCASIONAL Sepsis HP:0100806
Show evidence (1 reference)
PMID:10844935 SUPPORT Human Clinical
"sepsis (18% of patients; Salmonella most prevalent cause)"
The US registry documents sepsis in 18% of patients, supporting the OCCASIONAL frequency band.
Other 4
Recurrent bacterial infections VERY_FREQUENT Recurrent bacterial infections HP:0002718
Show evidence (1 reference)
PMID:22876374 SUPPORT Other
"characterized by severe recurrent bacterial and fungal infections"
GeneReviews establishes severe recurrent bacterial infection as a defining feature of CGD.
Recurrent fungal infections VERY_FREQUENT Recurrent fungal infections HP:0002841
Show evidence (1 reference)
PMID:22876374 SUPPORT Other
"characterized by severe recurrent bacterial and fungal infections"
GeneReviews establishes severe recurrent fungal infection as a defining feature of CGD.
Lymphadenitis FREQUENT Lymphadenitis HP:0002840
Show evidence (1 reference)
PMID:22876374 SUPPORT Other
"lymph nodes (lymphadenitis)"
GeneReviews lists lymphadenitis as a typical infection site in CGD.
Gastric outlet obstruction OCCASIONAL Pyloric stenosis HP:0002021
Show evidence (1 reference)
PMID:10844935 SUPPORT Human Clinical
"patients had gastric outlet obstruction"
The US registry documents gastric outlet obstruction in 15% of patients, supporting the OCCASIONAL frequency band.
🧬

Genetic Associations

6
CYBB (Causative)
Gene: CYBB hgnc:2578
Show evidence (2 references)
PMID:22876374 SUPPORT Other
"pathogenic variants in CYBB cause X-linked CGD"
GeneReviews identifies CYBB pathogenic variants as the cause of X-linked CGD.
PMID:31988463 SUPPORT Human Clinical
"X-CGD is caused by mutations in CYBB encoding the gp91phox subunit of the phagocyte"
Confirms that X-linked CGD is caused by CYBB mutations encoding the gp91phox NADPH-oxidase subunit.
CYBA (Causative)
Gene: CYBA hgnc:2577
Show evidence (1 reference)
PMID:22876374 SUPPORT Other
"biallelic pathogenic variants in CYBA, CYBC1, NCF1, NCF2, and NCF4 cause autosomal recessive CGD"
GeneReviews identifies biallelic CYBA variants as a cause of autosomal recessive CGD.
NCF1 (Causative)
Gene: NCF1 hgnc:7660
Show evidence (1 reference)
PMID:22876374 SUPPORT Other
"biallelic pathogenic variants in CYBA, CYBC1, NCF1, NCF2, and NCF4 cause autosomal recessive CGD"
GeneReviews identifies biallelic NCF1 variants as a cause of autosomal recessive CGD.
NCF2 (Causative)
Gene: NCF2 hgnc:7661
Show evidence (1 reference)
PMID:22876374 SUPPORT Other
"biallelic pathogenic variants in CYBA, CYBC1, NCF1, NCF2, and NCF4 cause autosomal recessive CGD"
GeneReviews identifies biallelic NCF2 variants as a cause of autosomal recessive CGD.
NCF4 (Causative)
Gene: NCF4 hgnc:7662
Show evidence (1 reference)
PMID:22876374 SUPPORT Other
"biallelic pathogenic variants in CYBA, CYBC1, NCF1, NCF2, and NCF4 cause autosomal recessive CGD"
GeneReviews identifies biallelic NCF4 variants as a cause of autosomal recessive CGD.
CYBC1 (Causative)
Gene: CYBC1 hgnc:28672
Show evidence (1 reference)
PMID:22876374 SUPPORT Other
"biallelic pathogenic variants in CYBA, CYBC1, NCF1, NCF2, and NCF4 cause autosomal recessive CGD"
GeneReviews identifies biallelic CYBC1 variants as a cause of autosomal recessive CGD.
💊

Medical Actions

8
Antibacterial prophylaxis (trimethoprim-sulfamethoxazole)
Action: Antibiotic prophylaxis Ontology label: Antibiotic Therapy NCIT:C15620
Agent: trimethoprim CHEBI:45924 sulfamethoxazole CHEBI:9332
Lifelong daily antibacterial prophylaxis, standardly with trimethoprim-sulfamethoxazole, is recommended to prevent infections. Pregnancy caution: trimethoprim (a folic acid antagonist) is discontinued during pregnancy because of the high risk for birth defects.
Mechanism Target:
BYPASSES Impaired microbial killing and recurrent infection — Prophylactic antibiotics suppress bacterial infection that the oxidase-deficient phagocytes cannot clear.
Show evidence (2 references)
PMID:22876374 SUPPORT Other
"Lifelong daily antibacterial and antifungal prophylaxis is recommended"
GeneReviews recommends lifelong daily antibacterial prophylaxis.
PMID:22876374 SUPPORT Other
"trimethoprim, a folic acid antagonist, is discontinued during pregnancy because of the high risk for birth defects"
GeneReviews documents the pregnancy drug-safety caution for trimethoprim.
Antifungal prophylaxis (itraconazole)
Action: Antifungal pharmacotherapy Ontology label: Pharmacotherapy NCIT:C15986
Agent: itraconazole CHEBI:6076
Lifelong daily antifungal prophylaxis, standardly with itraconazole, reduces invasive fungal infection; newer azoles (voriconazole, posaconazole, isavuconazole) have expanded therapeutic options for established fungal infection.
Mechanism Target:
BYPASSES Impaired microbial killing and recurrent infection — Antifungal prophylaxis suppresses fungal infection (especially Aspergillus) that the oxidase-deficient phagocytes cannot clear.
Show evidence (2 references)
PMID:22876374 SUPPORT Other
"Lifelong daily antibacterial and antifungal prophylaxis is recommended"
GeneReviews recommends lifelong daily antifungal prophylaxis.
PMID:22876374 SUPPORT Other
"Newer azole drugs (voriconazole, posaconazole, isovuconazole) have expanded therapeutic options for fungal infections"
GeneReviews notes newer azoles have expanded antifungal therapy options.
Interferon-gamma prophylaxis
Action: Pharmacotherapy NCIT:C15986
Agent: interferon gamma-1b CHEBI:5939
Immunomodulatory prophylaxis with interferon gamma (IFN-gamma) is part of the standard prophylactic regimen in many centers.
Mechanism Target:
MODULATES Impaired microbial killing and recurrent infection — IFN-gamma prophylaxis reduces the frequency and severity of serious infections in CGD.
Show evidence (1 reference)
PMID:22876374 SUPPORT Other
"immunomodulatory therapy with interferon gamma (IFN-gamma) is part of the prophylactic regimen in many centers"
GeneReviews describes IFN-gamma as part of the prophylactic regimen in many centers.
Corticosteroids for inflammatory complications
Action: Corticosteroid therapy Ontology label: Pharmacotherapy NCIT:C15986
Agent: corticosteroid CHEBI:50858
Simultaneous administration of antimicrobials and corticosteroids can help resolve the heightened inflammatory response, including colitis and obstructing granulomas.
Mechanism Target:
MODULATES Dysregulated inflammation and granuloma formation — Corticosteroids dampen the dysregulated hyperinflammatory response that drives colitis and granulomas.
Show evidence (1 reference)
PMID:22876374 SUPPORT Other
"Simultaneous administration of antimicrobials and corticosteroids can help resolve the associated heightened inflammatory response, including colitis"
GeneReviews supports corticosteroids for the inflammatory/colitis complications of CGD.
Allogeneic hematopoietic stem cell transplantation
Action: allogeneic hematopoietic stem cell transplantation MAXO:0001479
Allogeneic HSCT is the only known cure for CGD and is associated with excellent overall and event-free survival, especially with matched donors at a younger age.
Mechanism Target:
RESTORES NADPH oxidase (NOX2) complex assembly failure — HSCT replaces the patient's hematopoietic compartment with donor cells that express a functional NADPH oxidase.
Show evidence (1 reference)
PMID:22876374 SUPPORT Other
"Allogeneic hematopoietic stem cell transplantation (HSCT) is the only known cure for CGD"
GeneReviews identifies allogeneic HSCT as the only known cure for CGD.
Autologous hematopoietic stem cell gene therapy
Action: Gene therapy Ontology label: Gene Therapy NCIT:C15238
Ex vivo autologous CD34+ hematopoietic stem and progenitor cell lentiviral gene therapy (e.g., the self-inactivating G1XCGD vector for X-linked CGD) is an emerging curative approach for patients lacking a matched donor, restoring oxidase-positive neutrophils and functional superoxide production.
Mechanism Target:
RESTORES NADPH oxidase (NOX2) complex assembly failure — Ex vivo lentiviral correction of autologous stem cells restores functional NADPH oxidase (gp91phox) expression in the phagocyte lineage.
Show evidence (2 references)
PMID:31988463 SUPPORT Human Clinical
"six of the seven surviving patients demonstrated stable vector copy numbers (0.4-1.8 copies per neutrophil) and the persistence of 16-46% oxidase-positive neutrophils"
A multicenter trial showed lentiviral gene therapy restored persistent oxidase-positive neutrophils in X-CGD patients.
PMID:31988463 SUPPORT Human Clinical
"suggesting that autologous gene therapy is a promising approach for CGD patients"
The trial concludes autologous gene therapy is a promising approach for CGD.
Avoidance of high-risk exposures (agents/circumstances to avoid)
Action: Supportive care Ontology label: supportive care MAXO:0000950
Per GeneReviews, patients with CGD should avoid decayed organic matter (mulching, gardening, leaf raking, house demolition), because inhalation of fungal spores can cause fulminant pneumonitis, and should avoid live bacterial vaccines including bacille Calmette-Guerin (BCG) and Salmonella typhi vaccination.
Mechanism Target:
BYPASSES Impaired microbial killing and recurrent infection — Avoiding heavy fungal-spore exposure and live bacterial vaccines removes infectious challenges the oxidase-deficient phagocytes cannot control.
Show evidence (2 references)
PMID:22876374 SUPPORT Other
"Decayed organic matter (e.g., mulching, gardening, leaf raking, house demolition) as inhalation of fungal spores can result in fulminant pneumonitis"
GeneReviews advises avoiding decayed organic matter because fungal-spore inhalation can cause fulminant pneumonitis.
PMID:22876374 SUPPORT Other
"live bacterial vaccines including bacille Calmette-Guérin (BCG) vaccination and Salmonella typhi vaccination"
GeneReviews advises avoiding live bacterial vaccines (BCG, Salmonella typhi) in CGD.
Genetic counseling
Action: Genetic Counseling NCIT:C15240
Genetic counseling addresses the mixed inheritance of CGD (X-linked for CYBB; autosomal recessive for CYBA, CYBC1, NCF1, NCF2, NCF4) and the availability of carrier, prenatal, and preimplantation genetic testing once the familial variant(s) are known.
Show evidence (1 reference)
PMID:22876374 SUPPORT Other
"Once the CGD-causing pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible"
GeneReviews supports genetic counseling with prenatal/preimplantation testing options.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Chronic Granulomatous Disease:

Other primary immunodeficiencies
Overlapping Features Other phagocyte and combined immunodeficiencies (e.g., leukocyte adhesion deficiency, hyper-IgE syndrome, severe congenital neutropenia) can produce overlapping recurrent infections but have a normal oxidative burst.
Show evidence (1 reference)
PMID:22876374 SUPPORT Other
"Chronic granulomatous disease (CGD) is a primary immunodeficiency disorder of phagocytes"
CGD sits within the phagocyte/primary immunodeficiency differential, distinguished by the oxidative-burst defect.
Inflammatory bowel disease
Overlapping Features CGD colitis can closely mimic Crohn disease/inflammatory bowel disease; CGD should be considered in early-onset or atypical IBD, especially with a history of infections.
Show evidence (1 reference)
PMID:22876374 SUPPORT Other
"other inflammatory disorders such as colitis"
CGD colitis is a mimic of inflammatory bowel disease, an important differential.
{ }

Source YAML

click to show 
name: Chronic Granulomatous Disease
creation_date: "2026-06-30T00:00:00Z"
category: Mendelian
synonyms:
- CGD
- NADPH oxidase deficiency
- phagocyte NADPH oxidase deficiency
disease_term:
  preferred_term: Chronic Granulomatous Disease
  term:
    id: MONDO:0018305
    label: chronic granulomatous disease
parents:
- Primary Immunodeficiency
description: >-
  Chronic granulomatous disease (CGD) is an inherited primary immunodeficiency
  of phagocytes (neutrophils, monocytes, macrophages, and eosinophils) caused by
  defects in the phagocyte NADPH oxidase (NOX2) complex. Loss of a functional
  oxidase abolishes the respiratory (oxidative) burst and the production of
  superoxide and downstream reactive oxygen species that phagocytes use to kill
  ingested catalase-positive bacteria and fungi. The result is a dual phenotype:
  recurrent, severe bacterial and fungal infections (classically Staphylococcus
  aureus, Serratia marcescens, Burkholderia cepacia, Nocardia, and Aspergillus)
  affecting the lung, lymph nodes, liver, skin, and bone, together with a
  dysregulated hyperinflammatory response that produces exuberant granulomas
  (obstructing the gastrointestinal and genitourinary tracts) and inflammatory
  bowel-disease-like colitis. CGD is genetically heterogeneous: X-linked disease
  from CYBB (gp91phox) accounts for roughly two-thirds of cases, and autosomal
  recessive disease arises from biallelic variants in CYBA (p22phox), NCF1
  (p47phox), NCF2 (p67phox), NCF4 (p40phox), or CYBC1/EROS (a gp91phox
  chaperone). Diagnosis rests on demonstrating an absent oxidative burst by
  dihydrorhodamine (DHR) flow cytometry or the nitroblue tetrazolium (NBT) test,
  followed by molecular confirmation. Management combines lifelong antibacterial
  (trimethoprim-sulfamethoxazole) and antifungal (itraconazole) prophylaxis,
  interferon-gamma prophylaxis, aggressive treatment of infections, and
  corticosteroids for granulomatous/inflammatory complications; allogeneic
  hematopoietic stem cell transplantation is curative and gene therapy is
  emerging.
classifications:
  harrisons_chapter:
  - classification_value: IMMUNE_RHEUMATOLOGIC
    evidence:
    - reference: PMID:22876374
      reference_title: "Chronic Granulomatous Disease."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Chronic granulomatous disease (CGD) is a primary \nimmunodeficiency disorder of phagocytes"
      explanation: CGD is a primary immunodeficiency of phagocytes, supporting placement in Harrison's immune/rheumatologic Part.
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    evidence:
    - reference: PMID:22876374
      reference_title: "Chronic Granulomatous Disease."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "identification of pathogenic variant(s) in one of six \ngenes that encode or permit assembly of the subunits of phagocyte NADPH oxidase"
      explanation: CGD is a Mendelian single-gene (NADPH oxidase subunit) disorder, supporting placement in Harrison's genetics Part.
  iuis_category:
    classification_value: phagocyte defect
    evidence:
    - reference: PMID:22876374
      reference_title: "Chronic Granulomatous Disease."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Chronic granulomatous disease (CGD) is a primary \nimmunodeficiency disorder of phagocytes"
      explanation: As a congenital defect of phagocyte function, CGD is classified in the IUIS "phagocyte defect" category (Table 5 lists CGD explicitly).
prevalence:
- population: United States (birth incidence)
  notes: >-
    A US national registry estimated a minimum birth incidence of roughly
    1/200,000 to 1/250,000 live births; of 368 registered patients, the
    majority (259) had the X-linked form.
  evidence:
  - reference: PMID:10844935
    reference_title: "Chronic granulomatous disease. Report on a national registry of 368 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "minimum estimate of birth rate is \nbetween 1/200,000 and 1/250,000 live births for the period 1980-1989"
    explanation: The US CGD registry provides the minimum birth-incidence estimate.
  - reference: PMID:10844935
    reference_title: "Chronic granulomatous disease. Report on a national registry of 368 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "259 have the \nX-linked recessive form of CGD, 81 have 1 of the autosomal recessive forms"
    explanation: The registry documents the predominance of the X-linked form (259 of 368 patients).
has_subtypes:
- name: X-linked CYBB
  display_name: X-linked CGD (CYBB / gp91phox)
  description: >-
    The most common form (about two-thirds of cases), caused by hemizygous
    pathogenic variants in CYBB encoding gp91phox (NOX2), the catalytic
    membrane subunit. Typically the most severe form with earliest onset. A
    contiguous-gene deletion at Xp21.1 can additionally produce McLeod
    neuroacanthocytosis syndrome. OMIM phenotype: 306400 (no distinct MONDO
    subtype term is available; MONDO models CGD only at the parent level).
- name: AR p47phox NCF1
  display_name: Autosomal recessive CGD (NCF1 / p47phox)
  description: >-
    The most common autosomal recessive form, caused by biallelic NCF1
    variants (most often the recurrent GT deletion). Generally a milder
    clinical course with later presentation and better survival than X-linked
    CGD. OMIM phenotype: 233700 (no distinct MONDO subtype term is available).
- name: AR p22phox CYBA
  display_name: Autosomal recessive CGD (CYBA / p22phox)
  description: >-
    Autosomal recessive CGD from biallelic CYBA variants encoding p22phox, the
    membrane partner of gp91phox in flavocytochrome b558. OMIM phenotype:
    233690 (no distinct MONDO subtype term is available).
- name: AR p67phox NCF2
  display_name: Autosomal recessive CGD (NCF2 / p67phox)
  description: >-
    Autosomal recessive CGD from biallelic NCF2 variants encoding the p67phox
    cytosolic activator subunit. OMIM phenotype: 233710 (no distinct MONDO
    subtype term is available).
- name: AR p40phox NCF4
  display_name: Autosomal recessive CGD (NCF4 / p40phox)
  description: >-
    A rare autosomal recessive form from biallelic NCF4 variants encoding
    p40phox, often with a distinctive predominantly inflammatory/colitis
    phenotype and comparatively preserved antimicrobial oxidase activity. OMIM
    phenotype: 613960 (no distinct MONDO subtype term is available).
- name: AR CYBC1 EROS
  display_name: Autosomal recessive CGD (CYBC1 / EROS)
  description: >-
    Autosomal recessive CGD from biallelic CYBC1 (EROS) variants; CYBC1
    encodes an endoplasmic reticulum chaperone required for gp91phox-p22phox
    stability, so its loss produces a functional NADPH oxidase deficiency. OMIM
    phenotype: 618935 (no distinct MONDO subtype term is available).
pathophysiology:
- name: NADPH oxidase (NOX2) complex assembly failure
  description: >-
    Pathogenic variants in any one of the NOX2 complex subunits (membrane
    gp91phox/CYBB and p22phox/CYBA forming flavocytochrome b558; cytosolic
    p47phox/NCF1, p67phox/NCF2, and p40phox/NCF4; and the CYBC1/EROS chaperone
    that stabilizes gp91phox) prevent assembly of a functional phagocyte NADPH
    oxidase on the phagosomal and plasma membranes. Without a functional
    oxidase, electrons cannot be transferred from cytosolic NADPH across the
    membrane to molecular oxygen.
  genes:
  - preferred_term: CYBB
    term:
      id: hgnc:2578
      label: CYBB
  - preferred_term: NCF1
    term:
      id: hgnc:7660
      label: NCF1
  cell_types:
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  - preferred_term: monocyte
    term:
      id: CL:0000576
      label: monocyte
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  - preferred_term: eosinophil
    term:
      id: CL:0000771
      label: eosinophil
  biological_processes:
  - preferred_term: superoxide anion generation
    term:
      id: GO:0042554
      label: superoxide anion generation
    modifier: DECREASED
  evidence:
  - reference: PMID:22876374
    reference_title: "Chronic Granulomatous Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "identification of pathogenic variant(s) in one of six \ngenes that encode or permit assembly of the subunits of phagocyte NADPH oxidase"
    explanation: Establishes that CGD results from defects in the six NADPH oxidase subunit/assembly genes.
  downstream:
  - target: Failed respiratory burst and ROS deficiency
    causal_link_type: DIRECT
    description: A non-functional NADPH oxidase cannot generate superoxide, abolishing the respiratory burst and downstream reactive oxygen species.
- name: Failed respiratory burst and ROS deficiency
  description: >-
    The assembled NADPH oxidase normally catalyzes the respiratory (oxidative)
    burst, reducing molecular oxygen to superoxide, which is dismutated and
    converted to hydrogen peroxide, hypohalous acids, and other reactive oxygen
    species within the phagosome. In CGD this burst is absent or markedly
    reduced, so phagocytes ingest microbes but fail to generate the oxidants
    required for efficient microbicidal activity.
  cell_types:
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  biological_processes:
  - preferred_term: respiratory burst
    term:
      id: GO:0045730
      label: respiratory burst
    modifier: DECREASED
  - preferred_term: reactive oxygen species metabolic process
    term:
      id: GO:0072593
      label: reactive oxygen species metabolic process
    modifier: DECREASED
  evidence:
  - reference: PMID:22876374
    reference_title: "Chronic Granulomatous Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "resulting from impaired killing of bacteria and fungi"
    explanation: The oxidase defect produces impaired phagocyte killing of bacteria and fungi via loss of the oxidative burst.
  downstream:
  - target: Impaired microbial killing and recurrent infection
    causal_link_type: DIRECT
    description: Loss of oxidant-dependent killing leaves phagocytes unable to clear catalase-positive bacteria and fungi, producing recurrent severe infection.
  - target: Dysregulated inflammation and granuloma formation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - impaired resolution of inflammation
    - persistent macrophage activation
    description: Loss of ROS-dependent signaling impairs resolution of inflammation and drives exuberant granuloma formation and colitis.
- name: Impaired microbial killing and recurrent infection
  description: >-
    Because oxidant-dependent killing is lost, phagocytes cannot efficiently
    clear catalase-positive organisms (which detoxify their own hydrogen
    peroxide) such as Staphylococcus aureus, Serratia marcescens, Burkholderia
    cepacia, Nocardia, and Aspergillus, producing the characteristic recurrent
    and severe pneumonias, abscesses, lymphadenitis, and osteomyelitis.
  cell_types:
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  biological_processes:
  - preferred_term: defense response to bacterium
    term:
      id: GO:0042742
      label: defense response to bacterium
    modifier: DECREASED
  - preferred_term: defense response to fungus
    term:
      id: GO:0050832
      label: defense response to fungus
    modifier: DECREASED
  evidence:
  - reference: PMID:22876374
    reference_title: "Chronic Granulomatous Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "characterized by severe recurrent bacterial and fungal infections"
    explanation: The killing defect produces the hallmark severe recurrent bacterial and fungal infections of CGD.
- name: Dysregulated inflammation and granuloma formation
  description: >-
    Independent of infection, NADPH oxidase deficiency dysregulates innate
    immune signaling and impairs the resolution of inflammation, driving
    persistent macrophage activation, exuberant granuloma formation that can
    obstruct hollow viscera (gastrointestinal and genitourinary tracts), and an
    inflammatory-bowel-disease-like colitis.
  cell_types:
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: granuloma formation
    term:
      id: GO:0002432
      label: granuloma formation
    modifier: INCREASED
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  evidence:
  - reference: PMID:22876374
    reference_title: "Chronic Granulomatous Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "dysregulated inflammatory responses resulting in granuloma formation and other \ninflammatory disorders such as colitis"
    explanation: Establishes the dysregulated-inflammation arm of CGD producing granulomas and colitis.
phenotypes:
- name: Recurrent bacterial infections
  category: Immunologic
  frequency: VERY_FREQUENT
  description: >-
    Severe, recurrent bacterial infections with catalase-positive organisms
    (S. aureus, Serratia, Burkholderia, Nocardia) are a cardinal feature.
  phenotype_term:
    preferred_term: Recurrent bacterial infections
    term:
      id: HP:0002718
      label: Recurrent bacterial infections
  evidence:
  - reference: PMID:22876374
    reference_title: "Chronic Granulomatous Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "characterized by severe recurrent bacterial and fungal infections"
    explanation: GeneReviews establishes severe recurrent bacterial infection as a defining feature of CGD.
- name: Recurrent fungal infections
  category: Immunologic
  frequency: VERY_FREQUENT
  description: >-
    Invasive fungal infection, particularly aspergillosis, is a major cause of
    morbidity and mortality in CGD.
  phenotype_term:
    preferred_term: Recurrent fungal infections
    term:
      id: HP:0002841
      label: Recurrent fungal infections
  evidence:
  - reference: PMID:22876374
    reference_title: "Chronic Granulomatous Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "characterized by severe recurrent bacterial and fungal infections"
    explanation: GeneReviews establishes severe recurrent fungal infection as a defining feature of CGD.
- name: Pneumonia
  category: Respiratory
  frequency: FREQUENT
  description: >-
    The lung is the most commonly affected site, with recurrent bacterial and
    fungal pneumonia.
  phenotype_term:
    preferred_term: Pneumonia
    term:
      id: HP:0002090
      label: Pneumonia
  evidence:
  - reference: PMID:22876374
    reference_title: "Chronic Granulomatous Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Infections typically involve the lung \n(pneumonia)"
    explanation: GeneReviews lists pneumonia as a typical infection site in CGD.
  - reference: PMID:10844935
    reference_title: "Chronic granulomatous disease. Report on a national registry of 368 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pneumonia \nwas the most prevalent infection (79% of patients; Aspergillus most prevalent \ncause)"
    explanation: The US registry documents pneumonia in 79% of patients, supporting the FREQUENT frequency band.
- name: Lymphadenitis
  category: Immunologic
  frequency: FREQUENT
  description: >-
    Suppurative lymphadenitis is a common site of infection in CGD.
  phenotype_term:
    preferred_term: Lymphadenitis
    term:
      id: HP:0002840
      label: Lymphadenitis
  evidence:
  - reference: PMID:22876374
    reference_title: "Chronic Granulomatous Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "lymph nodes (lymphadenitis)"
    explanation: GeneReviews lists lymphadenitis as a typical infection site in CGD.
- name: Liver abscess
  category: Gastrointestinal
  frequency: OCCASIONAL
  description: >-
    Hepatic (often staphylococcal) abscesses are a characteristic deep-organ
    infection in CGD.
  phenotype_term:
    preferred_term: Liver abscess
    term:
      id: HP:0100523
      label: Liver abscess
  evidence:
  - reference: PMID:22876374
    reference_title: "Chronic Granulomatous Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "liver (abscess)"
    explanation: GeneReviews lists liver abscess as a typical infection site in CGD.
  - reference: PMID:10844935
    reference_title: "Chronic granulomatous disease. Report on a national registry of 368 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "liver abscess (27% of patients;"
    explanation: The US registry documents liver abscess in 27% of patients, supporting the OCCASIONAL frequency band.
- name: Osteomyelitis
  category: Musculoskeletal
  frequency: OCCASIONAL
  description: >-
    Bone infection (osteomyelitis), classically involving small bones of the
    hands and feet, occurs in CGD.
  phenotype_term:
    preferred_term: Osteomyelitis
    term:
      id: HP:0002754
      label: Osteomyelitis
  evidence:
  - reference: PMID:22876374
    reference_title: "Chronic Granulomatous Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "bone (osteomyelitis)"
    explanation: GeneReviews lists osteomyelitis as a typical infection site in CGD.
- name: Recurrent skin abscesses
  category: Dermatologic
  frequency: FREQUENT
  description: >-
    Recurrent skin abscesses and cellulitis are common cutaneous manifestations.
  phenotype_term:
    preferred_term: Recurrent skin abscesses
    term:
      id: HP:0002722
      label: Recurrent abscess formation
  evidence:
  - reference: PMID:22876374
    reference_title: "Chronic Granulomatous Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "skin (abscesses or cellulitis)"
    explanation: GeneReviews lists skin abscesses/cellulitis as a typical infection site in CGD.
- name: Granulomatous inflammation
  category: Immunologic
  frequency: VERY_FREQUENT
  description: >-
    Exuberant granuloma formation, frequently obstructing the genitourinary
    (bladder) and gastrointestinal tract, is a defining non-infectious feature.
  phenotype_term:
    preferred_term: Granulomatosis
    term:
      id: HP:0002955
      label: Granulomatosis
  evidence:
  - reference: PMID:22876374
    reference_title: "Chronic Granulomatous Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "dysregulated inflammatory responses resulting in granuloma formation"
    explanation: GeneReviews establishes granuloma formation as a defining feature of CGD.
- name: Colitis
  category: Gastrointestinal
  frequency: FREQUENT
  description: >-
    An inflammatory-bowel-disease-like colitis is a common non-infectious
    inflammatory complication of CGD.
  phenotype_term:
    preferred_term: Colitis
    term:
      id: HP:0002583
      label: Colitis
  evidence:
  - reference: PMID:22876374
    reference_title: "Chronic Granulomatous Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "other \ninflammatory disorders such as colitis"
    explanation: GeneReviews lists colitis among the dysregulated inflammatory disorders of CGD.
- name: Sepsis
  category: Immunologic
  frequency: OCCASIONAL
  description: >-
    Systemic infection (sepsis), classically due to Salmonella, is a
    life-threatening complication of CGD.
  phenotype_term:
    preferred_term: Sepsis
    term:
      id: HP:0100806
      label: Sepsis
  evidence:
  - reference: PMID:10844935
    reference_title: "Chronic granulomatous disease. Report on a national registry of 368 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "sepsis (18% of patients; Salmonella most prevalent cause)"
    explanation: The US registry documents sepsis in 18% of patients, supporting the OCCASIONAL frequency band.
- name: Gastric outlet obstruction
  category: Gastrointestinal
  frequency: OCCASIONAL
  description: >-
    Gastric outlet (antral/pyloric) obstruction from obstructing granulomas is
    a characteristic non-infectious gastrointestinal complication of CGD.
  phenotype_term:
    preferred_term: Gastric outlet obstruction
    term:
      id: HP:0002021
      label: Pyloric stenosis
  evidence:
  - reference: PMID:10844935
    reference_title: "Chronic granulomatous disease. Report on a national registry of 368 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "patients had gastric outlet obstruction"
    explanation: The US registry documents gastric outlet obstruction in 15% of patients, supporting the OCCASIONAL frequency band.
inheritance:
- name: X-linked (CYBB)
  description: >-
    CGD due to a CYBB pathogenic variant is inherited in an X-linked manner; a
    heterozygous mother has a 50% chance of transmitting the variant in each
    pregnancy, and males who inherit it are affected.
  evidence:
  - reference: PMID:22876374
    reference_title: "Chronic Granulomatous Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "CGD associated with a pathogenic variant in CYBB is \ninherited in an X-linked manner"
    explanation: GeneReviews states CYBB-associated CGD is X-linked.
- name: Autosomal recessive (CYBA/CYBC1/NCF1/NCF2/NCF4)
  description: >-
    CGD due to biallelic variants in CYBA, CYBC1, NCF1, NCF2, or NCF4 is
    inherited in an autosomal recessive manner; each sib of an affected
    individual has a 25% chance of being affected.
  evidence:
  - reference: PMID:22876374
    reference_title: "Chronic Granulomatous Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "CGD associated with biallelic pathogenic \nvariants in CYBA, CYBC1, NCF1, NCF2, or NCF4 is inherited in an autosomal \nrecessive manner"
    explanation: GeneReviews states CYBA/CYBC1/NCF1/NCF2/NCF4-associated CGD is autosomal recessive.
genetic:
- name: CYBB
  subtype: X-linked CYBB
  association: Causative
  gene_term:
    preferred_term: CYBB
    term:
      id: hgnc:2578
      label: CYBB
  notes: >-
    Hemizygous pathogenic variants in CYBB (Xp21.1) encoding gp91phox (NOX2),
    the catalytic membrane subunit of the phagocyte NADPH oxidase, cause
    X-linked CGD, the most common form. A contiguous-gene deletion can
    additionally cause McLeod neuroacanthocytosis syndrome.
  evidence:
  - reference: PMID:22876374
    reference_title: "Chronic Granulomatous Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "pathogenic variants in CYBB cause X-linked CGD"
    explanation: GeneReviews identifies CYBB pathogenic variants as the cause of X-linked CGD.
  - reference: PMID:31988463
    reference_title: "Lentiviral gene therapy for X-linked chronic granulomatous disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "X-CGD is caused by mutations in CYBB encoding the gp91phox subunit of the phagocyte"
    explanation: Confirms that X-linked CGD is caused by CYBB mutations encoding the gp91phox NADPH-oxidase subunit.
- name: CYBA
  subtype: AR p22phox CYBA
  association: Causative
  gene_term:
    preferred_term: CYBA
    term:
      id: hgnc:2577
      label: CYBA
  notes: Biallelic CYBA variants (encoding p22phox) cause autosomal recessive CGD.
  evidence:
  - reference: PMID:22876374
    reference_title: "Chronic Granulomatous Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "biallelic pathogenic variants in CYBA, CYBC1, NCF1, NCF2, and NCF4 cause \nautosomal recessive CGD"
    explanation: GeneReviews identifies biallelic CYBA variants as a cause of autosomal recessive CGD.
- name: NCF1
  subtype: AR p47phox NCF1
  association: Causative
  gene_term:
    preferred_term: NCF1
    term:
      id: hgnc:7660
      label: NCF1
  notes: >-
    Biallelic NCF1 variants (encoding p47phox) cause the most common autosomal
    recessive form of CGD, generally with a milder course.
  evidence:
  - reference: PMID:22876374
    reference_title: "Chronic Granulomatous Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "biallelic pathogenic variants in CYBA, CYBC1, NCF1, NCF2, and NCF4 cause \nautosomal recessive CGD"
    explanation: GeneReviews identifies biallelic NCF1 variants as a cause of autosomal recessive CGD.
- name: NCF2
  subtype: AR p67phox NCF2
  association: Causative
  gene_term:
    preferred_term: NCF2
    term:
      id: hgnc:7661
      label: NCF2
  notes: Biallelic NCF2 variants (encoding p67phox) cause autosomal recessive CGD.
  evidence:
  - reference: PMID:22876374
    reference_title: "Chronic Granulomatous Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "biallelic pathogenic variants in CYBA, CYBC1, NCF1, NCF2, and NCF4 cause \nautosomal recessive CGD"
    explanation: GeneReviews identifies biallelic NCF2 variants as a cause of autosomal recessive CGD.
- name: NCF4
  subtype: AR p40phox NCF4
  association: Causative
  gene_term:
    preferred_term: NCF4
    term:
      id: hgnc:7662
      label: NCF4
  notes: >-
    Biallelic NCF4 variants (encoding p40phox) cause a rare autosomal recessive
    form, often with a predominantly inflammatory/colitis phenotype.
  evidence:
  - reference: PMID:22876374
    reference_title: "Chronic Granulomatous Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "biallelic pathogenic variants in CYBA, CYBC1, NCF1, NCF2, and NCF4 cause \nautosomal recessive CGD"
    explanation: GeneReviews identifies biallelic NCF4 variants as a cause of autosomal recessive CGD.
- name: CYBC1
  subtype: AR CYBC1 EROS
  association: Causative
  gene_term:
    preferred_term: CYBC1
    term:
      id: hgnc:28672
      label: CYBC1
  notes: >-
    Biallelic CYBC1 (EROS) variants cause autosomal recessive CGD; CYBC1
    encodes a chaperone required to permit assembly of the NADPH oxidase.
  evidence:
  - reference: PMID:22876374
    reference_title: "Chronic Granulomatous Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "biallelic pathogenic variants in CYBA, CYBC1, NCF1, NCF2, and NCF4 cause \nautosomal recessive CGD"
    explanation: GeneReviews identifies biallelic CYBC1 variants as a cause of autosomal recessive CGD.
diagnosis:
- name: Neutrophil oxidative burst testing (DHR / NBT)
  description: >-
    The functional hallmark of CGD is an absent or markedly reduced phagocyte
    oxidative burst, demonstrated by dihydrorhodamine (DHR) flow cytometry
    (preferred) or the older nitroblue tetrazolium (NBT) slide test. Molecular
    genetic testing then confirms the specific subunit defect.
  diagnosis_term:
    preferred_term: flow cytometry procedure
    term:
      id: MAXO:0035055
      label: flow cytometry procedure
  results: Absent or markedly reduced neutrophil oxidative burst
  evidence:
  - reference: PMID:39836849
    reference_title: "Standardization of the use of opsonized zymosan as stimulus in the 1,2,3-dihydrorhodamine technique for the assessment of neutrophil respiratory burst."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "1,2,3-dihydrorhodamine oxidation technique, with phorbol-12-myristate-13-acetate \nas a stimulus, is performed to diagnose the classic chronic granulomatous \ndisease"
    explanation: Establishes the dihydrorhodamine (DHR) oxidative-burst assay as the diagnostic test for classic CGD.
- name: Molecular genetic testing
  description: >-
    Definitive diagnosis is established by identifying pathogenic variant(s) in
    one of the six NADPH oxidase genes (CYBB, CYBA, CYBC1, NCF1, NCF2, NCF4).
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: MAXO:0000533
      label: molecular genetic testing
  results: Pathogenic variant(s) in a NADPH oxidase subunit/assembly gene
  evidence:
  - reference: PMID:22876374
    reference_title: "Chronic Granulomatous Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The diagnosis of CGD is established in a proband with \nsuggestive findings by identification of pathogenic variant(s) in one of six \ngenes"
    explanation: GeneReviews states molecular identification of a pathogenic variant in one of the six genes establishes the diagnosis.
treatments:
- name: Antibacterial prophylaxis (trimethoprim-sulfamethoxazole)
  description: >-
    Lifelong daily antibacterial prophylaxis, standardly with
    trimethoprim-sulfamethoxazole, is recommended to prevent infections.
    Pregnancy caution: trimethoprim (a folic acid antagonist) is discontinued
    during pregnancy because of the high risk for birth defects.
  treatment_term:
    preferred_term: Antibiotic prophylaxis
    term:
      id: NCIT:C15620
      label: Antibiotic Therapy
    therapeutic_agent:
    - preferred_term: trimethoprim
      term:
        id: CHEBI:45924
        label: trimethoprim
    - preferred_term: sulfamethoxazole
      term:
        id: CHEBI:9332
        label: sulfamethoxazole
  target_mechanisms:
  - target: Impaired microbial killing and recurrent infection
    treatment_effect: BYPASSES
    description: Prophylactic antibiotics suppress bacterial infection that the oxidase-deficient phagocytes cannot clear.
  evidence:
  - reference: PMID:22876374
    reference_title: "Chronic Granulomatous Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Lifelong daily antibacterial and \nantifungal prophylaxis is recommended"
    explanation: GeneReviews recommends lifelong daily antibacterial prophylaxis.
  - reference: PMID:22876374
    reference_title: "Chronic Granulomatous Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "trimethoprim, a folic acid antagonist, is \ndiscontinued during pregnancy because of the high risk for birth defects"
    explanation: GeneReviews documents the pregnancy drug-safety caution for trimethoprim.
- name: Antifungal prophylaxis (itraconazole)
  description: >-
    Lifelong daily antifungal prophylaxis, standardly with itraconazole,
    reduces invasive fungal infection; newer azoles (voriconazole,
    posaconazole, isavuconazole) have expanded therapeutic options for
    established fungal infection.
  treatment_term:
    preferred_term: Antifungal pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: itraconazole
      term:
        id: CHEBI:6076
        label: itraconazole
  target_mechanisms:
  - target: Impaired microbial killing and recurrent infection
    treatment_effect: BYPASSES
    description: Antifungal prophylaxis suppresses fungal infection (especially Aspergillus) that the oxidase-deficient phagocytes cannot clear.
  evidence:
  - reference: PMID:22876374
    reference_title: "Chronic Granulomatous Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Lifelong daily antibacterial and \nantifungal prophylaxis is recommended"
    explanation: GeneReviews recommends lifelong daily antifungal prophylaxis.
  - reference: PMID:22876374
    reference_title: "Chronic Granulomatous Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Newer azole drugs (voriconazole, \nposaconazole, isovuconazole) have expanded therapeutic options for fungal \ninfections"
    explanation: GeneReviews notes newer azoles have expanded antifungal therapy options.
- name: Interferon-gamma prophylaxis
  description: >-
    Immunomodulatory prophylaxis with interferon gamma (IFN-gamma) is part of
    the standard prophylactic regimen in many centers.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: interferon gamma-1b
      term:
        id: CHEBI:5939
        label: Interferon gamma-1b
  target_mechanisms:
  - target: Impaired microbial killing and recurrent infection
    treatment_effect: MODULATES
    description: IFN-gamma prophylaxis reduces the frequency and severity of serious infections in CGD.
  evidence:
  - reference: PMID:22876374
    reference_title: "Chronic Granulomatous Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "immunomodulatory therapy with interferon \ngamma (IFN-gamma) is part of the prophylactic regimen in many centers"
    explanation: GeneReviews describes IFN-gamma as part of the prophylactic regimen in many centers.
- name: Corticosteroids for inflammatory complications
  description: >-
    Simultaneous administration of antimicrobials and corticosteroids can help
    resolve the heightened inflammatory response, including colitis and
    obstructing granulomas.
  treatment_term:
    preferred_term: Corticosteroid therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: corticosteroid
      term:
        id: CHEBI:50858
        label: corticosteroid
  target_mechanisms:
  - target: Dysregulated inflammation and granuloma formation
    treatment_effect: MODULATES
    description: Corticosteroids dampen the dysregulated hyperinflammatory response that drives colitis and granulomas.
  evidence:
  - reference: PMID:22876374
    reference_title: "Chronic Granulomatous Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Simultaneous administration of antimicrobials and corticosteroids can help \nresolve the associated heightened inflammatory response, including colitis"
    explanation: GeneReviews supports corticosteroids for the inflammatory/colitis complications of CGD.
- name: Allogeneic hematopoietic stem cell transplantation
  description: >-
    Allogeneic HSCT is the only known cure for CGD and is associated with
    excellent overall and event-free survival, especially with matched donors
    at a younger age.
  treatment_term:
    preferred_term: allogeneic hematopoietic stem cell transplantation
    term:
      id: MAXO:0001479
      label: allogeneic hematopoietic stem cell transplantation
  target_mechanisms:
  - target: NADPH oxidase (NOX2) complex assembly failure
    treatment_effect: RESTORES
    description: HSCT replaces the patient's hematopoietic compartment with donor cells that express a functional NADPH oxidase.
  evidence:
  - reference: PMID:22876374
    reference_title: "Chronic Granulomatous Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Allogeneic hematopoietic stem cell transplantation (HSCT) is the only known cure \nfor CGD"
    explanation: GeneReviews identifies allogeneic HSCT as the only known cure for CGD.
- name: Autologous hematopoietic stem cell gene therapy
  description: >-
    Ex vivo autologous CD34+ hematopoietic stem and progenitor cell lentiviral
    gene therapy (e.g., the self-inactivating G1XCGD vector for X-linked CGD)
    is an emerging curative approach for patients lacking a matched donor,
    restoring oxidase-positive neutrophils and functional superoxide production.
  treatment_term:
    preferred_term: Gene therapy
    term:
      id: NCIT:C15238
      label: Gene Therapy
  therapeutic_modality: GENE_THERAPY
  target_mechanisms:
  - target: NADPH oxidase (NOX2) complex assembly failure
    treatment_effect: RESTORES
    description: Ex vivo lentiviral correction of autologous stem cells restores functional NADPH oxidase (gp91phox) expression in the phagocyte lineage.
  evidence:
  - reference: PMID:31988463
    reference_title: "Lentiviral gene therapy for X-linked chronic granulomatous disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "six of the seven surviving patients demonstrated \nstable vector copy numbers (0.4-1.8 copies per neutrophil) and the persistence \nof 16-46% oxidase-positive neutrophils"
    explanation: A multicenter trial showed lentiviral gene therapy restored persistent oxidase-positive neutrophils in X-CGD patients.
  - reference: PMID:31988463
    reference_title: "Lentiviral gene therapy for X-linked chronic granulomatous disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "suggesting that autologous gene therapy is a \npromising approach for CGD patients"
    explanation: The trial concludes autologous gene therapy is a promising approach for CGD.
- name: Avoidance of high-risk exposures (agents/circumstances to avoid)
  description: >-
    Per GeneReviews, patients with CGD should avoid decayed organic matter
    (mulching, gardening, leaf raking, house demolition), because inhalation of
    fungal spores can cause fulminant pneumonitis, and should avoid live
    bacterial vaccines including bacille Calmette-Guerin (BCG) and Salmonella
    typhi vaccination.
  treatment_term:
    preferred_term: Supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  target_mechanisms:
  - target: Impaired microbial killing and recurrent infection
    treatment_effect: BYPASSES
    description: Avoiding heavy fungal-spore exposure and live bacterial vaccines removes infectious challenges the oxidase-deficient phagocytes cannot control.
  evidence:
  - reference: PMID:22876374
    reference_title: "Chronic Granulomatous Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Decayed \norganic matter (e.g., mulching, gardening, leaf raking, house demolition) as \ninhalation of fungal spores can result in fulminant pneumonitis"
    explanation: GeneReviews advises avoiding decayed organic matter because fungal-spore inhalation can cause fulminant pneumonitis.
  - reference: PMID:22876374
    reference_title: "Chronic Granulomatous Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "live \nbacterial vaccines including bacille Calmette-Guérin (BCG) vaccination and \nSalmonella typhi vaccination"
    explanation: GeneReviews advises avoiding live bacterial vaccines (BCG, Salmonella typhi) in CGD.
- name: Genetic counseling
  description: >-
    Genetic counseling addresses the mixed inheritance of CGD (X-linked for
    CYBB; autosomal recessive for CYBA, CYBC1, NCF1, NCF2, NCF4) and the
    availability of carrier, prenatal, and preimplantation genetic testing once
    the familial variant(s) are known.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:22876374
    reference_title: "Chronic Granulomatous Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Once the CGD-causing \npathogenic variant(s) have been identified in an affected family member, \nprenatal and preimplantation genetic testing are possible"
    explanation: GeneReviews supports genetic counseling with prenatal/preimplantation testing options.
differential_diagnoses:
- name: Other primary immunodeficiencies
  description: >-
    Other phagocyte and combined immunodeficiencies (e.g., leukocyte adhesion
    deficiency, hyper-IgE syndrome, severe congenital neutropenia) can produce
    overlapping recurrent infections but have a normal oxidative burst.
  evidence:
  - reference: PMID:22876374
    reference_title: "Chronic Granulomatous Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Chronic granulomatous disease (CGD) is a primary \nimmunodeficiency disorder of phagocytes"
    explanation: CGD sits within the phagocyte/primary immunodeficiency differential, distinguished by the oxidative-burst defect.
- name: Inflammatory bowel disease
  description: >-
    CGD colitis can closely mimic Crohn disease/inflammatory bowel disease;
    CGD should be considered in early-onset or atypical IBD, especially with a
    history of infections.
  evidence:
  - reference: PMID:22876374
    reference_title: "Chronic Granulomatous Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "other \ninflammatory disorders such as colitis"
    explanation: CGD colitis is a mimic of inflammatory bowel disease, an important differential.
references:
- reference: PMID:22876374
  title: "Chronic Granulomatous Disease."
  tags:
  - GeneReviews
📚

References & Deep Research

References

1
PMID:22876374
Chronic Granulomatous Disease.
No top-level findings curated for this source.

Deep Research

1
Claude Code ▸
1. Disease Information
claude-haiku-4-5-20251001, claude-opus-4-8[1m] 13 citations 2026-07-01T09:05:18.971659

1. Disease Information

Overview. Chronic granulomatous disease (CGD) is an inherited primary immunodeficiency (inborn error of immunity) caused by defects in the phagocyte NADPH oxidase complex (NOX2 system). Because neutrophils, monocytes, macrophages, and eosinophils cannot mount a normal respiratory burst — the burst of superoxide and downstream reactive oxygen species (ROS) that kills ingested microbes — patients suffer recurrent, life-threatening bacterial and fungal infections and a paradoxical tendency to granuloma formation and hyperinflammation (e.g., inflammatory bowel disease–like colitis). It is the prototypical defect of phagocyte killing (IUIS classification: "congenital defects of phagocyte number or function").

Think of the neutrophil as a cell that swallows a bacterium and is supposed to detonate a tiny oxidative bomb inside the phagosome. In CGD the fuse is cut — the microbe is engulfed but survives, and the frustrated immune system walls it off in a granuloma instead.

Key identifiers: - MONDO: MONDO:0018305 (chronic granulomatous disease, umbrella); X-linked form MONDO:0010071 - OMIM (phenotype series): - 306400 — CGD, X-linked (CYBB / gp91-phox) - 233690 — CGD, autosomal recessive, cytochrome b–negative (CYBA / p22-phox) - 233700 — CGD, autosomal recessive, cytochrome b–positive, type I (NCF1 / p47-phox) - 233710 — CGD, autosomal recessive, type II (NCF2 / p67-phox) - 613960 — CGD, autosomal recessive, type III (NCF4 / p40-phox) - 618935 — CGD due to CYBC1/EROS deficiency - Orphanet: ORPHA:379 - ICD-10: D71 (Functional disorders of polymorphonuclear neutrophils); ICD-11: 4A00.10 - MeSH: D006105 ("Granulomatous Disease, Chronic")

Synonyms / historical names: CGD; chronic granulomatous disease of childhood; congenital dysphagocytosis; "fatal granulomatosis of childhood" (historical, pre-antibiotic era); Bridges–Good syndrome; progressive septic granulomatosis; NADPH oxidase deficiency.

Data derivation. The knowledge base entry should be an aggregated disease-level synthesis (OMIM, Orphanet, GeneReviews, national/international CGD registries), not individual-EHR-derived. Major aggregate cohorts include the U.S. national registry of 368 patients (PMID 10844935, Winkelstein et al., Medicine 2000), the European experience (van den Berg et al., PLoS One 2009, PMID 19381301), and the residual-oxidase survival cohort of 287 patients (PMID 21190454, Kuhns et al., NEJM 2010).

Recent comprehensive reviews suitable as backbone citations: Roos D, Br Med Bull 2016; Arnold DE & Heimall JR, "A Review of Chronic Granulomatous Disease," Adv Ther 2017 (PMID ~29168050, verify); Yu JE et al., "Considerations in the Diagnosis of CGD," J Pediatric Infect Dis Soc 2018 (PMID 29746674); and the Justiz Vaillant/StatPearls chapter (PMID via NBK493171).

2. Etiology

Primary cause — genetic. CGD is monogenic. It results from loss-of-function variants in any one of six genes encoding subunits of the phagocyte NADPH oxidase (NOX2) complex or its assembly chaperone:

Gene Protein Locus Inheritance Approx. share of cases
CYBB gp91-phox (NOX2) Xp21.1–p11.4 X-linked recessive ~65–70% (∼2/3)
NCF1 p47-phox 7q11.23 Autosomal recessive ~20–25% (most common AR)
NCF2 p67-phox 1q25 Autosomal recessive ~5%
CYBA p22-phox 16q24 Autosomal recessive ~5%
NCF4 p40-phox 22q13.1 Autosomal recessive rare (<1%)
CYBC1 (EROS/C17orf62) Eros chaperone 17q25.3 Autosomal recessive rare, recently described

"Molecular defects in any of these five genes (CYBB for gp91phox … CYBA for p22phox, NCF1 for p47phox, NCF2 for p67phox, and NCF4 for p40phox) can occur in 90% of patients" — supported by GeneReviews and the MDPI review (verify exact wording against PMID before use).

CYBB is X-linked; the other five are autosomal recessive. In Western/outbred populations X-linked disease predominates (males ~80% of patients); in populations with high consanguinity, autosomal recessive forms rise to parity or majority.

Environmental/infectious triggers. No environmental exposure causes CGD, but infections are the clinical trigger. Catalase-positive organisms are the pathogenic linchpin (see §5). Live vaccines (notably BCG) can cause disseminated disease ("BCGosis") in undiagnosed infants.

Risk factors. - Genetic risk: hemizygous CYBB variant in males; biallelic pathogenic variants in an AR gene; carrier mother of an X-linked proband. Family history is the dominant risk factor. - Consanguinity markedly increases AR-form risk. - Sex: male (X-linked predominance). - No established modifiable lifestyle risk factors.

Protective factors. In a well-documented gene–environment/genotype–phenotype effect, residual NADPH oxidase activity is strongly protective: patients retaining measurable superoxide production have markedly better survival (PMID 21190454, Kuhns et al.). Certain "leaky" CYBB missense/splice variants (e.g., the X91⁻ and X91ᵛᵃʳⁱᵃᵇˡᵉ subtypes) confer milder disease. X-linked carrier females with skewed X-inactivation toward the wild-type allele (>10–20% oxidase-normal neutrophils) are usually clinically protected from infection, though they may develop lupus-like/photosensitive and inflammatory features.

Gene–environment interactions. The central interaction is genotype (residual ROS) × microbial exposure: the lower the residual oxidase, the more catalase-positive organisms establish infection. There is no classic toxicant GxE; the "environment" is the microbiome/pathogen load.

3. Phenotypes

CGD phenotypes fall into two arms: (A) infectious and (B) inflammatory/granulomatous. Onset is usually infancy to early childhood (most diagnosed at 1–3 years; milder AR/p47-phox cases may present in adolescence/adulthood). Course is chronic-lifelong, episodic/recurrent. Severity is variable, tracking residual oxidase activity.

A. Infectious phenotypes

  • Recurrent bacterial and fungal infections — the defining feature. Suggested HP: Recurrent bacterial infections (HP:0002718), Recurrent fungal infections (HP:0002841 — verify), Immunodeficiency (HP:0002721).
  • Pneumonia / recurrent pneumonia, often Aspergillus — HP:0002090 (Pneumonia); Aspergillosis HP:0033100 (verify). Frequency: very frequent (leading cause of infection and death).
  • Suppurative/lymphadenitis and abscesses — lymphadenitis (HP:0002716 — verify), liver abscess (staphylococcal, characteristically "dense/caseous") — Hepatic abscess (verify ID), perianal/perirectal abscess, skin abscesses/pustular dermatitis.
  • Osteomyelitis (including Serratia, Aspergillus, Burkholderia) — HP:0002754 (verify).
  • Septicemia / sepsis (Burkholderia, Salmonella) — Sepsis (verify).
  • Otitis, sinusitis, gingivitis/stomatitis, aphthous ulcers.

B. Inflammatory/granulomatous phenotypes

  • Granuloma formation — hallmark; obstructing granulomas of GU (bladder) and GI tract. Suggested HP: Granuloma (HP:0032252 — verify).
  • Inflammatory bowel disease (IBD)–like colitis — up to ~40–50% of patients, especially X-linked; diarrhea, failure to thrive, perianal disease, strictures. HP: Colitis (HP:0002583 — verify), Diarrhea (HP:0002014), Inflammatory abnormality of the large intestine.

    "…up to 50% of patients having gastrointestinal involvement meeting diagnostic criteria for inflammatory bowel disease" (USIDNET registry, PMID 35.../PMC9086117 — verify).

  • Gastric outlet obstruction / antral narrowing, esophageal/ureteral strictures.
  • Hepatosplenomegaly and lymphadenopathy — Splenomegaly (HP:0001744), Hepatomegaly (HP:0002240), Lymphadenopathy (verify).
  • Failure to thrive / growth delay / short stature — HP:0001508 (Failure to thrive), HP:0001510 (Growth delay).
  • Chorioretinitis / retinal lesions; discoid-lupus/photosensitive skin lesions (especially in X-linked carriers).
  • Autoimmune/autoinflammatory features (lupus-like, JIA-like, antiphospholipid).

Laboratory-abnormality phenotypes

  • Abnormal/absent neutrophil respiratory burst (DHR-123 flow cytometry, NBT) — the central lab phenotype.
  • Anemia of chronic disease, leukocytosis, elevated ESR/CRP, hypergammaglobulinemia, elevated IL-18/IFN-γ in inflamed tissue (PMC6813411).

Quality-of-life impact. Chronic infections, IBD-like colitis, frequent hospitalizations, prolonged IV antimicrobials, growth failure, and (historically) shortened lifespan substantially reduce QoL; colitis is a major driver of morbidity. Formal EQ-5D/SF-36 CGD datasets are sparse — flag as data-limited.

4. Genetic / Molecular Information

Causal genes & products (HGNC): - CYBB (hgnc:2578) → gp91-phox / NOX2 (catalytic β-subunit of flavocytochrome b₅₅₈). - CYBA (hgnc:2577) → p22-phox (α-subunit; stabilizes gp91-phox in the membrane). - NCF1 (hgnc:7660) → p47-phox ("organizer" cytosolic factor). - NCF2 (hgnc:7661) → p67-phox ("activator" cytosolic factor; binds Rac). - NCF4 (hgnc:7662) → p40-phox (cytosolic; phagosomal targeting via PX domain). - CYBC1 / EROS (verify HGNC) → chaperone required for gp91-phox/p22-phox expression.

Use lowercase hgnc: CURIEs per repo convention.

Variant landscape. - CYBB: highly heterogeneous — nonsense, frameshift, splice-site, missense, large deletions/insertions across the gene. Classified by residual protein/function: X91⁰ (absent gp91-phox, no oxidase — most severe), X91⁻ (reduced), X91⁺ (normal protein, non-functional). Large contiguous Xp21 deletions can produce a contiguous gene syndrome (CGD + McLeod/Kell phenotype ± Duchenne muscular dystrophy ± retinitis pigmentosa/ornithine transcarbamylase). - NCF1: the ΔGT dinucleotide deletion (c.75_76delGT) at the start of exon 2 accounts for the vast majority of p47-phox alleles; it arises from recombination with adjacent NCF1 pseudogenes (ψNCF1), complicating molecular diagnosis and gnomAD frequency estimates. - Variant classification (ACMG/AMP): most are pathogenic/likely pathogenic loss-of-function; consult ClinVar and the curated CYBB/NCF1 mutation databases (Roos et al.). Somatic vs germline: germline (X-linked hemizygous or AR biallelic); no somatic mechanism. - Functional consequence: loss of function (failure to assemble/activate the oxidase). A few missense variants are hypomorphic (partial function → milder phenotype). A distinct p40-phox (NCF4) defect selectively impairs intracellular/phagosomal ROS with relatively preserved extracellular burst, giving a colitis-predominant, infection-mild phenotype.

Modifier genes / genetic modifiers. Residual oxidase level is the dominant severity modifier (functionally, not a separate locus). Polymorphisms in myeloperoxidase, mannose-binding lectin, FcγR, and inflammatory loci have been proposed to modify infection/inflammation risk (weaker evidence). X-inactivation skewing modifies carrier-female phenotype.

Epigenetic information. No established primary epigenetic mechanism; X-linked carrier phenotype is governed by X-chromosome inactivation (lyonization) patterns. Flag as not-a-major-feature.

Chromosomal abnormalities. Large Xp21 contiguous deletions (structural) as above; detectable by MLPA/CMA/karyotype. Otherwise CGD is a single-gene disorder.

Allele frequency. Individual pathogenic variants are rare; because CGD is severe, causal alleles are at very low frequency in gnomAD. The NCF1 ΔGT is confounded by pseudogene mapping — treat gnomAD NCF1 frequencies with caution.

5. Environmental Information

Infectious agents (central to CGD). The classic vulnerability is to catalase-positive organisms (catalase degrades microbial H₂O₂ that could otherwise substitute for the missing host oxidant). The "big five" CGD pathogens: 1. Staphylococcus aureus (catalase⁺; liver abscess, lymphadenitis, osteomyelitis) — NCBITaxon:1280 2. Burkholderia (Pseudomonas) cepacia complex (pneumonia, sepsis — high mortality) — NCBITaxon:87882/292 3. Serratia marcescens (osteomyelitis, soft-tissue) — NCBITaxon:615 4. Nocardia species (necrotizing pneumonia) — NCBITaxon:1817 5. Aspergillus species (A. fumigatus, A. nidulans — the latter almost pathognomonic; invasive pulmonary/osteo aspergillosis; leading cause of death) — NCBITaxon:746128 (A. fumigatus)

Other important agents: Salmonella, Granulibacter bethesdensis, Chromobacterium violaceum, Mycobacterium (including BCG vaccine strain and M. tuberculosis), Candida spp.

"Aspergillus species was the first cause of infection and of death in cohorts, which underscores the importance of antifungal prophylaxis with itraconazole." (review; verify).

Environmental/lifestyle factors. Exposure to decaying organic matter/mulch/gardening (mold — Aspergillus, and mulch pneumonitis, an acute fulminant fungal alveolitis after heavy inhalation) is a recognized precipitant. Live vaccines (BCG, live Salmonella typhi) are contraindicated. Smoking/aerosolized fungal exposure worsens pulmonary risk. No dietary cause.

6. Mechanism / Pathophysiology

Core molecular defect. The phagocyte NADPH oxidase (NOX2 complex) normally assembles at the phagosomal/plasma membrane: the membrane flavocytochrome b₅₅₈ (gp91-phox + p22-phox) docks the cytosolic regulatory factors p47-phox, p67-phox, p40-phox and the small GTPase Rac2 (Rac1 in some cells). Assembly enables electron transfer from cytosolic NADPH across the membrane to molecular O₂, generating superoxide (O₂•⁻) — the respiratory (oxidative) burst. Superoxide dismutates to H₂O₂ and, with myeloperoxidase, forms hypochlorous acid and other microbicidal ROS.

Suggested GO terms: respiratory burst (GO:0045730), superoxide anion generation (GO:0042554), superoxide metabolic process (GO:0006801), superoxide-generating NAD(P)H oxidase activity (GO:0016175, MF), defense response to fungus (GO:0050832), phagocytosis (GO:0006909), inflammatory response (GO:0006954).

Causal chain (upstream → downstream): 1. Loss-of-function variant in a NOX2-complex gene → failure to assemble/activate NADPH oxidase (upstream trigger). 2. Absent/deficient respiratory burst → failure to generate O₂•⁻/H₂O₂/HOCl in the phagosome. 3. Impaired oxygen-dependent microbial killing → ingested catalase-positive organisms survive intracellularly (catalase-negative organisms self-supply H₂O₂ and are still killed). 4. Recurrent/persistent infection by the characteristic pathogens → abscesses, pneumonia, osteomyelitis, sepsis. 5. Failure to clear organisms/antigen + defective apoptosis/efferocytosis and dysregulated inflammation → persistent macrophage activation → granuloma formation and sterile hyperinflammation (colitis, obstructive granulomas). This is the paradox: too little killing and too much inflammation.

Why the hyperinflammation? (downstream mechanisms). ROS are not only microbicidal — they are anti-inflammatory signals. In their absence: - Defective NLRP3 inflammasome regulation and excess IL-1β / IL-18 (redox normally restrains inflammasome activity). - Impaired neutrophil apoptosis and macrophage efferocytosis → prolonged inflammatory cell persistence. - Defective autophagy/LC3-associated phagocytosis → failure to degrade cargo, sustained NF-κB and inflammasome signaling. - Reduced tryptophan→kynurenine (IDO) and impaired Nrf2 signaling, failure to inactivate pro-inflammatory mediators, and defective neutrophil extracellular trap (NET) formation (ROS-dependent NETosis is deficient). - Impaired resolution of inflammation and dysregulated Th17/IL-17 responses.

Backbone reviews for the inflammation mechanism: "Chronic granulomatous disease: why an inflammatory disease?" (PMC4230281); "Hyperinflammation in CGD and anti-inflammatory role of the phagocyte NADPH oxidase," Segal et al., Semin Immunopathol 2008; high tissue IL-18/IFN-γ (PMC6813411). Verify PMIDs.

Cell types (CL): neutrophil (CL:0000775), monocyte (CL:0000576), macrophage (CL:0000235), eosinophil (CL:0000771), granulocyte/myeloid leukocyte (CL:0000094 / CL:0000766).

Tissue-damage mechanisms: granulomatous/obstructive tissue remodeling, abscess/necrosis from uncontrolled infection, fibrosis (bladder/GI strictures), and inflammatory tissue injury from sustained cytokine output.

Molecular profiling. Transcriptomic/proteomic studies show heightened inflammatory-gene and inflammasome signatures in CGD phagocytes; single-cell and functional (CRISPR) work on NOX2 assembly exists but is not central to the clinical entry — flag as supplementary. Diagnostic "profiling" is functional (DHR flow), not omics.

7. Anatomical Structures Affected

Organ level (primary): - Lung (UBERON:0002048) — pneumonia, invasive aspergillosis, mulch pneumonitis, fibrosis. - Lymph nodes (UBERON:0000029) — suppurative lymphadenitis. - Liver (UBERON:0002107) — hepatic abscess (often staphylococcal), hepatomegaly, nodular regenerative hyperplasia/portal hypertension. - Spleen (UBERON:0002106) — splenomegaly, abscess. - Skin/soft tissue (UBERON:0002097) — abscesses, pustular/eczematoid dermatitis, granulomatous lesions. - Gastrointestinal tract — colon (UBERON:0001155) and small intestine (UBERON:0002108): IBD-like colitis, granulomas, strictures; stomach/gastric antrum (outlet obstruction). - Bone — osteomyelitis (small bones, ribs, vertebrae). - Genitourinary tract — bladder granulomas, ureteral obstruction. - Bone marrow (UBERON:0002371) — site of the defective myeloid progenitors and target of curative HSCT/gene therapy. - Eye — chorioretinal lesions.

Body systems: immune/hematopoietic (primary), respiratory, digestive, integumentary, musculoskeletal, genitourinary, hepatobiliary.

Cell/tissue level: myeloid phagocytes (neutrophils, monocytes/macrophages, eosinophils); granuloma = epithelioid macrophages ± multinucleated giant cells and lymphocytes; characteristic pigment-laden (lipofuscin) macrophages on histology.

Subcellular level (GO cellular component): phagocytic vesicle / phagosome membrane (GO:0045335), plasma membrane / specific (secondary) granule membrane, and the NADPH oxidase complex (GO:0043020, NADPH oxidase complex) localized to phagosome and plasma membrane. Flavocytochrome b₅₅₈ resides in secretory vesicles/specific granule and plasma membranes.

Localization/lateralization: multifocal and bilateral/systemic — infections and granulomas occur wherever phagocytes confront organisms; no consistent lateralization.

8. Temporal Development

Onset. Typically infancy/early childhood — most X-linked patients present and are diagnosed within the first 1–3 years of life; AR forms (especially p47-phox) skew later, with some diagnosed in adolescence or adulthood. Onset pattern is chronic with acute infectious exacerbations superimposed.

Progression. Chronic, lifelong, punctuated by recurrent infections and inflammatory flares (episodic/relapsing). Without curative therapy, cumulative organ damage (pulmonary fibrosis, GI strictures, hepatic disease) accrues. Inflammatory complications (colitis) often persist or worsen independent of infection control.

Stages / natural history: no formal staging. Historically, mortality was highest in the first decade; modern prophylaxis has shifted major morbidity/mortality into adolescence and adulthood, where Aspergillus and Burkholderia infections and progressive inflammatory/GI disease dominate.

Critical windows: infancy (BCG avoidance; early diagnosis prevents catastrophic first infections); pre-adolescence is the recommended window for HSCT in severe (low-residual-oxidase) patients while organ damage is limited (PMID 21190454 rationale). Remission of infections is treatment-induced (prophylaxis, curative HSCT/gene therapy); spontaneous remission does not occur.

9. Inheritance and Population

Epidemiology. - Incidence/prevalence: ~1 in 200,000–250,000 live births in the U.S. (Winkelstein registry, PMID 10844935); worldwide estimates ~1/100,000–1/250,000 depending on consanguinity. Approx. 20 new U.S. cases/year historically.

"A registry of United States residents with CGD was established in 1993 … 368 patients were registered; 259 had the X-linked recessive form … and 81 had one of the autosomal recessive forms." (PMID 10844935). - Sex ratio: ~80% male (X-linked predominance) in outbred populations. - Age distribution: diagnosis concentrated in early childhood; survival now often into 4th–5th decades and beyond.

Inheritance genetics. - Pattern: X-linked recessive (CYBB) + autosomal recessive (CYBA, NCF1, NCF2, NCF4, CYBC1). - Penetrance: essentially complete in affected males (X-linked) and biallelic AR individuals; expressivity is variable (residual-oxidase-dependent). - Carrier females (X-linked): mosaic neutrophil populations; usually asymptomatic for infection but may have discoid-lupus/photosensitive and autoimmune features; risk of symptomatic infection rises when wild-type neutrophils fall below ~10–20%. - Consanguinity: raises AR-form frequency; in high-consanguinity regions AR forms equal or exceed X-linked. - Founder effects: NCF1 ΔGT (pseudogene-mediated) is a recurrent, quasi-"founder" allele; regional founder variants reported (e.g., specific NCF2/CYBA alleles in Middle Eastern and Israeli Arab/Jewish populations). - Germline mosaicism / anticipation: not a feature (no repeat expansion). New (de novo) CYBB variants occur in a minority of X-linked cases. - Carrier frequency: low; population-specific for AR alleles.

Geographic distribution. Worldwide; relative gene-form distribution varies with consanguinity. No endemic clustering beyond that driven by founder alleles.

10. Diagnostics

Functional screening/confirmation (the core test): - Dihydrorhodamine-123 (DHR) flow cytometry — current gold-standard functional assay; measures the neutrophil oxidative burst after PMA stimulation. Quantifies residual oxidase and reveals the bimodal pattern of X-linked carriers. (LOINC-codable oxidative-burst assay — verify LOINC.) - Nitroblue tetrazolium (NBT) slide test — older qualitative assay, largely superseded by DHR. - Both detect the defining lab abnormality: absent/reduced respiratory burst.

Confirmatory protein/biochemical tests: immunoblot/flow for gp91-phox and p22-phox (cytochrome b₅₅₈ "positive/negative" typing); cytochrome b spectral assay; NADPH oxidase activity assays.

Genetic testing (definitive subtype/carrier assignment): - Targeted single-gene sequencing guided by DHR pattern + protein typing (e.g., CYBB in males with X-linked pattern). - CGD/primary-immunodeficiency NGS gene panels or WES/WGS when the pattern is ambiguous. WGS/CMA/MLPA needed for large deletions/contiguous Xp21 syndromes and to resolve NCF1 pseudogene complexity (NCF1 requires specialized assays — gene-specific PCR/pyrosequencing for the ΔGT and pseudogene ratio). - Carrier testing / prenatal diagnosis available once the familial variant is known.

Imaging & supportive tests: CT chest (pneumonia, fungal nodules, "halo" sign of aspergillosis), abdominal imaging/CT for liver abscess and bowel disease, endoscopy/biopsy for colitis. Histopathology: non-caseating granulomas, pigmented lipofuscin-laden macrophages, abscesses (SNOMED/pathology-codable).

Differential diagnosis: other phagocyte disorders (leukocyte adhesion deficiency, myeloperoxidase deficiency, Chédiak–Higashi, glucose-6-phosphate dehydrogenase deficiency with severe deficit — can mimic oxidase failure), hyper-IgE syndrome, Mendelian susceptibility to mycobacterial disease, Crohn disease (for the colitis phenotype), and other IEIs with granulomas. Key distinguisher: the abnormal DHR/NBT respiratory-burst assay.

Screening: not part of standard newborn screening (TREC-based SCID screening does not detect CGD). Cascade/carrier screening of at-risk relatives once a proband variant is identified is standard.

11. Outcome / Prognosis

Survival / mortality. - Prognosis has improved dramatically. Historically fatal in childhood; with modern prophylaxis, many patients survive into the 4th–5th decade. Contemporary mortality is ~1.5–3% per year in registry cohorts. - X-linked disease carries worse prognosis than AR (lower residual oxidase), and residual oxidase strongly predicts survival — patients in the lowest superoxide quartile have the highest mortality, with divergence after age ~20 (PMID 21190454, Kuhns et al.).

"…patients with the least residual … reactive oxygen intermediate production had the lowest survival." (Kuhns 2010 — verify exact wording). - Leading causes of death: invasive fungal (Aspergillus) infection and Burkholderia sepsis/pneumonia.

Morbidity / complications. Recurrent pneumonia and pulmonary fibrosis, hepatic abscess and portal hypertension/nodular regenerative hyperplasia, IBD-like colitis (major morbidity), GU/GI obstructive granulomas, growth failure, and inflammatory/autoimmune disease. Frequent hospitalizations and long antimicrobial courses.

Curative-therapy outcomes. Allogeneic HSCT now yields ~90% overall survival in modern series (matched-sibling and matched-unrelated donors), with best results in younger patients with matched donors and controlled infection at transplant. - 712-patient international HSCT study (Chiesa et al., Blood 2020, PMID ~32202630 — verify): low graft failure and mortality across ages. - Single-center late-survival cohort: OS ~90% at 2 years and ~81% at 5 years (JACI 2022). - Reduced-intensity conditioning HSCT: Güngör et al., Lancet 2014 (PMID 24161820) — 2-year survival ~96% in a prospective series.

Prognostic factors: residual oxidase activity (dominant), genotype/inheritance (X-linked worse), age and organ damage at HSCT, donor match, active infection at transplant, severity of inflammatory/GI disease.

12. Treatment

A. Lifelong prophylaxis (standard of care)

  • Antibacterial: trimethoprim–sulfamethoxazole (co-trimoxazole) (CHEBI: trimethoprim 45924; sulfamethoxazole 9332) — reduces bacterial infections. MAXO: antibiotic therapy / pharmacotherapy (verify MAXO ID).
  • Antifungal: itraconazole (CHEBI:6076) — landmark placebo-controlled prophylaxis trial (Gallin et al., NEJM 2003, PMID 12802026 — verify) significantly reduced serious fungal infections; posaconazole (CHEBI:64355)/voriconazole (CHEBI:10023) used for treatment/breakthrough.

    "Itraconazole … was effective in preventing fungal infections in patients with chronic granulomatous disease." (NEJMoa021931 — verify).

  • Immunomodulatory: Interferon-γ (IFN-γ, 1b) three-times-weekly SC — the International CGD Cooperative Study (NEJM 1991, PMID 1846940 — verify) showed ~70% reduction in serious infections.

    "…interferon gamma reduced the frequency of serious infections in patients with chronic granulomatous disease." (verify exact quote).

B. Acute infection management

Aggressive, culture-directed IV antibacterials/antifungals; often prolonged courses. Granulocyte transfusions for severe refractory infection (adjunct). Surgical drainage of abscesses.

C. Management of inflammatory/granulomatous disease

Corticosteroids for obstructive granulomas and colitis; steroid-sparing agents; anti-inflammatory/immunosuppressive therapy for IBD-like colitis. Caution: anti-TNF biologics increase severe infection risk in CGD (case reports of fatal fungal infection) — use judiciously.

D. Curative therapy

  • Allogeneic hematopoietic stem cell transplantation (HSCT) — the established cure; replaces defective myeloid lineage. MAXO: hematopoietic stem cell transplantation (verify MAXO ID; MAXO:0010039 organ transplantation is too generic). Reduced-intensity conditioning improves outcomes (Güngör 2014).
  • Autologous ex vivo lentiviral gene therapy (X-linked/gp91-phox) — corrects CD34⁺ HSPCs with a myeloid-specific promoter-driven gp91-phox vector.

    Kohn DB et al., Nat Med 2020 (PMID 31988463): nine X-CGD patients treated; "…six of the seven surviving patients demonstrated stable vector copy numbers (0.4–1.8 copies per neutrophil)" and stable oxidase-positive neutrophils sufficient for clinical benefit (verify exact wording). Modality: GENE_THERAPY; earlier retroviral trials were complicated by insertional myelodysplasia/clonal expansion, motivating self-inactivating lentiviral designs.

  • Investigational: gene-corrected p47-phox lentiviral vectors (preclinical, PMC8575060); CRISPR/base-editing approaches (preclinical).

Pharmacogenomics: azole levels vary widely (CYP3A4/itraconazole absorption); therapeutic drug monitoring recommended. No specific germline PGx gating beyond the disease genotype.

Supportive care: avoidance of mulch/decaying vegetation and live vaccines; dental/skin hygiene; nutritional support for colitis-related growth failure; genetic counseling.

13. Prevention

  • Primary prevention: the disease itself cannot be prevented (monogenic), but infection prevention is central — lifelong co-trimoxazole + itraconazole ± IFN-γ; avoidance of environmental mold exposure and contraindication of live vaccines (BCG, oral typhoid).
  • Secondary prevention: early diagnosis via family history and DHR testing of at-risk newborns; prompt cascade/carrier screening.
  • Tertiary prevention: aggressive early treatment of infections; surveillance for colitis, liver, and pulmonary complications; timely referral for HSCT/gene therapy before irreversible organ damage.
  • Genetic counseling & reproductive options: carrier testing, prenatal diagnosis, and preimplantation genetic diagnosis once the familial variant is known.
  • Prophylaxis (medication): co-trimoxazole (antibacterial), itraconazole (antifungal), IFN-γ (immunomodulatory) — see §12.

14. Other Species / Natural Disease

  • Taxonomy of affected species: primarily human (NCBITaxon:9606). Naturally occurring CGD-like NADPH-oxidase disease is documented in dogs (NCBITaxon:9615) and described in cattle.
  • Natural animal disease / OMIA: canine CGD-type leukocyte oxidase defects and, notably, Bovine Leukocyte Adhesion Deficiency is a distinct phagocyte disorder (do not conflate); search OMIA for "granulomatous"/NADPH oxidase entries in dog/cattle for veterinary orthologs.
  • Orthologous genes: CYBB/NCF1/NCF2/CYBA/NCF4 are conserved across mammals (mouse Cybb, Ncf1, Ncf2, Cyba, Ncf4 — NCBI Gene). Deep evolutionary conservation of the NOX2 phagocyte-oxidase system.
  • Comparative biology: knockout mice recapitulate the killing defect and granuloma/hyperinflammation, validating the anti-inflammatory role of NOX2-derived ROS across species.
  • Transmission: none — non-infectious, non-zoonotic (it is a germline genetic disorder).

15. Model Organisms

  • Mouse (Mus musculus, NCBITaxon:10090) — primary model.
  • Cybb (gp91-phox) knockout and Ncf1 (p47-phox) knockout mice are the workhorse models. They reproduce (a) defective respiratory burst and increased susceptibility to Aspergillus, Burkholderia, Staphylococcus, Salmonella, and (b) exaggerated/granulomatous inflammation and sterile hyperinflammation — directly demonstrating that NOX2-derived ROS restrain inflammation. Models: knockout, conditional, and humanized/gene-corrected lines used in gene-therapy preclinical work (MGI, IMSR).
  • Used to model prophylaxis, HSCT, and lentiviral gene-therapy correction (e.g., p47-phox lentiviral rescue restoring anti-Salmonella function, Gene Ther 2020).
  • Cellular/in vitro models: patient CD34⁺ HSPCs, iPSC-derived neutrophils/macrophages (for gene-editing/gene-therapy testing), immortalized myeloid lines (e.g., PLB-985 gp91-phox knockouts) — key IN_VITRO systems for oxidase-assembly studies and CRISPR correction.
  • Model characteristics / limitations: mouse models recapitulate the killing defect and hyperinflammation well but differ in pathogen spectrum and colitis phenotype severity; the human NCF1 pseudogene architecture has no direct murine counterpart, limiting modeling of the common human p47-phox ΔGT allele. Flag as HUMAN_MODEL_MISMATCH candidates where mouse inflammation/colitis does not fully mirror human IBD-like disease.
  • Resources: MGI (mouse), IMPC/KOMP (knockouts), Cellosaurus (PLB-985 and derivatives), Alliance of Genome Resources (orthology).

Suggested dismech Entry Scaffolding (quick reference)

  • MONDO: MONDO:0018305 (umbrella); consider modeling X-linked (MONDO:0010071) and AR forms as subtypes (has_subtypes: X-linked / CYBB, AR p47-phox / NCF1, AR p67-phox / NCF2, AR p22-phox / CYBA, AR p40-phox / NCF4, AR CYBC1/EROS).
  • Causal genes (hgnc): CYBB (hgnc:2578), CYBA (hgnc:2577), NCF1 (hgnc:7660), NCF2 (hgnc:7661), NCF4 (hgnc:7662), CYBC1 (verify).
  • Core GO/CL/UBERON/CHEBI/MAXO terms as listed in §§6–7, 12 — all require OAK validation.
  • Pathophysiology causal chain: NOX2-complex LoF variant → failed oxidase assembly → absent respiratory burst → impaired killing of catalase-positive microbes → recurrent infection and (parallel arm) impaired ROS-dependent inflammation control → granuloma/colitis/hyperinflammation.
  • Priority evidence PMIDs to fetch & verify: 10844935 (registry/epidemiology), 21190454 (residual oxidase/survival), 12802026 (itraconazole prophylaxis — verify), 1846940 (IFN-γ trial — verify), 31988463 (lentiviral gene therapy), 24161820 (RIC-HSCT — verify), plus the Blood 2020 712-patient HSCT study and the USIDNET IBD/CGD paper (verify PMIDs).

Sources (web-verified during this research)

Bottom line: CGD is a monogenic phagocyte NADPH-oxidase defect — the cell can swallow the bug but can't light the oxidative match — producing the twin signatures of recurrent catalase-positive infections and paradoxical granulomatous hyperinflammation. It's genetically well-mapped (six genes, X-linked CYBB dominant), functionally diagnosable (DHR flow), medically manageable (co-trimoxazole + itraconazole + IFN-γ), and increasingly curable (HSCT ~90% survival; lentiviral gene therapy maturing). Residual oxidase activity is the master dial for severity and survival. Remember: fetch and validate every PMID snippet and ontology ID before writing them into the YAML.