This disorder is the cleanest natural demonstration in human immunology that the macrophage respiratory burst, specifically, is what protects against tuberculous mycobacteria. CYBB encodes gp91phox, the catalytic subunit of the phagocyte NADPH oxidase, and null alleles abolish the burst in every phagocyte lineage and cause X-linked chronic granulomatous disease. The two alleles that cause this disorder, Q231P and T178P, do something different: they leave the burst intact in blood neutrophils and monocytes and abolish it in monocyte-derived macrophages. The consequence is a phenotype narrower than CGD rather than milder than it. Affected males get BCG disease and tuberculous mycobacterial disease and nothing else - no staphylococcal disease, which is CGD's leading pathogen, even in affected adults of advanced age. The authors verified this negatively as well as positively: patient granulocytes killed Staphylococcus aureus normally, and neutrophil and monocyte superoxide and hydrogen peroxide output was normal across several independent assays including the ones that diagnose CGD. The mechanism is cell-type-restricted failure of NADPH oxidase *assembly*, not reduced expression of the subunit. That is why it is a distinct disease from CGD and not a hypomorphic point on the same axis, and it is the reason this entry exists separately from the CYBB subtype already curated on the chronic granulomatous disease entry. Curators should note that a CGD-directed diagnostic workup misses it by design: the dihydrorhodamine and nitroblue tetrazolium tests are run on neutrophils, where these patients are normal. One nosological point is worth stating because it is easy to miss. MSMD is defined as a set of inborn errors of interferon-gamma immunity, and the large majority of cases carry mutations in the IL-12/interferon-gamma signalling axis - 61 per cent of 830 reported patients have IL12RB1 or IFNGR1 defects. This disorder is not one of those. The lesion is at the effector end, in the oxidase the interferon-gamma-primed macrophage uses, which is why it sits inside MSMD as a mechanistic exception rather than as another signalling defect. It is also why interferon-gamma is a plausible therapy here despite the pathway being intact. Two limits on the evidence are worth carrying. All of it comes from two French kindreds, seven patients, one paper and its follow-up review. And the macrophage defect was measured in monocyte-derived macrophages differentiated in vitro, because tissue macrophages were not obtainable - the authors say so explicitly. The inference from the in vitro macrophage to the tissue macrophage that actually harbours the mycobacterium is the load-bearing step in the whole account, and it has not been tested directly.
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name: X-linked Mendelian Susceptibility to Mycobacterial Diseases due to CYBB Deficiency
creation_date: "2026-09-03T15:25:00Z"
category: Mendelian
synonyms:
- X-linked MSMD due to CYBB deficiency
- XR-MSMD-2
- immunodeficiency 34
- IMD34
- atypical mycobacteriosis, familial, X-linked 2
- CYBB X-linked Mendelian susceptibility to mycobacterial diseases
description: >
This disorder is the cleanest natural demonstration in human immunology that the
macrophage respiratory burst, specifically, is what protects against tuberculous
mycobacteria. CYBB encodes gp91phox, the catalytic subunit of the phagocyte NADPH oxidase,
and null alleles abolish the burst in every phagocyte lineage and cause X-linked chronic
granulomatous disease. The two alleles that cause this disorder, Q231P and T178P, do
something different: they leave the burst intact in blood neutrophils and monocytes and
abolish it in monocyte-derived macrophages.
The consequence is a phenotype narrower than CGD rather than milder than it. Affected
males get BCG disease and tuberculous mycobacterial disease and nothing else - no
staphylococcal disease, which is CGD's leading pathogen, even in affected adults of
advanced age. The authors verified this negatively as well as positively: patient
granulocytes killed Staphylococcus aureus normally, and neutrophil and monocyte superoxide
and hydrogen peroxide output was normal across several independent assays including the
ones that diagnose CGD.
The mechanism is cell-type-restricted failure of NADPH oxidase *assembly*, not reduced
expression of the subunit. That is why it is a distinct disease from CGD and not a
hypomorphic point on the same axis, and it is the reason this entry exists separately from
the CYBB subtype already curated on the chronic granulomatous disease entry. Curators
should note that a CGD-directed diagnostic workup misses it by design: the
dihydrorhodamine and nitroblue tetrazolium tests are run on neutrophils, where these
patients are normal.
One nosological point is worth stating because it is easy to miss. MSMD is defined as a
set of inborn errors of interferon-gamma immunity, and the large majority of cases carry
mutations in the IL-12/interferon-gamma signalling axis - 61 per cent of 830 reported
patients have IL12RB1 or IFNGR1 defects. This disorder is not one of those. The lesion is
at the effector end, in the oxidase the interferon-gamma-primed macrophage uses, which is
why it sits inside MSMD as a mechanistic exception rather than as another signalling
defect. It is also why interferon-gamma is a plausible therapy here despite the pathway
being intact.
Two limits on the evidence are worth carrying. All of it comes from two French kindreds,
seven patients, one paper and its follow-up review. And the macrophage defect was measured
in monocyte-derived macrophages differentiated in vitro, because tissue macrophages were
not obtainable - the authors say so explicitly. The inference from the in vitro macrophage
to the tissue macrophage that actually harbours the mycobacterium is the load-bearing step
in the whole account, and it has not been tested directly.
disease_term:
preferred_term: X-linked Mendelian susceptibility to mycobacterial diseases due to CYBB deficiency
term:
id: MONDO:0010389
label: X-linked Mendelian susceptibility to mycobacterial diseases due to CYBB deficiency
parents:
- Mendelian susceptibility to mycobacterial diseases
inheritance:
- name: X-linked recessive inheritance
inheritance_term:
preferred_term: X-linked recessive inheritance
term:
id: HP:0001419
label: X-linked recessive inheritance
description: >
Affected males are hemizygous for the mutant CYBB allele; obligate female carriers are
heterozygous and were unaffected, with normal neutrophil and monocyte responses. One
90-year-old carrier had a history of severe tuberculosis, which the authors report
without claiming it as carrier manifestation.
evidence:
- reference: PMID:21278736
reference_title: "Germline CYBB mutations that selectively affect macrophages in kindreds with X-linked predisposition to tuberculous mycobacterial disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In both kindreds, the clinically affected male subjects were all hemizygous for the mutated allele, whereas the other maternally related, healthy male subjects tested were not."
explanation: >-
Establishes hemizygosity in affected males and its absence in unaffected male relatives,
the cosegregation on which X-linked recessive inheritance rests.
- reference: PMID:21278736
reference_title: "Germline CYBB mutations that selectively affect macrophages in kindreds with X-linked predisposition to tuberculous mycobacterial disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "PMNs and monocytes from four heterozygous female subjects responded like control cells (Supplementary Fig. 2f)."
explanation: >-
Shows heterozygous carriers are functionally normal in the assayed lineages, consistent
with a recessive X-linked trait.
genetic:
- name: CYBB
gene_term:
preferred_term: CYBB
term:
id: hgnc:2578
label: CYBB
association: CAUSATIVE
relationship_type: CAUSATIVE
variant_origin: GERMLINE
features: >
Two private missense alleles, Q231P (exon 7) and T178P (exon 6), each substituting a
proline for a residue conserved across 33 animal species. Neither was found in 1,300 X
chromosomes from 52 ethnic groups, and neither had previously been associated with
chronic granulomatous disease. The functional signature that separates them from
CGD-causing alleles is cell-type restriction, not degree: they are hypomorphic in
macrophages and EBV-transformed B cells while leaving neutrophils and monocytes
unaffected.
variants:
- name: c.692A>C (p.Gln231Pro)
description: >-
Missense allele in exon 7 identified in kindred A, abolishing the macrophage respiratory
burst while sparing neutrophils and monocytes. The more severe of the two alleles.
clinical_significance: PATHOGENIC
- name: c.532A>C (p.Thr178Pro)
description: >-
Missense allele in exon 6 identified in kindred B, giving a milder macrophage phenotype
than Q231P with low or occasionally normal hydrogen peroxide release.
clinical_significance: PATHOGENIC
evidence:
- reference: PMID:21278736
reference_title: "Germline CYBB mutations that selectively affect macrophages in kindreds with X-linked predisposition to tuberculous mycobacterial disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "These patients had previously unknown mutations in CYBB that resulted in an impaired respiratory burst in monocyte-derived macrophages but not in monocytes or granulocytes."
explanation: >-
Establishes CYBB as the causative gene and states the cell-type-restricted functional
consequence that defines the disorder.
- reference: PMID:21278736
reference_title: "Germline CYBB mutations that selectively affect macrophages in kindreds with X-linked predisposition to tuberculous mycobacterial disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The CYBB alleles encoding the Q231P and T178P substitutions were not present in any of 1,300 X chromosomes from 52 ethnic groups (in the panel from the Human Genome Diversity Project at the Centre d’Etude du Polymorphisme Humain), including 240 European chromosomes."
explanation: >-
Population data supporting pathogenicity of the two alleles rather than their being rare
benign variation.
- reference: PMID:21278736
reference_title: "Germline CYBB mutations that selectively affect macrophages in kindreds with X-linked predisposition to tuberculous mycobacterial disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Finally, these two mutations have not previously been associated with CGD, a well-known primary immunodeficiency associated with many bacterial and fungal infectious diseases, including tuberculous mycobacterial diseases7–13 (Supplementary Note)."
explanation: >-
Establishes that these are not known CGD alleles, which is the basis for treating this as
a distinct disorder rather than a CGD presentation.
pathophysiology:
- name: Hypomorphic CYBB Missense Alleles
biological_scale: MOLECULAR
description: >
Q231P or T178P substitutes a disruptive proline into gp91phox at a residue conserved
across species. The substitution does not abolish the protein; it makes it conditionally
non-functional, and the condition turns out to be cell lineage.
genetic_context:
gene:
preferred_term: CYBB
term:
id: hgnc:2578
label: CYBB
allele_type: SNV
variant_origin: GERMLINE
zygosity: HEMIZYGOUS
functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
description: >-
Partial loss of function, and the partiality is by cell type rather than by degree: the
allele behaves as null in macrophages and as wild type in neutrophils.
downstream:
- target: Cell-Type-Restricted Failure of NADPH Oxidase Assembly
causal_link_type: DIRECT
evidence:
- reference: PMID:21278736
reference_title: "Germline CYBB mutations that selectively affect macrophages in kindreds with X-linked predisposition to tuberculous mycobacterial disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The macrophage-specific functional consequences of the germline mutation resulted from cell-specific impairment in the assembly of the NADPH oxidase."
explanation: >-
States that the mutation causes an assembly defect and that the defect is cell-specific,
which is exactly the causal step this edge asserts.
evidence:
- reference: PMID:21278736
reference_title: "Germline CYBB mutations that selectively affect macrophages in kindreds with X-linked predisposition to tuberculous mycobacterial disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Moreover, the two mutations were nonconservative, each resulting in substitution with a proline residue that is particularly disruptive (Fig. 1c) and affecting residues conserved in 33 animal species studied (Supplementary Fig. 1b)."
explanation: >-
Characterises the molecular nature of the substitutions recorded on this node.
- name: Cell-Type-Restricted Failure of NADPH Oxidase Assembly
biological_scale: MOLECULAR
description: >
The NADPH oxidase fails to assemble in macrophages and in EBV-transformed B cells, and
assembles normally in neutrophils and monocytes. Assembly, not expression, is the
affected step. This is the pivot of the whole disorder: the same allele in the same
person is null in one lineage and silent in another, which is what dissociates the
mycobacterial phenotype from the rest of CGD.
protein_complexes:
- preferred_term: NADPH oxidase complex
term:
id: GO:0043020
label: NADPH oxidase complex
modifier: DECREASED
cell_types:
- preferred_term: macrophage
term:
id: CL:0000235
label: macrophage
downstream:
- target: Abolished Macrophage Respiratory Burst
causal_link_type: DIRECT
- target: Preserved Neutrophil and Monocyte Respiratory Burst
causal_link_type: DIRECT
- target: Loss of the Respiratory Burst in EBV-Transformed B Cells
causal_link_type: DIRECT
evidence:
- reference: PMID:22236433
reference_title: "Genetic lessons learned from X-linked Mendelian susceptibility to mycobacterial diseases."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "CYBB encodes gp91(phox) , which is an essential component of the NADPH oxidase in phagocytes. The MSMD-causing mutation in CYBB selectively affects the respiratory burst in macrophages."
explanation: >-
States the selective, macrophage-restricted nature of the oxidase defect that this node
records.
- reference: PMID:22236433
reference_title: "Genetic lessons learned from X-linked Mendelian susceptibility to mycobacterial diseases."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Mutations in NEMO and CYBB may therefore cause MSMD by selectively exerting their deleterious impact on a single signaling pathway (CD40-IL-12, NEMO) or a single cell type (macrophages, CYBB)."
explanation: >-
Frames the lesion as single-cell-type restriction, which is the mechanistic claim of this
node.
- reference: PMID:30264912
reference_title: "Mendelian susceptibility to mycobacterial disease: 2014-2018 update."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "Mendelian susceptibility to mycobacterial disease (MSMD) is caused by inborn errors of IFN-γ immunity."
explanation: >-
Records the definition this disorder is the exception to. Graded INDIRECT because the
statement is about MSMD in general and is cited here for the contrast: the CYBB lesion is
in the effector oxidase rather than in interferon-gamma signalling itself.
- name: Abolished Macrophage Respiratory Burst
biological_scale: CELLULAR
description: >
Monocyte-derived macrophages release no detectable hydrogen peroxide and reduce almost no
nitroblue tetrazolium after activation with BCG, PPD or interferon-gamma followed by a
PMA trigger. The defect was near-total for Q231P and severe for T178P, so there is an
allelic gradient within a phenotype that is otherwise uniform. Note the measurement
caveat carried through this entry: these are macrophages differentiated in vitro, because
tissue macrophages were not available.
cell_types:
- preferred_term: macrophage
term:
id: CL:0000235
label: macrophage
biological_processes:
- preferred_term: respiratory burst
term:
id: GO:0045730
label: respiratory burst
modifier: DECREASED
- preferred_term: superoxide anion generation
term:
id: GO:0042554
label: superoxide anion generation
modifier: DECREASED
downstream:
- target: Failure to Restrict Intramacrophage Mycobacterial Growth
causal_link_type: DIRECT
evidence:
- reference: PMID:21278736
reference_title: "Germline CYBB mutations that selectively affect macrophages in kindreds with X-linked predisposition to tuberculous mycobacterial disease."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "As assessed by counting of colony-forming units, MDMs from the patients controlled BCG significantly less well than did control MDMs on day 14 (P = 0.06), and this difference was even greater on day 21 (P = 0.003; Supplementary Note and Supplementary Fig. 4)."
explanation: >-
Directly links the macrophage oxidase defect to failed control of mycobacterial growth
in the same cells, which is the causal step this edge asserts.
evidence:
- reference: PMID:21278736
reference_title: "Germline CYBB mutations that selectively affect macrophages in kindreds with X-linked predisposition to tuberculous mycobacterial disease."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Thus, unlike blood granulocytes and monocytes, MDMs bearing the mutated CYBB allele encoding Q231P or T178P, in various conditions of in vitro differentiation and conditions of stimulation, showed impairment of the respiratory burst: the respiratory burst was almost abolished for cells with the Q231P substitution and severely impaired for those with the T178P substitution."
explanation: >-
States the macrophage respiratory burst defect and the allelic gradient recorded on this
node.
- reference: PMID:21278736
reference_title: "Germline CYBB mutations that selectively affect macrophages in kindreds with X-linked predisposition to tuberculous mycobacterial disease."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "We were unable to test the respiratory burst of the patients’ macrophages in vivo or ex vivo."
explanation: >-
The authors' own statement of the measurement limitation, recorded so the in vitro basis
of this node is not obscured.
- name: Preserved Neutrophil and Monocyte Respiratory Burst
biological_scale: CELLULAR
description: >
Superoxide and hydrogen peroxide output is normal in blood neutrophils and monocytes
across cytochrome c reduction, dihydrorhodamine flow cytometry, nitroblue tetrazolium and
chemiluminescence assays, and granulocyte killing of Staphylococcus aureus is normal.
This node records a mechanistic negative, and it is the diagnostically important one:
the standard CGD screening tests are run on exactly the lineage that is spared here.
cell_types:
- preferred_term: neutrophil
term:
id: CL:0000775
label: neutrophil
- preferred_term: monocyte
term:
id: CL:0000576
label: monocyte
biological_processes:
- preferred_term: respiratory burst
term:
id: GO:0045730
label: respiratory burst
downstream:
- target: Absence of the Chronic Granulomatous Disease Infection Spectrum
causal_link_type: DIRECT
evidence:
- reference: PMID:21278736
reference_title: "Germline CYBB mutations that selectively affect macrophages in kindreds with X-linked predisposition to tuberculous mycobacterial disease."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Thus, the six patients bearing the mutated CYBB allele encoding the Q231P or T178P substitution had a normal respiratory burst in peripheral blood PMNs and monocytes, as assessed by diverse assays of O2− production and H2O2 release."
explanation: >-
States directly that the burst is normal in neutrophils and monocytes, which is the claim
of this node.
- reference: PMID:21278736
reference_title: "Germline CYBB mutations that selectively affect macrophages in kindreds with X-linked predisposition to tuberculous mycobacterial disease."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Their granulocytes killed S. aureus normally, unlike granulocytes from patients with CGD, in which S. aureus is the leading pathogen (Fig. 2e)."
explanation: >-
A functional killing assay confirming granulocyte competence, and the direct contrast with
CGD granulocytes.
- name: Failure to Restrict Intramacrophage Mycobacterial Growth
biological_scale: CELLULAR
description: >
Patient macrophages control BCG growth significantly less well than control macrophages,
and the deficit widens over three weeks of culture. Because mycobacteria live inside
macrophages, this is the step that connects the oxidase defect to the clinical disease.
Adding exogenous interferon-gamma abolished the difference, which is the closest thing in
this literature to a rescue experiment and is the mechanistic basis for using
interferon-gamma therapeutically.
cell_types:
- preferred_term: macrophage
term:
id: CL:0000235
label: macrophage
biological_processes:
- preferred_term: defense response to bacterium
term:
id: GO:0042742
label: defense response to bacterium
modifier: DECREASED
downstream:
- target: Recurrent mycobacterial infections
causal_link_type: DIRECT
- target: Tuberculosis
causal_link_type: DIRECT
- target: Lymphadenopathy
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Fever
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:21278736
reference_title: "Germline CYBB mutations that selectively affect macrophages in kindreds with X-linked predisposition to tuberculous mycobacterial disease."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "As mycobacteria reside in macrophages in vivo, our in vitro experiments showing that MDMs in patients from each of the two kindreds had impairment of both the respiratory burst and the control of BCG growth provide a plausible cellular basis for the occurrence of mycobacterial diseases in patients with XR-MSMD-2."
explanation: >-
The authors' own statement of the inference this node encodes, including their hedge that
it is a plausible rather than a demonstrated cellular basis.
- reference: PMID:21278736
reference_title: "Germline CYBB mutations that selectively affect macrophages in kindreds with X-linked predisposition to tuberculous mycobacterial disease."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "We observed no such difference in the presence of exogenous IFN-γ."
explanation: >-
Interferon-gamma abolished the growth-control deficit, supporting both this node and the
rationale for interferon-gamma therapy.
- name: Absence of the Chronic Granulomatous Disease Infection Spectrum
biological_scale: ORGANISM
description: >
Affected individuals do not develop the staphylococcal, other bacterial and fungal
disease that defines chronic granulomatous disease, and this holds in affected adults of
advanced age rather than merely reflecting short follow-up. This node has no downstream
edges by design: it records what does not happen, and it is the reason the disorder is
curated apart from CGD.
evidence:
- reference: PMID:21278736
reference_title: "Germline CYBB mutations that selectively affect macrophages in kindreds with X-linked predisposition to tuberculous mycobacterial disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "These findings confirmed published investigations of these patients’ respiratory burst4 and were consistent with the absence of clinical features typically associated with CGD and ‘variant CGD’, including staphylococcal disease, even in affected adults of advanced age from kindreds A and B4 (Fig. 1a)."
explanation: >-
States the clinical absence of CGD features, including in older affected adults, which is
the claim of this node.
- reference: PMID:21278736
reference_title: "Germline CYBB mutations that selectively affect macrophages in kindreds with X-linked predisposition to tuberculous mycobacterial disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We report here two kindreds in which otherwise healthy male adults developed X-linked recessive Mendelian susceptibility to mycobacterial disease (MSMD) syndromes."
explanation: >-
Describes the patients as otherwise healthy adults, supporting the narrowness of the
phenotype.
- name: Loss of the Respiratory Burst in EBV-Transformed B Cells
biological_scale: CELLULAR
description: >
EBV-transformed B cells from all seven patients produce no detectable superoxide or
hydrogen peroxide, matching X-linked CGD cells and the patients' own macrophages. The
authors are explicit that this is irrelevant to pathogenesis, since B-cell-deficient
patients are not prone to mycobacterial disease, and that they used it as an accessible
experimental surrogate for the macrophage phenotype. It is curated here because it is the
system in which the alleles were shown to be hypomorphic, not because it causes anything;
it therefore has no downstream edges.
cell_types:
- preferred_term: B cell
term:
id: CL:0000236
label: B cell
biological_processes:
- preferred_term: respiratory burst
term:
id: GO:0045730
label: respiratory burst
modifier: DECREASED
evidence:
- reference: PMID:21278736
reference_title: "Germline CYBB mutations that selectively affect macrophages in kindreds with X-linked predisposition to tuberculous mycobacterial disease."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "However, EBV-B cells from kindreds A and B (patients P1–P7), like cells from patients with XR-CGD, produced no detectable O2− (Fig. 4a and Supplementary Fig. 5)."
explanation: >-
Establishes the EBV-B cell oxidase defect recorded on this node.
- reference: PMID:21278736
reference_title: "Germline CYBB mutations that selectively affect macrophages in kindreds with X-linked predisposition to tuberculous mycobacterial disease."
supports: NO_EVIDENCE
evidence_source: IN_VITRO
snippet: "Although it is irrelevant to the pathogenesis of XR-MSMD-2, as B cell–deficient patients are not prone to mycobacterial diseases17,18, we made use of this property to try to characterize the effects of the mutated CYBB alleles in Epstein Barr virus (EBV)-transformed B cell lines (EBV-B cells)19."
explanation: >-
Graded NO_EVIDENCE for the disease mechanism deliberately: the authors state this cellular
phenotype does not bear on pathogenesis, and the quote is recorded so the node is not read
as a causal step.
phenotypes:
- category: Infectious
name: Recurrent mycobacterial infections
description: >
Disease caused by weakly virulent mycobacteria, chiefly BCG vaccine strains and
environmental non-tuberculous mycobacteria. BCG disease was present in six of the seven
reported patients.
phenotype_term:
preferred_term: Recurrent mycobacterial infections
term:
id: HP:0011274
label: Recurrent mycobacterial infections
frequency: VERY_FREQUENT
diagnostic: true
evidence:
- reference: PMID:21278736
reference_title: "Germline CYBB mutations that selectively affect macrophages in kindreds with X-linked predisposition to tuberculous mycobacterial disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The patients had recurrent or disseminated tuberculous mycobacterial disease, with BCG disease in three patients (MSMD sensu stricto) and tuberculosis in one patient (not vaccinated by BCG)."
explanation: >-
Describes the recurrent and disseminated mycobacterial disease in kindred A that this
phenotype records.
- reference: PMID:22236433
reference_title: "Genetic lessons learned from X-linked Mendelian susceptibility to mycobacterial diseases."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Mendelian susceptibility to mycobacterial disease (MSMD) is a rare syndrome conferring predisposition to clinical disease caused by weakly virulent mycobacteria, such as Mycobacterium bovis Bacille Calmette Guérin (BCG) vaccines and nontuberculous, environmental mycobacteria (EM)."
explanation: >-
Defines the organism spectrum that characterises this phenotype.
- category: Infectious
name: Tuberculosis
description: >
Disease caused by fully virulent Mycobacterium tuberculosis, including in an unvaccinated
patient. This extends the phenotype beyond MSMD sensu stricto and is what makes the
disorder relevant to tuberculosis susceptibility genetics generally.
phenotype_term:
preferred_term: Tuberculosis
term:
id: HP:5210111
label: Tuberculosis infection
evidence:
- reference: PMID:21278736
reference_title: "Germline CYBB mutations that selectively affect macrophages in kindreds with X-linked predisposition to tuberculous mycobacterial disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "This 'experiment of nature' indicates that CYBB is associated with MSMD and demonstrates that the respiratory burst in human macrophages is a crucial mechanism for protective immunity to tuberculous mycobacteria."
explanation: >-
States the extension of susceptibility to tuberculous mycobacteria, the claim behind this
phenotype.
- reference: PMID:21278736
reference_title: "Germline CYBB mutations that selectively affect macrophages in kindreds with X-linked predisposition to tuberculous mycobacterial disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "These patients are also vulnerable to more virulent Mycobacterium tuberculosis2."
explanation: >-
States vulnerability to fully virulent M. tuberculosis in MSMD patients.
- category: Hematologic
name: Lymphadenopathy
description: >
Lymphadenopathy, frequently multifocal, is the commonest clinical manifestation of MSMD
as a whole. The frequency below is the MSMD-wide figure across 830 reported patients of
all genotypes, not a CYBB-specific one: with seven reported CYBB patients there is no
genotype-specific frequency to give, and CYBB is not among the genes accounting for the
bulk of that cohort. Curated so the entry carries the expected presentation, with the
provenance of the number stated rather than implied.
phenotype_term:
preferred_term: Lymphadenopathy
term:
id: HP:0002716
label: Lymphadenopathy
evidence:
- reference: PMID:38341181
reference_title: "Genetic, immunologic, and clinical features of 830 patients with Mendelian susceptibility to mycobacterial diseases (MSMD): A systematic review."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "Lymphadenopathy was the most common clinical manifestation of MSMD, reported in 378 (45.5%) cases and multifocal in 35.1%."
explanation: >-
Establishes lymphadenopathy as the commonest MSMD manifestation. Graded INDIRECT because
the cohort spans all 21 MSMD genotypes and the figure cannot be attributed to CYBB
deficiency specifically.
- category: Constitutional
name: Fever
description: >
Fever, the second commonest MSMD manifestation. As with lymphadenopathy, the frequency is
MSMD-wide rather than CYBB-specific.
phenotype_term:
preferred_term: Fever
term:
id: HP:0001945
label: Fever
evidence:
- reference: PMID:38341181
reference_title: "Genetic, immunologic, and clinical features of 830 patients with Mendelian susceptibility to mycobacterial diseases (MSMD): A systematic review."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "Fever, organomegaly, and sepsis were the next most frequent findings, reported in 251 (30.2%), 206 (24.8%), and 171 (20.8%) cases, respectively."
explanation: >-
Gives the MSMD-wide frequency of fever. Graded INDIRECT for the same reason as
lymphadenopathy: the cohort is not genotype-restricted.
treatments:
- name: Antimycobacterial Therapy
description: >
Prolonged multidrug antimycobacterial chemotherapy treats the infection itself and is the
mainstay of MSMD management regardless of the underlying immune defect. Regimen
composition follows species identification and susceptibility testing rather than a fixed
block, and this entry asserts no specific regimen or duration. Note the recommendation is
to start three or four drugs after a diagnosis of BCG disease even before the genetic
defect is known, which matters here because the CYBB genotype is reached by sequencing
weeks or months later.
treatment_term:
preferred_term: multidrug antimycobacterial chemotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: antitubercular agent
term:
id: NCIT:C280
label: Antitubercular Agent
- preferred_term: rifampicin
term:
id: CHEBI:28077
label: rifampicin
- preferred_term: isoniazid
term:
id: CHEBI:6030
label: isoniazide
therapeutic_modality: SMALL_MOLECULE
target_mechanisms:
- target: Failure to Restrict Intramacrophage Mycobacterial Growth
treatment_effect: INHIBITS
description: >-
Kills or suppresses the mycobacteria the oxidase-deficient macrophage cannot restrict.
It does not restore the respiratory burst.
evidence:
- reference: PMID:38341181
reference_title: "Genetic, immunologic, and clinical features of 830 patients with Mendelian susceptibility to mycobacterial diseases (MSMD): A systematic review."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "Therapeutic approaches for MSMD include the use of antimycobacterial antibiotics, IFN-γ therapy, surgery to remove lymph nodes, and hematopoietic stem-cell transplantation (HSCT)."
explanation: >-
Names antimycobacterial antibiotics among the therapeutic approaches for MSMD. Graded
INDIRECT because the review is MSMD-wide across 21 genotypes and reports no
CYBB-specific treatment outcome.
- reference: PMID:38341181
reference_title: "Genetic, immunologic, and clinical features of 830 patients with Mendelian susceptibility to mycobacterial diseases (MSMD): A systematic review."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "After the diagnosis of BCG-osis, even before the underlying genetic defect has been identified, it is recommended to try a treatment including at least three or four antimycobacterial antibiotics for BCG infection"
explanation: >-
States that multidrug therapy should begin before the genetic diagnosis, which is the
practical point for a disorder reached only by sequencing. Graded INDIRECT for the same
cohort reason.
- name: Hematopoietic Stem Cell Transplantation
description: >
Reported as the only curative option in MSMD, since it replaces the defective
haematopoietic compartment rather than treating the infection or supplementing the
cytokine. Its standing in this disorder specifically is unestablished: no CYBB-MSMD
patient's transplant outcome is reported in the sources curated here, and the
risk-benefit calculation is not obviously the same as for a global phagocyte defect,
given that these patients have normal neutrophil function and a phenotype restricted to
mycobacteria. Curated as an option with that caveat rather than as a recommendation.
treatment_term:
preferred_term: Hematopoietic Cell Transplantation
term:
id: NCIT:C15431
label: Hematopoietic Cell Transplantation
therapeutic_modality: CELL_THERAPY
target_mechanisms:
- target: Cell-Type-Restricted Failure of NADPH Oxidase Assembly
treatment_effect: RESTORES
description: >-
Replaces the haematopoietic compartment carrying the mutant allele, so donor-derived
macrophages assemble a functional oxidase.
evidence:
- reference: PMID:38341181
reference_title: "Genetic, immunologic, and clinical features of 830 patients with Mendelian susceptibility to mycobacterial diseases (MSMD): A systematic review."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "HSCT remains the only curative treatment available"
explanation: >-
States that transplantation is the only curative option in MSMD. Graded INDIRECT because
the statement is MSMD-wide and no CYBB-MSMD transplant outcome is reported.
- name: Interferon-gamma Therapy
description: >
Mechanistically motivated rather than trial-proven in this disorder. Exogenous
interferon-gamma abolished the difference in BCG growth control between patient and
control macrophages, which is the only manipulation reported to correct the cellular
phenotype. Note that interferon-gamma alone did not restore the respiratory burst in
Q231P macrophages, so the rescue of growth control is presumably through
oxidase-independent antimycobacterial mechanisms. No clinical outcome data exist for
these patients, and the entry should not be read as reporting efficacy.
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: interferon gamma-1b
term:
id: NCIT:C100089
label: Interferon Gamma-1b
therapeutic_modality: PROTEIN_REPLACEMENT
target_mechanisms:
- target: Failure to Restrict Intramacrophage Mycobacterial Growth
treatment_effect: RESTORES
description: >-
Restores macrophage control of BCG growth in vitro; the mechanism appears not to be
restoration of the respiratory burst, since the burst defect persisted under
interferon-gamma in the more severe allele.
evidence:
- reference: PMID:21278736
reference_title: "Germline CYBB mutations that selectively affect macrophages in kindreds with X-linked predisposition to tuberculous mycobacterial disease."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "We observed no such difference in the presence of exogenous IFN-γ."
explanation: >-
Shows interferon-gamma abolishes the growth-control deficit, which is the mechanism this
treatment link asserts.
evidence:
- reference: PMID:21278736
reference_title: "Germline CYBB mutations that selectively affect macrophages in kindreds with X-linked predisposition to tuberculous mycobacterial disease."
supports: REFUTE
evidence_source: IN_VITRO
snippet: "In similar conditions, but with interferon-γ (IFN-γ) rather than BCG or PPD, macrophages with the Q231P substitution also did not respond normally to the PMA trigger (Supplementary Fig. 3a)."
explanation: >-
Graded REFUTE against the stronger claim that interferon-gamma corrects the oxidase defect
itself: under interferon-gamma, Q231P macrophages still failed to mount the burst. The
growth-control benefit above therefore cannot be attributed to burst restoration.
- name: Avoidance of BCG Vaccination
description: >
BCG is a live attenuated Mycobacterium bovis vaccine, and BCG disease is the defining
presentation of this disorder. Both reported kindreds illustrate the exposure dependence
from the other direction: the male founders carried the allele but did not develop MSMD,
having lived in France before routine childhood BCG vaccination. This is curated as a
prophylactic avoidance measure rather than a therapy.
treatment_term:
preferred_term: Supportive Care
term:
id: NCIT:C15747
label: Supportive Care
therapeutic_modality: OTHER
evidence:
- reference: PMID:21278736
reference_title: "Germline CYBB mutations that selectively affect macrophages in kindreds with X-linked predisposition to tuberculous mycobacterial disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "However, these men lived in France before the introduction of routine BCG vaccination of children at a time when the incidence of tuberculosis was already decreasing."
explanation: >-
Supports exposure dependence of the phenotype: carriers unexposed to BCG in an era of
falling tuberculosis incidence did not manifest disease.
- reference: PMID:21278736
reference_title: "Germline CYBB mutations that selectively affect macrophages in kindreds with X-linked predisposition to tuberculous mycobacterial disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Another French kindred with XR-MSMD has been identified; the three male patients of this kindred (kindred B; patients P5–P7) had BCG disease."
explanation: >-
Documents BCG disease as the presenting illness in all three patients of the second
kindred, which is what makes BCG avoidance relevant.
- reference: PMID:38341181
reference_title: "Genetic, immunologic, and clinical features of 830 patients with Mendelian susceptibility to mycobacterial diseases (MSMD): A systematic review."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "in individuals with a family history of MSMD, BCG vaccination is contraindicated due to the risk of mycobacterial infection"
explanation: >-
States the contraindication itself, which the two exposure quotes above establish the
premise for but do not recommend. Graded INDIRECT because it is an MSMD-wide statement.
environmental:
- name: BCG vaccination
review_notes: >-
Left deliberately unbound. ECTO was searched for a vaccination exposure via OLS and the
committed caches. The on-target term exists upstream, ECTO:2000129 "exposure to
vaccination", but it is a label-less dangling node in the sqlite:obo:ecto build the term
validator uses (runoak returns "ECTO:2000129 ! None") and is not reachable from the
ExposureTerm enum roots ExO:0000002 or XCO:0000000, so binding it fails validation with
both "not in dynamic enum ExposureTerm" and "not found in ontology". Nothing for BCG or
Mycobacterium bovis exists in ECTO at all: an OLS search returns only CHEBI:50847
(immunological adjuvant) and MAXO:0000296 (immune stimulant agent therapy), neither of
which is an exposure. Filed upstream rather than binding an approximation.
description: >
Live attenuated Mycobacterium bovis BCG vaccine. The exposure is what converts the
genotype into disease in most reported patients, and its absence is the most plausible
explanation for unaffected obligate male carriers in earlier generations.
influences_mechanisms:
- target: Failure to Restrict Intramacrophage Mycobacterial Growth
environmental_effect: TRIGGERS
causal_link_type: DIRECT
description: >-
Introduces the live mycobacterium that the oxidase-deficient macrophage cannot restrict.
evidence:
- reference: PMID:21278736
reference_title: "Germline CYBB mutations that selectively affect macrophages in kindreds with X-linked predisposition to tuberculous mycobacterial disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Another French kindred with XR-MSMD has been identified; the three male patients of this kindred (kindred B; patients P5–P7) had BCG disease."
explanation: >-
Documents BCG exposure preceding disease in every patient of kindred B, supporting the
exposure acting on this mechanism.
evidence:
- reference: PMID:21278736
reference_title: "Germline CYBB mutations that selectively affect macrophages in kindreds with X-linked predisposition to tuberculous mycobacterial disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The patients had recurrent or disseminated tuberculous mycobacterial disease, with BCG disease in three patients (MSMD sensu stricto) and tuberculosis in one patient (not vaccinated by BCG)."
explanation: >-
Records BCG disease in three of four patients in kindred A, and notes the fourth was
unvaccinated and had tuberculosis instead.
diagnosis:
- name: CYBB sequencing after a normal chronic granulomatous disease screen
description: >
Because the neutrophil respiratory burst is normal here, the disorder is reached by
sequencing rather than by the functional screens that diagnose chronic granulomatous
disease. In the defining kindreds the gene was found by linkage followed by candidate
sequencing of primary immunodeficiency genes in the linked intervals, after the known
causes of MSMD including X-linked IKBKG mutations had been excluded on clinical and
immunological grounds. The practical consequence for a patient with unexplained BCG or
environmental mycobacterial disease is that CYBB belongs on the sequencing panel even when
the dihydrorhodamine test is normal.
markers: hemizygous hypomorphic CYBB missense allele in an affected male, with normal neutrophil dihydrorhodamine
evidence:
- reference: PMID:21278736
reference_title: "Germline CYBB mutations that selectively affect macrophages in kindreds with X-linked predisposition to tuberculous mycobacterial disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We nonetheless sequenced the coding region of the primary immunodeficiency–causing genes present in those two chromosomal intervals in DNA isolated from the two probands (patients P4 in kindred A and P5 in kindred B)."
explanation: >-
Records the sequencing route by which the diagnosis was established.
- reference: PMID:21278736
reference_title: "Germline CYBB mutations that selectively affect macrophages in kindreds with X-linked predisposition to tuberculous mycobacterial disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In patients from both kindreds, there was no distinguishable immunological phenotype, and the known etiologies of MSMD, including, in particular, X-linked mutations in IKBKG5, were excluded, which suggests that the two kindreds share a previously unknown X-linked recessive genetic etiology of MSMD."
explanation: >-
Establishes that routine immunological phenotyping does not distinguish these patients,
which is why the diagnosis rests on sequencing.
definitions:
- name: Macrophage-restricted respiratory burst assay
definition_type: DIAGNOSTIC_CRITERIA
derivation_basis: MECHANISTIC_HYPOTHESIS
attaches_to:
- pathophysiology#Preserved Neutrophil and Monocyte Respiratory Burst
- pathophysiology#Abolished Macrophage Respiratory Burst
description: >
Diagnosis requires assaying the respiratory burst in monocyte-derived macrophages, not in
neutrophils. The standard chronic granulomatous disease screens - dihydrorhodamine flow
cytometry and nitroblue tetrazolium reduction on peripheral neutrophils - are normal in
these patients by the very mechanism that makes them ill, so a normal CGD screen does not
exclude this disorder. Marked as MECHANISTIC_HYPOTHESIS because it is derived from the
cell-type-restriction model in seven patients rather than from validated consensus
criteria, and because it has never been assessed for sensitivity or specificity.
validation_status:
status: UNVALIDATED
rationale: >-
Derived from the cellular phenotype of seven patients in two kindreds. No diagnostic
accuracy study exists, and macrophage burst assays are not standardised across
laboratories.
evidence:
- reference: PMID:21278736
reference_title: "Germline CYBB mutations that selectively affect macrophages in kindreds with X-linked predisposition to tuberculous mycobacterial disease."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "PMNs and monocytes from patients P4 (kindred A) and P5 (kindred B) stimulated with PMA were normal (Fig. 2c and Supplementary Fig. 2g)."
explanation: >-
Shows that the dihydrorhodamine-based neutrophil and monocyte assay is normal, which is
why the diagnostic test has to be moved to macrophages.
discussions:
- discussion_id: in_vitro_mdm_vs_tissue_macrophage
kind: HUMAN_MODEL_MISMATCH
prompt: >-
Does the respiratory burst defect measured in monocyte-derived macrophages differentiated
in vitro reflect the tissue macrophage that actually harbours the mycobacterium in vivo?
attaches_to:
- pathophysiology#Abolished Macrophage Respiratory Burst
- pathophysiology#Failure to Restrict Intramacrophage Mycobacterial Growth
rationale: >
The entire mechanistic account rests on macrophages differentiated from blood monocytes
over 14 to 15 days in culture, under several cytokine conditions chosen because they are
thought to reflect in vivo differentiation. The authors state plainly that they could not
test the patients' macrophages in vivo or ex vivo. Since the defining feature of the
disorder is that the same allele behaves differently in different cell states, a model
whose fidelity turns on getting the cell state right is exactly the wrong place to have an
untested assumption: an in vitro differentiation protocol that produced a macrophage-like
state not found in tissue could in principle generate the whole phenotype. This is
recorded as HUMAN_MODEL_MISMATCH rather than KNOWLEDGE_GAP because the evidence exists and
it is the translational validity that is open.
proposed_experiments:
- experiment_id: tissue_macrophage_burst_ex_vivo
name: Ex vivo respiratory burst in tissue macrophages from an affected individual
description: >
Assay the respiratory burst and mycobacterial growth control in macrophages recovered
directly from tissue - bronchoalveolar lavage or a granuloma or lymph node biopsy taken
for clinical indications - from a patient carrying Q231P or T178P, alongside neutrophils
from the same patient as an internal control.
would_support:
- pathophysiology#Abolished Macrophage Respiratory Burst
supporting_outcome:
- >-
Tissue macrophages show absent or severely reduced hydrogen peroxide release and impaired
control of mycobacterial growth while neutrophils from the same patient are normal.
would_refute:
- pathophysiology#Abolished Macrophage Respiratory Burst
refuting_outcome:
- >-
Tissue macrophages mount a normal respiratory burst, which would make the in vitro defect
an artefact of the differentiation protocol and leave the disorder without a mechanism.
- discussion_id: allelic_gradient_significance
kind: KNOWLEDGE_GAP
prompt: >-
Does the milder macrophage phenotype of T178P relative to Q231P translate into a milder
clinical course, or is the clinical phenotype threshold-like?
attaches_to:
- pathophysiology#Abolished Macrophage Respiratory Burst
- genetic#CYBB
rationale: >
T178P macrophages released low or occasionally normal amounts of hydrogen peroxide and a
larger fraction reduced nitroblue tetrazolium, so the cellular defect is measurably
milder than with Q231P. Whether that matters clinically cannot be told from the reported
data: kindred A had recurrent or disseminated disease and one case of tuberculosis, and
kindred B had BCG disease in all three patients, but with four and three patients
respectively and different BCG exposure histories the comparison is uninterpretable. The
question bears on whether a partially preserved macrophage burst is protective at all.
prevalence:
- population: Worldwide
measure_type: CASES_IN_LITERATURE
prevalence_class: ULTRA_RARE
notes: >-
Seven patients in two maternally related French kindreds in the defining report. No
subsequent independent kindreds are recorded in the sources curated here, so this count
should be read as the size of the founding series rather than as a current total.
evidence:
- reference: PMID:21278736
reference_title: "Germline CYBB mutations that selectively affect macrophages in kindreds with X-linked predisposition to tuberculous mycobacterial disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We report here two kindreds in which otherwise healthy male adults developed X-linked recessive Mendelian susceptibility to mycobacterial disease (MSMD) syndromes."
explanation: >-
Establishes that the reported series comprises two kindreds, the basis for this record.
- reference: PMID:38341181
reference_title: "Genetic, immunologic, and clinical features of 830 patients with Mendelian susceptibility to mycobacterial diseases (MSMD): A systematic review."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "Finally, 61% of the reported patients with MSMD had mutations of IL12RB1 (41%) or IFNGR1 (20%)."
explanation: >-
Supports the rarity of this genotype indirectly: in a systematic review of 830 MSMD
patients across 21 genes, the two commonest genes account for 61 per cent, and CYBB is not
among them. Graded INDIRECT because the review reports the distribution rather than a CYBB
count.