Mendelian Susceptibility To Mycobacterial Diseases Due To Complete ISG15 Deficiency

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Classifications

IUIS Category

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Inheritance

1

Autosomal recessive inheritance HP:0000007

Disease requires biallelic loss-of-function ISG15 variants. Reported patients are homozygous (nonsense, frameshift, whole-gene deletion, or a functionally null missense allele) or compound heterozygous for a point variant and a contiguous microdeletion; parents are healthy heterozygotes and consanguinity is common in the reported kindreds. Expressivity within a family is wide: two siblings homozygous for the same novel null allele presented differently, one with skin lesions and the other with intracranial calcification and recurrent pneumonia, so a sibling's presentation does not predict the proband's.

Autosomal recessive inheritance

Show evidence (3 references)

PMID:22859821 SUPPORT Human Clinical

"In both families, the segregation of the ISG15 mutant alleles was consistent with autosomal recessive MSMD."

Establishes autosomal recessive segregation of the causal ISG15 alleles in the founding MSMD kindreds.

PMID:25307056 SUPPORT Human Clinical

"Familial segregation was consistent with an autosomal recessive mode of inheritance"

Confirms the same recessive mode in the independently ascertained kindred that presented with intracranial calcification rather than mycobacterial disease.

PMID:37984483 SUPPORT Human Clinical

"We report two sibling patients harboring the same novel ISG15 mutation showing diverse clinical features"

Documents divergent presentations between siblings carrying the same homozygous allele, the basis for the wide-expressivity sentence in this description.

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Discussions and Knowledge Gaps

1

Mouse Isg15 is an antiviral effector and Isg15-null mice are virus-susceptible, while ISG15-deficient humans have no unusual viral susceptibility and their fibroblasts are more virus-resistant than controls. Does any part of the murine antiviral ISGylation phenotype apply to human ISG15 deficiency?

HUMAN MODEL MISMATCH OPEN isg15_mouse_human_antiviral_mismatch

Attached to

pathophysiology#Enhanced Cellular Antiviral Resistance animal_models#Mouse

The divergence is not a matter of degree but of direction, and it has a stated mechanistic cause: human ISG15 is required to sustain USP18 and mouse Isg15 is not, so losing ISG15 raises the interferon set-point in humans and does not in mice. That makes murine inferences about ISGylation-dependent antiviral immunity unsafe to carry into the human disease, which matters because the mouse literature came first and framed the expectation the first patients were measured against. What remains genuinely open is whether human ISGylation has any antiviral role against pathogens these few patients have not met - the authors state the negative result cannot exclude it - and whether the enhanced antiviral state confers clinical protection rather than only a cell-culture advantage.

Show evidence (2 references)

PMID:22859821 SUPPORT Human Clinical

"This experiment of nature shows that human ISGylation is largely redundant for antiviral immunity, but that ISG15 plays an essential role as an IFN-γ-inducing secreted molecule for optimal antimycobacterial immunity."

States the human conclusion that contradicts the murine expectation, and the one function that does hold.

PMID:22859821 SUPPORT Human Clinical

"We cannot rule out enhanced susceptibility to other as yet unencountered viruses"

The authors' own statement of what the negative human result does not settle, which is the part of this gap that remains open.

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Pathophysiology

10

ISG15 Loss of Function

The initiating lesion is biallelic loss of function of ISG15. Because the protein is absent (or, for the reported missense allele, functionally inert), both of its activities are lost simultaneously: its secreted, cytokine-like activity outside the cell and its stabilising interaction with USP18 inside it. Interferon-driven transcription of the gene is intact, so the defect is at the level of the protein.

ISG15 hgnc:4053

Genetic context variant_origin: GERMLINE zygosity: HOMOZYGOUS functional_impact_category: LOSS_OF_FUNCTION

ISG15-protein conjugation GO:0032020 ↓ DECREASED

Downstream

Absent Extracellular ISG15 Release by Leukocytes With no ISG15 protein, mycobacteria-triggered secretion of free ISG15 does not occur.

Loss of Free Intracellular ISG15 The same null genotype removes the intracellular pool of free ISG15 that binds and protects USP18.

Show evidence (1 reference)

PMID:38115997 SUPPORT Human Clinical

"The ISG15 protein plays a dual role in both the type I and II interferon (IFN) immune pathways."

States the dual function of the protein that makes a single null lesion produce two mechanistically separate downstream arms.

Absent Extracellular ISG15 Release by Leukocytes

In healthy donors, contact with mycobacteria triggers leukocytes to release free ISG15 into the extracellular space, with granulocytes the dominant source; the stimulus is specific, since lipopolysaccharide and type I interferon do not trigger release. Patients secrete none. This is the arm that fails in the infectious presentation.

granulocyte CL:0000094

Downstream

Impaired ISG15-Dependent IFN-gamma Production by NK and T Cells Free extracellular ISG15 is the signal that drives IFN-gamma secretion by NK and T cells, so its absence removes that induction.

Show evidence (2 references)

PMID:22859821 SUPPORT In Vitro

"BCG induced the release of ISG15 into the supernatants of control leukocytes, with a concomitant decrease in the amount of intracellular ISG15."

Establishes mycobacteria-triggered secretion of ISG15 by normal leukocytes, the event that does not happen in patients.

PMID:22859821 SUPPORT In Vitro

"These experiments suggest that many cell types can secrete ISG15 and that granulocytes, via their secretory pathway, are a major source of extracellular ISG15 during phagocytosis."

Identifies granulocytes as the principal cellular source, which is why this node binds that cell type.

Impaired ISG15-Dependent IFN-gamma Production by NK and T Cells

NK cells are the key ISG15-responsive population, with T cells contributing. Without extracellular ISG15 these cells produce only small amounts of IFN-gamma on mycobacterial challenge - impaired but not abolished, the same quantitative picture as IL-12p40 and IL-12Rbeta1 deficiency and the reason the MSMD is relatively mild. Adding recombinant ISG15 back to patient blood restores IFN-gamma nearly to normal. The receptor is the LFA-1 integrin (CD11a/CD18): ISG15 binds the CD11a alphaI domain, and engagement drives SRC-family kinase activation and cytokine release, so what the deficiency removes is a defined outside-in signal rather than an unspecified soluble factor.

natural killer cell CL:0000623

type II interferon (IFN-gamma) production GO:0032609 ↓ DECREASED

Downstream

Failed IFN-gamma-Dependent Macrophage Activation Insufficient IFN-gamma fails to deliver the macrophage-activating signal required to kill intracellular mycobacteria.

Show evidence (5 references)

PMID:22859821 SUPPORT Human Clinical

"Whole blood leukocytes from P1, P2 and P3, like those from IL-12p40- and IL-12Rβ1-deficient patients, produced only small amounts of IFN-γ when stimulated with BCG or BCG and IL-12."

Quantifies the IFN-gamma defect in patients and places it alongside the two cytokine-production MSMD etiologies it most resembles.

PMID:22859821 SUPPORT In Vitro

"NK cells were the key ISG15-responsive leukocytes, in terms of IFN-γ induction"

Identifies the responding cell type bound on this node.

PMID:22859821 SUPPORT In Vitro

"The addition of recombinant human ISG15 restored IFN-γ concentrations to almost normal levels"

Add-back rescue shows the IFN-gamma defect is downstream of, and dependent on, the missing ISG15 signal rather than an independent lymphocyte defect.

+ 2 more references

Failed IFN-gamma-Dependent Macrophage Activation

IFN-gamma licenses macrophages to kill the intracellular mycobacteria they harbour. With IFN-gamma output insufficient, infected macrophages are not activated. This is the convergent final mechanism of MSMD, reached here through a failure of cytokine production rather than of the response to IFN-gamma.

macrophage CL:0000235

macrophage activation GO:0042116 ↓ DECREASED

Downstream

Uncontrolled Replication of Weakly Virulent Mycobacteria Without macrophage activation the intracellular organisms are not killed and replicate.

Show evidence (1 reference)

PMID:38025345 SUPPORT Human Clinical

"almost all genetic etiologies of MSMD alter the interferon-gamma (IFN-γ)- mediated immunity by impairing or abolishing IFN-γ production or the response to this cytokine."

Establishes impaired IFN-gamma-mediated immunity as the convergent mechanism of MSMD, which is what fails at this node.

Uncontrolled Replication of Weakly Virulent Mycobacteria

The organism-level consequence is disease caused by mycobacteria that an intact IFN-gamma response would contain: above all the BCG vaccine strain, and environmental non-tuberculous mycobacteria. This node initiates the infectious phenotypes.

Animal models

Isg15-deficient mouse Mouse partially recapitulates Accelerated death after M. tuberculosis infection in the knockout supports a non-redundant antimycobacterial role for Isg15 in vivo.

Downstream

BCG disease

Non-tuberculous mycobacterial infection

Show evidence (1 reference)

ORPHA:319563 SUPPORT Other

"Mendelian susceptibility to mycobacterial diseases (MSMD) due to complete ISG15 deficiency is a genetic variant of MSMD characterized by Bacille Calmette-Guérin (BCG) infections."

Orphanet's definition of the disease names BCG infection as its characteristic manifestation, the clinical expression of this node.

Loss of Free Intracellular ISG15

The second arm begins with the absence of the intracellular pool of free (unconjugated) ISG15. This activity is conjugation-independent: transducing patient cells with an ISG15 mutant that cannot be conjugated to substrates rescues the phenotype as well as wild-type ISG15 does, and silencing the ISGylation enzymes does not reproduce it. The disease-relevant intracellular function of ISG15 in humans is therefore not ISGylation.

Downstream

Accelerated Ubiquitin-Dependent USP18 Degradation Free ISG15 binds USP18 and antagonises its ubiquitination; without ISG15, USP18 is degraded rapidly.

Show evidence (1 reference)

PMID:25307056 SUPPORT In Vitro

"ISG15 appeared to act in its unconjugated free form, since silencing of UBE1L or of other ISGylation enzymes failed to reduce USP18 levels"

Establishes that the relevant species is free, unconjugated ISG15, not an ISGylated substrate - the claim this node makes.

Accelerated Ubiquitin-Dependent USP18 Degradation

USP18 is itself an interferon-stimulated gene and the principal negative regulator of type I interferon signalling. Free ISG15 binds USP18 and prevents assembly of the USP18-SKP2 complex, antagonising its ubiquitination and proteolysis. Without ISG15, USP18 protein falls even though USP18 mRNA is elevated - a protein-level brake failure in the face of an up-regulated transcript.

ubiquitin-dependent proteolysis of USP18 GO:0006511 ↑ INCREASED

Downstream

Sustained Type I Interferon Signalling and ISG Over-Amplification Loss of the USP18 brake leaves type I interferon signalling inadequately attenuated.

Show evidence (2 references)

PMID:25307056 SUPPORT In Vitro

"The formation of the USP18–SKP2 complex (Fig. 4e, lane 8), was prevented by co-expression of ISG15"

Identifies the molecular interaction ISG15 blocks - SKP2 engagement of USP18 - which is the degradation route this node names.

PMID:25307056 SUPPORT In Vitro

"Remarkably, however, levels of USP18 were low in patients’ cells (Fig. 3a, b), despite their higher levels of USP18 mRNA"

Records the protein-versus-transcript dissociation that establishes the lesion as post-translational destabilisation of USP18 rather than failed induction of it.

Sustained Type I Interferon Signalling and ISG Over-Amplification

With the USP18 brake degraded, STAT1 and STAT2 remain phosphorylated for longer than in control cells and the interferon-stimulated gene program is amplified rather than self-limiting. Patient blood carries a raised interferon signature across the same genes used to score Aicardi-Goutieres syndrome, and in peripheral blood the myeloid compartment shows the strongest signature. The disorder-specific output program at this node is therefore an interferon-stimulated gene signature.

monocyte CL:0000576

type I interferon-mediated signaling pathway GO:0060337 ↑ INCREASED negative regulation of type I interferon-mediated signaling pathway GO:0060339 ↓ DECREASED

Downstream

Type I Interferon-Driven Tissue Inflammation The amplified interferon response drives the inflammatory and neurological features, as in the other Mendelian type I interferonopathies.

Enhanced Cellular Antiviral Resistance The same sustained interferon-stimulated gene program leaves patient cells better protected against virus than control cells.

Show evidence (3 references)

PMID:25307056 SUPPORT In Vitro

"in patients’ cells, STAT1 and STAT2 were more persistently phosphorylated"

The direct signalling readout of this node: prolonged STAT1/STAT2 phosphorylation in patient cells.

PMID:25307056 SUPPORT Human Clinical

"all ISG15-deficient patients, like patients with AGS, had significantly higher levels of interferon-stimulated gene messenger RNA than unaffected relatives or healthy controls"

Establishes the interferon-stimulated gene signature in patients, the disorder-specific output program named at this node.

PMID:32402279 SUPPORT Human Clinical

"In peripheral blood, myeloid cells display the most robust IFN-I signatures."

Identifies the blood compartment carrying the strongest signature, which is why this node binds the monocyte cell type.

Enhanced Cellular Antiviral Resistance

A consequence of the same amplified interferon program, and the reason the deficiency does not behave as a classical antiviral immunodeficiency in humans. Patients have no unusual susceptibility to viruses in vivo, and their fibroblasts are more resistant to virus than control cells. This is the point at which the mouse model diverges from the human disease.

Animal models

Isg15-deficient mouse Mouse fails to recapitulate The mouse shows the opposite of the human phenotype: Isg15-deficient mice are susceptible to viruses, whereas ISG15-deficient humans are not and their cells are more virus-resistant than controls.

Show evidence (1 reference)

PMID:27193971 SUPPORT Human Clinical

"Here we describe ISG15-deficient patients who display no enhanced susceptibility to viruses in vivo, in stark contrast to Isg15-deficient mice."

Establishes the absence of a clinical antiviral phenotype in patients, which this node records.

Type I Interferon-Driven Tissue Inflammation

The amplified interferon response is expressed in tissue as inflammation. In affected skin, interferon signalling is seen in epidermal keratinocytes, in endothelium, and in dermal monocytes and macrophages - the cellular basis of the recurrent necrotising ulceration. In the central nervous system the counterpart is the intracranial calcification shared with Aicardi-Goutieres syndrome and spondyloenchondrodysplasia. This node initiates the inflammatory and neurological phenotypes.

keratinocyte CL:0000312 endothelial cell CL:0000115 macrophage CL:0000235

Downstream

Skin ulceration

Impaired healing of skin ulceration with fibrosis

Basal ganglia calcification

Seizure

Developmental delay

Interstitial lung disease

Recurrent pneumonia

Autoantibody positivity

Show evidence (2 references)

PMID:32402279 SUPPORT Human Clinical

"In the affected skin, IFN-I signaling is observed in the keratinocytes of the epidermis, endothelia, and the monocytes and macrophages of the dermis."

Localises interferon signalling to specific cell types in affected tissue, grounding the cell-type bindings on this node.

PMID:25307056 SUPPORT Human Clinical

"We show here that ISG15-deficient patients also display unanticipated cellular, immunological and clinical signs of enhanced IFN-α/β immunity, reminiscent of the Mendelian autoinflammatory interferonopathies Aicardi-Goutières syndrome and spondyloenchondrodysplasia."

Places the tissue phenotype of this disease within the Mendelian type I interferonopathies, the disease class this node's consequences belong to.

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Pathograph

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Phenotypes

12

Immune 6

BCG disease BCGosis HP:0020087

Onset: INFANTILE

Show evidence (3 references)

PMID:22859821 SUPPORT Human Clinical

"Here, we describe human patients with inherited ISG15 deficiency and mycobacterial, but not viral, diseases."

The founding report establishing mycobacterial disease, and specifically not viral disease, as the infectious phenotype of this deficiency.

PMID:32402279 SUPPORT Human Clinical

"At the age of one month, he was vaccinated with BCG, to which he displayed an exaggerated response, with right inguinal lymphadenopathy and erythema of the overlying skin."

A worked pediatric case of BCG disease following vaccination in infancy, and the basis for the infantile onset category.

PMID:25307056 SUPPORT Human Clinical

"The ISG15-deficient patients from China were not vaccinated with BCG at birth, consistent with their current lack of an MSMD phenotype."

Shows that unvaccinated patients with the same genotype have no mycobacterial phenotype, making BCG exposure rather than genotype the determinant of this presentation.

Non-tuberculous mycobacterial infection HP:5210115

Show evidence (1 reference)

PMID:39365299 SUPPORT Human Clinical

"ISG15 deficiency is a mixed syndrome of Mendelian susceptibility to mycobacterial infections (MSMD), a rare inherited condition characterized primarily by recurrent infections from low-virulence mycobacteria and monogenic type I interferonopathy."

States susceptibility to low-virulence mycobacteria as a defining feature of ISG15 deficiency, and names the dual syndrome this entry models.

Recurrent pneumonia HP:0006532

Show evidence (2 references)

PMID:37984483 SUPPORT Human Clinical

"The manifestation in patient 2 was skin lesions, while those in patient 1 were intracranial calcification and recurrent pneumonia."

Documents recurrent pneumonia as a presenting manifestation in a genetically confirmed patient.

PMID:37984483 SUPPORT Human Clinical

"one harbored a rare phenotype of pneumonia"

The authors' own characterisation of pneumonia as a rare rather than typical feature, which is why no frequency is recorded.

Autoantibody positivity Autoimmune antibody positivity HP:0030057

Show evidence (1 reference)

PMID:25307056 SUPPORT Human Clinical

"These patients also had autoantibody levels higher than those in age-matched controls"

Direct observation of raised autoantibody levels in the patient cohort.

Reduced mycobacteria-induced IFN-gamma production Reduced circulating interferon gamma concentration HP:0033253

Concept-fit caveat: HP:0033253 names a reduced circulating IFN-gamma concentration, whereas the cited measurement is reduced IFN-gamma production by BCG-stimulated whole blood ex vivo. The binding is the closest available HP term and preferred_term carries the specific assay reading; the term is broader than the assay rather than a different claim.

Show evidence (1 reference)

PMID:22859821 SUPPORT Human Clinical

"Whole blood leukocytes from P1, P2 and P3, like those from IL-12p40- and IL-12Rβ1-deficient patients, produced only small amounts of IFN-γ when stimulated with BCG or BCG and IL-12."

The measurement behind this laboratory phenotype.

Elevated type I interferon signature Increased circulating Interferon-alpha concentration HP:0034513

The bound HP term names a circulating IFN-alpha concentration, which is what the plasma antiviral-activity measurement reports. The interferon-stimulated gene signature that dominates the literature on this disease is a transcript score rather than a cytokine concentration, and HPO has no term for it; preferred_term and the description carry the distinction.

Show evidence (2 references)

PMID:25307056 SUPPORT Human Clinical

"The two Chinese patients who displayed seizures (P5 and P6) also had detectable IFN-α antiviral activity in their plasma"

The circulating IFN-alpha measurement that the bound HP term names.

PMID:25307056 SUPPORT Human Clinical

"all ISG15-deficient patients, like patients with AGS, had significantly higher levels of interferon-stimulated gene messenger RNA than unaffected relatives or healthy controls"

The interferon-stimulated gene signature, the transcript-level reading described alongside the cytokine measurement.

Integument 1

Skin ulceration HP:0200042

Temporal: RECURRENT

Show evidence (3 references)

PMID:32402279 SUPPORT Human Clinical

"Herein, we describe five new patients with six novel ISG15 mutations presenting with skin lesions who were managed for dermatologic disease."

Establishes dermatologic disease as a presentation of ISG15 deficiency in its own right, in five genetically confirmed patients.

PMID:32402279 SUPPORT Human Clinical

"At the age of one year, P5 presented ulcers of the inguinal region and vulva."

Gives the early-childhood onset and characteristic distribution of the ulceration.

PMID:38115997 SUPPORT Human Clinical

"In this report, we describe novel variants found in two different families that result in complete ISG15 deficiency and severe skin ulceration."

Independent replication of severe skin ulceration in two further ISG15-deficient families.

Musculoskeletal 2

Basal ganglia calcification HP:0002135

Show evidence (4 references)

PMID:25307056 SUPPORT Human Clinical

"We found that P1 and P2 displayed calcification of the basal ganglia, with CT imaging in P3 also showing calcification along the cerebral falx"

Documents basal ganglia calcification in the patients originally ascertained through mycobacterial disease, establishing it as a feature of the disease rather than of one kindred.

PMID:25307056 SUPPORT Human Clinical

"These findings strongly suggest that the three ISG15 alleles identified are disease-causing, not only for MSMD, but also for IBGC, an intracranial calcification phenotype unrelated to any obvious cerebral infection."

States that the calcification is caused by the ISG15 genotype and is not secondary to infection.

PMID:40318816 SUPPORT Human Clinical

"Here, we report a 4-month-old Chinese patient presenting with inflammatory skin lesions, interstitial pneumonia, and basal ganglia calcifications."

Establishes that the calcification is already present in infancy, the pediatric timing recorded in this phenotype's description.

+ 1 more reference

Impaired healing of skin ulceration with fibrosis Scarring HP:0100699

Show evidence (2 references)

PMID:41743834 SUPPORT Human Clinical

"Analysis of patient skin biopsies revealed increased IFN-I-dependent apoptosis, altered macrophage polarization, enhanced epithelial-to-mesenchymal transition (EMT), and myofibroblast activation."

The patient-tissue findings behind the fibrotic character of the skin lesions.

PMID:41743834 SUPPORT In Vitro

"ISG15 KO fibroblasts displayed impaired mechanical wound healing and increased IFN-I-induced apoptosis compared with WT cells"

The cell-based demonstration that loss of ISG15 itself impairs wound closure, which is the mechanism this phenotype names.

Nervous System 2

Developmental delay Global developmental delay HP:0001263

Show evidence (2 references)

PMID:38115997 SUPPORT Human Clinical

"He also had recurrent respiratory tract infections with chest radiograph changes, and global developmental delay was noted."

Documents global developmental delay in a genetically confirmed ISG15-deficient patient.

PMID:38115997 SUPPORT Human Clinical

"BII-3, the younger sister of BII-2, recently developed a single skin ulcerative lesion and mild developmental delay"

The affected sibling in the same family, establishing that the delay is not an isolated observation in one child.

Seizure FREQUENT HP:0001250

Show evidence (2 references)

PMID:25307056 SUPPORT Human Clinical

"Three of the six ISG15-deficient individuals experienced epileptic seizures, which were lethal in one case."

Gives the proportion affected - three of six, supporting the FREQUENT band - and the fatal outcome in one.

PMID:25307056 SUPPORT Human Clinical

"The eldest child (P4) died during an episode of epileptic seizures at the age of 13 years"

Records the age and circumstance of the one death in the cohort.

Respiratory 1

Interstitial lung disease Interstitial pneumonitis HP:0006515

Show evidence (3 references)

PMID:40318816 SUPPORT Human Clinical

"Here, we report a 4-month-old Chinese patient presenting with inflammatory skin lesions, interstitial pneumonia, and basal ganglia calcifications."

Documents interstitial pneumonia in a genetically confirmed ISG15-deficient infant.

PMID:38115997 SUPPORT Human Clinical

"ISG15 deficiency can present with various clinical phenotypes, ranging from susceptibility to mycobacterial infection to autoinflammation characterised by necrotising skin lesions, intracerebral calcification, and pulmonary involvement."

Names pulmonary involvement as part of the recognised autoinflammatory spectrum of the disease.

PMID:41743834 SUPPORT BACKGROUND Human Clinical

"ISG15 deficiency is a type I interferonopathy characterized by elevated circulating type I interferon (IFN-I), intracranial calcifications, fibrotic skin lesions, and occasionally inflammatory lung disease."

Independent statement that inflammatory lung disease is an occasional feature of the disease. Graded HUMAN_CLINICAL with quote_role BACKGROUND because the sentence states the established human clinical picture in the paper's opening, while the paper's own work is the spatial-transcriptomic and in vitro fibrosis study.

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Genetic Associations

1

ISG15 (CAUSATIVE)

Gene: ISG15 hgnc:4053 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (4 references)

PMID:22859821 SUPPORT Human Clinical

"These data suggest that the two mutant ISG15 alleles are loss-of-expression."

Establishes the founding causal alleles as loss-of-expression, the molecular basis of complete deficiency.

PMID:22859821 SUPPORT In Vitro

"Fibroblasts from P1 and P2 lacked detectable IFN-β-inducible ISGylation"

Demonstrates the functional consequence of the alleles in patient fibroblasts: no interferon-inducible protein ISGylation.

PMID:38115997 SUPPORT Human Clinical

"In the second family, a homozygous total ISG15 gene deletion was detected in two siblings."

Documents whole-gene deletion as one of the allele classes producing complete deficiency.

+ 1 more reference

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Medical Actions

3

Antimycobacterial Therapy

Action: multidrug antimycobacterial chemotherapy Ontology label: Pharmacotherapy NCIT:C15986

Agent: antitubercular agent NCIT:C280

Platform: Small molecule

Multidrug antimycobacterial chemotherapy treats the mycobacterial disease itself and is required regardless of the underlying immune defect. Regimen composition follows species identification and susceptibility testing; this entry does not assert a specific regimen or duration, because none has been established for this etiology separately from MSMD management generally.

Mechanism Target:

INHIBITS Uncontrolled Replication of Weakly Virulent Mycobacteria — Antimycobacterial drugs act on the organism, substituting pharmacological killing for the macrophage-mediated killing the host cannot perform.

Show evidence (1 reference)

PMID:32402279 SUPPORT INDIRECT Human Clinical

"ISG15-deficient patients have been identified on the basis of several different presentations: a reaction to BCG vaccination, intermittent seizures, or, as in the patients described here, dermatological features."

Establishes BCG reaction as one of the presentations of this disease, and so the indication for antimycobacterial treatment. Graded INDIRECT because the sentence states the indication rather than reporting the treatment or its effect.

Janus Kinase Inhibition

Action: Pharmacotherapy NCIT:C15986

Agent: baricitinib CHEBI:95341

Platform: Small molecule

Baricitinib blocks signalling downstream of the type I interferon receptor and so interrupts the arm of the disease that the ISG15 lesion drives by removing the USP18 brake. It is the mechanistically targeted treatment for the inflammatory and neurological features and does not address the mycobacterial arm. Reported responses are rapid and, in one sibling, complete; reported dosing in these case reports is 2 mg orally twice daily with a tapering course of oral prednisolone. The evidence is at the level of individual case reports, not trials. A caveat carried over from the wider type I interferonopathy literature rather than from ISG15 deficiency itself: in Aicardi-Goutieres syndrome, intracranial calcification has been found at post-mortem to be extensive despite baricitinib started at two months of age and continued for over four years, which the authors attribute to poor CNS bioavailability. No comparable long-term neurological follow-up has been published for ISG15 deficiency, so whether early JAK inhibition protects the brain in this disease is unknown.

Mechanism Target:

INHIBITS Sustained Type I Interferon Signalling and ISG Over-Amplification — JAK inhibition blocks signal transduction from the type I interferon receptor, so the amplified interferon-stimulated gene program is suppressed even though the USP18 brake remains absent.

Show evidence (1 reference)

PMID:40318816 SUPPORT Human Clinical

"Treatment with the Janus kinase (JAK) inhibitor baricitinib rapidly resolved the patient's clinical symptoms."

Clinical response to JAK inhibition in a patient whose disease was shown to run through defective USP18 stabilisation and excess type I interferon signalling, the node this treatment targets.

Show evidence (3 references)

PMID:38115997 SUPPORT Human Clinical

"Finally, we demonstrate the complete and rapid resolution of clinical symptoms associated with ISG15 deficiency in one sibling from the second family following treatment with the Janus kinase (JAK) inhibitor baricitinib."

The first report of JAK inhibition in ISG15 deficiency, documenting complete resolution of symptoms.

PMID:38115997 SUPPORT Human Clinical

"The patient was subsequently initiated on oral prednisolone 1mg/kg/day tapered over 8-10 weeks and the JAK inhibitor baricitinib (2mg orally twice daily)."

Records the reported regimen, the basis for the dosing sentence in this treatment's description.

PMID:38381212 SUPPORT INDIRECT Human Clinical

"This study showed profound central nervous system (CNS) sequelae despite early initiation of treatment."

The source of the CNS caveat in this treatment's description. Graded INDIRECT and flagged here because the patient had Aicardi-Goutieres syndrome, not ISG15 deficiency: it supports the caveat only by the class argument that JAK inhibition may not reach the brain in a type I interferonopathy, and no ISG15-specific neurological follow-up exists.

Avoidance of BCG Vaccination

Action: avoidance of live BCG vaccination Ontology label: Supportive Care NCIT:C15747

Platform: Behavioral / lifestyle

Live BCG vaccine is the commonest trigger of the mycobacterial arm, so it is contraindicated in an affected child and should be withheld from at-risk newborn siblings pending genetic testing. The pediatric timing problem is acute: in endemic countries BCG is given at or shortly after birth, months before any presentation that would prompt testing. The unvaccinated ISG15-deficient siblings have no mycobacterial phenotype, which is the clearest available evidence that withholding the exposure prevents that arm of the disease.

Mechanism Target:

INHIBITS Uncontrolled Replication of Weakly Virulent Mycobacteria — Withholding the live vaccine removes the mycobacterial challenge that the IFN-gamma-deficient host cannot contain.

Show evidence (1 reference)

PMID:25307056 SUPPORT Human Clinical

"The ISG15-deficient patients from China were not vaccinated with BCG at birth, consistent with their current lack of an MSMD phenotype."

Unvaccinated patients with the same genotype have no mycobacterial disease, the observation supporting avoidance as effective against this node.

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Environmental Factors

1

Bacille Calmette-Guerin (BCG) vaccination

The binding is deliberately broader than the exposure. ECTO has no BCG-, Calmette- or M. bovis-specific exposure class: `runoak -i sqlite:obo:ecto search "l~BCG"`, `"l~Calmette"` and `"l~bacille"` each return nothing, and `"l~mycobacter"` returns only exposure classes for M. tuberculosis and M. avium. ECTO:2000129 exposure to vaccination is the most specific true class available, and preferred_term carries the vaccine identity.

Routine BCG immunisation is the sentinel environmental exposure in this disorder. The attenuated Mycobacterium bovis BCG strain is harmless to immunocompetent infants but causes regional or disseminated disease in a host that cannot mount an adequate ISG15-dependent IFN-gamma response. Whether a patient develops the mycobacterial arm of this disease at all is largely decided by this exposure.

Show evidence (1 reference)

PMID:25307056 SUPPORT Human Clinical

"These patients (P1, P2 and P3, now aged 17, 14 and 17 years, respectively) displayed clinical disease caused by the BCG vaccine, which, in otherwise healthy individuals, defines Mendelian susceptibility to mycobacterial disease (MSMD)"

States that the BCG vaccine caused the clinical disease in the founding patients, establishing the exposure-disease relationship at entry level.

Mechanism Target:

TRIGGERS Uncontrolled Replication of Weakly Virulent Mycobacteria — The live BCG strain is the mycobacterial challenge that the IFN-gamma-deficient host cannot contain, initiating regional or disseminated disease.

Show evidence (1 reference)

PMID:32402279 SUPPORT Human Clinical

"At the age of one month, he was vaccinated with BCG, to which he displayed an exaggerated response, with right inguinal lymphadenopathy and erythema of the overlying skin."

Ties the vaccination exposure directly to mycobacterial disease in an ISG15-deficient infant.

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Diagnosis

2

ISG15 sequencing

Molecular confirmation identifies the biallelic ISG15 genotype. Because the two presentations look like two different diseases - a pediatric infectious-disease problem and a pediatric neurology or dermatology problem - the genotype is often what unifies them, and exome sequencing made the connection both in the founding MSMD kindreds and in the kindred labelled idiopathic basal ganglia calcification. A normal-appearing protein does not exclude the diagnosis: one reported allele is missense and functionally null.

Show evidence (1 reference)

PMID:25307056 SUPPORT Human Clinical

"Whole-exome sequencing (WES) of P5 and P6 and their healthy mother identified only one common nonsense homozygous mutation, which had not been reported in public databases or in in-house WES data for 1,500 other individuals"

Documents exome sequencing as the route to diagnosis in patients presenting without any infectious phenotype.

Cranial CT for intracranial calcification

Non-contrast cranial CT detects the basal ganglia calcification. It is worth doing in a patient with an MSMD phenotype and an ISG15 genotype even without neurological symptoms: scanning the Turkish and Iranian patients, who had been followed for mycobacterial disease, is how the calcification was found in them.

Show evidence (1 reference)

PMID:25307056 SUPPORT Human Clinical

"Following the identification of ISG15 mutations in Chinese children with a putative diagnosis of IBGC, we performed computed tomography (CT) scans on the Iranian and Turkish ISG15-deficient MSMD patients."

Describes the imaging step that revealed calcification in patients who had been managed for mycobacterial disease alone.

📊

Prevalence

1

Worldwide

Cases In Literature Unknown

No population rate has been established. The disease was described in 2012 in three patients from two consanguineous kindreds (Turkey, Iran), extended in 2015 by Chinese siblings ascertained through intracranial calcification, and by 2023 a review of the published literature put the total at fewer than 100 cases worldwide. Recorded as a literature case count rather than a rate.

Show evidence (1 reference)

PMID:38115997 SUPPORT Human Clinical

"ISG15 deficiency remains an extremely rare disease, with fewer than 100 cases reported worldwide."

Gives the published case count that is the basis for recording occurrence as a literature case count rather than a population rate.

⚖️

Clinical Burden

High

Burden comes from both arms. The mycobacterial arm produces BCG disease in infancy requiring prolonged multidrug chemotherapy; the interferon arm produces recurrent deep necrotising skin ulceration that is steroid-refractory, and seizures that were fatal in one of the six patients in the founding interferonopathy cohort. Against that, the MSMD component is relatively mild compared with IFN-gamma receptor deficiency, and JAK inhibition produces rapid resolution of the inflammatory features in the cases reported so far, so the burden is high but not uniformly lethal.

Show evidence (2 references)

PMID:25307056 SUPPORT Human Clinical

"Three of the six ISG15-deficient individuals experienced epileptic seizures, which were lethal in one case."

Records death from seizures in the interferonopathy arm, the most severe outcome documented and the main driver of the HIGH burden assessment.

PMID:32402279 SUPPORT Human Clinical

"The lesions were largely resistant to steroid treatment, and were recurrent and necrotizing, but they resolved spontaneously, leaving post-inflammatory hyperpigmentation."

Documents the recurrent, steroid-refractory necrotising skin disease that is the main chronic morbidity of the inflammatory arm.

🐁

Animal Models

1

Isg15-deficient mouse

Isg15-null mice die earlier than wild-type littermates after Mycobacterium tuberculosis infection, which supports the antimycobacterial role of ISG15. The same model is susceptible to several viruses, which the human disease is not, so the model is informative for one arm of the disease and misleading for the other.

Species

Mouse

Genotype

Isg15 knockout

Publication

PMID:22859821

Pathograph links

Uncontrolled Replication of Weakly Virulent Mycobacteria partially recapitulates fidelity: moderate observes: organism Accelerated death after M. tuberculosis infection in the knockout supports a non-redundant antimycobacterial role for Isg15 in vivo.

Limitations: The challenge organism is fully virulent M. tuberculosis rather than the weakly virulent BCG strain and environmental mycobacteria that define the human phenotype, and mouse Isg15 does not sustain USP18 as human ISG15 does, so the murine interferon state at the time of challenge is not the human one.

Show evidence (1 reference)

PMID:22859821 SUPPORT Model Organism

"Finally, we showed that ISG15−/− mice succumbed earlier than their WT littermates upon infection with M. tuberculosis"

The in vivo result in the knockout that supports this model-to-mechanism link.

Enhanced Cellular Antiviral Resistance fails to recapitulate fidelity: low observes: organism The mouse shows the opposite of the human phenotype: Isg15-deficient mice are susceptible to viruses, whereas ISG15-deficient humans are not and their cells are more virus-resistant than controls.

Limitations: The divergence is mechanistic rather than incidental: human ISG15 is required to sustain USP18 levels and mouse Isg15 is not, so the sustained interferon state that leaves human cells antivirally primed has no counterpart in the mouse. Murine Isg15 antiviral data therefore cannot be read across to the human deficiency.

Show evidence (2 references)

PMID:27193971 SUPPORT Human Clinical

"Here we describe ISG15-deficient patients who display no enhanced susceptibility to viruses in vivo, in stark contrast to Isg15-deficient mice."

States the contradiction between model and human disease that this negative link records.

+ 1 more reference

Show evidence (1 reference)

PMID:27193971 SUPPORT Model Organism

"Studies in mice have demonstrated a role for Isg15 in antiviral immunity."

States what the mouse model shows, which is the claim the human data then contradict.

{ }

Source YAML

click to show

name: Mendelian Susceptibility To Mycobacterial Diseases Due To Complete ISG15 Deficiency
creation_date: "2026-09-23T00:00:00Z"
category: Mendelian
synonyms:
- MSMD due to complete ISG15 deficiency
- ISG15 deficiency
- ISG15 deficiency, autosomal recessive
- Immunodeficiency 38
- IMD38
- Immunodeficiency 38 with basal ganglia calcification
description: >
  Mendelian susceptibility to mycobacterial disease (MSMD) due to complete ISG15
  deficiency is an autosomal recessive inborn error of immunity caused by biallelic
  loss-of-function variants in ISG15. It is unusual among the MSMD etiologies in carrying
  two mechanistically separate disease arms from one lesion, because ISG15 has two
  functions in two different compartments and the deficiency abolishes both at once.

  Extracellularly, free ISG15 is released by leukocytes - granulocytes in particular - on
  contact with mycobacteria and acts as an IFN-gamma-inducing cytokine on NK and T cells.
  Without it, IFN-gamma output after mycobacterial challenge is low, IFN-gamma-dependent
  macrophage activation fails, and weakly virulent mycobacteria replicate unchecked. That
  is the MSMD arm, and in BCG-vaccinating countries it presents in infancy as disease
  caused by the vaccine strain.

  Intracellularly, free ISG15 binds USP18 and protects it from SKP2-dependent
  ubiquitination and proteolysis. USP18 is the principal negative regulator of type I
  interferon signalling, so without ISG15 the brake is degraded, STAT1 and STAT2 stay
  phosphorylated, and interferon-stimulated genes are over-amplified. That is the type I
  interferonopathy arm: basal ganglia calcification, seizures, recurrent necrotising skin
  ulceration, and in some patients interstitial lung disease, a picture resembling
  Aicardi-Goutieres syndrome and spondyloenchondrodysplasia. Which arm a given child
  presents with depends substantially on whether they were BCG-vaccinated: an unvaccinated
  Chinese kindred came to attention through intracranial calcification and seizures alone,
  while the Turkish and Iranian MSMD patients turned out on CT to have the same
  calcification.

  The species contrast is a caution against reading mouse data across. Isg15-null mice are
  susceptible to several viruses; ISG15-deficient humans are not, and their fibroblasts are
  in fact more resistant to virus than controls, because the sustained interferon response
  that makes them ill also leaves their cells antivirally primed. Treatment splits along
  the same seam as the mechanism: antimycobacterial chemotherapy for the infectious arm,
  and JAK inhibition for the interferon-driven inflammatory arm.
disease_term:
  preferred_term: Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency
  term:
    id: MONDO:0014502
    label: Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency
parents:
- Primary immunodeficiency
- Mendelian susceptibility to mycobacterial disease
- Type I interferonopathy
notes: >-
  Lump/split. This entry is kept as a single disease covering both the mycobacterial and
  the type I interferonopathy presentations, rather than split into an MSMD entry and an
  interferonopathy entry, because both arise from the same biallelic ISG15 null genotype
  and the two presentations occur in the same individuals: CT scanning of the Turkish and
  Iranian MSMD patients found the same basal ganglia calcification that had brought the
  unvaccinated Chinese siblings to attention. The presentation split tracks BCG exposure
  rather than genotype. MONDO's own label names only the MSMD arm; the entry keeps that
  label on `disease_term` while the description and pathophysiology carry both arms.

  No GeneReviews chapter exists for ISG15 deficiency. PubMed `ISG15[TI] AND
  genereviews[book]` and the MSMD-titled equivalent both return zero records, so there is
  no expert-curated phenotype baseline for this entry and the phenotype list is assembled
  from the primary case series instead.

  Orphanet's definition of ORPHA:319563 names only BCG infection and does not mention the
  interferonopathy features, which post-date it. It is cited here for disease identity and
  the MONDO/OMIM cross-references rather than for the clinical spectrum.

  ClinGen has no gene-disease validity assertion for ISG15. The full Gene-Disease Validity
  table downloaded from `search.clinicalgenome.org/kb/gene-validity/download` (file created
  2026-09-23, 3,676 assertions) contains no ISG15 row, although it does carry other MSMD
  genes such as STAT1, so no `CGGV:` evidence is cited here.
references:
- reference: PMID:22859821
  title: "Mycobacterial disease and impaired IFN-γ immunity in humans with inherited ISG15 deficiency."
- reference: PMID:25307056
  title: "Human intracellular ISG15 prevents interferon-α/β over-amplification and auto-inflammation."
- reference: PMID:32402279
  title: "Systemic Type I IFN Inflammation in Human ISG15 Deficiency Leads to Necrotizing Skin Lesions."
- reference: PMID:27193971
  title: "ISG15 deficiency and increased viral resistance in humans but not mice."
- reference: PMID:38115997
  title: "Case Report: ISG15 deficiency caused by novel variants in two families and effective treatment with Janus kinase inhibition."
- reference: PMID:40318816
  title: "A novel homozygous ISG15 missense variant leads to severe inflammatory skin lesions, interstitial pneumonia, and basal ganglia calcifications in a Chinese infant with ISG15 deficiency."
- reference: PMID:39365299
  title: "First Brazilian Case Report of Unrelated Patients with Identical ISG15 Mutation."
- reference: PMID:29100055
  title: "Extracellular ISG15 Signals Cytokine Secretion through the LFA-1 Integrin Receptor."
- reference: PMID:37984483
  title: "A novel homozygous Y140X mutation of ISG15 causes diverse type I interferonopathies in sibling patients with cutaneous lesions or recurrent parenchymal pneumonia."
- reference: PMID:41743834
  title: "Human ISG15 deficiency unveils impaired healing of ulcerations via type I interferon-mediated fibrosis."
- reference: PMID:38381212
  title: "Neuropathologic Impacts of JAK Inhibitor Treatment in Aicardi-Goutières Syndrome."
- reference: PMID:38025345
  title: "Mendelian susceptibility to mycobacterial diseases: State of the puzzle."
- reference: ORPHA:319563
  title: "Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency"
classifications:
  iuis_category:
    classification_value: innate immunity defect
    notes: >-
      IUIS phenotypic classification of inborn errors of immunity, Mendelian susceptibility
      to mycobacterial disease (MSMD) table. ISG15 is one of the established MSMD genes.
      The type I interferonopathy features this entry also carries are an autoinflammatory
      phenotype of the same defect and do not move the IUIS assignment.
    evidence:
    - reference: PMID:38025345
      reference_title: "Mendelian susceptibility to mycobacterial diseases: State of the puzzle."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Mendelian susceptibility to mycobacterial diseases (MSMD) is the most characterized
        of these IEIs, with 36 different disorders found in 20 distinct genes (IFNGR1,
        IFNGR2, IFNG, IL12RB1, IL12RB2, IL23R, IL12B, ISG15, USP18, ZNFX1, TBX21, STAT1,
        TYK2, IRF8, IRF1, CYBB, JAK1, RORC, NEMO, and SPPL2A)
      explanation: >-
        Places ISG15 in the established gene set of Mendelian susceptibility to
        mycobacterial disease, the inborn-error-of-immunity syndrome under which this entry
        is classified.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: UNKNOWN
  notes: >-
    No population rate has been established. The disease was described in 2012 in three
    patients from two consanguineous kindreds (Turkey, Iran), extended in 2015 by Chinese
    siblings ascertained through intracranial calcification, and by 2023 a review of the
    published literature put the total at fewer than 100 cases worldwide. Recorded as a
    literature case count rather than a rate.
  evidence:
  - reference: PMID:38115997
    reference_title: "Case Report: ISG15 deficiency caused by novel variants in two families and effective treatment with Janus kinase inhibition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ISG15 deficiency remains an extremely rare disease, with fewer than 100 cases
      reported worldwide.
    explanation: >-
      Gives the published case count that is the basis for recording occurrence as a
      literature case count rather than a population rate.
clinical_burden:
  burden_level: HIGH
  rationale: >-
    Burden comes from both arms. The mycobacterial arm produces BCG disease in infancy
    requiring prolonged multidrug chemotherapy; the interferon arm produces recurrent deep
    necrotising skin ulceration that is steroid-refractory, and seizures that were fatal in
    one of the six patients in the founding interferonopathy cohort. Against that, the MSMD
    component is relatively mild compared with IFN-gamma receptor deficiency, and JAK
    inhibition produces rapid resolution of the inflammatory features in the cases reported
    so far, so the burden is high but not uniformly lethal.
  evidence:
  - reference: PMID:25307056
    reference_title: "Human intracellular ISG15 prevents interferon-α/β over-amplification and auto-inflammation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three of the six ISG15-deficient individuals experienced epileptic seizures, which
      were lethal in one case.
    explanation: >-
      Records death from seizures in the interferonopathy arm, the most severe outcome
      documented and the main driver of the HIGH burden assessment.
  - reference: PMID:32402279
    reference_title: "Systemic Type I IFN Inflammation in Human ISG15 Deficiency Leads to Necrotizing Skin Lesions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The lesions were largely resistant to steroid treatment, and were recurrent and
      necrotizing, but they resolved spontaneously, leaving post-inflammatory
      hyperpigmentation.
    explanation: >-
      Documents the recurrent, steroid-refractory necrotising skin disease that is the main
      chronic morbidity of the inflammatory arm.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >
    Disease requires biallelic loss-of-function ISG15 variants. Reported patients are
    homozygous (nonsense, frameshift, whole-gene deletion, or a functionally null missense
    allele) or compound heterozygous for a point variant and a contiguous microdeletion;
    parents are healthy heterozygotes and consanguinity is common in the reported kindreds.
    Expressivity within a family is wide: two siblings homozygous for the same novel null
    allele presented differently, one with skin lesions and the other with intracranial
    calcification and recurrent pneumonia, so a sibling's presentation does not predict the
    proband's.
  evidence:
  - reference: PMID:22859821
    reference_title: "Mycobacterial disease and impaired IFN-γ immunity in humans with inherited ISG15 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In both families, the segregation of the ISG15 mutant alleles was consistent with
      autosomal recessive MSMD.
    explanation: >-
      Establishes autosomal recessive segregation of the causal ISG15 alleles in the
      founding MSMD kindreds.
  - reference: PMID:25307056
    reference_title: "Human intracellular ISG15 prevents interferon-α/β over-amplification and auto-inflammation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Familial segregation was consistent with an autosomal recessive mode of inheritance
    explanation: >-
      Confirms the same recessive mode in the independently ascertained kindred that
      presented with intracranial calcification rather than mycobacterial disease.
  - reference: PMID:37984483
    reference_title: "A novel homozygous Y140X mutation of ISG15 causes diverse type I interferonopathies in sibling patients with cutaneous lesions or recurrent parenchymal pneumonia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report two sibling patients harboring the same novel ISG15 mutation showing diverse
      clinical features
    explanation: >-
      Documents divergent presentations between siblings carrying the same homozygous allele,
      the basis for the wide-expressivity sentence in this description.
genetic:
- name: ISG15
  gene_term:
    preferred_term: ISG15
    term:
      id: hgnc:4053
      label: ISG15
  association: CAUSATIVE
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  features: >
    ISG15 encodes a small ubiquitin-like protein induced by type I interferon. Disease
    alleles are biallelic and abolish protein function: the founding MSMD kindreds carried
    a homozygous nonsense variant in exon 2 and a homozygous frameshift insertion, the
    calcification kindred a homozygous nonsense variant, and later families a whole-gene
    deletion, a point variant in trans with a 1p36.33 microdeletion, and a homozygous
    missense allele that leaves protein expressed but functionally null. Patient cells show
    no detectable ISG15 protein and no interferon-inducible ISGylation, while ISG15 mRNA
    induction and ISGF3 binding are normal, so the truncating alleles act by loss of the
    protein rather than by a signalling defect upstream of it.
  evidence:
  - reference: PMID:22859821
    reference_title: "Mycobacterial disease and impaired IFN-γ immunity in humans with inherited ISG15 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These data suggest that the two mutant ISG15 alleles are loss-of-expression.
    explanation: >-
      Establishes the founding causal alleles as loss-of-expression, the molecular basis of
      complete deficiency.
  - reference: PMID:22859821
    reference_title: "Mycobacterial disease and impaired IFN-γ immunity in humans with inherited ISG15 deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Fibroblasts from P1 and P2 lacked detectable IFN-β-inducible ISGylation
    explanation: >-
      Demonstrates the functional consequence of the alleles in patient fibroblasts: no
      interferon-inducible protein ISGylation.
  - reference: PMID:38115997
    reference_title: "Case Report: ISG15 deficiency caused by novel variants in two families and effective treatment with Janus kinase inhibition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the second family, a homozygous total ISG15 gene deletion was detected in two
      siblings.
    explanation: >-
      Documents whole-gene deletion as one of the allele classes producing complete
      deficiency.
  - reference: PMID:40318816
    reference_title: "A novel homozygous ISG15 missense variant leads to severe inflammatory skin lesions, interstitial pneumonia, and basal ganglia calcifications in a Chinese infant with ISG15 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Functional analysis revealed that this variant impaired ISGylation and disrupted the
      stabilization of USP18, leading to defective negative regulation of IFN-I signaling
      and consequent excessive IFN-I production.
    explanation: >-
      Shows that a missense allele can be functionally null for both ISG15 activities, so
      the mutational spectrum is not restricted to truncating variants.
pathophysiology:
- name: ISG15 Loss of Function
  biological_scale: MOLECULAR
  genetic_context:
    variant_origin: GERMLINE
    zygosity: HOMOZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
  description: >
    The initiating lesion is biallelic loss of function of ISG15. Because the protein is
    absent (or, for the reported missense allele, functionally inert), both of its
    activities are lost simultaneously: its secreted, cytokine-like activity outside the
    cell and its stabilising interaction with USP18 inside it. Interferon-driven
    transcription of the gene is intact, so the defect is at the level of the protein.
  genes:
  - preferred_term: ISG15
    term:
      id: hgnc:4053
      label: ISG15
  biological_processes:
  - preferred_term: ISG15-protein conjugation
    term:
      id: GO:0032020
      label: ISG15-protein conjugation
    modifier: DECREASED
  downstream:
  - target: Absent Extracellular ISG15 Release by Leukocytes
    causal_link_type: DIRECT
    description: >-
      With no ISG15 protein, mycobacteria-triggered secretion of free ISG15 does not occur.
    evidence:
    - reference: PMID:22859821
      reference_title: "Mycobacterial disease and impaired IFN-γ immunity in humans with inherited ISG15 deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        ISG15 was not detectable in P1 leukocytes and supernatants, in any of the conditions
        tested.
      explanation: >-
        Shows directly that the loss-of-expression genotype abolishes both intracellular and
        secreted ISG15 in patient leukocytes.
  - target: Loss of Free Intracellular ISG15
    causal_link_type: DIRECT
    description: >-
      The same null genotype removes the intracellular pool of free ISG15 that binds and
      protects USP18.
    evidence:
    - reference: PMID:25307056
      reference_title: "Human intracellular ISG15 prevents interferon-α/β over-amplification and auto-inflammation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The c.163C>T/163C>T mutant allele showed no ISG15 protein on western blots
      explanation: >-
        Confirms absence of the intracellular ISG15 protein in the kindred ascertained
        through the interferonopathy arm.
  evidence:
  - reference: PMID:38115997
    reference_title: "Case Report: ISG15 deficiency caused by novel variants in two families and effective treatment with Janus kinase inhibition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The ISG15 protein plays a dual role in both the type I and II interferon (IFN) immune
      pathways.
    explanation: >-
      States the dual function of the protein that makes a single null lesion produce two
      mechanistically separate downstream arms.
- name: Absent Extracellular ISG15 Release by Leukocytes
  biological_scale: CELLULAR
  description: >
    In healthy donors, contact with mycobacteria triggers leukocytes to release free ISG15
    into the extracellular space, with granulocytes the dominant source; the stimulus is
    specific, since lipopolysaccharide and type I interferon do not trigger release.
    Patients secrete none. This is the arm that fails in the infectious presentation.
  cell_types:
  - preferred_term: granulocyte
    term:
      id: CL:0000094
      label: granulocyte
  downstream:
  - target: Impaired ISG15-Dependent IFN-gamma Production by NK and T Cells
    causal_link_type: DIRECT
    description: >-
      Free extracellular ISG15 is the signal that drives IFN-gamma secretion by NK and T
      cells, so its absence removes that induction.
    evidence:
    - reference: PMID:22859821
      reference_title: "Mycobacterial disease and impaired IFN-γ immunity in humans with inherited ISG15 deficiency."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        ISG15 blockade markedly decreased IFN-γ secretion.
      explanation: >-
        Blocking extracellular ISG15 in healthy donor blood reproduces the patients'
        IFN-gamma defect, establishing the direction of this edge independently of genotype.
  evidence:
  - reference: PMID:22859821
    reference_title: "Mycobacterial disease and impaired IFN-γ immunity in humans with inherited ISG15 deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      BCG induced the release of ISG15 into the supernatants of control leukocytes, with a
      concomitant decrease in the amount of intracellular ISG15.
    explanation: >-
      Establishes mycobacteria-triggered secretion of ISG15 by normal leukocytes, the event
      that does not happen in patients.
  - reference: PMID:22859821
    reference_title: "Mycobacterial disease and impaired IFN-γ immunity in humans with inherited ISG15 deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      These experiments suggest that many cell types can secrete ISG15 and that
      granulocytes, via their secretory pathway, are a major source of extracellular ISG15
      during phagocytosis.
    explanation: >-
      Identifies granulocytes as the principal cellular source, which is why this node binds
      that cell type.
- name: Impaired ISG15-Dependent IFN-gamma Production by NK and T Cells
  biological_scale: CELLULAR
  description: >
    NK cells are the key ISG15-responsive population, with T cells contributing. Without
    extracellular ISG15 these cells produce only small amounts of IFN-gamma on mycobacterial
    challenge - impaired but not abolished, the same quantitative picture as IL-12p40 and
    IL-12Rbeta1 deficiency and the reason the MSMD is relatively mild. Adding recombinant
    ISG15 back to patient blood restores IFN-gamma nearly to normal. The receptor is the
    LFA-1 integrin (CD11a/CD18): ISG15 binds the CD11a alphaI domain, and engagement drives
    SRC-family kinase activation and cytokine release, so what the deficiency removes is a
    defined outside-in signal rather than an unspecified soluble factor.
  biological_processes:
  - preferred_term: type II interferon (IFN-gamma) production
    term:
      id: GO:0032609
      label: type II interferon production
    modifier: DECREASED
  cell_types:
  - preferred_term: natural killer cell
    term:
      id: CL:0000623
      label: natural killer cell
  downstream:
  - target: Failed IFN-gamma-Dependent Macrophage Activation
    causal_link_type: DIRECT
    description: >-
      Insufficient IFN-gamma fails to deliver the macrophage-activating signal required to
      kill intracellular mycobacteria.
    evidence:
    - reference: PMID:22859821
      reference_title: "Mycobacterial disease and impaired IFN-γ immunity in humans with inherited ISG15 deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        the lack of mycobacterium-induced ISG15 secretion by leukocytes-granulocyte, in
        particular-reduced the production of IFN-γ by lymphocytes, including natural killer
        cells, probably accounting for the enhanced susceptibility to mycobacterial disease
      explanation: >-
        States the authors' causal reading of the chain from absent ISG15 secretion through
        reduced IFN-gamma to mycobacterial susceptibility.
  evidence:
  - reference: PMID:22859821
    reference_title: "Mycobacterial disease and impaired IFN-γ immunity in humans with inherited ISG15 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole blood leukocytes from P1, P2 and P3, like those from IL-12p40- and
      IL-12Rβ1-deficient patients, produced only small amounts of IFN-γ when stimulated with
      BCG or BCG and IL-12.
    explanation: >-
      Quantifies the IFN-gamma defect in patients and places it alongside the two
      cytokine-production MSMD etiologies it most resembles.
  - reference: PMID:22859821
    reference_title: "Mycobacterial disease and impaired IFN-γ immunity in humans with inherited ISG15 deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      NK cells were the key ISG15-responsive leukocytes, in terms of IFN-γ induction
    explanation: >-
      Identifies the responding cell type bound on this node.
  - reference: PMID:22859821
    reference_title: "Mycobacterial disease and impaired IFN-γ immunity in humans with inherited ISG15 deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The addition of recombinant human ISG15 restored IFN-γ concentrations to almost normal
      levels
    explanation: >-
      Add-back rescue shows the IFN-gamma defect is downstream of, and dependent on, the
      missing ISG15 signal rather than an independent lymphocyte defect.
  - reference: PMID:29100055
    reference_title: "Extracellular ISG15 Signals Cytokine Secretion through the LFA-1 Integrin Receptor."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We have established an NK-92 cell-based assay for IFN-γ release, identified residues
      critical for ISG15 signaling, and identified the cell surface receptor as LFA-1
      (CD11a/CD18; αLβ2 integrin).
    explanation: >-
      Identifies the receptor through which extracellular ISG15 induces IFN-gamma, which is
      the signalling step this node loses.
  - reference: PMID:29100055
    reference_title: "Extracellular ISG15 Signals Cytokine Secretion through the LFA-1 Integrin Receptor."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      LFA-1 inhibition blocked IFN-γ secretion, splenocytes from CD11a-/- mice did not
      respond to ISG15, and ISG15 bound directly to the αI domain of CD11a in vitro.
    explanation: >-
      Loss-of-function, binding and genetic evidence that the ISG15-to-IFN-gamma step runs
      through LFA-1, supporting the receptor claim in this node's description.
- name: Failed IFN-gamma-Dependent Macrophage Activation
  biological_scale: CELLULAR
  description: >
    IFN-gamma licenses macrophages to kill the intracellular mycobacteria they harbour.
    With IFN-gamma output insufficient, infected macrophages are not activated. This is the
    convergent final mechanism of MSMD, reached here through a failure of cytokine
    production rather than of the response to IFN-gamma.
  biological_processes:
  - preferred_term: macrophage activation
    term:
      id: GO:0042116
      label: macrophage activation
    modifier: DECREASED
  cell_types:
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  downstream:
  - target: Uncontrolled Replication of Weakly Virulent Mycobacteria
    causal_link_type: DIRECT
    description: >-
      Without macrophage activation the intracellular organisms are not killed and
      replicate.
  evidence:
  - reference: PMID:38025345
    reference_title: "Mendelian susceptibility to mycobacterial diseases: State of the puzzle."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      almost all genetic etiologies of MSMD alter the interferon-gamma (IFN-γ)- mediated
      immunity by impairing or abolishing IFN-γ production or the response to this cytokine.
    explanation: >-
      Establishes impaired IFN-gamma-mediated immunity as the convergent mechanism of MSMD,
      which is what fails at this node.
- name: Uncontrolled Replication of Weakly Virulent Mycobacteria
  biological_scale: ORGANISM
  description: >
    The organism-level consequence is disease caused by mycobacteria that an intact
    IFN-gamma response would contain: above all the BCG vaccine strain, and environmental
    non-tuberculous mycobacteria. This node initiates the infectious phenotypes.
  downstream:
  - target: BCG disease
  - target: Non-tuberculous mycobacterial infection
  evidence:
  - reference: ORPHA:319563
    reference_title: "Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Mendelian susceptibility to mycobacterial diseases (MSMD) due to complete ISG15
      deficiency is a genetic variant of MSMD characterized by Bacille Calmette-Guérin (BCG)
      infections.
    explanation: >-
      Orphanet's definition of the disease names BCG infection as its characteristic
      manifestation, the clinical expression of this node.
- name: Loss of Free Intracellular ISG15
  biological_scale: MOLECULAR
  description: >
    The second arm begins with the absence of the intracellular pool of free (unconjugated)
    ISG15. This activity is conjugation-independent: transducing patient cells with an
    ISG15 mutant that cannot be conjugated to substrates rescues the phenotype as well as
    wild-type ISG15 does, and silencing the ISGylation enzymes does not reproduce it. The
    disease-relevant intracellular function of ISG15 in humans is therefore not ISGylation.
  downstream:
  - target: Accelerated Ubiquitin-Dependent USP18 Degradation
    causal_link_type: DIRECT
    description: >-
      Free ISG15 binds USP18 and antagonises its ubiquitination; without ISG15, USP18 is
      degraded rapidly.
    evidence:
    - reference: PMID:25307056
      reference_title: "Human intracellular ISG15 prevents interferon-α/β over-amplification and auto-inflammation."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        In cells lacking ISG15, unlike control cells, USP18 levels began to decline after as
        little as one hour of cycloheximide (CHX) treatment
      explanation: >-
        Directly measures accelerated USP18 decay in ISG15-deficient cells, which is this
        causal step.
  evidence:
  - reference: PMID:25307056
    reference_title: "Human intracellular ISG15 prevents interferon-α/β over-amplification and auto-inflammation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      ISG15 appeared to act in its unconjugated free form, since silencing of UBE1L or of
      other ISGylation enzymes failed to reduce USP18 levels
    explanation: >-
      Establishes that the relevant species is free, unconjugated ISG15, not an ISGylated
      substrate - the claim this node makes.
- name: Accelerated Ubiquitin-Dependent USP18 Degradation
  biological_scale: MOLECULAR
  description: >
    USP18 is itself an interferon-stimulated gene and the principal negative regulator of
    type I interferon signalling. Free ISG15 binds USP18 and prevents assembly of the
    USP18-SKP2 complex, antagonising its ubiquitination and proteolysis. Without ISG15,
    USP18 protein falls even though USP18 mRNA is elevated - a protein-level brake failure
    in the face of an up-regulated transcript.
  biological_processes:
  - preferred_term: ubiquitin-dependent proteolysis of USP18
    term:
      id: GO:0006511
      label: ubiquitin-dependent protein catabolic process
    modifier: INCREASED
  downstream:
  - target: Sustained Type I Interferon Signalling and ISG Over-Amplification
    causal_link_type: DIRECT
    description: >-
      Loss of the USP18 brake leaves type I interferon signalling inadequately attenuated.
    evidence:
    - reference: PMID:25307056
      reference_title: "Human intracellular ISG15 prevents interferon-α/β over-amplification and auto-inflammation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        an absence of intracellular ISG15 in the patients' cells prevents the accumulation
        of USP18, a potent negative regulator of IFN-α/β signalling, resulting in the
        enhancement and amplification of IFN-α/β responses
      explanation: >-
        States the causal step from failed USP18 accumulation to amplified type I interferon
        responses.
  evidence:
  - reference: PMID:25307056
    reference_title: "Human intracellular ISG15 prevents interferon-α/β over-amplification and auto-inflammation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The formation of the USP18–SKP2 complex (Fig. 4e, lane 8), was prevented by
      co-expression of ISG15
    explanation: >-
      Identifies the molecular interaction ISG15 blocks - SKP2 engagement of USP18 - which
      is the degradation route this node names.
  - reference: PMID:25307056
    reference_title: "Human intracellular ISG15 prevents interferon-α/β over-amplification and auto-inflammation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Remarkably, however, levels of USP18 were low in patients’ cells (Fig. 3a, b),
      despite their higher levels of USP18 mRNA
    explanation: >-
      Records the protein-versus-transcript dissociation that establishes the lesion as
      post-translational destabilisation of USP18 rather than failed induction of it.
- name: Sustained Type I Interferon Signalling and ISG Over-Amplification
  biological_scale: CELLULAR
  conforms_to: "jak_stat_pathway_activation#Sustained STAT-Driven Target-Gene Transcription"
  description: >
    With the USP18 brake degraded, STAT1 and STAT2 remain phosphorylated for longer than in
    control cells and the interferon-stimulated gene program is amplified rather than
    self-limiting. Patient blood carries a raised interferon signature across the same genes
    used to score Aicardi-Goutieres syndrome, and in peripheral blood the myeloid
    compartment shows the strongest signature. The disorder-specific output program at this
    node is therefore an interferon-stimulated gene signature.
  biological_processes:
  - preferred_term: type I interferon-mediated signaling pathway
    term:
      id: GO:0060337
      label: type I interferon-mediated signaling pathway
    modifier: INCREASED
  - preferred_term: negative regulation of type I interferon-mediated signaling pathway
    term:
      id: GO:0060339
      label: negative regulation of type I interferon-mediated signaling pathway
    modifier: DECREASED
  cell_types:
  - preferred_term: monocyte
    term:
      id: CL:0000576
      label: monocyte
  downstream:
  - target: Type I Interferon-Driven Tissue Inflammation
    causal_link_type: DIRECT
    description: >-
      The amplified interferon response drives the inflammatory and neurological features,
      as in the other Mendelian type I interferonopathies.
    evidence:
    - reference: PMID:25307056
      reference_title: "Human intracellular ISG15 prevents interferon-α/β over-amplification and auto-inflammation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In the absence of ISG15, USP18 proteolysis is more rapid, driving the dysregulated
        IFN-α/β response and resulting in both the blood IFN-α/β signature and brain
        calcifications seen in the patients.
      explanation: >-
        States the causal link from the dysregulated interferon response to the clinical
        tissue phenotype.
  - target: Enhanced Cellular Antiviral Resistance
    causal_link_type: DIRECT
    description: >-
      The same sustained interferon-stimulated gene program leaves patient cells better
      protected against virus than control cells.
    evidence:
    - reference: PMID:27193971
      reference_title: "ISG15 deficiency and increased viral resistance in humans but not mice."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        fibroblasts derived from ISG15-deficient patients display enhanced antiviral
        protection, and expression of ISG15 attenuates viral resistance to WT control levels
      explanation: >-
        Shows the enhanced antiviral state and its reversal by ISG15 re-expression, which
        ties it to this node rather than to an unrelated property of the cells.
  evidence:
  - reference: PMID:25307056
    reference_title: "Human intracellular ISG15 prevents interferon-α/β over-amplification and auto-inflammation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      in patients’ cells, STAT1 and STAT2 were more persistently phosphorylated
    explanation: >-
      The direct signalling readout of this node: prolonged STAT1/STAT2 phosphorylation in
      patient cells.
  - reference: PMID:25307056
    reference_title: "Human intracellular ISG15 prevents interferon-α/β over-amplification and auto-inflammation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      all ISG15-deficient patients, like patients with AGS, had significantly higher levels
      of interferon-stimulated gene messenger RNA than unaffected relatives or healthy
      controls
    explanation: >-
      Establishes the interferon-stimulated gene signature in patients, the
      disorder-specific output program named at this node.
  - reference: PMID:32402279
    reference_title: "Systemic Type I IFN Inflammation in Human ISG15 Deficiency Leads to Necrotizing Skin Lesions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In peripheral blood, myeloid cells display the most robust IFN-I signatures.
    explanation: >-
      Identifies the blood compartment carrying the strongest signature, which is why this
      node binds the monocyte cell type.
- name: Enhanced Cellular Antiviral Resistance
  biological_scale: CELLULAR
  role: compensation
  description: >
    A consequence of the same amplified interferon program, and the reason the deficiency
    does not behave as a classical antiviral immunodeficiency in humans. Patients have no
    unusual susceptibility to viruses in vivo, and their fibroblasts are more resistant to
    virus than control cells. This is the point at which the mouse model diverges from the
    human disease.
  evidence:
  - reference: PMID:27193971
    reference_title: "ISG15 deficiency and increased viral resistance in humans but not mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we describe ISG15-deficient patients who display no enhanced susceptibility to
      viruses in vivo, in stark contrast to Isg15-deficient mice.
    explanation: >-
      Establishes the absence of a clinical antiviral phenotype in patients, which this node
      records.
- name: Type I Interferon-Driven Tissue Inflammation
  biological_scale: TISSUE
  description: >
    The amplified interferon response is expressed in tissue as inflammation. In affected
    skin, interferon signalling is seen in epidermal keratinocytes, in endothelium, and in
    dermal monocytes and macrophages - the cellular basis of the recurrent necrotising
    ulceration. In the central nervous system the counterpart is the intracranial
    calcification shared with Aicardi-Goutieres syndrome and spondyloenchondrodysplasia.
    This node initiates the inflammatory and neurological phenotypes.
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  - preferred_term: endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  downstream:
  - target: Skin ulceration
  - target: Impaired healing of skin ulceration with fibrosis
  - target: Basal ganglia calcification
  - target: Seizure
  - target: Developmental delay
  - target: Interstitial lung disease
  - target: Recurrent pneumonia
  - target: Autoantibody positivity
  evidence:
  - reference: PMID:32402279
    reference_title: "Systemic Type I IFN Inflammation in Human ISG15 Deficiency Leads to Necrotizing Skin Lesions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the affected skin, IFN-I signaling is observed in the keratinocytes of the
      epidermis, endothelia, and the monocytes and macrophages of the dermis.
    explanation: >-
      Localises interferon signalling to specific cell types in affected tissue, grounding
      the cell-type bindings on this node.
  - reference: PMID:25307056
    reference_title: "Human intracellular ISG15 prevents interferon-α/β over-amplification and auto-inflammation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We show here that ISG15-deficient patients also display unanticipated cellular,
      immunological and clinical signs of enhanced IFN-α/β immunity, reminiscent of the
      Mendelian autoinflammatory interferonopathies Aicardi-Goutières syndrome and
      spondyloenchondrodysplasia.
    explanation: >-
      Places the tissue phenotype of this disease within the Mendelian type I
      interferonopathies, the disease class this node's consequences belong to.
phenotypes:
- category: Infectious
  name: BCG disease
  description: >
    Disease caused by the live M. bovis BCG vaccine strain, ranging from an exaggerated
    regional reaction with inguinal lymphadenopathy to disseminated disease. In
    BCG-vaccinating countries this is the presenting event of the mycobacterial arm, because
    vaccination at or shortly after birth is the first mycobacterial challenge an affected
    infant meets. Patients with the same genotype who were not BCG-vaccinated have no
    mycobacterial phenotype at all, which is the clearest evidence that the exposure rather
    than the genotype decides this presentation.
  phenotype_term:
    preferred_term: BCGosis
    term:
      id: HP:0020087
      label: BCGosis
    onset:
      onset_category: INFANTILE
      notes: >-
        In the reported dermatologic cohort one patient was vaccinated at one month and
        reacted with regional lymphadenopathy and overlying erythema. Age at BCG disease
        therefore tracks the vaccination schedule rather than an intrinsic disease onset. No
        pooled mean age at onset has been published for this etiology, so none is recorded.
  evidence:
  - reference: PMID:22859821
    reference_title: "Mycobacterial disease and impaired IFN-γ immunity in humans with inherited ISG15 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we describe human patients with inherited ISG15 deficiency and mycobacterial,
      but not viral, diseases.
    explanation: >-
      The founding report establishing mycobacterial disease, and specifically not viral
      disease, as the infectious phenotype of this deficiency.
  - reference: PMID:32402279
    reference_title: "Systemic Type I IFN Inflammation in Human ISG15 Deficiency Leads to Necrotizing Skin Lesions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At the age of one month, he was vaccinated with BCG, to which he displayed an
      exaggerated response, with right inguinal lymphadenopathy and erythema of the overlying
      skin.
    explanation: >-
      A worked pediatric case of BCG disease following vaccination in infancy, and the basis
      for the infantile onset category.
  - reference: PMID:25307056
    reference_title: "Human intracellular ISG15 prevents interferon-α/β over-amplification and auto-inflammation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The ISG15-deficient patients from China were not vaccinated with BCG at birth,
      consistent with their current lack of an MSMD phenotype.
    explanation: >-
      Shows that unvaccinated patients with the same genotype have no mycobacterial
      phenotype, making BCG exposure rather than genotype the determinant of this
      presentation.
- category: Infectious
  name: Non-tuberculous mycobacterial infection
  description: >
    Susceptibility extends to weakly virulent environmental mycobacteria, which in countries
    that do not vaccinate with BCG are the organisms that reveal an MSMD genotype.
  phenotype_term:
    preferred_term: Non-tuberculous mycobacterial infection
    term:
      id: HP:5210115
      label: Non-tuberculous mycobacterial infection
  evidence:
  - reference: PMID:39365299
    reference_title: "First Brazilian Case Report of Unrelated Patients with Identical ISG15 Mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ISG15 deficiency is a mixed syndrome of Mendelian susceptibility to mycobacterial
      infections (MSMD), a rare inherited condition characterized primarily by recurrent
      infections from low-virulence mycobacteria and monogenic type I interferonopathy.
    explanation: >-
      States susceptibility to low-virulence mycobacteria as a defining feature of ISG15
      deficiency, and names the dual syndrome this entry models.
- category: Dermatologic
  name: Skin ulceration
  description: >
    Recurrent, deep, necrotising ulceration, typically of the groin, vulva, neck and limbs,
    sometimes preceded by hypopigmented or erythematous indurated patches. The lesions are
    largely steroid-refractory and can resolve spontaneously with post-inflammatory
    hyperpigmentation. Onset is in early childhood - ulceration from six months and from one
    year of age in the reported series - and in five patients this, rather than infection or
    seizures, was the presentation that brought them to medical attention.
  phenotype_term:
    preferred_term: Recurrent necrotising skin ulceration
    term:
      id: HP:0200042
      label: Skin ulcer
    temporality: RECURRENT
  evidence:
  - reference: PMID:32402279
    reference_title: "Systemic Type I IFN Inflammation in Human ISG15 Deficiency Leads to Necrotizing Skin Lesions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Herein, we describe five new patients with six novel ISG15 mutations presenting with
      skin lesions who were managed for dermatologic disease.
    explanation: >-
      Establishes dermatologic disease as a presentation of ISG15 deficiency in its own
      right, in five genetically confirmed patients.
  - reference: PMID:32402279
    reference_title: "Systemic Type I IFN Inflammation in Human ISG15 Deficiency Leads to Necrotizing Skin Lesions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At the age of one year, P5 presented ulcers of the inguinal region and vulva.
    explanation: >-
      Gives the early-childhood onset and characteristic distribution of the ulceration.
  - reference: PMID:38115997
    reference_title: "Case Report: ISG15 deficiency caused by novel variants in two families and effective treatment with Janus kinase inhibition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In this report, we describe novel variants found in two different families that result
      in complete ISG15 deficiency and severe skin ulceration.
    explanation: >-
      Independent replication of severe skin ulceration in two further ISG15-deficient
      families.
- category: Neurologic
  name: Basal ganglia calcification
  description: >
    Calcification of the cerebral basal ganglia, the radiological sign shared with
    Aicardi-Goutieres syndrome and spondyloenchondrodysplasia, and in one kindred the
    finding that led to the genetic diagnosis under a working label of idiopathic basal
    ganglia calcification. It is not a consequence of cerebral infection: CT scanning of the
    Turkish and Iranian patients ascertained through mycobacterial disease found the same
    calcification. Calcification along the cerebral falx has also been reported. It is
    detectable in infancy - the youngest reported patient had basal ganglia calcification at
    four months of age. It is not universal: in one reported family the affected siblings
    had seizures and developmental delay with no calcification on imaging, and remain under
    neuroimaging surveillance, so a normal early scan does not exclude the diagnosis.
  phenotype_term:
    preferred_term: Basal ganglia calcification
    term:
      id: HP:0002135
      label: Basal ganglia calcification
  evidence:
  - reference: PMID:25307056
    reference_title: "Human intracellular ISG15 prevents interferon-α/β over-amplification and auto-inflammation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We found that P1 and P2 displayed calcification of the basal ganglia, with CT imaging
      in P3 also showing calcification along the cerebral falx
    explanation: >-
      Documents basal ganglia calcification in the patients originally ascertained through
      mycobacterial disease, establishing it as a feature of the disease rather than of one
      kindred.
  - reference: PMID:25307056
    reference_title: "Human intracellular ISG15 prevents interferon-α/β over-amplification and auto-inflammation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These findings strongly suggest that the three ISG15 alleles identified are
      disease-causing, not only for MSMD, but also for IBGC, an intracranial calcification
      phenotype unrelated to any obvious cerebral infection.
    explanation: >-
      States that the calcification is caused by the ISG15 genotype and is not secondary to
      infection.
  - reference: PMID:40318816
    reference_title: "A novel homozygous ISG15 missense variant leads to severe inflammatory skin lesions, interstitial pneumonia, and basal ganglia calcifications in a Chinese infant with ISG15 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we report a 4-month-old Chinese patient presenting with inflammatory skin
      lesions, interstitial pneumonia, and basal ganglia calcifications.
    explanation: >-
      Establishes that the calcification is already present in infancy, the pediatric timing
      recorded in this phenotype's description.
  - reference: PMID:38115997
    reference_title: "Case Report: ISG15 deficiency caused by novel variants in two families and effective treatment with Janus kinase inhibition."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Notably, affected individuals in family B exhibited mild developmental delay and
      seizures, without evidence of cerebral inflammation or calcification; ongoing
      neuroimaging surveillance is underway.
    explanation: >-
      Two affected siblings had the neurological features without calcification on imaging,
      which refutes treating calcification as an obligate finding and is why the description
      says a normal early scan does not exclude the diagnosis.
- category: Neurologic
  name: Developmental delay
  description: >
    Global developmental delay has been reported in both affected siblings of one family,
    described as mild, alongside seizures. Psychomotor delay is characteristic of the type I
    interferonopathies as a class, and in this disease it belongs to the interferon arm
    rather than to mycobacterial infection. Reported in a small number of patients; the
    founding cohorts did not report it, so no frequency is recorded and the entry does not
    claim it is typical.
  phenotype_term:
    preferred_term: Mild global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:38115997
    reference_title: "Case Report: ISG15 deficiency caused by novel variants in two families and effective treatment with Janus kinase inhibition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He also had recurrent respiratory tract infections with chest radiograph changes, and
      global developmental delay was noted.
    explanation: >-
      Documents global developmental delay in a genetically confirmed ISG15-deficient
      patient.
  - reference: PMID:38115997
    reference_title: "Case Report: ISG15 deficiency caused by novel variants in two families and effective treatment with Janus kinase inhibition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      BII-3, the younger sister of BII-2, recently developed a single skin ulcerative lesion
      and mild developmental delay
    explanation: >-
      The affected sibling in the same family, establishing that the delay is not an
      isolated observation in one child.
- category: Neurologic
  name: Seizure
  description: >
    Epileptic seizures occurred in three of the six patients in the founding
    interferonopathy cohort and were fatal in one, who died during a seizure episode at
    thirteen years; in the other two affected siblings seizures were occasional. Seizures
    belong to the interferon arm and occur in patients with no mycobacterial disease at all.
  phenotype_term:
    preferred_term: Epileptic seizure
    term:
      id: HP:0001250
      label: Seizure
  frequency: FREQUENT
  evidence:
  - reference: PMID:25307056
    reference_title: "Human intracellular ISG15 prevents interferon-α/β over-amplification and auto-inflammation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three of the six ISG15-deficient individuals experienced epileptic seizures, which
      were lethal in one case.
    explanation: >-
      Gives the proportion affected - three of six, supporting the FREQUENT band - and the
      fatal outcome in one.
  - reference: PMID:25307056
    reference_title: "Human intracellular ISG15 prevents interferon-α/β over-amplification and auto-inflammation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The eldest child (P4) died during an episode of epileptic seizures at the age of 13
      years
    explanation: >-
      Records the age and circumstance of the one death in the cohort.
- category: Respiratory
  name: Interstitial lung disease
  description: >
    Interstitial pneumonia has been reported as part of the inflammatory arm, in a
    four-month-old infant alongside skin lesions and basal ganglia calcification, and
    pulmonary involvement is named in the reported clinical spectrum of the disease. No
    frequency is recorded because none has been published for this feature.
  phenotype_term:
    preferred_term: Interstitial pneumonia
    term:
      id: HP:0006515
      label: Interstitial pneumonitis
  evidence:
  - reference: PMID:40318816
    reference_title: "A novel homozygous ISG15 missense variant leads to severe inflammatory skin lesions, interstitial pneumonia, and basal ganglia calcifications in a Chinese infant with ISG15 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we report a 4-month-old Chinese patient presenting with inflammatory skin
      lesions, interstitial pneumonia, and basal ganglia calcifications.
    explanation: >-
      Documents interstitial pneumonia in a genetically confirmed ISG15-deficient infant.
  - reference: PMID:38115997
    reference_title: "Case Report: ISG15 deficiency caused by novel variants in two families and effective treatment with Janus kinase inhibition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ISG15 deficiency can present with various clinical phenotypes, ranging from
      susceptibility to mycobacterial infection to autoinflammation characterised by
      necrotising skin lesions, intracerebral calcification, and pulmonary involvement.
    explanation: >-
      Names pulmonary involvement as part of the recognised autoinflammatory spectrum of the
      disease.
  - reference: PMID:41743834
    reference_title: "Human ISG15 deficiency unveils impaired healing of ulcerations via type I interferon-mediated fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      ISG15 deficiency is a type I interferonopathy characterized by elevated circulating
      type I interferon (IFN-I), intracranial calcifications, fibrotic skin lesions, and
      occasionally inflammatory lung disease.
    explanation: >-
      Independent statement that inflammatory lung disease is an occasional feature of the
      disease. Graded HUMAN_CLINICAL with quote_role BACKGROUND because the sentence states
      the established human clinical picture in the paper's opening, while the paper's own
      work is the spatial-transcriptomic and in vitro fibrosis study.
- category: Respiratory
  name: Recurrent pneumonia
  description: >
    Recurrent parenchymal pneumonia was the dominant manifestation in one of two siblings
    sharing the same ISG15 null allele, while the other sibling presented with skin lesions
    alone. It is described by those authors as a rare phenotype of the disease.
  phenotype_term:
    preferred_term: Recurrent parenchymal pneumonia
    term:
      id: HP:0006532
      label: Recurrent pneumonia
  evidence:
  - reference: PMID:37984483
    reference_title: "A novel homozygous Y140X mutation of ISG15 causes diverse type I interferonopathies in sibling patients with cutaneous lesions or recurrent parenchymal pneumonia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The manifestation in patient 2 was skin lesions, while those in patient 1 were
      intracranial calcification and recurrent pneumonia.
    explanation: >-
      Documents recurrent pneumonia as a presenting manifestation in a genetically confirmed
      patient.
  - reference: PMID:37984483
    reference_title: "A novel homozygous Y140X mutation of ISG15 causes diverse type I interferonopathies in sibling patients with cutaneous lesions or recurrent parenchymal pneumonia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      one harbored a rare phenotype of pneumonia
    explanation: >-
      The authors' own characterisation of pneumonia as a rare rather than typical feature,
      which is why no frequency is recorded.
- category: Dermatologic
  name: Impaired healing of skin ulceration with fibrosis
  description: >
    Ulcers in this disease heal poorly and scar. Patient skin biopsies show interferon-driven
    apoptosis, skewed macrophage polarisation, epithelial-to-mesenchymal transition and
    myofibroblast activation, and ISG15-knockout fibroblasts close a mechanical wound less
    well than wild-type cells. This is the fibrotic counterpart of the ulceration phenotype
    rather than a separate organ involvement, and it is what makes the skin disease chronic.
  phenotype_term:
    preferred_term: Fibrotic scarring of healed skin ulceration
    term:
      id: HP:0100699
      label: Scarring
  evidence:
  - reference: PMID:41743834
    reference_title: "Human ISG15 deficiency unveils impaired healing of ulcerations via type I interferon-mediated fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Analysis of patient skin biopsies revealed increased IFN-I-dependent apoptosis, altered
      macrophage polarization, enhanced epithelial-to-mesenchymal transition (EMT), and
      myofibroblast activation.
    explanation: >-
      The patient-tissue findings behind the fibrotic character of the skin lesions.
  - reference: PMID:41743834
    reference_title: "Human ISG15 deficiency unveils impaired healing of ulcerations via type I interferon-mediated fibrosis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      ISG15 KO fibroblasts displayed impaired mechanical wound healing and increased
      IFN-I-induced apoptosis compared with WT cells
    explanation: >-
      The cell-based demonstration that loss of ISG15 itself impairs wound closure, which is
      the mechanism this phenotype names.
- category: Immunologic
  name: Autoantibody positivity
  description: >
    ISG15-deficient patients carry higher autoantibody levels than age-matched controls, a
    finding consistent with the lupus-like serology seen in other type I interferonopathies.
    No specific autoimmune disease has been attributed to the deficiency, and this entry
    does not assert one.
  phenotype_term:
    preferred_term: Autoantibody positivity
    term:
      id: HP:0030057
      label: Autoimmune antibody positivity
  evidence:
  - reference: PMID:25307056
    reference_title: "Human intracellular ISG15 prevents interferon-α/β over-amplification and auto-inflammation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These patients also had autoantibody levels higher than those in age-matched controls
    explanation: >-
      Direct observation of raised autoantibody levels in the patient cohort.
- category: Laboratory
  name: Reduced mycobacteria-induced IFN-gamma production
  description: >
    Whole-blood IFN-gamma output after BCG stimulation is low, and the deficit is corrected
    by adding recombinant ISG15. This is the functional assay that localises the lesion to
    the IFN-gamma production arm and distinguishes it from a defect in the response to
    IFN-gamma.
  phenotype_term:
    preferred_term: Reduced IFN-gamma production on mycobacterial stimulation
    term:
      id: HP:0033253
      label: Reduced circulating interferon gamma concentration
  notes: >-
    Concept-fit caveat: HP:0033253 names a reduced circulating IFN-gamma concentration,
    whereas the cited measurement is reduced IFN-gamma production by BCG-stimulated whole
    blood ex vivo. The binding is the closest available HP term and preferred_term carries
    the specific assay reading; the term is broader than the assay rather than a different
    claim.
  evidence:
  - reference: PMID:22859821
    reference_title: "Mycobacterial disease and impaired IFN-γ immunity in humans with inherited ISG15 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole blood leukocytes from P1, P2 and P3, like those from IL-12p40- and
      IL-12Rβ1-deficient patients, produced only small amounts of IFN-γ when stimulated with
      BCG or BCG and IL-12.
    explanation: >-
      The measurement behind this laboratory phenotype.
  reports_on:
  - target: Impaired ISG15-Dependent IFN-gamma Production by NK and T Cells
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      The assay measurement of that node. Recorded as an observational readout rather than a
      causal edge, because deficient IFN-gamma production is the node being measured, not
      something the node causes.
- category: Laboratory
  name: Elevated type I interferon signature
  description: >
    Peripheral blood carries a raised interferon-stimulated gene signature, measured across
    the same gene set used to score Aicardi-Goutieres syndrome, and two patients had
    detectable IFN-alpha antiviral activity in plasma. This is the laboratory counterpart of
    the interferon arm.
  phenotype_term:
    preferred_term: Increased circulating interferon-alpha
    term:
      id: HP:0034513
      label: Increased circulating Interferon-alpha concentration
  notes: >-
    The bound HP term names a circulating IFN-alpha concentration, which is what the plasma
    antiviral-activity measurement reports. The interferon-stimulated gene signature that
    dominates the literature on this disease is a transcript score rather than a cytokine
    concentration, and HPO has no term for it; preferred_term and the description carry the
    distinction.
  evidence:
  - reference: PMID:25307056
    reference_title: "Human intracellular ISG15 prevents interferon-α/β over-amplification and auto-inflammation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The two Chinese patients who displayed seizures (P5 and P6) also had detectable IFN-α
      antiviral activity in their plasma
    explanation: >-
      The circulating IFN-alpha measurement that the bound HP term names.
  - reference: PMID:25307056
    reference_title: "Human intracellular ISG15 prevents interferon-α/β over-amplification and auto-inflammation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      all ISG15-deficient patients, like patients with AGS, had significantly higher levels
      of interferon-stimulated gene messenger RNA than unaffected relatives or healthy
      controls
    explanation: >-
      The interferon-stimulated gene signature, the transcript-level reading described
      alongside the cytokine measurement.
  reports_on:
  - target: Sustained Type I Interferon Signalling and ISG Over-Amplification
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      The clinical measurement of that node.
diagnosis:
- name: ISG15 sequencing
  description: >
    Molecular confirmation identifies the biallelic ISG15 genotype. Because the two
    presentations look like two different diseases - a pediatric infectious-disease problem
    and a pediatric neurology or dermatology problem - the genotype is often what unifies
    them, and exome sequencing made the connection both in the founding MSMD kindreds and in
    the kindred labelled idiopathic basal ganglia calcification. A normal-appearing protein
    does not exclude the diagnosis: one reported allele is missense and functionally null.
  evidence:
  - reference: PMID:25307056
    reference_title: "Human intracellular ISG15 prevents interferon-α/β over-amplification and auto-inflammation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole-exome sequencing (WES) of P5 and P6 and their healthy mother identified only one
      common nonsense homozygous mutation, which had not been reported in public databases
      or in in-house WES data for 1,500 other individuals
    explanation: >-
      Documents exome sequencing as the route to diagnosis in patients presenting without any
      infectious phenotype.
- name: Cranial CT for intracranial calcification
  description: >
    Non-contrast cranial CT detects the basal ganglia calcification. It is worth doing in a
    patient with an MSMD phenotype and an ISG15 genotype even without neurological symptoms:
    scanning the Turkish and Iranian patients, who had been followed for mycobacterial
    disease, is how the calcification was found in them.
  evidence:
  - reference: PMID:25307056
    reference_title: "Human intracellular ISG15 prevents interferon-α/β over-amplification and auto-inflammation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Following the identification of ISG15 mutations in Chinese children with a putative
      diagnosis of IBGC, we performed computed tomography (CT) scans on the Iranian and
      Turkish ISG15-deficient MSMD patients.
    explanation: >-
      Describes the imaging step that revealed calcification in patients who had been managed
      for mycobacterial disease alone.
treatments:
- name: Antimycobacterial Therapy
  description: >
    Multidrug antimycobacterial chemotherapy treats the mycobacterial disease itself and is
    required regardless of the underlying immune defect. Regimen composition follows species
    identification and susceptibility testing; this entry does not assert a specific regimen
    or duration, because none has been established for this etiology separately from MSMD
    management generally.
  therapeutic_modality: SMALL_MOLECULE
  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
  target_mechanisms:
  - target: Uncontrolled Replication of Weakly Virulent Mycobacteria
    treatment_effect: INHIBITS
    description: >-
      Antimycobacterial drugs act on the organism, substituting pharmacological killing for
      the macrophage-mediated killing the host cannot perform.
  evidence:
  - reference: PMID:32402279
    reference_title: "Systemic Type I IFN Inflammation in Human ISG15 Deficiency Leads to Necrotizing Skin Lesions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      ISG15-deficient patients have been identified on the basis of several different
      presentations: a reaction to BCG vaccination, intermittent seizures, or, as in the
      patients described here, dermatological features.
    explanation: >-
      Establishes BCG reaction as one of the presentations of this disease, and so the
      indication for antimycobacterial treatment. Graded INDIRECT because the sentence states
      the indication rather than reporting the treatment or its effect.
- name: Janus Kinase Inhibition
  description: >
    Baricitinib blocks signalling downstream of the type I interferon receptor and so
    interrupts the arm of the disease that the ISG15 lesion drives by removing the USP18
    brake. It is the mechanistically targeted treatment for the inflammatory and
    neurological features and does not address the mycobacterial arm. Reported responses are
    rapid and, in one sibling, complete; reported dosing in these case reports is 2 mg
    orally twice daily with a tapering course of oral prednisolone. The evidence is at the
    level of individual case reports, not trials.

    A caveat carried over from the wider type I interferonopathy literature rather than from
    ISG15 deficiency itself: in Aicardi-Goutieres syndrome, intracranial calcification has
    been found at post-mortem to be extensive despite baricitinib started at two months of
    age and continued for over four years, which the authors attribute to poor CNS
    bioavailability. No comparable long-term neurological follow-up has been published for
    ISG15 deficiency, so whether early JAK inhibition protects the brain in this disease is
    unknown.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: baricitinib
      term:
        id: CHEBI:95341
        label: baricitinib
  target_mechanisms:
  - target: Sustained Type I Interferon Signalling and ISG Over-Amplification
    treatment_effect: INHIBITS
    description: >-
      JAK inhibition blocks signal transduction from the type I interferon receptor, so the
      amplified interferon-stimulated gene program is suppressed even though the USP18 brake
      remains absent.
    evidence:
    - reference: PMID:40318816
      reference_title: "A novel homozygous ISG15 missense variant leads to severe inflammatory skin lesions, interstitial pneumonia, and basal ganglia calcifications in a Chinese infant with ISG15 deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Treatment with the Janus kinase (JAK) inhibitor baricitinib rapidly resolved the
        patient's clinical symptoms.
      explanation: >-
        Clinical response to JAK inhibition in a patient whose disease was shown to run
        through defective USP18 stabilisation and excess type I interferon signalling, the
        node this treatment targets.
  evidence:
  - reference: PMID:38115997
    reference_title: "Case Report: ISG15 deficiency caused by novel variants in two families and effective treatment with Janus kinase inhibition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Finally, we demonstrate the complete and rapid resolution of clinical symptoms
      associated with ISG15 deficiency in one sibling from the second family following
      treatment with the Janus kinase (JAK) inhibitor baricitinib.
    explanation: >-
      The first report of JAK inhibition in ISG15 deficiency, documenting complete resolution
      of symptoms.
  - reference: PMID:38115997
    reference_title: "Case Report: ISG15 deficiency caused by novel variants in two families and effective treatment with Janus kinase inhibition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient was subsequently initiated on oral prednisolone 1mg/kg/day tapered over
      8-10 weeks and the JAK inhibitor baricitinib (2mg orally twice daily).
    explanation: >-
      Records the reported regimen, the basis for the dosing sentence in this treatment's
      description.
  - reference: PMID:38381212
    reference_title: "Neuropathologic Impacts of JAK Inhibitor Treatment in Aicardi-Goutières Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      This study showed profound central nervous system (CNS) sequelae despite early
      initiation of treatment.
    explanation: >-
      The source of the CNS caveat in this treatment's description. Graded INDIRECT and
      flagged here because the patient had Aicardi-Goutieres syndrome, not ISG15 deficiency:
      it supports the caveat only by the class argument that JAK inhibition may not reach
      the brain in a type I interferonopathy, and no ISG15-specific neurological follow-up
      exists.
- name: Avoidance of BCG Vaccination
  description: >
    Live BCG vaccine is the commonest trigger of the mycobacterial arm, so it is
    contraindicated in an affected child and should be withheld from at-risk newborn
    siblings pending genetic testing. The pediatric timing problem is acute: in endemic
    countries BCG is given at or shortly after birth, months before any presentation that
    would prompt testing. The unvaccinated ISG15-deficient siblings have no mycobacterial
    phenotype, which is the clearest available evidence that withholding the exposure
    prevents that arm of the disease.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: avoidance of live BCG vaccination
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Uncontrolled Replication of Weakly Virulent Mycobacteria
    treatment_effect: INHIBITS
    description: >-
      Withholding the live vaccine removes the mycobacterial challenge that the
      IFN-gamma-deficient host cannot contain.
    evidence:
    - reference: PMID:25307056
      reference_title: "Human intracellular ISG15 prevents interferon-α/β over-amplification and auto-inflammation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The ISG15-deficient patients from China were not vaccinated with BCG at birth,
        consistent with their current lack of an MSMD phenotype.
      explanation: >-
        Unvaccinated patients with the same genotype have no mycobacterial disease, the
        observation supporting avoidance as effective against this node.
environmental:
- name: Bacille Calmette-Guerin (BCG) vaccination
  description: >
    Routine BCG immunisation is the sentinel environmental exposure in this disorder. The
    attenuated Mycobacterium bovis BCG strain is harmless to immunocompetent infants but
    causes regional or disseminated disease in a host that cannot mount an adequate
    ISG15-dependent IFN-gamma response. Whether a patient develops the mycobacterial arm of
    this disease at all is largely decided by this exposure.
  exposure_term:
    preferred_term: exposure to Bacille Calmette-Guerin vaccine
    term:
      id: ECTO:2000129
      label: exposure to vaccination
  influences_mechanisms:
  - target: Uncontrolled Replication of Weakly Virulent Mycobacteria
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      The live BCG strain is the mycobacterial challenge that the IFN-gamma-deficient host
      cannot contain, initiating regional or disseminated disease.
    evidence:
    - reference: PMID:32402279
      reference_title: "Systemic Type I IFN Inflammation in Human ISG15 Deficiency Leads to Necrotizing Skin Lesions."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        At the age of one month, he was vaccinated with BCG, to which he displayed an
        exaggerated response, with right inguinal lymphadenopathy and erythema of the
        overlying skin.
      explanation: >-
        Ties the vaccination exposure directly to mycobacterial disease in an ISG15-deficient
        infant.
  notes: >-
    The binding is deliberately broader than the exposure. ECTO has no BCG-, Calmette- or
    M. bovis-specific exposure class: `runoak -i sqlite:obo:ecto search "l~BCG"`,
    `"l~Calmette"` and `"l~bacille"` each return nothing, and `"l~mycobacter"` returns only
    exposure classes for M. tuberculosis and M. avium. ECTO:2000129 exposure to vaccination
    is the most specific true class available, and preferred_term carries the vaccine
    identity.
  evidence:
  - reference: PMID:25307056
    reference_title: "Human intracellular ISG15 prevents interferon-α/β over-amplification and auto-inflammation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These patients (P1, P2 and P3, now aged 17, 14 and 17 years, respectively) displayed
      clinical disease caused by the BCG vaccine, which, in otherwise healthy individuals,
      defines Mendelian susceptibility to mycobacterial disease (MSMD)
    explanation: >-
      States that the BCG vaccine caused the clinical disease in the founding patients,
      establishing the exposure-disease relationship at entry level.
animal_models:
- name: Isg15-deficient mouse
  species: Mouse
  genotype: Isg15 knockout
  publication: PMID:22859821
  description: >
    Isg15-null mice die earlier than wild-type littermates after Mycobacterium tuberculosis
    infection, which supports the antimycobacterial role of ISG15. The same model is
    susceptible to several viruses, which the human disease is not, so the model is
    informative for one arm of the disease and misleading for the other.
  modeled_mechanisms:
  - target: Uncontrolled Replication of Weakly Virulent Mycobacteria
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Accelerated death after M. tuberculosis infection in the knockout supports a
      non-redundant antimycobacterial role for Isg15 in vivo.
    limitations: >-
      The challenge organism is fully virulent M. tuberculosis rather than the weakly
      virulent BCG strain and environmental mycobacteria that define the human phenotype, and
      mouse Isg15 does not sustain USP18 as human ISG15 does, so the murine interferon state
      at the time of challenge is not the human one.
    evidence:
    - reference: PMID:22859821
      reference_title: "Mycobacterial disease and impaired IFN-γ immunity in humans with inherited ISG15 deficiency."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Finally, we showed that ISG15−/− mice succumbed earlier than their WT littermates
        upon infection with M. tuberculosis
      explanation: >-
        The in vivo result in the knockout that supports this model-to-mechanism link.
  - target: Enhanced Cellular Antiviral Resistance
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    model_scale: ORGANISM
    description: >-
      The mouse shows the opposite of the human phenotype: Isg15-deficient mice are
      susceptible to viruses, whereas ISG15-deficient humans are not and their cells are more
      virus-resistant than controls.
    limitations: >-
      The divergence is mechanistic rather than incidental: human ISG15 is required to
      sustain USP18 levels and mouse Isg15 is not, so the sustained interferon state that
      leaves human cells antivirally primed has no counterpart in the mouse. Murine Isg15
      antiviral data therefore cannot be read across to the human deficiency.
    evidence:
    - reference: PMID:27193971
      reference_title: "ISG15 deficiency and increased viral resistance in humans but not mice."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Here we describe ISG15-deficient patients who display no enhanced susceptibility to
        viruses in vivo, in stark contrast to Isg15-deficient mice.
      explanation: >-
        States the contradiction between model and human disease that this negative link
        records.
    - reference: PMID:27193971
      reference_title: "ISG15 deficiency and increased viral resistance in humans but not mice."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        The species-specific gain-of-function in antiviral immunity observed in ISG15
        deficiency is explained by the requirement of ISG15 to sustain USP18 levels in humans,
        a mechanism not operating in mice.
      explanation: >-
        Gives the mechanistic reason for the species divergence, which is what makes this a
        structural limitation of the model rather than a strain or challenge artifact.
  evidence:
  - reference: PMID:27193971
    reference_title: "ISG15 deficiency and increased viral resistance in humans but not mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Studies in mice have demonstrated a role for Isg15 in antiviral immunity.
    explanation: >-
      States what the mouse model shows, which is the claim the human data then contradict.
discussions:
- discussion_id: isg15_mouse_human_antiviral_mismatch
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Mouse Isg15 is an antiviral effector and Isg15-null mice are virus-susceptible, while
    ISG15-deficient humans have no unusual viral susceptibility and their fibroblasts are
    more virus-resistant than controls. Does any part of the murine antiviral ISGylation
    phenotype apply to human ISG15 deficiency?
  rationale: >-
    The divergence is not a matter of degree but of direction, and it has a stated
    mechanistic cause: human ISG15 is required to sustain USP18 and mouse Isg15 is not, so
    losing ISG15 raises the interferon set-point in humans and does not in mice. That makes
    murine inferences about ISGylation-dependent antiviral immunity unsafe to carry into the
    human disease, which matters because the mouse literature came first and framed the
    expectation the first patients were measured against. What remains genuinely open is
    whether human ISGylation has any antiviral role against pathogens these few patients have
    not met - the authors state the negative result cannot exclude it - and whether the
    enhanced antiviral state confers clinical protection rather than only a cell-culture
    advantage.
  attaches_to:
  - pathophysiology#Enhanced Cellular Antiviral Resistance
  - animal_models#Mouse
  evidence:
  - reference: PMID:22859821
    reference_title: "Mycobacterial disease and impaired IFN-γ immunity in humans with inherited ISG15 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This experiment of nature shows that human ISGylation is largely redundant for
      antiviral immunity, but that ISG15 plays an essential role as an IFN-γ-inducing secreted
      molecule for optimal antimycobacterial immunity.
    explanation: >-
      States the human conclusion that contradicts the murine expectation, and the one
      function that does hold.
  - reference: PMID:22859821
    reference_title: "Mycobacterial disease and impaired IFN-γ immunity in humans with inherited ISG15 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We cannot rule out enhanced susceptibility to other as yet unencountered viruses
    explanation: >-
      The authors' own statement of what the negative human result does not settle, which is
      the part of this gap that remains open.

📚

References & Deep Research

References

13

PMID:22859821

Mycobacterial disease and impaired IFN-γ immunity in humans with inherited ISG15 deficiency.

No top-level findings curated for this source.

PMID:25307056

Human intracellular ISG15 prevents interferon-α/β over-amplification and auto-inflammation.

No top-level findings curated for this source.

PMID:32402279

Systemic Type I IFN Inflammation in Human ISG15 Deficiency Leads to Necrotizing Skin Lesions.

No top-level findings curated for this source.

PMID:27193971

ISG15 deficiency and increased viral resistance in humans but not mice.

No top-level findings curated for this source.

PMID:38115997

Case Report: ISG15 deficiency caused by novel variants in two families and effective treatment with Janus kinase inhibition.

No top-level findings curated for this source.

PMID:40318816

A novel homozygous ISG15 missense variant leads to severe inflammatory skin lesions, interstitial pneumonia, and basal ganglia calcifications in a Chinese infant with ISG15 deficiency.

No top-level findings curated for this source.

PMID:39365299

First Brazilian Case Report of Unrelated Patients with Identical ISG15 Mutation.

No top-level findings curated for this source.

PMID:29100055

Extracellular ISG15 Signals Cytokine Secretion through the LFA-1 Integrin Receptor.

No top-level findings curated for this source.

PMID:37984483

A novel homozygous Y140X mutation of ISG15 causes diverse type I interferonopathies in sibling patients with cutaneous lesions or recurrent parenchymal pneumonia.

No top-level findings curated for this source.

PMID:41743834

Human ISG15 deficiency unveils impaired healing of ulcerations via type I interferon-mediated fibrosis.

No top-level findings curated for this source.

PMID:38381212

Neuropathologic Impacts of JAK Inhibitor Treatment in Aicardi-Goutières Syndrome.

No top-level findings curated for this source.

PMID:38025345

Mendelian susceptibility to mycobacterial diseases: State of the puzzle.

No top-level findings curated for this source.

ORPHA:319563

Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency

No top-level findings curated for this source.

Deep Research

1

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Evaluations and curation notes (1)

Create: Mendelian Susceptibility To Mycobacterial Diseases Due To Complete ISG15 Deficiency · 2026-09-23T15:23:03Z · View source

New Disease entry for MSMD due to complete ISG15 deficiency (MONDO:0014502, OMIM:616126, ORPHA:319563), gene ISG15 (hgnc:4053), autosomal recessive. Lump/split decision: curated as ONE entry covering both the mycobacterial (MSMD) and the type I interferonopathy presentations, not split. Both come from the same biallelic ISG15 null genotype, and the founding MSMD patients were later found on CT to have the same basal ganglia calcification that brought an unvaccinated kindred to attention through neurology. The presentation split tracks BCG exposure, not genotype. Recorded in the entry `notes` so the decision is visible without the PR thread. Pathophysiology is modelled as one lesion with two arms: (a) loss of secreted free ISG15 -> reduced IFN-gamma from NK/T cells -> failed macrophage activation -> uncontrolled mycobacterial replication; (b) loss of free intracellular ISG15 -> accelerated SKP2/ubiquitin-dependent USP18 degradation -> sustained type I IFN signalling and ISG over-amplification -> tissue inflammation (skin ulceration, basal ganglia calcification, seizures, interstitial lung disease, autoantibodies), with enhanced cellular antiviral resistance as a separate consequence of the same node. The ISG-amplification node declares `conforms_to: jak_stat_pathway_activation#Sustained STAT-Driven Target-Gene Transcription`; that module node's own description names an interferon-stimulated gene signature as one of its disorder-specific output programs. The module's sibling node `Loss of SOCS-Mediated Negative Feedback` was considered and rejected: it names SOCS1/SOCS3 explicitly, and USP18 is a different brake. Sources: PMID:22859821 (Science 2012, founding MSMD report, full text), PMID:25307056 (Nature 2015, USP18 stabilisation and interferonopathy, full text), PMID:32402279 (Cell Rep 2020, necrotising skin lesions, full text), PMID:27193971 (Nat Commun 2016, species divergence in antiviral immunity), PMID:38115997 (Front Immunol 2023, baricitinib), PMID:40318816 (Gene 2025, missense allele, infant), PMID:39365299 (J Clin Immunol 2024), PMID:38025345 (MSMD review, for the IUIS gene set), ORPHA:319563. Negative-existence claims, each verified by running the query rather than asserted: - No GeneReviews chapter. `just check-genereviews --online` returns GeneReviews NO_CHAPTER=1 / StatPearls NO_CHAPTER=1; PubMed `ISG15[TI] AND genereviews[book]` returns zero records. - No ClinGen gene-disease validity assertion for ISG15. The full Gene-Disease Validity table was downloaded (file created 2026-09-23, 3,676 assertions) and contains no ISG15 row, while carrying other MSMD genes such as STAT1. - ECTO has no BCG-specific exposure class. `runoak -i sqlite:obo:ecto search` for `l~BCG`, `l~Calmette` and `l~bacille` each return nothing; `l~mycobacter` returns only M. tuberculosis and M. avium exposure classes. The environmental entry is therefore bound to ECTO:2000129 `exposure to vaccination`, the most specific true class, with the vaccine identity in `preferred_term`. An earlier draft of this entry would have claimed ECTO had no vaccination class at all, following the sibling IL12B entry's note; re-running the search refuted that, which is why the binding exists. Species mismatch recorded as a HUMAN_MODEL_MISMATCH discussion (`isg15_mouse_human_antiviral_mismatch`) plus a `FAILS_TO_RECAPITULATE` animal-model link, rather than as prose: Isg15-null mice are virus-susceptible and ISG15-deficient humans are not, and PMID:27193971 gives the mechanistic reason (human ISG15 sustains USP18, mouse Isg15 does not). Known gaps, left open rather than filled: no published frequency for interstitial lung disease, recurrent pneumonia, developmental delay or skin ulceration; no pooled age at onset for BCG disease in this etiology specifically (the onset descriptor carries the category and a note saying why no mean is recorded); no recombinant IFN-gamma treatment entry, because no cited source reports it being given in ISG15 deficiency - the MSMD-general production-versus-response therapeutic split would have been a weaker adjacent citation; no `datasets:` block; HPO has no term for a transcript-level interferon signature, so the laboratory phenotype binds the circulating IFN-alpha term and the notes record the difference. Deep research: one report, `just dr_fallback='--fallback' research-disorder falcon <Slug>`. Falcon returned HTTP 402 (account out of credits) and the run fell back to openscientist, which produced the report in 1,950 s. The output file keeps the `-falcon` suffix, but its frontmatter records `provider: openscientist`, `fell_back: true`, `requested_provider: falcon` and the full `provider_attempts` list. `just preflight-dr <report> MONDO:0014502` returned WARN, not FAIL: the expected gene ISG15 is mentioned 63 times and the rival gene USP18 26 times, which here reflects USP18 being ISG15's binding partner in the mechanism rather than a second disease mixed into the report. The report carried no validation sections, so they were added in place with `just validate-research-reference` and `just validate-research-terms`: 12/12 references resolved with no confabulations, and of 39 terms, 3 are named as a different term and 6 are worth a second look. Three CURIEs the report suggested were rejected after independent lookup, none of which reached the entry: CHEBI:145303 offered as baricitinib resolves to MG(18:1(11Z)/0:0/0:0) (the entry uses CHEBI:95341, whose canonical label is baricitinib); HP:0031381 offered as "increased circulating interferon" resolves to Decreased mitogen-induced T-cell proliferation; NCIT:C1471 offered as Interferon Gamma resolves to Lamivudine. The report's own term-validation section flags the latter two. Four references were added from the report as leads and then read against the primary source before use: PMID:37984483 (two siblings with the same Y140X allele presenting differently, one with recurrent parenchymal pneumonia - the source for the recurrent-pneumonia phenotype and the intrafamilial-expressivity sentence in `inheritance`), PMID:41743834 (interferon-driven fibrosis and impaired wound healing - the source for the fibrotic-scarring phenotype), PMID:38381212 (an Aicardi-Goutieres post-mortem showing extensive intracranial calcification despite baricitinib from two months of age, added to the JAK inhibition treatment as an explicitly cross-disease caveat graded INDIRECT, because no ISG15-specific long-term neurological follow-up exists), and PMID:38115997's developmental-delay observations. PMID:29100055 was taken the same way, and names the receptor for the extracellular arm: free ISG15 signals through LFA-1 (CD11a/CD18), binding the CD11a alphaI domain. The committed report's reference validation resolved and cached five PMIDs the entry does not itself cite (20591702, 23579383, 28165509, 29100055, 38381212 - the last is now cited). Those cache files are committed with the report, since the validation section the report carries was produced from them. Validation: `just validate`, `just count-verified-snippets` (80/80), `just validate-terms`, `just check-duplicate-keys`, `just check-entity-refs`, `just check-causal-targets`, `just check-qualifier-terms`, `just check-enum-values`, `just list-gene-term-mismatches` (0 findings, 2/2 compared), `just check-genereviews --online`, `just check-snippet-length`, `just check-title-snippets`, `just check-snippet-grading`, `just check-folded-hyphens`, `just check-environmental-evidence`, `just check-coarse-phenotypes`, `just check-reference-titles`, `just backfill-reference-titles` (added 0 titles - every item already had one), `just list-disconnected-phenotypes` (10 of 12 phenotypes causally connected; the two laboratory readouts attach via `reports_on`, which is observational by design), and `just validate-disorders` as the final gate.

OpenScientist ▸

1. Disease Information

openscientist-autonomous 2026-09-23T15:29:15.856865

1. Disease Information

Overview: An autosomal recessive primary immunodeficiency / inborn error of immunity in which complete absence of the ISG15 protein produces a combined phenotype of susceptibility to weakly virulent mycobacteria and a monogenic type I interferonopathy with intracranial calcification and inflammatory skin disease.
Key identifiers:
MONDO: MONDO:0014502
OMIM disease: #616126 "Immunodeficiency 38 with basal ganglia calcification; IMD38"
OMIM gene (ISG15): *147571
Orphanet: ORPHA:319563 ("Immunodeficiency due to ISG15 deficiency")
HGNC: HGNC:4053 (ISG15) | NCBI Gene: 9636 | Ensembl: ENSG00000187608 | UniProt: P05161
ICD-10: D84.8 (other specified immunodeficiencies); ICD-11: 4A00.x (primary immunodeficiencies); basal ganglia calcification coded separately.
MeSH: related terms — "Immunologic Deficiency Syndromes"; "Interferon-Stimulated Gene 15"; "Ubiquitins."
Synonyms / alternative names: Complete ISG15 deficiency; ISG15 deficiency; Immunodeficiency 38 (IMD38); Immunodeficiency 38 with basal ganglia calcification; Mendelian susceptibility to mycobacterial disease due to ISG15 deficiency; ISG15-related type I interferonopathy.
Information source: Aggregated from individual patient case reports and small kindreds (the disease is ultra-rare; total reported patients are in the low dozens worldwide), synthesized with disease-level resources (OMIM, Orphanet). Not derived from EHR/population cohorts.

2. Etiology

Primary cause (genetic): Biallelic (homozygous or compound heterozygous) loss-of-function variants in ISG15 producing complete absence of ISG15 protein and ISGylation. This is a monogenic Mendelian disorder.
Genetic risk factors: The causal variants themselves; consanguinity is a major contributor (most families are consanguineous, from Turkey, Iran, Middle East, China, Brazil). No common susceptibility loci or modifier genes are established; MPO variants co-segregating in one kindred were shown to be non-pathogenic (PMID 37984483).
Environmental risk factors / triggers: BCG vaccination (live attenuated Mycobacterium bovis) is the principal environmental trigger of the infectious phenotype — most patients present after BCG with regional or disseminated BCG disease (BCGitis/BCGosis). Environmental (non-tuberculous) mycobacteria are the other trigger. There is no strong sex or occupational exposure signal.
Protective factors: None established genetically. From a preventive standpoint, avoidance of BCG vaccination in known-affected families prevents BCG disease.
Gene–environment interaction: The genetic lesion (low IFN-γ inducibility) is clinically unmasked by mycobacterial exposure (BCG/environmental mycobacteria). Individuals never exposed to mycobacteria may present instead with the neurologic or dermatologic (interferonopathy) phenotype, which is exposure-independent.

3. Phenotypes

The syndrome has three co-dominant clinical presentations (infectious, neurologic, dermatologic); individual patients may show one, two, or all three.

Phenotype	Type	HPO suggestion	Onset	Frequency/notes
Susceptibility to BCG / environmental mycobacteria (BCGitis, BCGosis, lymphadenitis)	clinical/infectious	HP:0002754 (osteomyelitis), HP:0032262 (atypical mycobacterial infection), HP:0004432 (abnormal mycobacterial immunity)	Infancy/childhood (post-BCG)	Common in exposed patients
Intracranial/basal ganglia calcification	imaging/neurologic	HP:0002514 (cerebral calcification), HP:0007146 (bilateral basal ganglia calcification)	Childhood; often asymptomatic detection	Frequent; may be subclinical
Seizures	clinical sign	HP:0001250 (seizure)	Variable	Reported subset
Necrotizing / ulcerative skin lesions	physical manifestation	HP:0200041 (skin ulcer), HP:0000951 (abnormal skin morphology)	Childhood–adult	Third phenotype (PMID 32402279)
Skin fibrosis / impaired wound healing	physical manifestation	HP:0100699 (scarring), HP:0001075 (atrophic scars)	Chronic	PMID 41743834
Recurrent pneumonia / inflammatory lung disease	clinical	HP:0006532 (recurrent pneumonia)	Variable	PMID 37984483
Elevated blood type I IFN signature (ISG upregulation)	laboratory abnormality	HP:0031381 (increased circulating interferon)	Constitutive	Universal (biomarker)
Low mycobacterium-induced IFN-γ production	laboratory abnormality	HP:0032218 (decreased IFN-γ production)	Constitutive	Universal in vitro (PMID 22859821)

Severity: Variable; ranges from asymptomatic calcification to life-threatening disseminated mycobacterial disease. The interferonopathy is generally milder than USP18 deficiency (which is lethal in infancy).
Progression: Intracranial calcification tends to be stable/slowly progressive; skin disease can be chronic-relapsing; infections are episodic and exposure-linked.
Quality-of-life impact: Chronic skin ulcers, recurrent infections, and (in some) neurologic sequelae/seizures impair daily functioning; formal QoL instrument data are not available for this ultra-rare disease.

4. Genetic / Molecular Information

Causal gene: ISG15 (ISG15 ubiquitin-like modifier), chromosome 1p36.33; encodes a ~17 kDa precursor cleaved to a 15 kDa mature ubiquitin-like protein bearing a C-terminal LRLRGG motif used for conjugation (ISGylation).
Pathogenic variants:
Type/class: Predominantly null / loss-of-function — nonsense, frameshift, and destabilizing missense variants, all resulting in complete deficiency. Reported examples include p.Leu28Gln (c.83T>A) — a destabilizing missense (ΔΔG −2.4 kcal/mol; PMID 39365299); p.Tyr140* (Y140X) nonsense (PMID 37984483); and various frameshift/nonsense alleles in the original Turkish/Iranian kindreds (PMID 22859821, 25307056).
Classification: Pathogenic/likely pathogenic per ACMG/AMP (loss-of-function is the established disease mechanism; PVS1-supporting).
Allele frequency: Individually ultra-rare/private; homozygosity typically arises through consanguinity. Not present at appreciable frequency in gnomAD.
Origin: Germline, biallelic. No somatic mechanism.
Functional consequence: Loss of function — absence of both free ISG15 (secreted) and conjugated ISG15 (ISGylation), and secondary loss of USP18 stabilization.
Modifier genes: None validated. Digenic contributions have been excluded in reported kindreds (e.g., MPO co-variants non-pathogenic, PMID 37984483).
Epigenetics: No disease-specific methylation/chromatin defect described; however, the disease produces a strongly altered transcriptional (IFN-driven) program rather than a primary epigenetic lesion.
Chromosomal abnormalities: None; this is a single-gene disorder, not a copy-number/structural syndrome.

5. Environmental Information

Environmental factors / infectious agents (central to the infectious phenotype):
Mycobacterium bovis BCG (vaccine strain) — NCBI Taxon 33892 — principal trigger.
Environmental / non-tuberculous mycobacteria (e.g., M. avium complex) — low-virulence mycobacteria.
Predisposition is essentially restricted to weakly virulent mycobacteria; classical M. tuberculosis and Salmonella susceptibility is variable, as in other MSMD.
Lifestyle factors: Not applicable/none identified.
Non-infectious environmental toxins/radiation: No established role.

6. Mechanism / Pathophysiology

Causal chain (initiating lesion → clinical manifestation)

Branch A — Infectious/MSMD phenotype: 1. Biallelic ISG15 loss-of-function variant leads to absence of ISG15 protein. 2. Absence of secreted (extracellular) ISG15 from leukocytes (especially granulocytes/neutrophils) and epithelial cells results in loss of a non-redundant IFN-γ-inducing signal. 3. Loss of ISG15 binding to the LFA-1 integrin (CD11a/CD18; αLβ2) receptor on NK and T cells results in failure to trigger IFN-γ release (Swaim et al., PMID 29100055, 32553163). 4. Reduced mycobacterium-induced IFN-γ production leads to impaired macrophage activation and killing of intracellular mycobacteria. 5. This results in susceptibility to BCG and environmental mycobacteria (MSMD). (demonstrated: PMID 22859821, 29100055)

Branch B — Neurologic/dermatologic interferonopathy: 1. Absence of intracellular ISG15 leads to failure to stabilize USP18 (ISG15 normally protects USP18 from proteasomal degradation). 2. Loss of USP18 results in failure to sterically block JAK1 at IFNAR2 → sustained/amplified IFN-α/β (JAK-STAT/ISGF3) signaling. 3. Chronic type I IFN over-activity leads to an autoinflammatory state resembling Aicardi-Goutières syndrome — basal ganglia/intracranial calcification (inferred to arise from IFN-driven vascular/glial injury), autoinflammation. 4. In skin, IFN-I signaling in keratinocytes, endothelia, and dermal monocytes/macrophages results in apoptosis, altered macrophage polarization, epithelial-to-mesenchymal transition, and myofibroblast activation → necrotizing and fibrotic skin lesions and impaired wound healing. (demonstrated: PMID 25307056, 32402279, 41743834)

Category checklist

Molecular pathways: Type I IFN JAK–STAT (JAK1/TYK2 → STAT1/STAT2/IRF9/ISGF3) signaling (overactive); IL-12/IFN-γ axis (underactive); secreted ISG15 → LFA-1 integrin (ITGAL/ITGB2, CD11a/CD18) → IFN-γ release (GO:0005178 integrin binding); ISG15/ISGylation ubiquitin-like conjugation cascade (E1 UBE1L/UBA7, E2 UBCH8/UBE2L6, E3 HERC5); deISGylation by USP18.
Reactome/KEGG: IFN-α/β signaling; ISG15 antiviral mechanism.
Cellular processes: Chronic inflammation, IFN-I-induced apoptosis, EMT, myofibroblast activation, altered macrophage polarization.
Protein dysfunction: Complete loss of function of ISG15; secondary destabilization/loss of USP18. ISG15 is a diubiquitin-like protein comprising two tandem ubiquitin-like (Ubl) domains with a C-terminal LRLRGG conjugation motif (InterPro IPR000626 ubiquitin-like domain; Pfam PF00240; UniProt P05161). Structural studies of the USP18–ISG15 complex show USP18 recognizes only the C-terminal Ubl domain of ISG15 via a small hydrophobic interface, explaining USP18's ISG15-specific (not ubiquitin) deconjugation activity and the mutual stabilization relationship (mouse USP18–ISG15 crystal structures, PMID 28165509; PDB e.g. 5CHV/5CHW). Destabilizing missense variants (e.g., p.Leu28Gln) increase protein flexibility/ΔΔG and abolish function (PMID 39365299).
Immune system involvement: Combined defect — immunodeficiency (hypomorphic IFN-γ, antimycobacterial) plus autoinflammation (excess IFN-α/β).
Tissue damage mechanisms: IFN-I-mediated apoptosis, fibrosis, dystrophic calcification.
Molecular profiling: Patient RNA-seq shows strong upregulation of interferon-stimulated genes and JAK/STAT hyperactivation (PMID 39365299, 37984483); spatial transcriptomics localizes IFN-I signatures to epidermis/dermal myeloid cells (PMID 41743834).
Suggested GO terms: GO:0060337 (type I interferon signaling pathway), GO:0032479 (regulation of type I interferon production), GO:0032020 (ISG15-protein conjugation), GO:0006954 (inflammatory response), GO:0060333 (interferon-gamma-mediated signaling).
Suggested CL terms: CL:0000775 (neutrophil), CL:0000623 (NK cell), CL:0000576 (monocyte), CL:0000235 (macrophage), CL:0000312 (keratinocyte), CL:0000057 (fibroblast/myofibroblast).

7. Anatomical Structures Affected

Organ level:
Brain — basal ganglia and other intracranial sites (calcification). UBERON:0002420 (basal ganglion); UBERON:0000955 (brain).
Skin — necrotizing/fibrotic lesions, ulcers. UBERON:0002097 (skin of body); UBERON:0001003 (epidermis).
Lymph nodes / lymphatic system — mycobacterial lymphadenitis. UBERON:0000029 (lymph node).
Lungs — recurrent pneumonia/inflammatory lung disease. UBERON:0002048 (lung).
Body systems: Immune, nervous (CNS), integumentary; secondarily lymphatic and respiratory.
Tissue/cell level: Epidermal keratinocytes, dermal endothelium, monocytes/macrophages, neutrophils (secretion source), NK/T lymphocytes (IFN-γ effectors), fibroblasts/myofibroblasts (fibrosis).
Subcellular level (GO Cellular Component): Cytoplasm/cytosol (GO:0005829) — site of ISGylation and JAK-STAT signaling; ISG15 conjugated to targets throughout cytoplasm and nucleus.
Localization / lateralization: Intracranial calcification is characteristically bilateral/symmetric (basal ganglia); skin lesions are variable in distribution.

8. Temporal Development

Onset: Typically infancy to childhood. Infectious presentation follows BCG vaccination (first months–years of life). Interferonopathy features (calcification) may be detected incidentally in childhood; dermatologic disease can present later, including adulthood.
Onset pattern: Infections are acute/subacute and episodic; the interferonopathy is chronic/insidious.
Progression: Basal ganglia calcification is generally stable or slowly progressive; skin disease chronic-relapsing; the overall interferonopathy is milder and more survivable than complete USP18 deficiency (neonatal lethal).
Disease course/duration: Chronic, lifelong. No spontaneous cure; remission of inflammation is treatment-induced (JAK inhibition).
Critical periods: The peri-BCG-vaccination window (infancy) is the key window for the infectious phenotype; earlier initiation of JAK inhibition may better limit inflammatory sequelae, though CNS damage may still progress.

9. Inheritance and Population

Inheritance: Autosomal recessive (biallelic loss-of-function).
Penetrance/expressivity: Effectively complete at the biochemical level (absent ISG15), but variable clinical expressivity — which of the three phenotypes manifests depends partly on environmental (mycobacterial) exposure and unknown modifiers; siblings with identical variants can show divergent presentations (PMID 37984483).
Consanguinity / founder effects: Strong consanguinity association; most kindreds are from Turkey, Iran, the Middle East, China, and Brazil. Recurrent identical variants in unrelated families suggest possible local founder alleles (e.g., c.83T>A in Brazil, PMID 39365299).
Carrier frequency: Very low; heterozygous carriers are asymptomatic. No established population carrier screening.
Epidemiology: Ultra-rare (Orphanet class; prevalence <1/1,000,000). Fewer than ~several dozen patients reported worldwide since 2012. No reliable incidence/prevalence estimates.
Sex ratio: No strong sex bias reported (autosomal recessive).
Geographic distribution: Reported predominantly in consanguineous populations; specific variants show regional clustering.

10. Diagnostics

Laboratory / functional tests:
Absent ISG15 protein and ISGylation by immunoblot of patient cells (diagnostic hallmark).
Reduced IFN-γ production by PBMCs/whole blood upon BCG or BCG+IL-12 stimulation (PMID 22859821, 39365299).
Elevated type I IFN signature — interferon-stimulated gene (ISG) expression score in blood; hyperactivated JAK/STAT (phospho-STAT1) signaling (PMID 37984483).
Absence of USP18 accumulation in patient cells (research assay).
Biomarkers: Blood IFN signature (ISG score) — quantified by RT-qPCR of a panel of interferon-stimulated genes (e.g., IFI27, IFI44L, IFIT1, ISG15, RSAD2, SIGLEC1) or by SIGLEC1/CD169 surface expression on monocytes (standard type I interferonopathy biomarkers); low mycobacterium-induced IFN-γ; absent ISG15 protein on Western blot (the specific molecular hallmark). LOINC-codable functional assay: IFN-γ release after BCG±IL-12 stimulation.
Imaging: CT/MRI of brain showing bilateral basal ganglia (and other intracranial) calcifications — a key diagnostic clue (RadLex; overlaps AGS/SPENCD imaging).
Genetic testing (definitive): Whole-exome (WES) or whole-genome sequencing, or targeted MSMD/inborn-errors-of-immunity gene panels including ISG15, followed by Sanger confirmation (PMID 39365299). Single-gene ISG15 sequencing is diagnostic once suspected.
Clinical criteria / context: Diagnosis is suspected in a child with BCG/environmental mycobacterial disease and/or unexplained basal ganglia calcification and/or necrotizing skin lesions, confirmed molecularly.
Differential diagnosis: Other MSMD genes (IFNGR1/2, IL12B, IL12RB1, STAT1, IRF8, TYK2, SPPL2A) for the infectious phenotype; other type I interferonopathies — Aicardi-Goutières syndrome, spondyloenchondrodysplasia (SPENCD), USP18 deficiency, STAT2 gain-of-function (R148Q) — for the neurologic/calcification phenotype (PMID 25307056, 32092142, 35258551). USP18 deficiency is far more severe (neonatal lethal).
Screening: Cascade genetic testing of relatives in known families; consider avoiding BCG in at-risk newborns.

11. Outcome / Prognosis

Survival/mortality: Generally better than USP18 deficiency (which is lethal in infancy). Prognosis depends on control of mycobacterial infections and the severity of the interferonopathy; disseminated mycobacterial disease can be life-threatening. No formal survival statistics exist (ultra-rare).
Morbidity/function: Chronic morbidity from recurrent infections, seizures/neurologic sequelae, and chronic skin ulceration/fibrosis; disability is variable.
Complications: Disseminated BCG disease, mycobacterial lymphadenitis/osteomyelitis, recurrent pneumonia, neurologic impairment from calcification/inflammation, and multi-organ fibrosis (skin, lung).
Prognostic factors: Extent of mycobacterial dissemination; magnitude of IFN-I signature; timing of JAK-inhibitor initiation; degree of CNS involvement.
Recovery potential: Infections are treatable; the interferonopathy is controllable but not curable pharmacologically; established CNS damage may be irreversible.

12. Treatment

Therapy is split along the two mechanisms (NCIT concepts noted):

Anti-mycobacterial therapy for BCG/environmental mycobacterial disease (multidrug regimens; e.g., rifampin, isoniazid, ethambutol, macrolides per species). NCIT: antimycobacterial agents.
Adjunctive IFN-γ: Recombinant IFN-γ (IFN-γ1b) may be considered for refractory mycobacterial infection, as in other MSMD with hypomorphic IFN-γ. NCIT:C1471 (Interferon Gamma).
JAK1/2 inhibitors for the type I interferonopathy (skin, autoinflammation, and to attempt to limit neurologic disease): baricitinib and ruxolitinib; tofacitinib (JAK1/3) has shown benefit for inflammatory skin lesions in related interferonopathies. RNA-seq in ISG15-deficient patients nominated baricitinib (PMID 37984483; class evidence PMID 41871482, 37087470, 40176112). NCIT: baricitinib (C123899), ruxolitinib (C79809), tofacitinib (C97662). CHEBI: baricitinib (CHEBI:145303), ruxolitinib (CHEBI:66919), tofacitinib (CHEBI:71200).
Caveat: JAK inhibitors give limited/heterogeneous benefit on established neurologic manifestations, and CNS calcification can progress despite early treatment (PMID 38381212, 41871482) — likely due to poor CNS bioavailability.
Supportive/rehabilitative: Wound care for skin ulcers; management of seizures; immunization counseling.
Advanced/experimental: No approved gene/cell therapy; hematopoietic stem cell transplantation is not standard. Recombinant ISG15 or ISG15-blocking agents were proposed conceptually (PMID 23579383) but are not clinical therapies.
Pharmacogenomics: None specific established.

13. Prevention

Primary prevention: In families with a known affected child, avoid BCG vaccination in at-risk newborns to prevent BCG disease; genetic counseling for consanguineous families.
Secondary prevention: Early molecular diagnosis (WES/panel), cascade/carrier testing, and prenatal/preimplantation genetic testing where families opt for it.
Tertiary prevention: Prompt anti-mycobacterial treatment; early JAK inhibition to limit inflammatory complications; surveillance neuroimaging and dermatologic care.
Counseling: Autosomal recessive recurrence risk = 25% for future offspring of carrier couples.
Immunization/public health: The key public-health action is withholding live BCG in known-affected kindreds (BCG is routine in many endemic regions, which is why patients often present post-BCG).

14. Other Species / Natural Disease

Taxonomy: Human disease (Homo sapiens, NCBI Taxon 9606). Orthologs studied in mouse (Mus musculus, Taxon 10090; gene Isg15, NCBI Gene 100038882).
Comparative biology — critical caveat: In mice, ISG15/ISGylation is a bona fide antiviral effector of type I IFN, and mouse Usp18 does not require Isg15 for stabilization. In humans, ISGylation is redundant for antiviral defense, and the disease-defining role is USP18 stabilization/IFN-I regulation (PMID 22859821, 25307056). Thus the human phenotype (interferonopathy) is not recapitulated by Isg15-knockout mice, which instead show altered antiviral responses.
Natural disease in other species: No well-characterized naturally occurring ISG15-deficiency disease reported in companion animals/wildlife (not in OMIA as a defined phenotype). No zoonotic component.

15. Model Organisms

Mouse (Isg15−/−, Ube1L/Uba7−/−): Model the antiviral ISGylation role and hematopoietic effects (PMID 20591702) but do not reproduce the human USP18-dependent interferonopathy — a major limitation. Resources: MGI, IMPC.
Human cellular models: Patient-derived fibroblasts, B-cell lines, PBMCs, and ISG15-knockout human epithelial/fibroblast lines best recapitulate the human phenotype — showing hyperactive JAK/STAT, IFN-I-induced apoptosis, EMT, and impaired wound healing (PMID 41743834, 37984483). iPSC/organoid and spatial-transcriptomic ex vivo skin models have been used.
Applications: Dissecting IFN-I regulation (USP18/ISG15/STAT2 axis), fibrosis mechanisms, and testing JAK-inhibitor efficacy.

Evidence Table (Key PMIDs)

PMID	Contribution	Evidence type
22859821	First description; MSMD via loss of secreted ISG15 → low IFN-γ; ISGylation redundant for antiviral immunity	Human clinical + in vitro
29100055 / 32553163	Extracellular ISG15 receptor is LFA-1 (CD11a/CD18); drives IFN-γ release from NK/T cells	In vitro / mechanistic
25307056	Intracellular ISG15 stabilizes USP18; loss → IFN-α/β over-amplification, interferonopathy, calcification	Human clinical + mechanistic
32402279	Third (dermatologic) phenotype; cell-type-specific IFN-I signaling in skin	Human clinical + molecular
41743834	IFN-I-driven fibrosis: apoptosis, EMT, myofibroblast activation, impaired healing	Ex vivo + in vitro
37984483	Novel Y140X; divergent sibling phenotypes; JAK/STAT hyperactivation; baricitinib nominated	Human clinical + RNA-seq
39365299	Recurrent c.83T>A (L28Q) in unrelated Brazilian families; low IFN-γ; transcriptomics	Human clinical + in silico
35258551	USP18 deficiency (I60N) — mechanistic/differential context	Human clinical
32092142	STAT2 R148Q phenocopy of USP18 deficiency — differential context	Human clinical
42643649	MSMD genetic heterogeneity (~22 genes, IFN-γ axis)	Review/case
38381212 / 41871482	JAK-inhibitor efficacy/limits in interferonopathies (CNS)	Clinical
23579383	ISG15 as secreted IFN-γ-inducing molecule; therapeutic concepts	Review
28165509	Crystal structure of USP18–ISG15; C-terminal Ubl domain specificity	Structural
20591702	Ube1L/ISGylation mouse hematopoietic model	Mouse model

Supported vs. Refuted Hypotheses

Supported: - ISG15 loss causes MSMD through impaired IFN-γ (secreted-ISG15 mechanism). ✔ (PMID 22859821) - ISG15 loss causes a type I interferonopathy via failed USP18 stabilization. ✔ (PMID 25307056) - Disease has three co-dominant phenotypes (infectious/neurologic/dermatologic). ✔ (PMID 32402279) - JAK1/2 inhibition is the rational therapy for the interferonopathy. ✔ (PMID 37984483, 41871482)

Refuted / negative findings: - Human ISG15 deficiency causes severe viral disease — refuted (no unusual viral susceptibility; PMID 22859821). - Mouse Isg15 knockouts model the human disease — largely refuted (species divergence; mice model antiviral role only). - Co-inherited MPO variants contribute to pathology — refuted in the reported kindred (PMID 37984483).

Limitations and Future Directions

Ultra-rare disease: no population epidemiology, survival statistics, or QoL instrument data; evidence rests on case reports/small kindreds.
Genotype–phenotype determinants of which phenotype manifests remain unexplained (modifiers, exposure).
CNS-penetrant anti-IFN therapies are an unmet need; current JAK inhibitors inadequately protect the brain.
Better human models (organoids, iPSC-derived neurons/microglia) are needed given mouse divergence.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	12
Resolved	12
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	12
On topic	8
Off topic	0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	39
Resolved	37
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	2
Terms whose name was checked	23
Terms named correctly	14
Terms named as a different term	3
Terms whose name is worth a second look	6

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

MONDO:0014502 (3 mentions) - the report calls it "if available"; MONDO calls it Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency
HP:0031381 (1 mention) - the report calls it "increased circulating interferon"; HP calls it Decreased mitogen-induced T-cell proliferation
NCIT:C1471 (1 mention) - the report calls it "Interferon Gamma"; NCIT calls it Lamivudine

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

HP:0032218 (1 mention) - the report calls it "decreased IFN-γ production"; HP calls it Decreased total CD4+ T cell proportion, and lists "Decreased helper T cell proportion" among its other names
GO:0060337 (1 mention) - the report calls it "type I interferon signaling pathway"; GO calls it type I interferon-mediated signaling pathway, and lists "type I interferon signaling pathway" among its other names
GO:0060333 (1 mention) - the report calls it "interferon-gamma-mediated signaling"; GO calls it type II interferon-mediated signaling pathway, and lists "interferon-gamma-mediated signaling pathway" among its other names
CL:0000623 (1 mention) - the report calls it "NK cell"; CL calls it natural killer cell, and lists "NK cell" among its other names
CL:0000057 (1 mention) - the report calls it "fibroblast/myofibroblast"; CL calls it fibroblast
UBERON:0001003 (1 mention) - the report calls it "epidermis"; UBERON calls it skin epidermis, and lists "epidermis" among its other names

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.

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Classifications

Inheritance

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Environmental Factors

Diagnosis

Prevalence

Clinical Burden

Animal Models

Source YAML

References & Deep Research

References

Deep Research

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic / Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

Causal chain (initiating lesion → clinical manifestation)

Category checklist

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Evidence Table (Key PMIDs)

Supported vs. Refuted Hypotheses

Limitations and Future Directions

Artifacts

Reference Validation

Term Validation

Terms the report names something else

Terms whose name is worth a second look

Prefixes with no resolver