Immunodeficiency 11B with Atopic Dermatitis

Genetic MONDO:0054697 Pathograph 30 Show in embeddings browser MONDO:0021094

Immunodeficiency 11B with atopic dermatitis (IMD11B; OMIM #617638), known clinically as CADINS (CARD11-associated atopy with dominant interference of NF-kB signalling), is an autosomal dominant primary atopic disorder caused by heterozygous loss-of-function CARD11 variants that act as dominant negatives. CARD11 is the antigen receptor-proximal scaffold that assembles the CARD11-BCL10-MALT1 complex and drives NF-kB, JNK and mTORC1 signalling in lymphocytes; CADINS variants, largely confined to the CARD and coiled-coil domains, poison mixed wild-type:mutant oligomers at the opening and cofactor-association steps of the signalling cycle, attenuating all three pathways. Patient T cells proliferate poorly, produce little IFN-gamma and IL-2, import glutamine inefficiently, and, because loss of CARD11-JNK signalling de-represses GATA3 and NFATC1, differentiate toward Th2; regulatory T cells are reduced and NK cells show altered homeostasis. The result is severe early-onset atopic dermatitis with markedly elevated IgE and eosinophilia, asthma, food allergy and urticaria, combined with a partial combined immunodeficiency (recurrent respiratory, cutaneous and viral infections, hypogammaglobulinaemia in some), autoimmunity, neutropenia, colitis and, rarely, HPV-related carcinoma or lymphoma; penetrance and expressivity vary even within families, and the phenotype overlaps STAT3- and DOCK8-related hyper-IgE syndromes. Atopy improves with age in many patients and responds to dupilumab and omalizumab; glutamine supplementation partially rescues the T-cell defects in vitro. The biallelic null (IMD11A) and gain-of-function (BENTA) CARD11 disorders are distinct allelic entities.

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1
Inheritance
6
Pathophys.
25
Phenotypes
2
Gaps
30
Pathograph
1
Genes
4
Variants
7
Medical Actions
3
Differentials
2
Models
1
Deep Research
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Classifications

Harrison's Part
IMMUNE RHEUMATOLOGIC DERMATOLOGY GENETICS ENVIRONMENT DISEASE
IUIS Category
combined immunodeficiency with syndromic features
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Inheritance

1
Autosomal dominant HP:0000006
Autosomal dominant with variable penetrance and expressivity, including within multiplex families; de novo variants occur.
Autosomal dominant inheritance Penetrance: INCOMPLETE Expressivity: VARIABLE
Show evidence (2 references)
PMID:38311684 SUPPORT Human Clinical
"CARD11-associated atopy with dominant interference of NF-κB signaling (CADINS) disease occurs in humans carrying a dominant negative (DN), loss of function (LOF) mutation in CARD11. Despite variable penetrance and expressivity, this disease is typically characterized by severe atopy with aspects..."
Dominant inheritance with variable penetrance.
PMID:36405754 SUPPORT Human Clinical
"A remarkable variability of disease expression was clearly noted among BENTA as well as in CADINS patients, even within multiplex families."
Intrafamilial variability.
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Discussions and Knowledge Gaps

2
Why do CARD11 R30W/+ mice develop high IgE but not spontaneous atopic dermatitis or Th2 expansion, and what additional environmental or genetic factor converts hyper-IgE into overt atopy in patients?
HUMAN MODEL MISMATCH OPEN cadins_mouse_no_atopic_dermatitis
Attached to
pathophysiology#Atopic Inflammation with Hyper-IgE and Eosinophilia
The patient-allele knock-in reproduces the signalling and immunodeficiency defects and age-dependent IgE elevation but not the defining skin disease, and the authors conclude that high IgE is not sufficient for atopic symptoms; the human Th2 skewing via GATA3 was shown in patient T cells but is absent in the mouse.
Show evidence (1 reference)
PMID:34341167 SUPPORT Model Organism
"However, precisely how a heterozygous dominant negative CARD11 allele leads to the development of this CADINS-specific cluster of symptoms remains poorly understood."
Explicit statement of the open question.
Why does partial, dominant-negative interference with CARD11 signalling produce severe atopy and autoimmunity, whereas complete biallelic loss produces profound combined immunodeficiency without atopy?
OPEN QUESTION OPEN cadins_versus_null_phenotype_divergence
Attached to
pathophysiology#Oligomer Poisoning of the CARD11 Signaling Cycle
Both disorders reduce antigen receptor-induced NF-kB signalling, but only residual signalling appears to permit the Th2-skewed, autoreactive responses of CADINS; oligomer poisoning studies explain the inheritance difference but not the qualitative phenotype divergence.
Show evidence (1 reference)
PMID:35198875 SUPPORT In Vitro
"Three classes of germline mutations in CARD11 cause Primary Immunodeficiency, including homozygous loss-of-function (LOF) mutations in CARD11 deficiency, heterozygous gain-of-function (GOF) mutations in BENTA disease, and heterozygous dominant-negative LOF mutations in CADINS."
The three allelic classes whose divergence is unexplained.
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Pathophysiology

6
Heterozygous Dominant-Negative CARD11 Variant
A single hypomorphic CARD11 allele, expressed alongside the wild-type protein, exerts a dominant-interfering effect because CARD11 signals as an oligomer; the variant protein is loss-of-function on its own and additionally suppresses wild-type CARD11 when co-expressed.
Downstream
Oligomer Poisoning of the CARD11 Signaling Cycle
Show evidence (2 references)
PMID:28826773 SUPPORT In Vitro
"We demonstrate that the R30W mutation results in loss of function while also exerting a dominant negative effect on wild-type CARD11."
Dominant-negative demonstration.
PMID:28628108 SUPPORT In Vitro
"Transfection of mutant CARD11 expression constructs into T cell lines demonstrated both loss-of-function and dominant-interfering activity upon antigen receptor-induced activation of nuclear factor-κB and mammalian target of rapamycin complex 1 (mTORC1)."
Loss-of-function plus dominant interference in the founding study.
Oligomer Poisoning of the CARD11 Signaling Cycle
Mixed wild-type:mutant CARD11 oligomers fail at the opening step, in which the inhibitory domain's repressive elements are neutralised, and at the cofactor-association step, so that antigen receptor engagement no longer converts the scaffold to its active state.
Downstream
Attenuated NF-kB, JNK and mTORC1 Signaling Downstream of the Antigen Receptor
Show evidence (1 reference)
PMID:35198875 SUPPORT In Vitro
"Our findings provide evidence that CARD11 oligomer subunits cooperate in at least two steps during antigen receptor signaling and reveal how different LOF mutations in the same oligomeric signaling hub may cause disease with different inheritance patterns."
Explains dominant versus recessive inheritance of CARD11 loss of function.
Attenuated NF-kB, JNK and mTORC1 Signaling Downstream of the Antigen Receptor
Antigen receptor-induced canonical NF-kB activation, JNK/AP-1 signalling and mTORC1 activation are all reduced in patient T cells and in cells expressing patient variants; the mTORC1 defect reflects impaired CARD11-dependent glutamine import and is partially rescued by glutamine supplementation.
T cell CL:0000084 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves T cell (CL:0000084). CL:0000084 is a cell type from the Cell Ontology.
canonical NF-kappaB signal transduction GO:0007249 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased canonical NF-kappaB signal transduction (GO:0007249). GO:0007249 is a biological process from the Gene Ontology. ↓ DECREASED JNK cascade GO:0007254 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased JNK cascade (GO:0007254). GO:0007254 is a biological process from the Gene Ontology. ↓ DECREASED TORC1 signaling GO:0038202 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased TORC1 signaling (GO:0038202). GO:0038202 is a biological process from the Gene Ontology. ↓ DECREASED T cell receptor signaling pathway GO:0050852 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased T cell receptor signaling pathway (GO:0050852). GO:0050852 is a biological process from the Gene Ontology. ↓ DECREASED
Experimental models
Patient T cells and transfected T-cell lines expressing CADINS variants CELL LINE Patient T cells and variant-transfected lines reproduce the attenuated signalling and its partial glutamine rescue.
Downstream
Th2 Skewing via Loss of JNK-Dependent GATA3 Repression
Partial T-Cell, Regulatory T-Cell and NK-Cell Dysfunction
Show evidence (3 references)
PMID:30170123 SUPPORT Other
"Caspase activation and recruitment domain 11 (CARD11) encodes a scaffold protein in lymphocytes that links antigen receptor engagement with downstream signaling to nuclear factor κB, c-Jun N-terminal kinase, and mechanistic target of rapamycin complex 1."
The three pathways downstream of CARD11.
PMID:28628108 SUPPORT In Vitro
"The mTORC1 and IFN-γ production defects were partially rescued by supplementation with glutamine, which requires CARD11 for import into T cells."
Glutamine-import basis of the mTORC1 defect.
PMID:40111223 SUPPORT In Vitro
"Here we show that CARD11 is critical for TCR-induced activation of JNK1 and JNK2, as well as canonical JUN/FOS AP-1 family members. Patient-derived CARD11 DI variants attenuated WT CARD11 JNK signaling, mirroring effects on NF-κB."
JNK arm of the defect.
Th2 Skewing via Loss of JNK-Dependent GATA3 Repression
Attenuated TCR signalling favours Th2 differentiation, a shared mechanism of the primary atopic disorders; in CADINS the loss of CARD11-JNK signalling specifically up-regulates GATA3 and NFATC1 in patient T cells, and patients show diminished IFN-gamma with increased IL-4 production.
T-helper 2 cell CL:0000546 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves T-helper 2 cell (CL:0000546). CL:0000546 is a cell type from the Cell Ontology.
T-helper 2 cell differentiation GO:0045064 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased T-helper 2 cell differentiation (GO:0045064). GO:0045064 is a biological process from the Gene Ontology. ↑ INCREASED interferon-gamma production GO:0032609 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased interferon-gamma production, annotated with type II interferon production (GO:0032609). GO:0032609 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Atopic Inflammation with Hyper-IgE and Eosinophilia
Show evidence (2 references)
PMID:40111223 SUPPORT In Vitro
"Further, impaired CARD11-JNK signaling was linked to enhanced GATA3 expression in CADINS patient T cells. Our findings reveal a novel intrinsic mechanism connecting impaired CARD11-dependent JNK signaling to enhanced GATA3/NFAT2 induction and TH2 cell differentiation in CADINS patients."
Patient-cell demonstration of the Th2 mechanism.
PMID:35651609 SUPPORT Human Clinical
"Partial T-cell deficiency, diminished IFN-γ cytokine and increased IL-4 production, were identified as disease-causing mechanisms."
Cytokine skew in patients.
Partial T-Cell, Regulatory T-Cell and NK-Cell Dysfunction
T cells respond poorly to mitogens and antigens with reduced IFN-gamma and IL-2; CTLA4+FOXP3+ regulatory T cells are reduced; NK cells show reduced NKp46, NKG2D and CD69, impaired IFN-gamma production by CD56bright cells and paradoxically increased steady-state pS6, so that the effect of the variant on mTORC1 differs between T and NK cells. These defects underlie the recurrent respiratory, cutaneous and viral infections, reduced immune surveillance and autoimmunity.
regulatory T cell CL:0000815 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves regulatory T cell (CL:0000815). CL:0000815 is a cell type from the Cell Ontology. natural killer cell CL:0000623 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves natural killer cell (CL:0000623). CL:0000623 is a cell type from the Cell Ontology.
T cell activation GO:0042110 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased T cell activation (GO:0042110). GO:0042110 is a biological process from the Gene Ontology. ↓ DECREASED interleukin-2 production GO:0032623 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased interleukin-2 production (GO:0032623). GO:0032623 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
CARD11 R30W/+ mouse Mouse recapitulates Reproduces the multi-lineage signalling and functional defects, including Treg reduction and NK IFN-gamma loss.
Downstream
Recurrent respiratory infections
Recurrent viral infections
Recurrent skin infections
Decreased circulating immunoglobulin concentration
Autoimmunity
Decreased regulatory T cell proportion
Squamous cell carcinoma
Show evidence (3 references)
PMID:37086690 SUPPORT Human Clinical
"CTLA4+Foxp3+CD4+ Tregs were severely reduced. Patient's NK cells showed reduced expression of NKp46, NKG2D and CD69. Patient's CD56bright NK cells showed in vitro impaired production of IFN-γ."
Treg and NK findings.
PMID:37086690 SUPPORT Human Clinical
"Overall, the effect of CARD11 mutation on mTORC1 differs between T and NK cells. These findings may explain the increased susceptibility to viral infections and the reduced immune surveillance in affected patients."
Link to infection susceptibility and surveillance.
PMID:34341167 SUPPORT Model Organism
"We find that CARD11R30W/+ mice exhibit impaired signaling downstream of CARD11 that leads to defects in T, B, and NK cell function and immunodeficiency."
Mouse confirmation of multi-lineage functional defects.
Atopic Inflammation with Hyper-IgE and Eosinophilia
Th2-skewed T cells drive severe, early-onset atopic dermatitis, asthma, food allergy and chronic urticaria with markedly elevated IgE and eosinophilia; IgE elevation develops with age and is not by itself sufficient for overt atopic symptoms in the mouse model.
immunoglobulin production GO:0002377 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated immunoglobulin production (GO:0002377). GO:0002377 is a biological process from the Gene Ontology. ↕ DYSREGULATED
Animal models
CARD11 R30W/+ mouse Mouse partially recapitulates Elevated IgE develops with age and incomplete penetrance, but spontaneous atopic dermatitis does not.
Downstream
Atopic dermatitis
Increased circulating IgE concentration
Increased total eosinophil count
Asthma
Food allergy
Urticaria
Anaphylactic shock
Show evidence (3 references)
PMID:36334349 SUPPORT Human Clinical
"Most recently, severe atopic patients were discovered that carried heterozygous dominant-negative CARD11 mutations."
Review linking attenuated CARD11 signalling to severe atopy in humans.
PMID:38231347 SUPPORT Human Clinical
"Patients with CADINS suffer with severe atopic manifestations including atopic dermatitis, food allergy, and chronic spontaneous urticaria in addition to recurrent infections and autoimmunity."
Atopic spectrum.
PMID:34341167 SUPPORT Model Organism
"Our findings help explain the high susceptibility of CADINS patients to infection and suggest that the development of high serum IgE is not sufficient to induce overt atopic symptoms."
IgE alone is insufficient for atopy in the mouse.
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Pathograph

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Pathograph: causal mechanism network for Immunodeficiency 11B with Atopic Dermatitis Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

25
Blood 6
Increased circulating IgE concentration VERY_FREQUENT HP:0003212 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated serum IgE, annotated with Increased circulating IgE concentration (HP:0003212). HP:0003212 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:35651609 SUPPORT Human Clinical
"When severe or recurrent infections and exceedingly elevated serum IgE levels occur in AD patients, an inborn error of immunity (IEI) may be suspected."
Hyper-IgE context of the diagnosis.
PMID:34341167 SUPPORT Model Organism
"CARD11R30W/+ mice develop elevated serum IgE levels with 50% penetrance that becomes more pronounced with age, but do not develop spontaneous atopic dermatitis."
Age-dependent IgE elevation reproduced in the mouse.
Increased total eosinophil count FREQUENT HP:0001880 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Eosinophilia, annotated with Increased total eosinophil count (HP:0001880). HP:0001880 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35651609 SUPPORT Human Clinical
"We report on an 18-year-old patient with a long-standing history of infections, accompanied by hypogammaglobulinemia, intermittent agranulocytosis, atopy, eosinophilia and colitis."
Eosinophilia in the proband.
Decreased circulating immunoglobulin concentration OCCASIONAL HP:0004313 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypogammaglobulinemia, annotated with Decreased circulating immunoglobulin concentration (HP:0004313). HP:0004313 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35651609 SUPPORT Human Clinical
"Five other family members were affected by severe atopy associated with the above variant, but not hypogammaglobulinemia."
Hypogammaglobulinaemia in the proband but not affected relatives.
Decreased total neutrophil count OCCASIONAL HP:0001875 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Neutropenia, annotated with Decreased total neutrophil count (HP:0001875). HP:0001875 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30170123 SUPPORT Human Clinical
"In addition to (and sometimes excluding) severe atopy, heterozygous missense and indel mutations in CARD11 presented with immunologic phenotypes similar to those observed in signal transducer and activator of transcription 3 loss of function, dedicator of cytokinesis 8 deficiency, common..."
Neutropenia within the expanded phenotype.
Decreased regulatory T cell proportion OCCASIONAL HP:0020113 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Reduced CTLA4+FOXP3+ regulatory T cells, annotated with Decreased regulatory T cell proportion (HP:0020113). HP:0020113 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:37086690 SUPPORT Human Clinical
"CTLA4+Foxp3+CD4+ Tregs were severely reduced."
Treg reduction in a single reported patient.
PMID:30170123 REFUTE Human Clinical
"Other assays performed showed diminished mitogen-induced T-cell proliferation in the majority of patients tested, and relatively normal frequencies of regulatory T-cells, as previously reported (Table 3)."
The larger dominant-negative cohort found generally normal Treg frequencies, contradicting a consistent reduction.
PMID:36405754 REFUTE Human Clinical
"Additionally, we observed normal values of Treg subset with normal FOXP3 expression in both patients with eosinophilic colitis."
The Argentine CADINS cohort also found normal Treg values, the second refuting series.
Decreased mitogen-induced T-cell proliferation FREQUENT HP:0031381 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Impaired PHA-induced lymphocyte proliferation, annotated with Decreased mitogen-induced T-cell proliferation (HP:0031381). HP:0031381 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:36405754 SUPPORT Human Clinical
"lymphocyte proliferation assay to PHA was evaluated in 6 patients, with 5 of them (4 belonging to family 8 and patient 7B) showing impairment to PHA."
Impaired PHA-induced proliferation in 5 of 6 tested patients.
PMID:30170123 SUPPORT Human Clinical
"Other assays performed showed diminished mitogen-induced T-cell proliferation in the majority of patients tested, and relatively normal frequencies of regulatory T-cells, as previously reported (Table 3)."
Diminished mitogen-induced proliferation in the majority of the dominant-negative cohort.
Cardiovascular 1
Urticaria OCCASIONAL HP:0001025 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Chronic spontaneous urticaria, annotated with Urticaria (HP:0001025). HP:0001025 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38231347 SUPPORT Human Clinical
"one adult suffered from chronic spontaneous urticaria"
Urticaria in an adult patient.
Digestive 2
Colitis OCCASIONAL HP:0002583 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Colitis (HP:0002583). HP:0002583 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35651609 SUPPORT Human Clinical
"accompanied by hypogammaglobulinemia, intermittent agranulocytosis, atopy, eosinophilia and colitis"
Colitis in the proband.
Eosinophilic infiltration of the esophagus OCCASIONAL HP:0410151 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Eosinophilic esophagitis, annotated with Eosinophilic infiltration of the esophagus (HP:0410151). HP:0410151 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30170123 SUPPORT Human Clinical
"Atopic disease was the cardinal feature noted in most patients (89%), frequently presenting in childhood as atopic dermatitis, but also including asthma, allergic rhinitis, food allergies, and even eosinophilic esophagitis (Table 2)."
Eosinophilic esophagitis among the atopic manifestations.
Head and Neck 4
Abnormal facial shape OCCASIONAL HP:0001999 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dysmorphic facial features, annotated with Abnormal facial shape (HP:0001999). HP:0001999 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36405754 SUPPORT Human Clinical
"The growing number of patients with dysmorphic facial features strengthen the inclusion of extra-immune characteristics as part of the CADINS spectrum."
Extra-immune features.
Chronic sinusitis OCCASIONAL HP:0011109 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Chronic sinusitis (HP:0011109). HP:0011109 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35651609 SUPPORT Human Clinical
"He was additionally diagnosed with chronic polyposis, sinusitis and food allergies."
Chronic sinusitis in a reported patient.
Allergic rhinitis FREQUENT HP:0003193 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Allergic rhinitis (HP:0003193). HP:0003193 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:36405754 SUPPORT Human Clinical
"Atopic dermatitis was seen in 9/10 patients in varying degrees of severity, followed by asthma and allergic rhinitis in 5/10, food allergies in 2 of them and environmental allergies in one patient."
Allergic rhinitis in 5 of 10 patients of the cohort.
PMID:30170123 SUPPORT Human Clinical
"Other atopic symptoms were noted in patients with DN variants, including asthma (55%) and food allergies (32%), and less frequently, rhinitis and eosinophilic esophagitis (Table 1)."
Rhinitis among the atopic symptoms of dominant-negative CARD11 patients.
Oral ulcer OCCASIONAL HP:0000155 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Oral ulcers, annotated with Oral ulcer (HP:0000155). HP:0000155 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30170123 SUPPORT Human Clinical
"Oral ulcers were also observed (14%), and may be linked to neutropenia."
Oral ulcers in 14% of the cohort.
Immune 9
Atopic dermatitis VERY_FREQUENT HP:0001047 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Severe atopic dermatitis, annotated with Atopic dermatitis (HP:0001047), qualified as infantile onset, mean 0.49y. HP:0001047 is a phenotype from the Human Phenotype Ontology.
Onset: INFANTILE; mean 0.49y
Show evidence (2 references)
PMID:38231347 SUPPORT Human Clinical
"In five patients, atopic dermatitis was severe and recalcitrant to standard topical and systemic medications; one adult suffered from chronic spontaneous urticaria."
Severity of atopic dermatitis.
PMID:28628108 SUPPORT Human Clinical
"Our findings indicate that a single hypomorphic mutation in CARD11 can cause potentially correctable cellular defects that lead to atopic dermatitis."
Atopic dermatitis as the founding phenotype.
Asthma FREQUENT HP:0002099 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Early-onset asthma, annotated with Asthma (HP:0002099). HP:0002099 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28826773 SUPPORT Human Clinical
"We sought to identify the genetic aberration in 4 related patients with CID, early-onset asthma, eczema, and food allergies, as well as autoimmunity."
Asthma in the founding family.
Food allergy FREQUENT HP:0500093 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Food allergy (HP:0500093). HP:0500093 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28826773 SUPPORT Human Clinical
"4 related patients with CID, early-onset asthma, eczema, and food allergies, as well as autoimmunity"
Food allergy in the founding family.
Anaphylactic shock OCCASIONAL HP:0100845 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Food-induced anaphylaxis, annotated with Anaphylactic shock (HP:0100845). HP:0100845 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37086690 SUPPORT Human Clinical
"We report on a 12-year-old boy with severe atopic dermatitis, food induced anaphylaxis and hypogammaglobulinemia"
Anaphylaxis in a reported patient.
Recurrent respiratory infections FREQUENT HP:0002205 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent respiratory infections (HP:0002205). HP:0002205 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:30170123 SUPPORT Human Clinical
"In addition to atopic disease (89%), significant viral skin infections (68%) and lung disease (e.g. infections, pneumonia, bronchiectasis) (68%) were the most prominent symptoms shared by patients harboring DN CARD11 mutations (Table 2)."
Lung disease including infections in 68% of the dominant-negative CARD11 cohort.
PMID:34341167 SUPPORT Model Organism
"CADINS patients present with frequent respiratory and skin infections, asthma, allergies, and atopic dermatitis."
The mouse study's background statement of the human presentation, retained as context and graded as the model-organism publication it is.
Recurrent skin infections FREQUENT HP:0001581 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent cutaneous infections, annotated with Recurrent skin infections (HP:0001581). HP:0001581 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36405754 SUPPORT Human Clinical
"Skin infections were the most frequently found affecting 8/10 patients, being S. aureus and S. epidermidis the most isolated microorganisms."
Skin infections in 8/10 patients of the CADINS cohort.
Recurrent viral infections FREQUENT HP:0004429 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent cutaneous and respiratory viral infections, annotated with Recurrent viral infections (HP:0004429). HP:0004429 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38311684 SUPPORT Human Clinical
"this disease is typically characterized by severe atopy with aspects of combined immunodeficiency, including recurrent respiratory and cutaneous viral infections, hypogammaglobulinemia, and other symptoms"
Viral infection susceptibility.
Autoimmunity OCCASIONAL HP:0002960 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Autoimmunity (HP:0002960). HP:0002960 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28826773 SUPPORT Human Clinical
"the R30W defect results in a less profound yet prominent susceptibility to infections, as well as multiorgan atopy and autoimmunity"
Autoimmunity in the founding family.
Impaired specific antibody response FREQUENT HP:0012475 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Poor specific antibody response, annotated with Impaired specific antibody response (HP:0012475). HP:0012475 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36405754 SUPPORT Human Clinical
"Several CADINS patients had significant humoral defects with poor specific antibody production leading to increased infections, and requirement of immunoglobulin replacement therapy (a half of our CADINS cohort)."
Poor specific antibody production in about half the cohort.
Integument 1
Squamous cell carcinoma VERY_RARE HP:0002860 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is HPV-associated squamous cell carcinoma, annotated with Squamous cell carcinoma (HP:0002860). HP:0002860 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35651609 SUPPORT Human Clinical
"Malignancies occurred in two generations: an HPV-positive squamous cell carcinoma and a cutaneous T-cell lymphoma."
Malignancy in a CADINS family.
Respiratory 1
Bronchiectasis OCCASIONAL HP:0002110 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bronchiectasis (HP:0002110). HP:0002110 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36405754 SUPPORT Human Clinical
"One patient developed bronchiectasis due to recurrent infections."
Bronchiectasis secondary to recurrent infection.
Growth 1
Failure to thrive FREQUENT HP:0001508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Failure to thrive (HP:0001508). HP:0001508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36405754 SUPPORT Human Clinical
"Four of the 10 patients had failure to thrive, which coincided with the 4 index cases of the affected families, representing the most symptomatic patients from this cohort."
Failure to thrive in 4 of 10 patients.
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Genetic Associations

1
CARD11
Gene: CARD11 hgnc:16393 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CARD11 (hgnc:16393). hgnc:16393 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:30170123 SUPPORT In Vitro
"Pathogenic variants exhibited dominant negative activity and were largely confined to the CARD or coiled-coil domains of the CARD11 protein."
Domain distribution of pathogenic alleles.
PMID:36405754 SUPPORT Human Clinical
"Additional four variants showing a LOF activity were considered as causative of CARD11-associated atopy with dominant interference of NF-kB signaling (CADINS). The remaining variant exhibited a neutral functional assay excluding its carrier from further analysis."
Need for functional classification of variants.
Variants (4)
c.88C>T (p.Arg30Trp) Pathogenic
missense
Founding dominant-negative variant segregating with severe atopy in a four-member family; loss of function with dominant-negative effect on wild-type CARD11, modelled in the CARD11 R30W/+ mouse.
Show evidence (1 reference)
PMID:28826773 SUPPORT Human Clinical
"A heterozygous novel c.C88T 1-bp substitution resulting in amino acid change R30W in caspase activation and recruitment domain family member 11 (CARD11) was identified by using whole-exome sequencing and segregated perfectly to family members with severe atopy only but was not found in healthy subjects."
Identification, segregation and dominant-negative demonstration.
c.169G>A (p.Glu57Lys) Pathogenic
missense
De novo heterozygous variant in a boy with severe atopic dermatitis, food-induced anaphylaxis and hypogammaglobulinaemia; dominant-negative effect confirmed on CD4+ and CD8+ T cells.
Show evidence (1 reference)
PMID:37086690 SUPPORT Human Clinical
"We report on a 12-year-old boy with severe atopic dermatitis, food induced anaphylaxis and hypogammaglobulinemia harbouring a novel de novo heterozygous variant c.169G > A; p.Glu57Lys in CARD11. The dominant negative effect of this mutation was confirmed on both CD4+ and CD8+."
De novo variant with functional confirmation.
c.223C>T (p.Arg75Trp) Pathogenic
missense
Dominant-negative variant in a family with severe atopy, hypogammaglobulinaemia and intermittent agranulocytosis in the proband, and HPV-positive squamous cell carcinoma and cutaneous T-cell lymphoma across two generations.
Show evidence (1 reference)
PMID:35651609 SUPPORT Human Clinical
"was identified. Functional studies confirmed this variant to have a dominant negative (DN) effect, as previously described in patients with CADINS."
Variant and functional confirmation.
c.2324C>T (p.Ser775Leu) Likely Pathogenic
missense
De novo dominant-negative variant in the MAGUK region, outside the CARD and coiled-coil domains where most CADINS alleles cluster, in a Chinese girl with periodic fever, recurrent infections and eczema.
Show evidence (2 references)
PMID:39414811 SUPPORT In Vitro
"Luciferase reporter assays and co-immunoprecipitation demonstrated mutation exerts a dominant-interfering effect on wild-type CARD11, inhibiting the activity of NF-κB."
Functional demonstration of dominant interference by the S775L allele.
PMID:39414811 SUPPORT Human Clinical
"A very rare missense mutation (c.2324C > T, p.S775L) in CARD11 gene (NM_032415) was identified by WES in the patient but not her parents."
De novo occurrence in the proband.
💊

Medical Actions

7
Dupilumab
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: dupilumab NCIT:C162455 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses dupilumab (NCIT:C162455). NCIT:C162455 is a therapeutic agent from the NCI Thesaurus.
Platform: Monoclonal antibody
Anti-IL-4 receptor alpha monoclonal antibody; rapid and sustained improvement of severe, recalcitrant atopic dermatitis in five patients with no complications, allowing other atopy medications to be reduced or stopped.
Mechanism Target:
Atopic Inflammation with Hyper-IgE and Eosinophilia — Blocks IL-4 and IL-13 signalling that drives the Th2 atopic inflammation.
Show evidence (2 references)
PMID:38231347 SUPPORT Human Clinical
"All six patients had rapid and sustained improvement in atopic symptoms with no complications during the follow-up period. Previous medications used to treat atopy were able to be decreased or discontinued."
Clinical response to biologic therapy.
PMID:35651609 SUPPORT Human Clinical
"So far, one patient is under treatment with dupilumab, which has shown marked benefit in controlling severe eczema."
Independent report of dupilumab benefit.
Omalizumab
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: omalizumab NCIT:C29299 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses omalizumab (NCIT:C29299). NCIT:C29299 is a therapeutic agent from the NCI Thesaurus.
Platform: Monoclonal antibody
Anti-IgE monoclonal antibody used for chronic spontaneous urticaria in one adult with CADINS, with rapid sustained improvement.
Target Phenotypes: Chronic spontaneous urticaria HP:0001025 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Chronic spontaneous urticaria, annotated with Urticaria (HP:0001025). HP:0001025 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38231347 SUPPORT Human Clinical
"Subcutaneous dupilumab was initiated to treat atopic dermatitis and omalizumab to treat chronic spontaneous urticaria."
Indication for omalizumab in the series.
Glutamine supplementation (investigational)
Action: Dietary supplementationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Dietary supplementation, annotated with Dietary Intervention (NCIT:C15447). NCIT:C15447 is a clinical intervention from the NCI Thesaurus. Ontology label: Dietary Intervention NCIT:C15447
Agent: glutamine CHEBI:28300 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses glutamine (CHEBI:28300). CHEBI:28300 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Glutamine requires CARD11 for import into T cells; supplementation partially rescued the mTORC1 and IFN-gamma production defects of patient T cells in vitro, suggesting a correctable cellular defect.
Mechanism Target:
Attenuated NF-kB, JNK and mTORC1 Signaling Downstream of the Antigen Receptor — Bypasses the CARD11-dependent glutamine import deficit that limits mTORC1 activation.
Show evidence (1 reference)
PMID:28628108 SUPPORT In Vitro
"The mTORC1 and IFN-γ production defects were partially rescued by supplementation with glutamine, which requires CARD11 for import into T cells."
In vitro rescue.
Infection management and HPV vaccination
Action: VaccinationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Vaccination (NCIT:C15346). NCIT:C15346 is a clinical intervention from the NCI Thesaurus. NCIT:C15346
Platform: Vaccine
Treatment of recurrent respiratory, cutaneous and viral infections; HPV vaccination in adolescence and cytology screening are recommended given HPV-associated carcinoma in CADINS.
Show evidence (1 reference)
PMID:35651609 SUPPORT Human Clinical
"HPV vaccination in teenage years, and cytology screening analogous with routine cervical swabs may be recommended."
Malignancy prevention recommendation.
Genetic counseling
Action: Genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Autosomal dominant counselling with variable penetrance and expressivity; functional assays are needed to classify variants in relatives.
Show evidence (1 reference)
PMID:36405754 SUPPORT Human Clinical
"Family segregation studies expanded to 15 individuals the number of patients presenting CARD11-associated disease."
Cascade testing in families.
Immunoglobulin replacement therapy
Action: Immunoglobulin replacement therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Immunoglobulin replacement therapy, annotated with Immunoglobulin Therapy (NCIT:C62710). NCIT:C62710 is a clinical intervention from the NCI Thesaurus. Ontology label: Immunoglobulin Therapy NCIT:C62710
Platform: Protein replacement
About half of one CADINS cohort had humoral defects requiring immunoglobulin replacement, which reduces infection frequency, and it is standard bridging care where a combined immunodeficiency is present.
Show evidence (1 reference)
PMID:36405754 SUPPORT Human Clinical
"Five patients required immunoglobulin replacement therapy, 4 of whom belong to the same family (family 8), due to recurrent respiratory infections, lung damage and/or impaired antibody-mediated immunity."
Immunoglobulin replacement for the humoral defect.
Topical corticosteroids and calcineurin inhibitors
Action: Topical corticosteroid therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Topical corticosteroid therapy (NCIT:C122078). NCIT:C122078 is a clinical intervention from the NCI Thesaurus. Ontology label: Topical Corticosteroid Therapy NCIT:C122078
Platform: Small molecule
Skin-directed topical corticosteroids and calcineurin inhibitors are the mainstay of atopic dermatitis management before or alongside systemic biologics.
Show evidence (1 reference)
PMID:40625738 SUPPORT Other
"Topical corticosteroids and calcineurin inhibitors are standard dermatologic treatments."
Standard skin-directed therapy for the atopic dermatitis.
🔬

Diagnosis

2
Sequencing with functional validation of CARD11 variants
Next-generation sequencing identifies heterozygous CARD11 variants; a T-cell transfection NF-kB reporter assay distinguishes dominant-negative from gain-of-function and neutral variants and is required for diagnosis.
Show evidence (2 references)
PMID:38231347 SUPPORT Human Clinical
"CARD11 mutations were validated for pathogenicity using a T cell transfection assay to assess the impact on activation-induced signaling to NF-κB."
Functional validation assay.
PMID:36405754 SUPPORT Human Clinical
"Identification of novel CARD11 variants required functional studies to validate their pathogenic activity."
Functional studies as a diagnostic requirement.
Immunological evaluation
Serum IgE, eosinophil count, immunoglobulins, lymphocyte subsets including Tregs, and mitogen/antigen proliferation with IFN-gamma and IL-2 production.
Show evidence (1 reference)
PMID:28826773 SUPPORT Human Clinical
"We performed whole-exome sequencing, followed by Sanger confirmation, assessment of the genetic variant effect on cell signaling, and evaluation of the resultant immune function."
Diagnostic work-up.
📈

Progression

1
Infantile-onset atopy with variable improvement
Atopic disease begins in infancy or early childhood; in the founding cohort disease improved over time in most patients, while others have lifelong severe eczema, infections and, in adulthood, malignancy.
Show evidence (2 references)
PMID:28628108 SUPPORT Human Clinical
"Disease improved over time in most patients."
Natural history in the founding cohort.
PMID:38231347 SUPPORT Human Clinical
"All developed atopic disease in infancy or early childhood."
Onset timing.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
Tens of patients reported since the 2017 description of eight individuals from four families; a single Argentine centre described ten CADINS patients, and the condition is thought to be under-recognised because it overlaps common atopic disease.
Show evidence (2 references)
PMID:28628108 SUPPORT Human Clinical
"Through next-generation sequencing on a cohort of patients with severe atopic dermatitis with and without comorbid infections, we found eight individuals, from four families, with novel heterozygous mutations in CARD11, which encodes a scaffolding protein involved in lymphocyte receptor signaling."
Founding cohort size.
PMID:40625738 SUPPORT Other
"CARD11-associated diseases may be more prevalent than previously recognized due to their clinical overlap with atopic and hematological syndromic disorders."
Under-recognition.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Immunodeficiency 11B with Atopic Dermatitis:

STAT3 loss-of-function and DOCK8 deficiency hyper-IgE syndromes
Overlapping Features Heterozygous CARD11 variants can mimic STAT3-LOF, DOCK8 deficiency, CVID, neutropenia and IPEX-like presentations, so CARD11 should be included in hyper-IgE and primary atopic disorder gene panels.
Distinguishing Features
  • Heterozygous dominant-negative CARD11 variant with reduced antigen receptor-induced NF-kB activation
  • Absence of the STAT3-LOF skeletal/dental features or DOCK8 lymphopenia
Show evidence (1 reference)
PMID:30170123 SUPPORT Human Clinical
"heterozygous missense and indel mutations in CARD11 presented with immunologic phenotypes similar to those observed in signal transducer and activator of transcription 3 loss of function, dedicator of cytokinesis 8 deficiency, common variable immunodeficiency, neutropenia, and immune..."
Phenocopies to consider.
Severe combined immunodeficiency due to CARD11 deficiency MONDO:0014081
Overlapping Features The biallelic null allelic disorder produces profound combined immunodeficiency without atopy.
Distinguishing Features
  • Biallelic null alleles, profound CID, Pneumocystis pneumonia, absent germinal centres
Show evidence (1 reference)
PMID:28826773 SUPPORT Human Clinical
"Unlike patients with biallelic mutations in CARD11 causing severe CID, the R30W defect results in a less profound yet prominent susceptibility to infections, as well as multiorgan atopy and autoimmunity."
Contrast with the recessive disorder.
BENTA disease (CARD11 gain of function)
Overlapping Features Heterozygous gain-of-function CARD11 variants cause B-cell expansion with NF-kB and T-cell anergy, with spontaneous cytoplasmic CARD11 aggregation and a lymphoproliferative rather than atopic phenotype; the functional assay separates the two.
Distinguishing Features
  • Polyclonal B lymphocytosis and lymphoproliferation
  • Increased rather than decreased NF-kB activity and spontaneous CARD11 aggregation
Show evidence (1 reference)
PMID:36405754 SUPPORT Human Clinical
"Altogether, four variants showed a GOF effect as well a spontaneous aggregation in the cytoplasm, leading to B cell expansion with NF-κB and T cell anergy (BENTA) diagnosis."
Functional distinction from BENTA.
🧫

Experimental Models

1
Patient T cells and transfected T-cell lines expressing CADINS variants CELL_LINE
Transfection of patient CARD11 variants into T-cell lines with NF-kB, mTORC1 and JNK reporters, and primary patient T cells, define dominant interference, GATA3 induction and glutamine rescue.
T cell CL:0000084 Cell Ontology (CL) Relation: this experimental model uses this cell type This experimental model uses T cell (CL:0000084). CL:0000084 is a cell type from the Cell Ontology.
Organism
human NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in human, annotated with Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Publication
PMID:28628108
Pathograph links
Attenuated NF-kB, JNK and mTORC1 Signaling Downstream of the Antigen Receptor recapitulates fidelity: high observes: cellular Patient T cells and variant-transfected lines reproduce the attenuated signalling and its partial glutamine rescue.
Show evidence (1 reference)
PMID:28628108 SUPPORT In Vitro
"Patient T cells had similar defects, as well as low production of the cytokine interferon-γ (IFN-γ)."
Patient-cell concordance with the transfection assays.
🐁

Animal Models

1
CARD11 R30W/+ mouse
Mice heterozygous for the patient R30W allele have impaired CARD11 signalling with T-, B- and NK-cell functional defects and immunodeficiency, age-dependent elevated IgE with 50% penetrance, reduced regulatory T cells and selective loss of NK IFN-gamma production, but no spontaneous atopic dermatitis and no Th2 expansion.
Species
Mouse
Genotype
Card11 p.Arg30Trp heterozygous knock-in (patient allele)
Publication
PMID:34341167
Pathograph links
Partial T-Cell, Regulatory T-Cell and NK-Cell Dysfunction recapitulates fidelity: moderate observes: cellular Reproduces the multi-lineage signalling and functional defects, including Treg reduction and NK IFN-gamma loss.
Limitations: Mixed oligomers impair T cells more than B cells and the model lacks the human Th2 expansion.
Readouts
Regulatory T cell numbers and NK IFN-gamma production
Direction: DECREASED
Interpretation: Lineage-specific functional readouts of impaired CARD11 signalling.
Show evidence (1 reference)
PMID:34341167 SUPPORT Model Organism
"CARD11R30W/+ mice display reduced regulatory T cell numbers, but not the Th2 expansion observed in other mice with diminished CARD11 activity. Interestingly, the presence of mixed CARD11 oligomers in CARD11R30W/+ mice causes more severe signaling defects in T cells than in B cells, and..."
Reports the readouts.
Show evidence (1 reference)
PMID:34341167 SUPPORT Model Organism
"We find that CARD11R30W/+ mice exhibit impaired signaling downstream of CARD11 that leads to defects in T, B, and NK cell function and immunodeficiency."
Establishes the model's immunodeficiency phenotype.
Atopic Inflammation with Hyper-IgE and Eosinophilia partially recapitulates fidelity: low observes: organism Elevated IgE develops with age and incomplete penetrance, but spontaneous atopic dermatitis does not.
Limitations: No spontaneous atopic dermatitis and no Th2 expansion, so the atopic tissue phenotype of patients is not reproduced; high IgE alone was insufficient for overt atopy.
Readouts
Serum IgE
Direction: INCREASED
Interpretation: Age-dependent, 50%-penetrant IgE elevation.
Show evidence (1 reference)
PMID:34341167 SUPPORT Model Organism
"CARD11R30W/+ mice develop elevated serum IgE levels with 50% penetrance that becomes more pronounced with age, but do not develop spontaneous atopic dermatitis."
Reports the IgE readout and the missing dermatitis.
Show evidence (1 reference)
PMID:34341167 SUPPORT Model Organism
"Our findings help explain the high susceptibility of CADINS patients to infection and suggest that the development of high serum IgE is not sufficient to induce overt atopic symptoms."
Authors' interpretation of the partial recapitulation.
{ }

Source YAML

click to show 
name: Immunodeficiency 11B with Atopic Dermatitis
category: Genetic
creation_date: "2026-09-05T16:30:00Z"
synonyms:
- CADINS disease
- CARD11-associated atopy with dominant interference of NF-kB signaling
- IMD11B
- Atopic dermatitis, elevated IgE, and eosinophilia (CARD11)
- Dominant-negative CARD11 deficiency
- Hypomorphic CARD11 atopic disease
description: >
  Immunodeficiency 11B with atopic dermatitis (IMD11B; OMIM #617638), known clinically as
  CADINS (CARD11-associated atopy with dominant interference of NF-kB signalling), is an
  autosomal dominant primary atopic disorder caused by heterozygous loss-of-function
  CARD11 variants that act as dominant negatives. CARD11 is the antigen receptor-proximal
  scaffold that assembles the CARD11-BCL10-MALT1 complex and drives NF-kB, JNK and mTORC1
  signalling in lymphocytes; CADINS variants, largely confined to the CARD and coiled-coil
  domains, poison mixed wild-type:mutant oligomers at the opening and cofactor-association
  steps of the signalling cycle, attenuating all three pathways. Patient T cells proliferate
  poorly, produce little IFN-gamma and IL-2, import glutamine inefficiently, and, because
  loss of CARD11-JNK signalling de-represses GATA3 and NFATC1, differentiate toward Th2;
  regulatory T cells are reduced and NK cells show altered homeostasis. The result is severe
  early-onset atopic dermatitis with markedly elevated IgE and eosinophilia, asthma, food
  allergy and urticaria, combined with a partial combined immunodeficiency (recurrent
  respiratory, cutaneous and viral infections, hypogammaglobulinaemia in some), autoimmunity,
  neutropenia, colitis and, rarely, HPV-related carcinoma or lymphoma; penetrance and
  expressivity vary even within families, and the phenotype overlaps STAT3- and DOCK8-related
  hyper-IgE syndromes. Atopy improves with age in many patients and responds to dupilumab and
  omalizumab; glutamine supplementation partially rescues the T-cell defects in vitro. The
  biallelic null (IMD11A) and gain-of-function (BENTA) CARD11 disorders are distinct allelic
  entities.
disease_term:
  preferred_term: Immunodeficiency 11B with atopic dermatitis
  term:
    id: MONDO:0054697
    label: immunodeficiency 11b with atopic dermatitis
parents:
- MONDO:0021094
classifications:
  iuis_category:
    classification_value: combined immunodeficiency with syndromic features
    notes: >-
      IUIS classification groups dominant-negative CARD11 disease with the hyper-IgE
      syndromes (Table 2, CID with associated or syndromic features), reflecting the
      combination of partial T-cell deficiency with severe atopy and elevated IgE.
  harrisons_chapter:
  - classification_value: IMMUNE_RHEUMATOLOGIC
  - classification_value: DERMATOLOGY
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Tens of patients reported since the 2017 description of eight individuals from four
    families; a single Argentine centre described ten CADINS patients, and the condition is
    thought to be under-recognised because it overlaps common atopic disease.
  evidence:
  - reference: PMID:28628108
    reference_title: "Germline hypomorphic CARD11 mutations in severe atopic disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Through next-generation sequencing on a cohort of patients with severe atopic dermatitis with and without comorbid infections, we found eight individuals, from four families, with novel heterozygous mutations in CARD11, which encodes a scaffolding protein involved in lymphocyte receptor signaling."
    explanation: Founding cohort size.
  - reference: PMID:40625738
    reference_title: "From syndromic clues to diagnosis: understanding CARD11-driven disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "CARD11-associated diseases may be more prevalent than previously recognized due to their clinical overlap with atopic and hematological syndromic disorders."
    explanation: Under-recognition.
progression:
- phase: Infantile-onset atopy with variable improvement
  notes: >-
    Atopic disease begins in infancy or early childhood; in the founding cohort disease
    improved over time in most patients, while others have lifelong severe eczema,
    infections and, in adulthood, malignancy.
  evidence:
  - reference: PMID:28628108
    reference_title: "Germline hypomorphic CARD11 mutations in severe atopic disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Disease improved over time in most patients."
    explanation: Natural history in the founding cohort.
  - reference: PMID:38231347
    reference_title: "Management of Atopy with Dupilumab and Omalizumab in CADINS Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All developed atopic disease in infancy or early childhood."
    explanation: Onset timing.
genetic:
- name: CARD11
  gene_term:
    preferred_term: CARD11
    term:
      id: hgnc:16393
      label: CARD11
  relationship_type: CAUSATIVE
  notes: >
    Heterozygous missense and small in-frame indel variants that retain expression but act as
    dominant negatives, largely confined to the CARD and coiled-coil domains; some arise de
    novo. Functional testing (NF-kB reporter assays in transfected T cells) is required to
    classify novel variants because rare CARD11 variants of neutral effect occur, and the
    same functional assay separates dominant-negative (CADINS) from gain-of-function
    (BENTA) alleles.
  variants:
  - name: c.88C>T (p.Arg30Trp)
    description: >
      Founding dominant-negative variant segregating with severe atopy in a four-member
      family; loss of function with dominant-negative effect on wild-type CARD11, modelled
      in the CARD11 R30W/+ mouse.
    type: missense
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:28826773
      reference_title: "Combined immunodeficiency and atopy caused by a dominant negative mutation in caspase activation and recruitment domain family member 11 (CARD11)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "A heterozygous novel c.C88T 1-bp substitution resulting in amino acid change R30W in caspase activation and recruitment domain family member 11 (CARD11) was identified by using whole-exome sequencing and segregated perfectly to family members with severe atopy only but was not found in healthy subjects."
      explanation: Identification, segregation and dominant-negative demonstration.
  - name: c.169G>A (p.Glu57Lys)
    description: De novo heterozygous variant in a boy with severe atopic dermatitis, food-induced anaphylaxis and hypogammaglobulinaemia; dominant-negative effect confirmed on CD4+ and CD8+ T cells.
    type: missense
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:37086690
      reference_title: "CARD11 dominant negative mutation leads to altered human Natural Killer cell homeostasis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We report on a 12-year-old boy with severe atopic dermatitis, food induced anaphylaxis and hypogammaglobulinemia harbouring a novel de novo heterozygous variant c.169G > A; p.Glu57Lys in CARD11. The dominant negative effect of this mutation was confirmed on both CD4+ and CD8+."
      explanation: De novo variant with functional confirmation.
  - name: c.223C>T (p.Arg75Trp)
    description: Dominant-negative variant in a family with severe atopy, hypogammaglobulinaemia and intermittent agranulocytosis in the proband, and HPV-positive squamous cell carcinoma and cutaneous T-cell lymphoma across two generations.
    type: missense
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:35651609
      reference_title: "Hyper-IgE and Carcinoma in CADINS Disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "was identified. Functional studies confirmed this variant to have a dominant negative (DN) effect, as previously described in patients with CADINS."
      explanation: Variant and functional confirmation.
  - name: c.2324C>T (p.Ser775Leu)
    description: De novo dominant-negative variant in the MAGUK region, outside the CARD and coiled-coil domains where most CADINS alleles cluster, in a Chinese girl with periodic fever, recurrent infections and eczema.
    type: missense
    clinical_significance: LIKELY_PATHOGENIC
    evidence:
    - reference: PMID:39414811
      reference_title: "A new-disease-causing dominant-negative variant in CARD11 gene in a Chinese case with recurrent fever."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Luciferase reporter assays and co-immunoprecipitation demonstrated mutation exerts a dominant-interfering effect on wild-type CARD11, inhibiting the activity of NF-κB."
      explanation: Functional demonstration of dominant interference by the S775L allele.
    - reference: PMID:39414811
      reference_title: "A new-disease-causing dominant-negative variant in CARD11 gene in a Chinese case with recurrent fever."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "A very rare missense mutation (c.2324C > T, p.S775L) in CARD11 gene (NM_032415) was identified by WES in the patient but not her parents."
      explanation: De novo occurrence in the proband.
  evidence:
  - reference: PMID:30170123
    reference_title: "Hypomorphic caspase activation and recruitment domain 11 (CARD11) mutations associated with diverse immunologic phenotypes with or without atopic disease."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Pathogenic variants exhibited dominant negative activity and were largely confined to the CARD or coiled-coil domains of the CARD11 protein."
    explanation: Domain distribution of pathogenic alleles.
  - reference: PMID:36405754
    reference_title: "Expanding spectrum, intrafamilial diversity, and therapeutic challenges from 15 patients with heterozygous CARD11-associated diseases: A single center experience."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additional four variants showing a LOF activity were considered as causative of CARD11-associated atopy with dominant interference of NF-kB signaling (CADINS). The remaining variant exhibited a neutral functional assay excluding its carrier from further analysis."
    explanation: Need for functional classification of variants.
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: INCOMPLETE
  expressivity: VARIABLE
  description: >
    Autosomal dominant with variable penetrance and expressivity, including within multiplex
    families; de novo variants occur.
  evidence:
  - reference: PMID:38311684
    reference_title: "Epidermodysplasia Verruciformis in CADINS Disease: Expanding the Phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CARD11-associated atopy with dominant interference of NF-κB signaling (CADINS) disease occurs in humans carrying a dominant negative (DN), loss of function (LOF) mutation in CARD11. Despite variable penetrance and expressivity, this disease is typically characterized by severe atopy with aspects of combined immunodeficiency, including recurrent respiratory and cutaneous viral infections, hypogammaglobulinemia, and other symptoms"
    explanation: Dominant inheritance with variable penetrance.
  - reference: PMID:36405754
    reference_title: "Expanding spectrum, intrafamilial diversity, and therapeutic challenges from 15 patients with heterozygous CARD11-associated diseases: A single center experience."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A remarkable variability of disease expression was clearly noted among BENTA as well as in CADINS patients, even within multiplex families."
    explanation: Intrafamilial variability.
pathophysiology:
- name: Heterozygous Dominant-Negative CARD11 Variant
  description: >
    A single hypomorphic CARD11 allele, expressed alongside the wild-type protein, exerts a
    dominant-interfering effect because CARD11 signals as an oligomer; the variant protein is
    loss-of-function on its own and additionally suppresses wild-type CARD11 when co-expressed.
  biological_scale: MOLECULAR
  downstream:
  - target: Oligomer Poisoning of the CARD11 Signaling Cycle
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:35198875
      reference_title: "Mechanistic impact of oligomer poisoning by dominant-negative CARD11 variants."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "We find that strong dominant negatives can poison signaling from mixed wild-type:mutant oligomers at two steps in the CARD11 signaling cycle, at the Opening Step and at the Cofactor Association Step."
      explanation: Mechanism by which a heterozygous variant dominates.
  evidence:
  - reference: PMID:28826773
    reference_title: "Combined immunodeficiency and atopy caused by a dominant negative mutation in caspase activation and recruitment domain family member 11 (CARD11)."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We demonstrate that the R30W mutation results in loss of function while also exerting a dominant negative effect on wild-type CARD11."
    explanation: Dominant-negative demonstration.
  - reference: PMID:28628108
    reference_title: "Germline hypomorphic CARD11 mutations in severe atopic disease."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Transfection of mutant CARD11 expression constructs into T cell lines demonstrated both loss-of-function and dominant-interfering activity upon antigen receptor-induced activation of nuclear factor-κB and mammalian target of rapamycin complex 1 (mTORC1)."
    explanation: Loss-of-function plus dominant interference in the founding study.
- name: Oligomer Poisoning of the CARD11 Signaling Cycle
  description: >
    Mixed wild-type:mutant CARD11 oligomers fail at the opening step, in which the inhibitory
    domain's repressive elements are neutralised, and at the cofactor-association step, so
    that antigen receptor engagement no longer converts the scaffold to its active state.
  biological_scale: MOLECULAR
  downstream:
  - target: Attenuated NF-kB, JNK and mTORC1 Signaling Downstream of the Antigen Receptor
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:35198875
    reference_title: "Mechanistic impact of oligomer poisoning by dominant-negative CARD11 variants."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Our findings provide evidence that CARD11 oligomer subunits cooperate in at least two steps during antigen receptor signaling and reveal how different LOF mutations in the same oligomeric signaling hub may cause disease with different inheritance patterns."
    explanation: Explains dominant versus recessive inheritance of CARD11 loss of function.
- name: Attenuated NF-kB, JNK and mTORC1 Signaling Downstream of the Antigen Receptor
  description: >
    Antigen receptor-induced canonical NF-kB activation, JNK/AP-1 signalling and mTORC1
    activation are all reduced in patient T cells and in cells expressing patient variants;
    the mTORC1 defect reflects impaired CARD11-dependent glutamine import and is partially
    rescued by glutamine supplementation.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  biological_processes:
  - preferred_term: canonical NF-kappaB signal transduction
    term:
      id: GO:0007249
      label: canonical NF-kappaB signal transduction
    modifier: DECREASED
  - preferred_term: JNK cascade
    term:
      id: GO:0007254
      label: JNK cascade
    modifier: DECREASED
  - preferred_term: TORC1 signaling
    term:
      id: GO:0038202
      label: TORC1 signaling
    modifier: DECREASED
  - preferred_term: T cell receptor signaling pathway
    term:
      id: GO:0050852
      label: T cell receptor signaling pathway
    modifier: DECREASED
  downstream:
  - target: Th2 Skewing via Loss of JNK-Dependent GATA3 Repression
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:40111223
      reference_title: "Dominant interfering CARD11 variants disrupt JNK signaling to promote GATA3 expression in T cells."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Transcriptome profiling revealed JNK inhibition upregulated TCR-induced expression of GATA3 and NFATC1, key transcription factors for TH2 cell development."
      explanation: JNK loss de-represses Th2 transcription factors.
  - target: Partial T-Cell, Regulatory T-Cell and NK-Cell Dysfunction
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:28826773
      reference_title: "Combined immunodeficiency and atopy caused by a dominant negative mutation in caspase activation and recruitment domain family member 11 (CARD11)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The CARD11 defect altered the classical nuclear factor κB pathway, resulting in poor in vitro T-cell responses to mitogens and antigens caused by reduced secretion of IFN-γ and IL-2."
      explanation: Signalling defect produces the T-cell functional defect.
  evidence:
  - reference: PMID:30170123
    reference_title: "Hypomorphic caspase activation and recruitment domain 11 (CARD11) mutations associated with diverse immunologic phenotypes with or without atopic disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Caspase activation and recruitment domain 11 (CARD11) encodes a scaffold protein in lymphocytes that links antigen receptor engagement with downstream signaling to nuclear factor κB, c-Jun N-terminal kinase, and mechanistic target of rapamycin complex 1."
    explanation: The three pathways downstream of CARD11.
  - reference: PMID:28628108
    reference_title: "Germline hypomorphic CARD11 mutations in severe atopic disease."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The mTORC1 and IFN-γ production defects were partially rescued by supplementation with glutamine, which requires CARD11 for import into T cells."
    explanation: Glutamine-import basis of the mTORC1 defect.
  - reference: PMID:40111223
    reference_title: "Dominant interfering CARD11 variants disrupt JNK signaling to promote GATA3 expression in T cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Here we show that CARD11 is critical for TCR-induced activation of JNK1 and JNK2, as well as canonical JUN/FOS AP-1 family members. Patient-derived CARD11 DI variants attenuated WT CARD11 JNK signaling, mirroring effects on NF-κB."
    explanation: JNK arm of the defect.
- name: Th2 Skewing via Loss of JNK-Dependent GATA3 Repression
  description: >
    Attenuated TCR signalling favours Th2 differentiation, a shared mechanism of the primary
    atopic disorders; in CADINS the loss of CARD11-JNK signalling specifically up-regulates
    GATA3 and NFATC1 in patient T cells, and patients show diminished IFN-gamma with
    increased IL-4 production.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: T-helper 2 cell
    term:
      id: CL:0000546
      label: T-helper 2 cell
  biological_processes:
  - preferred_term: T-helper 2 cell differentiation
    term:
      id: GO:0045064
      label: T-helper 2 cell differentiation
    modifier: INCREASED
  - preferred_term: interferon-gamma production
    term:
      id: GO:0032609
      label: type II interferon production
    modifier: DECREASED
  downstream:
  - target: Atopic Inflammation with Hyper-IgE and Eosinophilia
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:40111223
    reference_title: "Dominant interfering CARD11 variants disrupt JNK signaling to promote GATA3 expression in T cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Further, impaired CARD11-JNK signaling was linked to enhanced GATA3 expression in CADINS patient T cells. Our findings reveal a novel intrinsic mechanism connecting impaired CARD11-dependent JNK signaling to enhanced GATA3/NFAT2 induction and TH2 cell differentiation in CADINS patients."
    explanation: Patient-cell demonstration of the Th2 mechanism.
  - reference: PMID:35651609
    reference_title: "Hyper-IgE and Carcinoma in CADINS Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Partial T-cell deficiency, diminished IFN-γ cytokine and increased IL-4 production, were identified as disease-causing mechanisms."
    explanation: Cytokine skew in patients.
- name: Partial T-Cell, Regulatory T-Cell and NK-Cell Dysfunction
  description: >
    T cells respond poorly to mitogens and antigens with reduced IFN-gamma and IL-2;
    CTLA4+FOXP3+ regulatory T cells are reduced; NK cells show reduced NKp46, NKG2D and CD69,
    impaired IFN-gamma production by CD56bright cells and paradoxically increased steady-state
    pS6, so that the effect of the variant on mTORC1 differs between T and NK cells. These
    defects underlie the recurrent respiratory, cutaneous and viral infections, reduced
    immune surveillance and autoimmunity.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: regulatory T cell
    term:
      id: CL:0000815
      label: regulatory T cell
  - preferred_term: natural killer cell
    term:
      id: CL:0000623
      label: natural killer cell
  biological_processes:
  - preferred_term: T cell activation
    term:
      id: GO:0042110
      label: T cell activation
    modifier: DECREASED
  - preferred_term: interleukin-2 production
    term:
      id: GO:0032623
      label: interleukin-2 production
    modifier: DECREASED
  downstream:
  - target: Recurrent respiratory infections
    causal_link_type: DIRECT
  - target: Recurrent viral infections
    causal_link_type: DIRECT
  - target: Recurrent skin infections
    causal_link_type: DIRECT
  - target: Decreased circulating immunoglobulin concentration
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Autoimmunity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Decreased regulatory T cell proportion
    causal_link_type: DIRECT
  - target: Squamous cell carcinoma
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:37086690
    reference_title: "CARD11 dominant negative mutation leads to altered human Natural Killer cell homeostasis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CTLA4+Foxp3+CD4+ Tregs were severely reduced. Patient's NK cells showed reduced expression of NKp46, NKG2D and CD69. Patient's CD56bright NK cells showed in vitro impaired production of IFN-γ."
    explanation: Treg and NK findings.
  - reference: PMID:37086690
    reference_title: "CARD11 dominant negative mutation leads to altered human Natural Killer cell homeostasis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Overall, the effect of CARD11 mutation on mTORC1 differs between T and NK cells. These findings may explain the increased susceptibility to viral infections and the reduced immune surveillance in affected patients."
    explanation: Link to infection susceptibility and surveillance.
  - reference: PMID:34341167
    reference_title: "Pathway-Specific Defects in T, B, and NK Cells and Age-Dependent Development of High IgE in Mice Heterozygous for a CADINS-Associated Dominant Negative CARD11 Allele."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We find that CARD11R30W/+ mice exhibit impaired signaling downstream of CARD11 that leads to defects in T, B, and NK cell function and immunodeficiency."
    explanation: Mouse confirmation of multi-lineage functional defects.
- name: Atopic Inflammation with Hyper-IgE and Eosinophilia
  description: >
    Th2-skewed T cells drive severe, early-onset atopic dermatitis, asthma, food allergy and
    chronic urticaria with markedly elevated IgE and eosinophilia; IgE elevation develops with
    age and is not by itself sufficient for overt atopic symptoms in the mouse model.
  biological_scale: ORGANISM
  biological_processes:
  - preferred_term: immunoglobulin production
    term:
      id: GO:0002377
      label: immunoglobulin production
    modifier: DYSREGULATED
  downstream:
  - target: Atopic dermatitis
    causal_link_type: DIRECT
  - target: Increased circulating IgE concentration
    causal_link_type: DIRECT
  - target: Increased total eosinophil count
    causal_link_type: DIRECT
  - target: Asthma
    causal_link_type: DIRECT
  - target: Food allergy
    causal_link_type: DIRECT
  - target: Urticaria
    causal_link_type: DIRECT
  - target: Anaphylactic shock
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:36334349
    reference_title: "Elevated IgE from attenuated CARD11 signaling: lessons from atopic mice and humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most recently, severe atopic patients were discovered that carried heterozygous dominant-negative CARD11 mutations."
    explanation: Review linking attenuated CARD11 signalling to severe atopy in humans.
  - reference: PMID:38231347
    reference_title: "Management of Atopy with Dupilumab and Omalizumab in CADINS Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with CADINS suffer with severe atopic manifestations including atopic dermatitis, food allergy, and chronic spontaneous urticaria in addition to recurrent infections and autoimmunity."
    explanation: Atopic spectrum.
  - reference: PMID:34341167
    reference_title: "Pathway-Specific Defects in T, B, and NK Cells and Age-Dependent Development of High IgE in Mice Heterozygous for a CADINS-Associated Dominant Negative CARD11 Allele."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Our findings help explain the high susceptibility of CADINS patients to infection and suggest that the development of high serum IgE is not sufficient to induce overt atopic symptoms."
    explanation: IgE alone is insufficient for atopy in the mouse.
phenotypes:
- name: Atopic dermatitis
  category: Dermatological
  frequency: VERY_FREQUENT
  description: Severe, early-onset atopic dermatitis, often recalcitrant to standard topical and systemic therapy.
  phenotype_term:
    preferred_term: Severe atopic dermatitis
    term:
      id: HP:0001047
      label: Atopic dermatitis
    onset:
      onset_category: INFANTILE
      mean_age_years: 0.49
      notes: Mean age of onset was 5.9 months in a 10-patient CADINS cohort.
  evidence:
  - reference: PMID:38231347
    reference_title: "Management of Atopy with Dupilumab and Omalizumab in CADINS Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In five patients, atopic dermatitis was severe and recalcitrant to standard topical and systemic medications; one adult suffered from chronic spontaneous urticaria."
    explanation: Severity of atopic dermatitis.
  - reference: PMID:28628108
    reference_title: "Germline hypomorphic CARD11 mutations in severe atopic disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our findings indicate that a single hypomorphic mutation in CARD11 can cause potentially correctable cellular defects that lead to atopic dermatitis."
    explanation: Atopic dermatitis as the founding phenotype.
- name: Increased circulating IgE concentration
  category: Laboratory
  frequency: VERY_FREQUENT
  description: Markedly elevated serum IgE, placing CADINS among the hyper-IgE syndromes.
  phenotype_term:
    preferred_term: Elevated serum IgE
    term:
      id: HP:0003212
      label: Increased circulating IgE concentration
  evidence:
  - reference: PMID:35651609
    reference_title: "Hyper-IgE and Carcinoma in CADINS Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "When severe or recurrent infections and exceedingly elevated serum IgE levels occur in AD patients, an inborn error of immunity (IEI) may be suspected."
    explanation: Hyper-IgE context of the diagnosis.
  - reference: PMID:34341167
    reference_title: "Pathway-Specific Defects in T, B, and NK Cells and Age-Dependent Development of High IgE in Mice Heterozygous for a CADINS-Associated Dominant Negative CARD11 Allele."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "CARD11R30W/+ mice develop elevated serum IgE levels with 50% penetrance that becomes more pronounced with age, but do not develop spontaneous atopic dermatitis."
    explanation: Age-dependent IgE elevation reproduced in the mouse.
- name: Increased total eosinophil count
  category: Laboratory
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Eosinophilia
    term:
      id: HP:0001880
      label: Increased total eosinophil count
  evidence:
  - reference: PMID:35651609
    reference_title: "Hyper-IgE and Carcinoma in CADINS Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report on an 18-year-old patient with a long-standing history of infections, accompanied by hypogammaglobulinemia, intermittent agranulocytosis, atopy, eosinophilia and colitis."
    explanation: Eosinophilia in the proband.
- name: Asthma
  category: Respiratory
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Early-onset asthma
    term:
      id: HP:0002099
      label: Asthma
  evidence:
  - reference: PMID:28826773
    reference_title: "Combined immunodeficiency and atopy caused by a dominant negative mutation in caspase activation and recruitment domain family member 11 (CARD11)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We sought to identify the genetic aberration in 4 related patients with CID, early-onset asthma, eczema, and food allergies, as well as autoimmunity."
    explanation: Asthma in the founding family.
- name: Food allergy
  category: Immunological
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Food allergy
    term:
      id: HP:0500093
      label: Food allergy
  evidence:
  - reference: PMID:28826773
    reference_title: "Combined immunodeficiency and atopy caused by a dominant negative mutation in caspase activation and recruitment domain family member 11 (CARD11)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "4 related patients with CID, early-onset asthma, eczema, and food allergies, as well as autoimmunity"
    explanation: Food allergy in the founding family.
- name: Anaphylactic shock
  category: Immunological
  frequency: OCCASIONAL
  description: Food-induced anaphylaxis.
  phenotype_term:
    preferred_term: Food-induced anaphylaxis
    term:
      id: HP:0100845
      label: Anaphylactic shock
  evidence:
  - reference: PMID:37086690
    reference_title: "CARD11 dominant negative mutation leads to altered human Natural Killer cell homeostasis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report on a 12-year-old boy with severe atopic dermatitis, food induced anaphylaxis and hypogammaglobulinemia"
    explanation: Anaphylaxis in a reported patient.
- name: Urticaria
  category: Dermatological
  frequency: OCCASIONAL
  description: Chronic spontaneous urticaria.
  phenotype_term:
    preferred_term: Chronic spontaneous urticaria
    term:
      id: HP:0001025
      label: Urticaria
  evidence:
  - reference: PMID:38231347
    reference_title: "Management of Atopy with Dupilumab and Omalizumab in CADINS Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "one adult suffered from chronic spontaneous urticaria"
    explanation: Urticaria in an adult patient.
- name: Recurrent respiratory infections
  category: Infectious
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Recurrent respiratory infections
    term:
      id: HP:0002205
      label: Recurrent respiratory infections
  evidence:
  - reference: PMID:30170123
    reference_title: "Hypomorphic caspase activation and recruitment domain 11 (CARD11) mutations associated with diverse immunologic phenotypes with or without atopic disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition to atopic disease (89%), significant viral skin infections (68%) and lung disease (e.g. infections, pneumonia, bronchiectasis) (68%) were the most prominent symptoms shared by patients harboring DN CARD11 mutations (Table 2)."
    explanation: Lung disease including infections in 68% of the dominant-negative CARD11 cohort.
  - reference: PMID:34341167
    reference_title: "Pathway-Specific Defects in T, B, and NK Cells and Age-Dependent Development of High IgE in Mice Heterozygous for a CADINS-Associated Dominant Negative CARD11 Allele."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "CADINS patients present with frequent respiratory and skin infections, asthma, allergies, and atopic dermatitis."
    explanation: The mouse study's background statement of the human presentation, retained as context and graded as the model-organism publication it is.
- name: Recurrent skin infections
  category: Infectious
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Recurrent cutaneous infections
    term:
      id: HP:0001581
      label: Recurrent skin infections
  evidence:
  - reference: PMID:36405754
    reference_title: "Expanding spectrum, intrafamilial diversity, and therapeutic challenges from 15 patients with heterozygous CARD11-associated diseases: A single center experience."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Skin infections were the most frequently found affecting 8/10 patients, being S. aureus and S. epidermidis the most isolated microorganisms."
    explanation: Skin infections in 8/10 patients of the CADINS cohort.
- name: Recurrent viral infections
  category: Infectious
  frequency: FREQUENT
  description: Recurrent respiratory and cutaneous viral infections, including molluscum contagiosum and HPV-related epidermodysplasia verruciformis.
  phenotype_term:
    preferred_term: Recurrent cutaneous and respiratory viral infections
    term:
      id: HP:0004429
      label: Recurrent viral infections
  evidence:
  - reference: PMID:38311684
    reference_title: "Epidermodysplasia Verruciformis in CADINS Disease: Expanding the Phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "this disease is typically characterized by severe atopy with aspects of combined immunodeficiency, including recurrent respiratory and cutaneous viral infections, hypogammaglobulinemia, and other symptoms"
    explanation: Viral infection susceptibility.
- name: Decreased circulating immunoglobulin concentration
  category: Immunological
  frequency: OCCASIONAL
  description: Hypogammaglobulinaemia in a subset, sometimes initially diagnosed as common variable immunodeficiency.
  phenotype_term:
    preferred_term: Hypogammaglobulinemia
    term:
      id: HP:0004313
      label: Decreased circulating immunoglobulin concentration
  evidence:
  - reference: PMID:35651609
    reference_title: "Hyper-IgE and Carcinoma in CADINS Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Five other family members were affected by severe atopy associated with the above variant, but not hypogammaglobulinemia."
    explanation: Hypogammaglobulinaemia in the proband but not affected relatives.
- name: Autoimmunity
  category: Immunological
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Autoimmunity
    term:
      id: HP:0002960
      label: Autoimmunity
  evidence:
  - reference: PMID:28826773
    reference_title: "Combined immunodeficiency and atopy caused by a dominant negative mutation in caspase activation and recruitment domain family member 11 (CARD11)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the R30W defect results in a less profound yet prominent susceptibility to infections, as well as multiorgan atopy and autoimmunity"
    explanation: Autoimmunity in the founding family.
- name: Decreased total neutrophil count
  category: Laboratory
  frequency: OCCASIONAL
  description: Neutropenia, including intermittent agranulocytosis.
  phenotype_term:
    preferred_term: Neutropenia
    term:
      id: HP:0001875
      label: Decreased total neutrophil count
  evidence:
  - reference: PMID:30170123
    reference_title: "Hypomorphic caspase activation and recruitment domain 11 (CARD11) mutations associated with diverse immunologic phenotypes with or without atopic disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition to (and sometimes excluding) severe atopy, heterozygous missense and indel mutations in CARD11 presented with immunologic phenotypes similar to those observed in signal transducer and activator of transcription 3 loss of function, dedicator of cytokinesis 8 deficiency, common variable immunodeficiency, neutropenia, and immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like syndrome."
    explanation: Neutropenia within the expanded phenotype.
- name: Colitis
  category: Gastrointestinal
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Colitis
    term:
      id: HP:0002583
      label: Colitis
  evidence:
  - reference: PMID:35651609
    reference_title: "Hyper-IgE and Carcinoma in CADINS Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "accompanied by hypogammaglobulinemia, intermittent agranulocytosis, atopy, eosinophilia and colitis"
    explanation: Colitis in the proband.
- name: Decreased regulatory T cell proportion
  category: Laboratory
  frequency: OCCASIONAL
  description: >-
    Severely reduced regulatory T cells were reported in one patient, but two larger CADINS
    series found generally normal Treg frequencies, so the reduction is inconsistent across
    the human literature; the two refuting cohorts are recorded as REFUTE evidence below.
  phenotype_term:
    preferred_term: Reduced CTLA4+FOXP3+ regulatory T cells
    term:
      id: HP:0020113
      label: Decreased regulatory T cell proportion
  evidence:
  - reference: PMID:37086690
    reference_title: "CARD11 dominant negative mutation leads to altered human Natural Killer cell homeostasis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CTLA4+Foxp3+CD4+ Tregs were severely reduced."
    explanation: Treg reduction in a single reported patient.
  - reference: PMID:30170123
    reference_title: "Hypomorphic caspase activation and recruitment domain 11 (CARD11) mutations associated with diverse immunologic phenotypes with or without atopic disease."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Other assays performed showed diminished mitogen-induced T-cell proliferation in the majority of patients tested, and relatively normal frequencies of regulatory T-cells, as previously reported (Table 3)."
    explanation: The larger dominant-negative cohort found generally normal Treg frequencies, contradicting a consistent reduction.
  - reference: PMID:36405754
    reference_title: "Expanding spectrum, intrafamilial diversity, and therapeutic challenges from 15 patients with heterozygous CARD11-associated diseases: A single center experience."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Additionally, we observed normal values of Treg subset with normal FOXP3 expression in both patients with eosinophilic colitis."
    explanation: The Argentine CADINS cohort also found normal Treg values, the second refuting series.
- name: Squamous cell carcinoma
  category: Neoplastic
  frequency: VERY_RARE
  description: HPV-positive squamous cell carcinoma and cutaneous T-cell lymphoma occurred across two generations of one family, prompting HPV vaccination and cytology screening recommendations.
  phenotype_term:
    preferred_term: HPV-associated squamous cell carcinoma
    term:
      id: HP:0002860
      label: Squamous cell carcinoma
  evidence:
  - reference: PMID:35651609
    reference_title: "Hyper-IgE and Carcinoma in CADINS Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Malignancies occurred in two generations: an HPV-positive squamous cell carcinoma and a cutaneous T-cell lymphoma."
    explanation: Malignancy in a CADINS family.
- name: Abnormal facial shape
  category: Craniofacial
  frequency: OCCASIONAL
  description: Dysmorphic facial features are increasingly reported as part of the CADINS spectrum.
  phenotype_term:
    preferred_term: Dysmorphic facial features
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:36405754
    reference_title: "Expanding spectrum, intrafamilial diversity, and therapeutic challenges from 15 patients with heterozygous CARD11-associated diseases: A single center experience."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The growing number of patients with dysmorphic facial features strengthen the inclusion of extra-immune characteristics as part of the CADINS spectrum."
    explanation: Extra-immune features.
- name: Impaired specific antibody response
  category: Immunologic
  frequency: FREQUENT
  description: >-
    About half of one CADINS cohort had significant humoral defects with poor specific
    antibody production, driving infection and the need for immunoglobulin replacement.
  phenotype_term:
    preferred_term: Poor specific antibody response
    term:
      id: HP:0012475
      label: Impaired specific antibody response
  evidence:
  - reference: PMID:36405754
    reference_title: "Expanding spectrum, intrafamilial diversity, and therapeutic challenges from 15 patients with heterozygous CARD11-associated diseases: A single center experience."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Several CADINS patients had significant humoral defects with poor specific antibody production leading to increased infections, and requirement of immunoglobulin replacement therapy (a half of our CADINS cohort)."
    explanation: Poor specific antibody production in about half the cohort.
- name: Decreased mitogen-induced T-cell proliferation
  category: Immunologic
  frequency: FREQUENT
  description: >-
    Diminished lymphocyte proliferation to phytohaemagglutinin and other mitogens is common
    and is the cellular readout marking CADINS as a combined immunodeficiency.
  phenotype_term:
    preferred_term: Impaired PHA-induced lymphocyte proliferation
    term:
      id: HP:0031381
      label: Decreased mitogen-induced T-cell proliferation
  evidence:
  - reference: PMID:36405754
    reference_title: "Expanding spectrum, intrafamilial diversity, and therapeutic challenges from 15 patients with heterozygous CARD11-associated diseases: A single center experience."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "lymphocyte proliferation assay to PHA was evaluated in 6 patients, with 5 of them (4 belonging to family 8 and patient 7B) showing impairment to PHA."
    explanation: Impaired PHA-induced proliferation in 5 of 6 tested patients.
  - reference: PMID:30170123
    reference_title: "Hypomorphic caspase activation and recruitment domain 11 (CARD11) mutations associated with diverse immunologic phenotypes with or without atopic disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other assays performed showed diminished mitogen-induced T-cell proliferation in the majority of patients tested, and relatively normal frequencies of regulatory T-cells, as previously reported (Table 3)."
    explanation: Diminished mitogen-induced proliferation in the majority of the dominant-negative cohort.
- name: Failure to thrive
  category: Growth
  frequency: FREQUENT
  description: Failure to thrive affected the most symptomatic, index cases of the cohort.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:36405754
    reference_title: "Expanding spectrum, intrafamilial diversity, and therapeutic challenges from 15 patients with heterozygous CARD11-associated diseases: A single center experience."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Four of the 10 patients had failure to thrive, which coincided with the 4 index cases of the affected families, representing the most symptomatic patients from this cohort."
    explanation: Failure to thrive in 4 of 10 patients.
- name: Bronchiectasis
  category: Respiratory
  frequency: OCCASIONAL
  description: Bronchiectasis develops in a minority as a consequence of recurrent lung infection.
  phenotype_term:
    preferred_term: Bronchiectasis
    term:
      id: HP:0002110
      label: Bronchiectasis
  evidence:
  - reference: PMID:36405754
    reference_title: "Expanding spectrum, intrafamilial diversity, and therapeutic challenges from 15 patients with heterozygous CARD11-associated diseases: A single center experience."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One patient developed bronchiectasis due to recurrent infections."
    explanation: Bronchiectasis secondary to recurrent infection.
- name: Chronic sinusitis
  category: Infectious
  frequency: OCCASIONAL
  description: Chronic sinusitis is part of the recurrent respiratory infection burden.
  phenotype_term:
    preferred_term: Chronic sinusitis
    term:
      id: HP:0011109
      label: Chronic sinusitis
  evidence:
  - reference: PMID:35651609
    reference_title: "Hyper-IgE and Carcinoma in CADINS Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He was additionally diagnosed with chronic polyposis, sinusitis and food allergies."
    explanation: Chronic sinusitis in a reported patient.
- name: Allergic rhinitis
  category: Allergic
  frequency: FREQUENT
  description: Allergic rhinitis is among the atopic manifestations, seen in half of one cohort.
  phenotype_term:
    preferred_term: Allergic rhinitis
    term:
      id: HP:0003193
      label: Allergic rhinitis
  evidence:
  - reference: PMID:36405754
    reference_title: "Expanding spectrum, intrafamilial diversity, and therapeutic challenges from 15 patients with heterozygous CARD11-associated diseases: A single center experience."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Atopic dermatitis was seen in 9/10 patients in varying degrees of severity, followed by asthma and allergic rhinitis in 5/10, food allergies in 2 of them and environmental allergies in one patient."
    explanation: Allergic rhinitis in 5 of 10 patients of the cohort.
  - reference: PMID:30170123
    reference_title: "Hypomorphic caspase activation and recruitment domain 11 (CARD11) mutations associated with diverse immunologic phenotypes with or without atopic disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other atopic symptoms were noted in patients with DN variants, including asthma (55%) and food allergies (32%), and less frequently, rhinitis and eosinophilic esophagitis (Table 1)."
    explanation: Rhinitis among the atopic symptoms of dominant-negative CARD11 patients.
- name: Eosinophilic infiltration of the esophagus
  category: Gastrointestinal
  frequency: OCCASIONAL
  description: Eosinophilic oesophagitis and colitis occur as part of the atopic and IPEX-like spectrum.
  phenotype_term:
    preferred_term: Eosinophilic esophagitis
    term:
      id: HP:0410151
      label: Eosinophilic infiltration of the esophagus
  evidence:
  - reference: PMID:30170123
    reference_title: "Hypomorphic caspase activation and recruitment domain 11 (CARD11) mutations associated with diverse immunologic phenotypes with or without atopic disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Atopic disease was the cardinal feature noted in most patients (89%), frequently presenting in childhood as atopic dermatitis, but also including asthma, allergic rhinitis, food allergies, and even eosinophilic esophagitis (Table 2)."
    explanation: Eosinophilic esophagitis among the atopic manifestations.
- name: Oral ulcer
  category: Dermatological
  frequency: OCCASIONAL
  description: Oral ulcers occur in a minority and may be linked to neutropenia.
  phenotype_term:
    preferred_term: Oral ulcers
    term:
      id: HP:0000155
      label: Oral ulcer
  evidence:
  - reference: PMID:30170123
    reference_title: "Hypomorphic caspase activation and recruitment domain 11 (CARD11) mutations associated with diverse immunologic phenotypes with or without atopic disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Oral ulcers were also observed (14%), and may be linked to neutropenia."
    explanation: Oral ulcers in 14% of the cohort.
treatments:
- name: Dupilumab
  description: Anti-IL-4 receptor alpha monoclonal antibody; rapid and sustained improvement of severe, recalcitrant atopic dermatitis in five patients with no complications, allowing other atopy medications to be reduced or stopped.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: dupilumab
      term:
        id: NCIT:C162455
        label: Dupilumab
  target_mechanisms:
  - target: Atopic Inflammation with Hyper-IgE and Eosinophilia
    description: Blocks IL-4 and IL-13 signalling that drives the Th2 atopic inflammation.
  evidence:
  - reference: PMID:38231347
    reference_title: "Management of Atopy with Dupilumab and Omalizumab in CADINS Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All six patients had rapid and sustained improvement in atopic symptoms with no complications during the follow-up period. Previous medications used to treat atopy were able to be decreased or discontinued."
    explanation: Clinical response to biologic therapy.
  - reference: PMID:35651609
    reference_title: "Hyper-IgE and Carcinoma in CADINS Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "So far, one patient is under treatment with dupilumab, which has shown marked benefit in controlling severe eczema."
    explanation: Independent report of dupilumab benefit.
- name: Omalizumab
  description: Anti-IgE monoclonal antibody used for chronic spontaneous urticaria in one adult with CADINS, with rapid sustained improvement.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: omalizumab
      term:
        id: NCIT:C29299
        label: Omalizumab
  target_phenotypes:
  - preferred_term: Chronic spontaneous urticaria
    term:
      id: HP:0001025
      label: Urticaria
  evidence:
  - reference: PMID:38231347
    reference_title: "Management of Atopy with Dupilumab and Omalizumab in CADINS Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Subcutaneous dupilumab was initiated to treat atopic dermatitis and omalizumab to treat chronic spontaneous urticaria."
    explanation: Indication for omalizumab in the series.
- name: Glutamine supplementation (investigational)
  description: Glutamine requires CARD11 for import into T cells; supplementation partially rescued the mTORC1 and IFN-gamma production defects of patient T cells in vitro, suggesting a correctable cellular defect.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Dietary supplementation
    term:
      id: NCIT:C15447
      label: Dietary Intervention
    therapeutic_agent:
    - preferred_term: glutamine
      term:
        id: CHEBI:28300
        label: glutamine
  target_mechanisms:
  - target: Attenuated NF-kB, JNK and mTORC1 Signaling Downstream of the Antigen Receptor
    description: Bypasses the CARD11-dependent glutamine import deficit that limits mTORC1 activation.
  evidence:
  - reference: PMID:28628108
    reference_title: "Germline hypomorphic CARD11 mutations in severe atopic disease."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The mTORC1 and IFN-γ production defects were partially rescued by supplementation with glutamine, which requires CARD11 for import into T cells."
    explanation: In vitro rescue.
- name: Infection management and HPV vaccination
  description: Treatment of recurrent respiratory, cutaneous and viral infections; HPV vaccination in adolescence and cytology screening are recommended given HPV-associated carcinoma in CADINS.
  treatment_term:
    preferred_term: Vaccination
    term:
      id: NCIT:C15346
      label: Vaccination
  therapeutic_modality: VACCINE
  evidence:
  - reference: PMID:35651609
    reference_title: "Hyper-IgE and Carcinoma in CADINS Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HPV vaccination in teenage years, and cytology screening analogous with routine cervical swabs may be recommended."
    explanation: Malignancy prevention recommendation.
- name: Genetic counseling
  description: Autosomal dominant counselling with variable penetrance and expressivity; functional assays are needed to classify variants in relatives.
  treatment_term:
    preferred_term: Genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:36405754
    reference_title: "Expanding spectrum, intrafamilial diversity, and therapeutic challenges from 15 patients with heterozygous CARD11-associated diseases: A single center experience."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Family segregation studies expanded to 15 individuals the number of patients presenting CARD11-associated disease."
    explanation: Cascade testing in families.
- name: Immunoglobulin replacement therapy
  description: >-
    About half of one CADINS cohort had humoral defects requiring immunoglobulin replacement,
    which reduces infection frequency, and it is standard bridging care where a combined
    immunodeficiency is present.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: Immunoglobulin replacement therapy
    term:
      id: NCIT:C62710
      label: Immunoglobulin Therapy
  evidence:
  - reference: PMID:36405754
    reference_title: "Expanding spectrum, intrafamilial diversity, and therapeutic challenges from 15 patients with heterozygous CARD11-associated diseases: A single center experience."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Five patients required immunoglobulin replacement therapy, 4 of whom belong to the same family (family 8), due to recurrent respiratory infections, lung damage and/or impaired antibody-mediated immunity."
    explanation: Immunoglobulin replacement for the humoral defect.
- name: Topical corticosteroids and calcineurin inhibitors
  description: >-
    Skin-directed topical corticosteroids and calcineurin inhibitors are the mainstay of
    atopic dermatitis management before or alongside systemic biologics.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Topical corticosteroid therapy
    term:
      id: NCIT:C122078
      label: Topical Corticosteroid Therapy
  evidence:
  - reference: PMID:40625738
    reference_title: "From syndromic clues to diagnosis: understanding CARD11-driven disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Topical corticosteroids and calcineurin inhibitors are standard dermatologic treatments."
    explanation: Standard skin-directed therapy for the atopic dermatitis.
diagnosis:
- name: Sequencing with functional validation of CARD11 variants
  description: Next-generation sequencing identifies heterozygous CARD11 variants; a T-cell transfection NF-kB reporter assay distinguishes dominant-negative from gain-of-function and neutral variants and is required for diagnosis.
  evidence:
  - reference: PMID:38231347
    reference_title: "Management of Atopy with Dupilumab and Omalizumab in CADINS Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CARD11 mutations were validated for pathogenicity using a T cell transfection assay to assess the impact on activation-induced signaling to NF-κB."
    explanation: Functional validation assay.
  - reference: PMID:36405754
    reference_title: "Expanding spectrum, intrafamilial diversity, and therapeutic challenges from 15 patients with heterozygous CARD11-associated diseases: A single center experience."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Identification of novel CARD11 variants required functional studies to validate their pathogenic activity."
    explanation: Functional studies as a diagnostic requirement.
- name: Immunological evaluation
  description: Serum IgE, eosinophil count, immunoglobulins, lymphocyte subsets including Tregs, and mitogen/antigen proliferation with IFN-gamma and IL-2 production.
  evidence:
  - reference: PMID:28826773
    reference_title: "Combined immunodeficiency and atopy caused by a dominant negative mutation in caspase activation and recruitment domain family member 11 (CARD11)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We performed whole-exome sequencing, followed by Sanger confirmation, assessment of the genetic variant effect on cell signaling, and evaluation of the resultant immune function."
    explanation: Diagnostic work-up.
differential_diagnoses:
- name: STAT3 loss-of-function and DOCK8 deficiency hyper-IgE syndromes
  description: Heterozygous CARD11 variants can mimic STAT3-LOF, DOCK8 deficiency, CVID, neutropenia and IPEX-like presentations, so CARD11 should be included in hyper-IgE and primary atopic disorder gene panels.
  distinguishing_features:
  - Heterozygous dominant-negative CARD11 variant with reduced antigen receptor-induced NF-kB activation
  - Absence of the STAT3-LOF skeletal/dental features or DOCK8 lymphopenia
  evidence:
  - reference: PMID:30170123
    reference_title: "Hypomorphic caspase activation and recruitment domain 11 (CARD11) mutations associated with diverse immunologic phenotypes with or without atopic disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "heterozygous missense and indel mutations in CARD11 presented with immunologic phenotypes similar to those observed in signal transducer and activator of transcription 3 loss of function, dedicator of cytokinesis 8 deficiency, common variable immunodeficiency, neutropenia, and immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like syndrome"
    explanation: Phenocopies to consider.
- name: Severe combined immunodeficiency due to CARD11 deficiency
  description: The biallelic null allelic disorder produces profound combined immunodeficiency without atopy.
  disease_term:
    preferred_term: severe combined immunodeficiency due to CARD11 deficiency
    term:
      id: MONDO:0014081
      label: severe combined immunodeficiency due to CARD11 deficiency
  distinguishing_features:
  - Biallelic null alleles, profound CID, Pneumocystis pneumonia, absent germinal centres
  evidence:
  - reference: PMID:28826773
    reference_title: "Combined immunodeficiency and atopy caused by a dominant negative mutation in caspase activation and recruitment domain family member 11 (CARD11)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Unlike patients with biallelic mutations in CARD11 causing severe CID, the R30W defect results in a less profound yet prominent susceptibility to infections, as well as multiorgan atopy and autoimmunity."
    explanation: Contrast with the recessive disorder.
- name: BENTA disease (CARD11 gain of function)
  description: Heterozygous gain-of-function CARD11 variants cause B-cell expansion with NF-kB and T-cell anergy, with spontaneous cytoplasmic CARD11 aggregation and a lymphoproliferative rather than atopic phenotype; the functional assay separates the two.
  distinguishing_features:
  - Polyclonal B lymphocytosis and lymphoproliferation
  - Increased rather than decreased NF-kB activity and spontaneous CARD11 aggregation
  evidence:
  - reference: PMID:36405754
    reference_title: "Expanding spectrum, intrafamilial diversity, and therapeutic challenges from 15 patients with heterozygous CARD11-associated diseases: A single center experience."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Altogether, four variants showed a GOF effect as well a spontaneous aggregation in the cytoplasm, leading to B cell expansion with NF-κB and T cell anergy (BENTA) diagnosis."
    explanation: Functional distinction from BENTA.
animal_models:
- name: CARD11 R30W/+ mouse
  species: Mouse
  genotype: Card11 p.Arg30Trp heterozygous knock-in (patient allele)
  publication: PMID:34341167
  description: >
    Mice heterozygous for the patient R30W allele have impaired CARD11 signalling with T-,
    B- and NK-cell functional defects and immunodeficiency, age-dependent elevated IgE with
    50% penetrance, reduced regulatory T cells and selective loss of NK IFN-gamma production,
    but no spontaneous atopic dermatitis and no Th2 expansion.
  modeled_mechanisms:
  - target: Partial T-Cell, Regulatory T-Cell and NK-Cell Dysfunction
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Reproduces the multi-lineage signalling and functional defects, including Treg reduction and NK IFN-gamma loss.
    limitations: >-
      Mixed oligomers impair T cells more than B cells and the model lacks the human
      Th2 expansion.
    readouts:
    - name: Regulatory T cell numbers and NK IFN-gamma production
      target: Partial T-Cell, Regulatory T-Cell and NK-Cell Dysfunction
      direction: DECREASED
      interpretation: Lineage-specific functional readouts of impaired CARD11 signalling.
      evidence:
      - reference: PMID:34341167
        reference_title: "Pathway-Specific Defects in T, B, and NK Cells and Age-Dependent Development of High IgE in Mice Heterozygous for a CADINS-Associated Dominant Negative CARD11 Allele."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "CARD11R30W/+ mice display reduced regulatory T cell numbers, but not the Th2 expansion observed in other mice with diminished CARD11 activity. Interestingly, the presence of mixed CARD11 oligomers in CARD11R30W/+ mice causes more severe signaling defects in T cells than in B cells, and specifically impacts IFN-γ production by NK cells, but not NK cell cytotoxicity."
        explanation: Reports the readouts.
    evidence:
    - reference: PMID:34341167
      reference_title: "Pathway-Specific Defects in T, B, and NK Cells and Age-Dependent Development of High IgE in Mice Heterozygous for a CADINS-Associated Dominant Negative CARD11 Allele."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We find that CARD11R30W/+ mice exhibit impaired signaling downstream of CARD11 that leads to defects in T, B, and NK cell function and immunodeficiency."
      explanation: Establishes the model's immunodeficiency phenotype.
  - target: Atopic Inflammation with Hyper-IgE and Eosinophilia
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: ORGANISM
    description: Elevated IgE develops with age and incomplete penetrance, but spontaneous atopic dermatitis does not.
    limitations: >-
      No spontaneous atopic dermatitis and no Th2 expansion, so the atopic tissue phenotype
      of patients is not reproduced; high IgE alone was insufficient for overt atopy.
    readouts:
    - name: Serum IgE
      target: Atopic Inflammation with Hyper-IgE and Eosinophilia
      direction: INCREASED
      interpretation: Age-dependent, 50%-penetrant IgE elevation.
      evidence:
      - reference: PMID:34341167
        reference_title: "Pathway-Specific Defects in T, B, and NK Cells and Age-Dependent Development of High IgE in Mice Heterozygous for a CADINS-Associated Dominant Negative CARD11 Allele."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "CARD11R30W/+ mice develop elevated serum IgE levels with 50% penetrance that becomes more pronounced with age, but do not develop spontaneous atopic dermatitis."
        explanation: Reports the IgE readout and the missing dermatitis.
    evidence:
    - reference: PMID:34341167
      reference_title: "Pathway-Specific Defects in T, B, and NK Cells and Age-Dependent Development of High IgE in Mice Heterozygous for a CADINS-Associated Dominant Negative CARD11 Allele."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Our findings help explain the high susceptibility of CADINS patients to infection and suggest that the development of high serum IgE is not sufficient to induce overt atopic symptoms."
      explanation: Authors' interpretation of the partial recapitulation.
experimental_models:
- name: Patient T cells and transfected T-cell lines expressing CADINS variants
  experimental_model_type: CELL_LINE
  description: Transfection of patient CARD11 variants into T-cell lines with NF-kB, mTORC1 and JNK reporters, and primary patient T cells, define dominant interference, GATA3 induction and glutamine rescue.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_types:
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  publication: PMID:28628108
  modeled_mechanisms:
  - target: Attenuated NF-kB, JNK and mTORC1 Signaling Downstream of the Antigen Receptor
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: CELLULAR
    description: Patient T cells and variant-transfected lines reproduce the attenuated signalling and its partial glutamine rescue.
    evidence:
    - reference: PMID:28628108
      reference_title: "Germline hypomorphic CARD11 mutations in severe atopic disease."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Patient T cells had similar defects, as well as low production of the cytokine interferon-γ (IFN-γ)."
      explanation: Patient-cell concordance with the transfection assays.
discussions:
- discussion_id: cadins_mouse_no_atopic_dermatitis
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Atopic Inflammation with Hyper-IgE and Eosinophilia
  prompt: >
    Why do CARD11 R30W/+ mice develop high IgE but not spontaneous atopic dermatitis or Th2
    expansion, and what additional environmental or genetic factor converts hyper-IgE into
    overt atopy in patients?
  rationale: >
    The patient-allele knock-in reproduces the signalling and immunodeficiency defects and
    age-dependent IgE elevation but not the defining skin disease, and the authors conclude
    that high IgE is not sufficient for atopic symptoms; the human Th2 skewing via GATA3 was
    shown in patient T cells but is absent in the mouse.
  evidence:
  - reference: PMID:34341167
    reference_title: "Pathway-Specific Defects in T, B, and NK Cells and Age-Dependent Development of High IgE in Mice Heterozygous for a CADINS-Associated Dominant Negative CARD11 Allele."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "However, precisely how a heterozygous dominant negative CARD11 allele leads to the development of this CADINS-specific cluster of symptoms remains poorly understood."
    explanation: Explicit statement of the open question.
- discussion_id: cadins_versus_null_phenotype_divergence
  kind: OPEN_QUESTION
  status: OPEN
  attaches_to:
  - pathophysiology#Oligomer Poisoning of the CARD11 Signaling Cycle
  prompt: >
    Why does partial, dominant-negative interference with CARD11 signalling produce severe
    atopy and autoimmunity, whereas complete biallelic loss produces profound combined
    immunodeficiency without atopy?
  rationale: >
    Both disorders reduce antigen receptor-induced NF-kB signalling, but only residual
    signalling appears to permit the Th2-skewed, autoreactive responses of CADINS; oligomer
    poisoning studies explain the inheritance difference but not the qualitative phenotype
    divergence.
  evidence:
  - reference: PMID:35198875
    reference_title: "Mechanistic impact of oligomer poisoning by dominant-negative CARD11 variants."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Three classes of germline mutations in CARD11 cause Primary Immunodeficiency, including homozygous loss-of-function (LOF) mutations in CARD11 deficiency, heterozygous gain-of-function (GOF) mutations in BENTA disease, and heterozygous dominant-negative LOF mutations in CADINS."
    explanation: The three allelic classes whose divergence is unexplained.
notes: >
  Curated as a Disease entry (stub entry_type decision: DISEASE), separate from the allelic
  recessive Severe_Combined_Immunodeficiency_Due_To_CARD11_Deficiency curated in the same
  tranche; BENTA (CARD11 gain of function) is not yet in the KB. Sources: the 2017
  discovery papers (PMID:28628108, PMID:28826773), the 2019 allelic series (PMID:30170123),
  mechanism papers (PMID:35198875, PMID:40111223, PMID:37086690), the R30W mouse
  (PMID:34341167), clinical series and case reports (PMID:36405754, PMID:35651609,
  PMID:38311684, PMID:38231347, PMID:39414811) and reviews (PMID:31060714, PMID:36334349,
  PMID:40625738). No GeneReviews chapter exists. The Edison/falcon deep-research report
  completed after the first draft and passed preflight; its reference list was
  cross-checked and the S775L case report and the Pomerantz review it added are cited. Epidermodysplasia verruciformis and molluscum are
  described in the viral-infection phenotype rather than bound separately; the closest HP
  terms (chronic warts, unusual molluscum contagiosum) describe the lesions rather than the
  syndromic susceptibility, so the recurrent-viral-infection phenotype carries them instead.
📚

References & Deep Research

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Evaluations and curation notes (2)

Record notes

Curated as a Disease entry (stub entry_type decision: DISEASE), separate from the allelic recessive Severe_Combined_Immunodeficiency_Due_To_CARD11_Deficiency curated in the same tranche; BENTA (CARD11 gain of function) is not yet in the KB. Sources: the 2017 discovery papers (PMID:28628108, PMID:28826773), the 2019 allelic series (PMID:30170123), mechanism papers (PMID:35198875, PMID:40111223, PMID:37086690), the R30W mouse (PMID:34341167), clinical series and case reports (PMID:36405754, PMID:35651609, PMID:38311684, PMID:38231347, PMID:39414811) and reviews (PMID:31060714, PMID:36334349, PMID:40625738). No GeneReviews chapter exists. The Edison/falcon deep-research report completed after the first draft and passed preflight; its reference list was cross-checked and the S775L case report and the Pomerantz review it added are cited. Epidermodysplasia verruciformis and molluscum are described in the viral-infection phenotype rather than bound separately; the closest HP terms (chronic warts, unusual molluscum contagiosum) describe the lesions rather than the syndromic susceptibility, so the recurrent-viral-infection phenotype carries them instead.

Create: Immunodeficiency_11B_With_Atopic_Dermatitis (CARD11 dominant negative, MONDO:0054697) · 2026-09-06T03:14:33Z · View source

Created CADINS (immunodeficiency 11B with atopic dermatitis) as a Disease entry (stub entry_type decision: DISEASE), separate from the allelic recessive complete CARD11 deficiency entry curated in the same tranche. Chain: heterozygous dominant-negative CARD11 variant, oligomer poisoning of the CARD11 signalling cycle, attenuated NF-kB/JNK/mTORC1 signalling downstream of the antigen receptor, Th2 skewing via loss of JNK-dependent GATA3 repression, partial T/Treg/NK dysfunction, atopic inflammation with hyper-IgE and eosinophilia. Variants R30W, E57K, R75W and the de novo MAGUK-region S775L. Treatments: dupilumab and omalizumab (case series), investigational glutamine supplementation, infection management and HPV vaccination, genetic counselling. Models: the R30W/+ knock-in mouse and patient/transfected T-cell assays. Sources: PMID:28628108, PMID:28826773 (2017 discovery), PMID:30170123 (allelic series), PMID:35198875, PMID:40111223, PMID:37086690 (mechanism), PMID:34341167 (mouse), PMID:36405754, PMID:35651609, PMID:38311684, PMID:38231347, PMID:39414811 (clinical), PMID:31060714, PMID:36334349, PMID:40625738 (reviews). Deep research: the first Edison/falcon run died with a provider connection error and the entry was drafted from PubMed abstracts; the relaunched run completed afterwards and passed just preflight-dr (CARD11 59 mentions, OMIM 617638); its reference list was cross-checked and added the S775L case report and the Pomerantz 2022 review. The report's own term-validation pass could not be completed because the OLS service timed out; the report is committed without that section. Corrections during validation: one snippet trimmed because a bracketed HGVS span is stripped before matching. Validation: just validate pass, just validate-terms pass, count-verified-snippets 68/68, check-causal-targets and check-entity-refs clean.

Falcon ▸
Immunodeficiency 11B with Atopic Dermatitis (IMD11B/CADINS): Disease-Characteristics Report
Edison Scientific Literature 40 citations 2026-09-06T02:58:57.725357

Immunodeficiency 11B with Atopic Dermatitis (IMD11B/CADINS): Disease-Characteristics Report

Executive summary and evidence scope

Immunodeficiency 11B with atopic dermatitis (IMD11B) is a rare, autosomal-dominant inborn error of immunity caused by heterozygous germline loss-of-function variants in CARD11 that dominantly interfere with the wild-type protein. The preferred mechanistic name is CARD11-associated atopy with dominant interference of NF-κB signaling (CADINS). It combines early-onset atopic disease—particularly dermatitis—with variably penetrant humoral and cellular immunodeficiency, recurrent respiratory or cutaneous infections, and occasional autoimmunity, neutropenia, gastrointestinal inflammation, or malignancy. It must not be conflated with autosomal-recessive complete CARD11 deficiency (OMIM 615206) or gain-of-function CARD11-associated BENTA syndrome. (pietzsch2022hyperigeandcarcinoma pages 1-2, urdinez2022expandingspectrumintrafamilial pages 1-2, garciamartinez2025fromsyndromicclues pages 1-2)

Published evidence remains limited to small, genetically heterogeneous cohorts, families, case reports, patient-cell experiments, and mouse models. A 2024 review table compiled 63 reported patients across approximately 25 families/case groups, but this is not a population registry and does not establish prevalence. The strongest aggregate estimates are approximately 89% with atopy, 75% with elevated IgE, 73% with atopic dermatitis, 68% with respiratory or viral infections, 20% with autoimmune manifestations, 15% each with neutropenia or oral ulcers, and fewer than 10% with lymphoma. These estimates are vulnerable to referral and ascertainment bias. (zhao2024anewdiseasecausingdominantnegative pages 8-9, pomerantz2022elevatedigefrom pages 4-6)

Domain Evidence-backed finding Quantitative data Suggested ontology terms Evidence type / limitations
Identity Immunodeficiency 11B with atopic dermatitis, commonly called CARD11-associated atopy with dominant interference of NF-κB signaling (CADINS) OMIM 617638; MONDO:0054697 MONDO:0054697; HP:0002721 Immunodeficiency Aggregated disease-resource and human genetic evidence; distinct from autosomal-recessive complete CARD11 deficiency (OMIM 615206) and gain-of-function BENTA (OpenTargets Search: Immunodeficiency 11B with atopic dermatitis-CARD11, pietzsch2022hyperigeandcarcinoma pages 1-2)
Genetic cause Heterozygous germline loss-of-function CARD11 variants dominantly interfere with wild-type CARD11 signaling; inheritance is autosomal dominant, with de novo and familial cases Literature review summarized 63 patients across 25 families/case groups CARD11; HGNC:16393; GO:0030154 cell differentiation Human pedigrees plus in-vitro functional assays; penetrance is incomplete and expressivity highly variable (zhao2024anewdiseasecausingdominantnegative pages 8-9, pomerantz2022elevatedigefrom pages 8-10)
Onset Usually infantile or early-childhood onset; severe dermatitis is commonly the first manifestation Mean onset 5.9 months in a 10-person CADINS cohort; dermatitis was initial in 7/10 (70%) HP:0003593 Infantile onset; HP:0007354 Atopic dermatitis Single-center cohort; ascertainment favored symptomatic pediatric index cases (urdinez2022expandingspectrumintrafamilial pages 12-13)
Atopic disease Multisystem atopy includes dermatitis, asthma, food allergy, allergic rhinitis, and sometimes eosinophilic gastrointestinal disease Any atopy 89%; atopic dermatitis 73% HP:0001047 Atopic dermatitis; HP:0002099 Asthma; HP:0500093 Food allergy; HP:0004403 Allergic rhinitis International-cohort summary; denominators and manifestations vary across reports (pomerantz2022elevatedigefrom pages 8-10, pomerantz2022elevatedigefrom pages 4-6)
Laboratory allergy phenotype Elevated IgE and eosinophilia are common but not obligatory Elevated IgE 75%; persistent eosinophilia 8/10 (80%) in one cohort HP:0003212 Elevated serum IgE; HP:0001880 Eosinophilia Cohort-level observations; values vary with age and treatment (urdinez2022expandingspectrumintrafamilial pages 12-13, pomerantz2022elevatedigefrom pages 4-6)
Infection susceptibility Recurrent respiratory and viral cutaneous infections reflect variable combined or humoral immunodeficiency; bronchiectasis may develop Respiratory/viral infections approximately 68% HP:0002205 Recurrent respiratory infections; HP:0004429 Recurrent viral infections; HP:0002110 Bronchiectasis Human cohorts and case reports; pathogen-specific frequencies are unavailable (pietzsch2022hyperigeandcarcinoma pages 2-4, pomerantz2022elevatedigefrom pages 4-6)
Immune dysregulation Autoimmunity, neutropenia, oral ulcers, and rare lymphoma broaden the phenotype beyond allergy Autoimmunity approximately 20%; neutropenia approximately 15%; oral ulcers approximately 15%; lymphoma <10% HP:0002960 Autoimmunity; HP:0001875 Neutropenia; HP:0000155 Oral ulcer; HP:0002665 Lymphoma Small heterogeneous cohorts; malignancy association remains uncertain and may be variant- or infection-dependent (pomerantz2022elevatedigefrom pages 4-6, pietzsch2022hyperigeandcarcinoma pages 6-7)
Immunologic testing T- and B-cell counts may be normal, but antigen/mitogen proliferation and specific-antibody production can be impaired; IgG may be reduced PHA proliferation impaired in 5/6 tested in one cohort; about half of another cohort required immunoglobulin replacement HP:0032130 Abnormal lymphocyte proliferation; HP:0004315 Decreased circulating antibody level; HP:0004432 Abnormality of specific antibody response Functional abnormalities are variable; normal lymphocyte subsets do not exclude CADINS (urdinez2022expandingspectrumintrafamilial pages 12-13, izadi2021cadinsinan pages 1-3, urdinez2022expandingspectrumintrafamilial pages 15-17)
Molecular mechanism Mutant CARD11 poisons mixed oligomers, impairing scaffold opening and CARD11–BCL10–MALT1 signalosome assembly; this reduces antigen-receptor-induced canonical NF-κB and usually JNK/mTORC1 signaling, glutamine uptake, proliferation, and IFN-γ, while favoring IL-4/GATA3-associated T-helper-2 skewing All validated dominant-negative variants in the cited cohort impaired TCR-induced NF-κB; mTORC1 effects were variable GO:0038063 collagen-activated signaling pathway; GO:0043123 positive regulation of IκB kinase/NF-κB signaling; GO:0007254 JNK cascade; GO:0031929 TOR signaling; GO:0042092 type 2 immune response; CL:0000624 CD4-positive alpha-beta T cell Human cells, transfected cell lines, and mechanistic synthesis; relative contribution of each pathway differs by variant (hutcherson2021pathwayspecificdefectsin pages 1-3, pomerantz2022elevatedigefrom pages 4-6, pomerantz2022elevatedigefrom pages 8-10, izadi2021cadinsinan pages 3-4)
Diagnosis Suspect CADINS with very-early-onset or treatment-resistant atopy plus recurrent/unusual infections, poor vaccine responses, autoimmunity, or family history. Confirm a heterozygous CARD11 variant by panel/WES/WGS and segregation testing; functional demonstration of dominant interference is important for novel variants A 2024 case used trio WES, Sanger validation, NF-κB reporter/co-immunoprecipitation, and RNA sequencing NCIT:C17607 Genetic Testing; NCIT:C101295 Whole Exome Sequencing; HP:0000005 Mode of inheritance No consensus disease-specific criteria; sequence variants may remain VUS without functional validation (urdinez2022expandingspectrumintrafamilial pages 1-2, zhao2024anewdiseasecausingdominantnegative pages 8-9, izadi2021cadinsinan pages 3-4)
Treatment Treat dermatitis conventionally; targeted IL-4/IL-13 blockade with dupilumab has produced marked benefit in case reports. Immunoglobulin replacement and antimicrobial prophylaxis are used for clinically significant antibody deficiency/infections. Glutamine partially rescued cellular defects in vitro but is not established clinical therapy Dupilumab benefit reported at case level; no controlled response rate; immunoglobulin replacement reduced infections in one patient but did not prevent bronchiectasis NCIT:C1576 Dupilumab; NCIT:C270 Immunoglobulin Therapy; NCIT:C1589 Tacrolimus; CHEBI:28300 glutamine Observational reports and expert extrapolation; no disease-specific randomized trials, validated algorithm, or established HSCT indication for typical CADINS (pietzsch2022hyperigeandcarcinoma pages 2-4, izadi2021cadinsinan pages 3-4, giancotta2023tailoredtreatmentsin pages 5-6, giancotta2023tailoredtreatmentsin pages 4-5)
Prevention Routine vaccination should be individualized after immune evaluation; HPV vaccination and surveillance have been proposed because HPV-positive carcinoma has occurred in affected families HPV-positive squamous carcinoma reported in one family across the broader malignancy history NCIT:C1746 HPV Vaccine; NCIT:C17139 Cancer Screening Expert recommendation based on isolated familial malignancy observations, not prospective prevention studies (pietzsch2022hyperigeandcarcinoma pages 6-7, pietzsch2022hyperigeandcarcinoma pages 1-2)
R30W mouse model Heterozygous Card11 R30W/+ mice reproduce impaired T-, B-, and NK-cell signaling, reduced Treg numbers, reduced NK-cell IFN-γ, and age-dependent hyper-IgE, but not spontaneous dermatitis Elevated IgE showed approximately 50% penetrance and increased with age CL:0000815 regulatory T cell; CL:0000623 natural killer cell; HP:0003212 Elevated serum IgE; GO:0032649 regulation of interferon-gamma production Patient-variant knock-in model; failure to develop spontaneous dermatitis shows that high IgE alone is insufficient and limits direct phenotypic translation (hutcherson2021pathwayspecificdefectsin pages 1-3, pomerantz2022elevatedigefrom pages 8-10)

Table: Concise knowledge-base summary of IMD11B/CADINS identity, clinical frequencies, mechanism, diagnosis, management, and the Card11 R30W mouse model. Quantitative estimates derive from small, heterogeneous cohorts and should not be interpreted as population prevalence.

1. Disease information

Definition and identifiers

  • Disease: Immunodeficiency 11B with atopic dermatitis.
  • Preferred synonym: CARD11-associated atopy with dominant interference of NF-κB signaling (CADINS).
  • Other names: CARD11-associated atopy; dominant-negative CARD11 deficiency; heterozygous CARD11 loss-of-function disease; CARD11-related hyper-IgE-like syndrome.
  • MONDO: MONDO:0054697.
  • OMIM/MIM: 617638.
  • Causal gene: CARD11, caspase recruitment domain family member 11; Ensembl ENSG00000198286. Open Targets identifies CARD11 as the sole associated target for MONDO:0054697, supported by five evidence records. (OpenTargets Search: Immunodeficiency 11B with atopic dermatitis-CARD11)
  • Orphanet: A dedicated, confidently verified Orpha number was not identified in the retrieved evidence.
  • ICD-10/ICD-11: No disease-specific code was identified. Cases generally require broader immunodeficiency and manifestation codes.
  • MeSH: No disease-specific MeSH descriptor was identified; concepts such as primary immunodeficiency, atopic dermatitis, and CARD11 protein are used.

The evidence is primarily aggregated disease-level literature, supplemented by individual-patient and family data. It is not derived from a large EHR cohort or population registry.

Disease-boundary warning

Monoallelic dominant-negative CADINS differs from: (1) biallelic complete CARD11 deficiency, an autosomal-recessive combined immunodeficiency/SCID-like disorder (OMIM 615206), and (2) BENTA, caused by activating CARD11 variants and characterized by B-cell expansion and lymphoproliferation. Variant zygosity and functional direction are therefore essential to classification. (pietzsch2022hyperigeandcarcinoma pages 1-2, urdinez2022expandingspectrumintrafamilial pages 1-2, garciamartinez2025fromsyndromicclues pages 1-2)

2. Etiology, risk, protective factors, and gene–environment interaction

Causal factor

The established cause is a germline heterozygous CARD11 variant with loss-of-function and dominant-interfering activity. Mutant and wild-type CARD11 form dysfunctional mixed oligomers, impairing antigen-receptor-induced CARD11 opening, cofactor recruitment, and downstream signaling. Both inherited and de novo cases occur. A 2024 Chinese case carried de novo NM_032415:c.2324C>T, p.Ser775Leu; reporter, co-immunoprecipitation, and RNA-sequencing experiments showed dominant interference and reduced NF-κB transcriptional activity. (zhao2024anewdiseasecausingdominantnegative pages 8-9, pomerantz2022elevatedigefrom pages 8-10)

Genetic risk and modifiers

Disease risk is determined principally by the causal allele. Functional severity differs among variants: R30W and R72Q have been characterized as stronger NF-κB inhibitors than variants such as N25Y or K83M. Nevertheless, no reliable genotype–phenotype correlation has been established, and marked variability occurs even within families. (zhao2024anewdiseasecausingdominantnegative pages 8-9)

No validated modifier genes, protective alleles, founder variants, carrier-frequency estimates, or epigenetic signatures are known. Formal penetrance is undefined; published families indicate incomplete or high-but-not-complete penetrance and markedly variable expressivity. A p.Arg75Trp family showed severe disease in the index patient but predominantly atopy without hypogammaglobulinemia in five relatives. (pietzsch2022hyperigeandcarcinoma pages 1-2, pietzsch2022hyperigeandcarcinoma pages 6-7)

Environmental and infectious factors

No toxin, occupation, smoking pattern, diet, radiation exposure, or lifestyle factor has been shown to cause CADINS. Allergens and microbial exposure likely shape expression of eczema and infection burden, but CADINS-specific gene–environment studies are absent. Impaired CARD11-dependent upregulation of the glutamine transporter ASCT2 suggests that nutrient availability can modify lymphocyte signaling in vitro; supplemental glutamine partially rescued proliferation and IFN-γ production, but this has not established dietary prevention or clinical efficacy. (pomerantz2022elevatedigefrom pages 4-6, izadi2021cadinsinan pages 3-4)

Respiratory pathogens and cutaneous viruses—including herpesviruses, molluscum contagiosum, varicella-zoster virus, and HPV—are complications or phenotypic probes of immunodeficiency, not primary causes. Skin-barrier disruption and microbial colonization may amplify dermatitis, but CADINS-specific microbiome data are lacking. (pietzsch2022hyperigeandcarcinoma pages 2-4, (henry)2023definingthepathogenesis pages 75-79)

No proven genetic or environmental protective factor exists. Improvement of dermatitis with age in some patients is a natural-history observation, not evidence of protection. (zhao2024anewdiseasecausingdominantnegative pages 8-9, giancotta2023tailoredtreatmentsin pages 5-6)

3. Phenotypes

Major clinical and laboratory manifestations

Phenotype Character/course and frequency Suggested HPO term
Atopic dermatitis/eczema Usually infantile, often severe or recalcitrant; approximately 73% overall. Initial manifestation in 7/10 patients in one cohort; may improve during childhood/adolescence. HP:0001047
Atopy, broadly defined Approximately 89%; includes food allergy, asthma, rhinitis, and eosinophilic GI disease. HP:0001026/individual manifestation terms
Elevated serum IgE Approximately 75%; variable and not required. HP:0003212
Eosinophilia Persistent in 8/10 in one cohort; one patient reached 5,900/µL. HP:0001880
Asthma Common but less frequent than dermatitis; often early-onset. HP:0002099
Food allergy Variable; immediate hypersensitivity may be prominent. HP:0500093
Allergic rhinitis Variable. HP:0004403
Eosinophilic esophagitis/colitis Uncommon but clinically important; may resemble IPEX-like disease. HP:0002027 / HP:0100279
Recurrent respiratory infection/pneumonia/sinusitis Respiratory or viral infection in approximately 68%; may cause bronchiectasis. HP:0002205, HP:0002110
Viral skin infection/warts HPV, herpesvirus, molluscum, VZV, eczema herpeticum reported. HP:0004429, HP:0001070
Hypogammaglobulinemia or impaired specific antibodies Variable; total immunoglobulins may be normal. Poor vaccine antibody responses are diagnostically useful. HP:0004315, HP:0004432
Reduced lymphocyte proliferation Counts can be normal despite impaired mitogen/antigen responses; PHA response abnormal in 5/6 tested in one cohort. HP:0032130
Neutropenia/agranulocytosis Approximately 15%; sometimes transient and possibly autoimmune. HP:0001875
Autoimmunity/inflammation Approximately 20%; colitis and other manifestations reported. HP:0002960
Oral ulcers Approximately 15%. HP:0000155
Failure to thrive 4/10 in one pediatric cohort. HP:0001508
Lymphoma/HPV-associated carcinoma Rare; lymphoma under 10% in summaries. Causality and absolute risk remain uncertain. HP:0002665 / HP:0030731

These frequency estimates derive from different cohorts and should not be combined as though they came from one prospective denominator. (urdinez2022expandingspectrumintrafamilial pages 12-13, pomerantz2022elevatedigefrom pages 4-6)

The mean onset in a 10-person CADINS cohort was 5.9 months; mean age at assessment was 7.5 years, range 2–33 years. Severe dermatitis was the first manifestation in 70%. One 2024 case had severe eczema before 18 months that later resolved, illustrating a fluctuating or improving cutaneous course despite persistent genetic disease. (urdinez2022expandingspectrumintrafamilial pages 12-13, zhao2024anewdiseasecausingdominantnegative pages 8-9)

No CADINS-specific EQ-5D, SF-36, PROMIS, sleep, or dermatitis quality-of-life studies were found. Severe pruritus, food restriction, recurrent infections, repeated antibiotics, bronchiectasis, and chronic gastrointestinal disease plausibly impair daily functioning, but quantitative disease-specific quality-of-life effects remain unmeasured.

4. Genetic and molecular information

Gene and variant classes

CARD11 encodes a lymphocyte-enriched intracellular scaffold also called CARMA1. Pathogenic CADINS alleles are germline, heterozygous, and usually missense or in-frame changes; nonsense variants also occur. Dominant-negative variants are enriched in the N-terminal CARD, LATCH, and coiled-coil regions, although C-terminal MAGUK/GUK-domain variants are documented. Twelve of 14 variants in one early summary affected the CARD/coiled-coil region, with two in the C-terminal GUK region. (hutcherson2021pathwayspecificdefectsin pages 1-3, pomerantz2022elevatedigefrom pages 4-6)

Reported variants include p.Arg30Gly, p.Arg30Gln, p.Arg30Trp, p.Thr43Arg, p.Arg47His, p.Ile52Thr, p.Glu57Asp, p.Arg72Gly/p.Arg72Leu, p.Arg75Gln/p.Arg75Trp, p.Glu96Lys, p.Leu92Trp, p.Lys143Ter, p.Arg187Pro, p.Leu194Pro, an in-frame alteration involving residues 183–196, p.Ser775Leu, p.Arg974Cys, and p.Arg975Trp. This is not a definitive ClinVar catalog, and transcript normalization should precede database ingestion. (zhao2024anewdiseasecausingdominantnegative pages 8-9, (henry)2023definingthepathogenesis pages 75-79, izadi2021cadinsinan pages 3-4)

Examples with direct functional evidence include:

  • c.223C>T, p.Arg75Trp: absent from gnomAD in the reported family; reduced CARD11 reporter activity even with wild-type co-expression, consistent with dominant interference. (pietzsch2022hyperigeandcarcinoma pages 2-4, pietzsch2022hyperigeandcarcinoma pages 6-7)
  • p.Arg72Leu: failed to rescue NF-κB reporter activity or IL-2 secretion when coexpressed with wild-type CARD11; patient B cells showed absent PMA-induced IκBα degradation. (izadi2021cadinsinan pages 3-4)
  • c.2324C>T, p.Ser775Leu: de novo and very rare; dominant interference shown by luciferase, co-immunoprecipitation, and RNA-seq. (zhao2024anewdiseasecausingdominantnegative pages 8-9)

Population allele frequencies should be obtained variant by variant from current gnomAD/ClinVar releases. The retrieved literature does not provide reliable frequencies for the full set. Variants are constitutional/germline, not somatic drivers. Novel variants should not be upgraded solely because CARD11 is plausible: functional demonstration of impaired signaling and dominant interference is particularly important. Multiplex functional work has assessed 2,542 CARD11 variants across residues 4–146, offering an important interpretation resource (PMID 33202260). (pomerantz2022elevatedigefrom pages 10-12)

No recurrent chromosomal rearrangement, aneuploidy, methylation signature, histone abnormality, or established structural variant defines IMD11B. No validated modifier gene has been reported.

5. Environmental information

There is no evidence that pollution, toxins, occupational exposure, alcohol, tobacco, or physical activity modifies inherited disease penetrance. Standard avoidance of patient-specific allergens and skin irritants may reduce manifestations but cannot prevent the genetic disorder. Infectious organisms are opportunistic or recurrent complications. HPV deserves particular attention because persistent HPV infection and HPV-positive squamous carcinoma have occurred in affected families, although the magnitude of excess risk is unknown. (pietzsch2022hyperigeandcarcinoma pages 6-7, pietzsch2022hyperigeandcarcinoma pages 1-2)

6. Mechanism and pathophysiology

Ordered causal chain

  1. A heterozygous germline loss-of-function CARD11 variant leads to production of mutant CARD11 capable of associating with wild-type CARD11.
  2. Mixed mutant/wild-type oligomers lead to dominant “oligomer poisoning,” defective signal-induced opening of CARD11, and impaired recruitment of BCL10, MALT1, HOIP and other cofactors. (hutcherson2021pathwayspecificdefectsin pages 1-3, pomerantz2022elevatedigefrom pages 8-10)
  3. Defective CARD11–BCL10–MALT1 signalosome assembly leads to attenuated antigen-receptor-induced canonical NF-κB signaling and, in most variants, impaired JNK and mTORC1 signaling. (pomerantz2022elevatedigefrom pages 4-6, izadi2021cadinsinan pages 3-4)
  4. Reduced mTORC1 activation and ASCT2-dependent glutamine uptake lead to impaired lymphocyte metabolic activation, proliferation, and IFN-γ production; the degree is variant dependent. (pomerantz2022elevatedigefrom pages 4-6)
  5. Impaired CARD11/JNK and IFN-γ signaling leads to increased GATA3/IL-4-associated T-helper-2 differentiation; the exact contribution of each branch is partly inferred from human cells and experimental systems. (bauman2025dominantinterferingcard11 pages 14-15, pomerantz2022elevatedigefrom pages 4-6)
    6A. Th2 bias results in IgE elevation, eosinophilia, food allergy, asthma, and inflamed/pruritic skin.
    6B. Impaired T-cell activation, B-cell help/specific-antibody formation, and NK-cell IFN-γ production result in recurrent respiratory and viral skin infections. (hutcherson2021pathwayspecificdefectsin pages 1-3, urdinez2022expandingspectrumintrafamilial pages 15-17)
    6C. Immune imbalance may lead to autoimmunity, neutropenia, inflammatory colitis, and possibly impaired HPV tumor surveillance; these downstream links are clinically associated but not fully demonstrated. (pietzsch2022hyperigeandcarcinoma pages 6-7)
  6. Recurrent airway infection and inflammation can result in chronic sinus disease and bronchiectasis, while epidermal inflammation and infection reinforce dermatitis. (pietzsch2022hyperigeandcarcinoma pages 2-4, izadi2021cadinsinan pages 1-3)

Cells, pathways, metabolism, and tissue injury

Relevant cells include conventional CD4 T cells (CL:0000624), Th2 cells (CL:0000546), regulatory T cells (CL:0000815), B cells (CL:0000236), plasma cells (CL:0000786), and NK cells (CL:0000623). Human T- and B-cell numbers may be normal, emphasizing a functional rather than obligatory numerical defect. Human Treg findings are inconsistent; aggregate human data suggest generally preserved frequency/suppression, whereas the Card11-R30W mouse has reduced Treg numbers. (hutcherson2021pathwayspecificdefectsin pages 1-3, pomerantz2022elevatedigefrom pages 4-6)

Suggested GO terms include antigen receptor-mediated signaling (GO:0050851), positive regulation of IκB kinase/NF-κB signaling (GO:0043123), JNK cascade (GO:0007254), TOR signaling (GO:0031929), T-cell activation (GO:0042110), B-cell activation (GO:0042113), type 2 immune response (GO:0042092), regulation of IFN-γ production (GO:0032649), and glutamine transport (GO:0006868). CARD11 acts in a cytoplasmic/membrane-proximal signalosome rather than through a primary nuclear, mitochondrial, lysosomal, or extracellular defect.

Molecular profiling and recent developments

The 2024 p.Ser775Leu study used RNA sequencing to confirm reduced downstream NF-κB transcriptional activity, representing disease-relevant transcriptomic evidence. Broad patient proteomics, metabolomics, lipidomics, single-cell, spatial-transcriptomic, and integrated multi-omic profiles have not been reported in the retrieved evidence. (zhao2024anewdiseasecausingdominantnegative pages 8-9)

A major subsequent mechanistic advance, published in March 2025, showed that CARD11 is required for TCR-induced JNK1/JNK2 activation; dominant-interfering variants attenuated this branch, and CADINS patient CD4 T cells showed increased GATA3 and NFAT2 after stimulation. This provides a direct mechanistic bridge from defective CARD11–JNK signaling to Th2 differentiation, but it postdates the requested 2023–2024 priority window. DOI: 10.1084/jem.20240272, published March 2025. (bauman2025dominantinterferingcard11 pages 14-15)

7. Anatomical structures affected

  • Primary: skin/epidermis (UBERON:0002097, skin; UBERON:0001003, epidermis), particularly diffuse rather than lateralized involvement.
  • Immune/lymphoid: blood, lymphocytes, lymph nodes, spleen, and thymic immune development; abnormalities are primarily functional.
  • Respiratory: upper airways/sinuses and lungs; recurrent sinusitis, pneumonia, asthma, and secondary bronchiectasis. Suggested terms include UBERON:0002048 lung and UBERON:0000004 nose.
  • Gastrointestinal: esophagus and colon in eosinophilic esophagitis/colitis.
  • Secondary: nails in fungal disease and anogenital/cutaneous epithelium in persistent HPV disease.

No consistent laterality is reported. At the subcellular level, the key compartment is the cytoplasmic CARD11–BCL10–MALT1 signaling complex assembled after antigen-receptor stimulation.

8. Temporal development

Onset is usually chronic and insidious in infancy, often beginning with dermatitis. The mean onset of 5.9 months in one cohort supports the HPO term Infantile onset (HP:0003593). Infections, asthma, food allergy, antibody deficiency, gastrointestinal inflammation, or autoimmunity may emerge later. (urdinez2022expandingspectrumintrafamilial pages 12-13)

The disorder is lifelong genetically but clinically variable. Dermatitis may be severe in infancy and improve or remit during adolescence; immune defects and infection risk do not necessarily resolve in parallel. One patient developed hypogammaglobulinemia at age 5 and bronchiectasis at 13, illustrating the value of longitudinal immune and pulmonary surveillance. (pietzsch2022hyperigeandcarcinoma pages 2-4, zhao2024anewdiseasecausingdominantnegative pages 8-9, giancotta2023tailoredtreatmentsin pages 5-6)

There is no validated staging system, defined progression rate, or critical therapeutic window. Early recognition before irreversible bronchiectasis, nutritional impairment, or severe infection is the most plausible intervention opportunity.

9. Inheritance and population

Inheritance is autosomal dominant. Both familial transmission and de novo variants occur. Penetrance is incomplete or variably described as high in individual families, while expressivity ranges from isolated/severe atopy to combined immune dysfunction. Genetic anticipation has not been reported. Germline mosaicism remains theoretically possible but is not documented. No founder effect, geographic concentration, ethnic predisposition, sex bias, or carrier-frequency estimate is established. (pietzsch2022hyperigeandcarcinoma pages 6-7, zhao2024anewdiseasecausingdominantnegative pages 8-9)

No incidence or prevalence per 100,000 is available. The literature summary of approximately 63 affected individuals reflects reported cases rather than epidemiology. Men and women and multiple ancestry groups have been reported; the 2024 Chinese case broadens geographic representation. (zhao2024anewdiseasecausingdominantnegative pages 8-9)

10. Diagnostics

Clinical suspicion and immunologic workup

Red flags are severe or treatment-resistant dermatitis beginning in infancy; multiple atopic manifestations; recurrent, severe, or unusual respiratory/viral infections; poor growth; hypogammaglobulinemia or poor vaccine responses; autoimmunity, neutropenia, oral ulcers, eosinophilic GI disease; and an affected parent or multiple generations.

Recommended baseline evaluation is CBC/differential, eosinophils, quantitative IgG/IgA/IgM/IgE, lymphocyte subsets, vaccine-specific antibodies, T-cell proliferation to mitogens/antigens, and directed infection assessment. Normal lymphocyte counts and Treg numbers do not exclude CADINS. One adult had absent Hib antibody despite vaccination and lacked baseline antibodies to 20/23 pneumococcal serotypes; only four serotypes became protective after PPSV23. (urdinez2022expandingspectrumintrafamilial pages 12-13, izadi2021cadinsinan pages 1-3, urdinez2022expandingspectrumintrafamilial pages 15-17)

Imaging is manifestation-directed: chest CT for recurrent pneumonia/bronchiectasis and sinus CT for refractory sinusitis. Endoscopy/biopsy may demonstrate eosinophilic esophagitis or colitis. No pathognomonic skin histology, metabolite, circulating protein biomarker, electrophysiologic test, or liquid biopsy exists.

Genetic testing

An inborn-error-of-immunity/primary-atopy panel including CARD11, or early WES/WGS, is appropriate. Trio sequencing is especially valuable in apparently sporadic disease. Confirm variants by orthogonal sequencing and perform segregation/cascade testing. RNA-seq can clarify splice or transcriptional consequences, but it is not routine. CMA, karyotype, FISH, mitochondrial testing, and repeat-expansion testing have low expected yield unless another phenotype suggests them.

Novel CARD11 variants require cautious ACMG/AMP interpretation and ideally functional analysis: NF-κB reporter assays, IκBα degradation, IL-2/IFN-γ production, T-cell proliferation, mTORC1/JNK readouts, and coexpression with wild-type CARD11 to demonstrate dominant interference. Functional validation changed or excluded variant interpretation in a 15-person CARD11 cohort. (urdinez2022expandingspectrumintrafamilial pages 1-2, izadi2021cadinsinan pages 3-4)

Differential diagnosis

Important alternatives include DOCK8 deficiency, STAT3-HIES, PGM3 deficiency, Wiskott–Aldrich syndrome, IPEX, Omenn syndrome, severe combined immunodeficiency, MALT1/BCL10 defects, CARD11 gain-of-function BENTA, CARD11 biallelic deficiency, common variable immunodeficiency, and common polygenic atopic dermatitis. DOCK8 deficiency can closely resemble CADINS through food allergy, asthma, viral skin infection, and recurrent respiratory infection but is usually autosomal recessive and often more severe. (izadi2021cadinsinan pages 3-4, pietzsch2022hyperigeandcarcinoma pages 1-2)

There are no validated disease-specific diagnostic criteria or population/newborn screening program. Cascade testing is appropriate after a familial pathogenic variant is established.

11. Outcome and prognosis

No 5- or 10-year survival, life-expectancy, mortality, disability, or standardized quality-of-life data exist. Many patients survive into adulthood, and dermatitis improves with age in a subset. Major morbidity includes severe eczema, food allergy, repeated infection, chronic sinusitis, bronchiectasis, gastrointestinal inflammation, treatment burden, and occasional autoimmunity or malignancy. (pietzsch2022hyperigeandcarcinoma pages 2-4, zhao2024anewdiseasecausingdominantnegative pages 8-9)

Poor prognostic indicators are inferred rather than validated: severe early infections, impaired T-cell proliferation, hypogammaglobulinemia/poor vaccine responses, persistent viral infection, bronchiectasis, inflammatory GI disease, and refractory dermatitis. In one patient, immunoglobulin reduced infections but did not prevent bronchiectasis. HPV-positive squamous carcinoma and cutaneous T-cell lymphoma have been reported, but absolute cancer risk is unknown. (pietzsch2022hyperigeandcarcinoma pages 2-4)

12. Treatment and current implementation

No curative, regulatory-approved CADINS-specific therapy or consensus algorithm exists. Treatment is individualized across dermatology, allergy, immunology, infectious disease, gastroenterology, and pulmonology.

  1. Skin-directed care: emollients, trigger avoidance, topical corticosteroids, and topical calcineurin inhibitors are used as in conventional dermatitis, with infection surveillance. Topical tacrolimus controlled skin disease in one adult. Suggested NCIt concepts: Topical Therapy, Corticosteroid Therapy, and Tacrolimus (NCIt:C1589). (izadi2021cadinsinan pages 1-3)
  2. Dupilumab: IL-4Rα blockade targeting IL-4/IL-13 is mechanistically attractive. Marked eczema benefit has been reported in individual patients, apparently without reported adverse effects in the cited cases; controlled CADINS response rates are unavailable. Suggested NCIt: Dupilumab (NCIt:C1576). (pietzsch2022hyperigeandcarcinoma pages 1-2, giancotta2023tailoredtreatmentsin pages 5-6)
  3. Other biologics: mepolizumab and omalizumab have been proposed or reported in small experiences, but the retrieved evidence does not support a quantitative efficacy estimate or standard recommendation. (taietti2025inbornerrorsof pages 6-8)
  4. Immunoglobulin replacement: indicated by clinically significant antibody deficiency, poor vaccine responses, and recurrent infections—not merely by genotype. Approximately half of one cohort had important humoral defects and required replacement. Benefit can be partial. Suggested NCIt: Immunoglobulin Therapy (NCIt:C270). (izadi2021cadinsinan pages 1-3, urdinez2022expandingspectrumintrafamilial pages 15-17)
  5. Antimicrobials: prompt treatment and, in selected patients, prophylaxis for persistent/severe infections. Evidence is expert practice rather than a CADINS trial. (izadi2021cadinsinan pages 3-4)
  6. Glutamine: supplemental glutamine partially rescued mTORC1, proliferation, and IFN-γ defects in patient cells. This is in-vitro proof of correctability, not established dietary or pharmacologic therapy. Chemical ontology: CHEBI:28300. (pomerantz2022elevatedigefrom pages 4-6, izadi2021cadinsinan pages 3-4)
  7. HSCT: not established for typical dominant-negative CADINS and was not listed as a standard CADINS option in a 2023 tailored-treatment summary. It may be considered only exceptionally for severe combined immune disease after specialist review; evidence from recessive CARD11 deficiency should not be extrapolated automatically. (giancotta2023tailoredtreatmentsin pages 4-5)

Allergen immunotherapy warrants caution: one adult stopped it because of frequent adverse reactions. No CARD11-directed gene therapy, CRISPR therapy, RNA therapy, or approved pharmacogenomic dosing guidance exists. Searches found no clearly relevant registered interventional CADINS trial; current implementation is therefore case-based precision management rather than trial-validated care.

13. Prevention

Primary prevention of the germline disorder is limited to reproductive options after molecular diagnosis: genetic counseling, familial cascade testing, prenatal diagnosis, and preimplantation genetic testing. For an affected heterozygous parent, the Mendelian transmission risk is 50% per pregnancy, although clinical severity cannot be predicted reliably because expressivity is variable.

Secondary/tertiary prevention includes early genomic diagnosis, periodic immunoglobulin and vaccine-antibody assessment, prompt infection treatment, pulmonary surveillance, skin-barrier care, nutritional/growth monitoring, and prevention of irreversible bronchiectasis. Live vaccines should be individualized according to measured cellular immune competence rather than prohibited solely because of the CARD11 genotype.

HPV vaccination, ideally with the 9-valent vaccine, plus age- and anatomy-appropriate HPV/cytology surveillance has been proposed after HPV-positive carcinoma in a CADINS family. This is expert precaution based on sparse observations, not prospective evidence. Suggested NCIt terms: Human Papillomavirus Vaccine (NCIt:C1746) and Cancer Screening (NCIt:C17139). (pietzsch2022hyperigeandcarcinoma pages 6-7, pietzsch2022hyperigeandcarcinoma pages 1-2)

No lifestyle, dietary, environmental, or public-health measure can prevent inherited CADINS. Glutamine supplementation should not be represented as proven prophylaxis.

14. Other species and natural disease

No naturally occurring veterinary disorder confidently equivalent to human CADINS was identified. Accordingly, no affected breed, VBO term, animal incidence, zoonotic potential, or cross-species transmission applies. Mus musculus (NCBI Taxonomy 10090) has the orthologous Card11 gene and is used experimentally. The antigen-receptor/CBM signaling role is evolutionarily conserved, supporting comparative mechanistic inference, but mouse atopy does not fully reproduce human disease.

15. Model organisms and experimental systems

Card11-R30W heterozygous mouse

A knock-in mouse expressing the patient-derived Card11 R30W allele models the dominant-negative state. It shows impaired T-, B-, and NK-cell signaling, a stronger signaling defect in T than B cells, reduced NK-cell IFN-γ with preserved cytotoxicity, reduced Treg numbers, and age-dependent elevated IgE with approximately 50% penetrance. It does not develop spontaneous atopic dermatitis or clear Th2 expansion, demonstrating that elevated IgE alone is insufficient for the complete human phenotype. Primary study: Hutcherson et al., Journal of Immunology 207:1150–1164, published August 2021; PMID 34341167; DOI 10.4049/jimmunol.2001233. (hutcherson2021pathwayspecificdefectsin pages 1-3, pomerantz2022elevatedigefrom pages 8-10)

Other models

Hypomorphic “unmodulated” Card11 mice develop pruritic dermatitis, elevated IgE, and allergy through differential impairment of Foxp3-positive Tregs versus Th2 effector cells. They are useful for studying signaling thresholds but do not model every human dominant-negative allele. Transfected Jurkat/JPM50.6 cells, primary patient T and B cells, reporter assays, and co-immunoprecipitation remain central for variant classification. Saturation functional assays provide scalable evidence for variant effects, although they cannot reproduce organism-level penetrance. (hutcherson2021pathwayspecificdefectsin pages 1-3, pietzsch2022hyperigeandcarcinoma pages 6-7, pomerantz2022elevatedigefrom pages 10-12)

No validated CADINS organoid, zebrafish, Drosophila, rat, iPSC, or humanized-mouse model was identified.

Key primary sources and exact abstract excerpts

  • Ma et al., Nature Genetics, published June 2017; PMID 28628108; DOI 10.1038/ng.3898. The discovery study reported: “Through next-generation sequencing on a cohort of patients with severe atopic dermatitis with and without comorbid infections, we found eight individuals, from four families, with novel heterozygous mutations in CARD11.” It further stated: “The mTORC1 and IFN-γ production defects were partially rescued by supplementation with glutamine.” (pomerantz2022elevatedigefrom pages 8-10)
  • Dorjbal et al., Journal of Allergy and Clinical Immunology, 2019; PMID 30170123. The international cohort established that validated mutations disrupted TCR-induced NF-κB activation and that atopy occurred in approximately 89%. (pomerantz2022elevatedigefrom pages 8-10)
  • Hutcherson et al., Journal of Immunology, published August 2021; PMID 34341167; DOI 10.4049/jimmunol.2001233. The abstract states: “CARD11R30W/+ mice develop elevated serum IgE levels with 50% penetrance that becomes more pronounced with age, but do not develop spontaneous atopic dermatitis.” (hutcherson2021pathwayspecificdefectsin pages 1-3)
  • Pietzsch et al., Frontiers in Immunology, published 16 May 2022; DOI 10.3389/fimmu.2022.878989. The abstract reports that the p.Arg75Trp variant had a dominant-negative effect and that “one patient is under treatment with dupilumab, which has shown marked benefit in controlling severe eczema.” (pietzsch2022hyperigeandcarcinoma pages 1-2)
  • Urdinez et al., Frontiers in Immunology, published 3 November 2022; DOI 10.3389/fimmu.2022.1020927. This single-center series included 15 CARD11-associated cases—10 CADINS and 5 BENTA—and emphasized “remarkable variability of disease expression…even within multiplex families.” (urdinez2022expandingspectrumintrafamilial pages 1-2)
  • Zhao et al., Scientific Reports 14:24247, published October 2024; DOI 10.1038/s41598-024-71673-z. The abstract defines IMD11B as caused by germline dominant-negative CARD11 variants and reports that RNA sequencing “confirmed that mutant CARD11 inhibited down-stream transcriptional activity of NF-κB.” (zhao2024anewdiseasecausingdominantnegative pages 8-9)

Knowledge gaps and curation cautions

The most important missing data are unbiased prevalence and incidence, prospective natural history, standardized penetrance, variant-level population frequencies, validated genotype–phenotype relationships, patient-reported outcomes, malignancy-risk estimates, controlled treatment trials, and single-cell/spatial/multi-omic profiling. Frequencies in this report should be encoded with their source cohort and denominator, not treated as universal. Variant classification should distinguish heterozygous dominant-negative CADINS from heterozygous activating BENTA and biallelic CARD11 deficiency. Finally, dupilumab is supported by case-level clinical benefit, whereas glutamine is principally an in-vitro mechanistic intervention; these evidence levels should remain separate in the knowledge base.

References

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