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)

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

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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13. (hutcherson2021pathwayspecificdefectsin pages 1-3): Shelby M Hutcherson, Jacquelyn R Bedsaul, and Joel L Pomerantz. 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. Journal of immunology (Baltimore, Md. : 1950), 207:1150-1164, Aug 2021. URL: https://doi.org/10.4049/jimmunol.2001233, doi:10.4049/jimmunol.2001233. This article has 23 citations.

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17. ((henry)2023definingthepathogenesis pages 75-79): Yi-Chin (Henry) Lu. Defining the pathogenesis of human inborn errors of immunity affecting the card11-bcl10-malt1 complex. ArXiv, Jan 2023. URL: https://doi.org/10.14288/1.0394898, doi:10.14288/1.0394898. This article has 0 citations.

18. (pomerantz2022elevatedigefrom pages 10-12): Joel L Pomerantz, Joshua D Milner, and Andrew L Snow. Elevated ige from attenuated card11 signaling: lessons from atopic mice and humans. Dec 2022. URL: https://doi.org/10.1016/j.coi.2022.102255, doi:10.1016/j.coi.2022.102255. This article has 13 citations and is from a peer-reviewed journal.

19. (bauman2025dominantinterferingcard11 pages 14-15): Bradly M. Bauman, Jeffrey R. Stinson, Melissa A. Kallarakal, Lei Haley Huang, Andrew M. Frank, Gauthaman Sukumar, Nermina Saucier, Clifton L. Dalgard, Alice Y. Chan, Joshua D. Milner, Megan A. Cooper, and Andrew L. Snow. Dominant interfering card11 variants disrupt jnk signaling to promote gata3 expression in t cells. The Journal of experimental medicine, Mar 2025. URL: https://doi.org/10.1084/jem.20240272, doi:10.1084/jem.20240272. This article has 5 citations.

20. (taietti2025inbornerrorsof pages 6-8): Ivan Taietti, Francesco Catamerò, Lorenzo Lodi, Mattia Giovannini, and Riccardo Castagnoli. Inborn errors of immunity with atopic phenotypes in the allergy and immunology clinic: a practical review. Feb 2025. URL: https://doi.org/10.1097/aci.0000000000001059, doi:10.1097/aci.0000000000001059. This article has 14 citations and is from a peer-reviewed journal.

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