Atopic dermatitis (AD) is one of the most common childhood diagnoses in Western European countries. It affects up to 25% of children and 10% of adults (2). AD is a common type of eczema; other atopic diseases (e.g. asthma, rhinitis, food allergies) are often associated. Certain inborn errors of immunity (IEI) may also present with eczema and highly elevated serum IgE levels. However, patients with classic IEI such as severe combined immunodeficiency (SCID) or with Omenn, Wiskott-Aldrich, DiGeorge syndromes or DOCK8 deficiency usually manifest in early infancy or childhood, accompanied by infection susceptibility in addition to early-onset severe AD. Other so-called Hyper IgE syndromes (HIES) include susceptibility to bacterial, fungal or viral infections such as molluscum contagiosum and the human papilloma virus (HPV). These include classical autosomal dominant HIES due to STAT3 loss-of-function (LOF) and autosomal recessive entities linked to variants in ZNF341, PGM3, and genes more recently associated with HIES such as SOCS1 genes and CARD11 (Caspase recruitment domain family member 11) (3–7). Autosomal dominant CARD11 variants were first published in 2017 in children and teenagers with the triad of AD/asthma, Hyper-IgE and recurrent infections (8).

CARD11, a multi-domain scaffold protein, belongs to the membrane-associated guanylate kinase (MAGUK) protein family as well as the caspase-associated recruitment domain (CARD) protein family. The protein structure is illustrated in Supplementary Figure 1 . As a constituent of the CARD11-BCL10-MALT1 (CBM) complex, it plays a critical role in intracellular signaling cascades, most notably NF-κB activation downstream of antigen receptor signalling in lymphocytes. The phosphorylation of CARD11 leads to a conformational change which allows CARD11 to recruit cofactors including BCL10, MALT1 and TRAF6. This multi-protein signalosome then activates the IKK complex, leading to phosphorylation of the inhibitory IκBα protein, its ubiquitinylation, and subsequent proteasomal degradation. Activated NF-κB translocates to the nucleus and regulates transcription of proliferative, pro-inflammatory, and anti-apoptotic genes essential for lymphocyte function. The CBM complex is also involved in the activation of c-Jun N-terminal kinase (JNK) and mechanistic target of rapamycin (mTORC1) signalling following T cell receptor (TCR) engagement (9).

The phenotypic spectrum for patients with germline variants in CARD11 is broad. Bi-allelic loss-of-function variants cause a form of severe combined immunodeficiency (SCID, MIM: 615206) (10), whereas heterozygous gain-of-function (GOF) variants result in a B-cell lymphoproliferative disease known as BENTA (B-cell expansion with NF-κB and T-cell anergy, MIM: 616452) (11). More recently, heterozygous LOF, dominant negative (DN) variants were shown to drive an autosomal dominant HIES featuring atopy and hypogammaglobulinemia (MIM: 617638) (8). Individuals with CARD11-associated atopy with dominant interference of NF-κB signaling (CADINS) disease often appear with AD, but signs and symptoms may vary between kindreds and even within families, encompassing atopic disease such as asthma or allergies, autoimmune diseases, and infections such as viral skin and respiratory tract infections. These clinical manifestations may be associated with immunologic abnormalities, such as hypogammaglobulinemia, neutropenia or abnormal T-cell proliferation and differentiation (1, 12).

This multi-generation family has clinical and immunological features in common with formerly described patients suffering from CADINS disease (1, 8). As described for other CARD11 DN variants, there is a high penetrance but variable intrafamilial expressivity caused by the (p.Arg75Trp) variant. As an infant, the index patient had atopic dermatitis-like rash, but was more severely affected by infections and early-onset asthma. Other family members suffered from moderate to severe atopic symptoms that raised no suspicion for an IEI. The agranulocytosis of the index patient was detected at three months of age, after one year the neutrophil count had normalized. Dorjbal et al. observed neutropenia in 4 patients with functional DN variants not associated with bone marrow abnormalities suggesting an autoimmune origin (1).

Although T-cell subpopulations were normal in numbers and distribution, the proliferation of the index patient’s T cells was impaired upon stimulation with mitogens such as IL-2 and in mixed lymphocyte culture, but also after stimulation with specific antigens such as tetanus, CMV and candidin. This was also observed in all other affected family members and is consistent with impaired CARD11-dependent T-cell activation after TCR (CD3) and CD28 ligation. Indeed, impaired T-cell function predisposes to viral infections, and poor CD28 stimulation seems to have a special significance in the predisposition for HPV infection (14, 15). Apart from CARD11 deficiency, signaling via CD28 is also disturbed in other IEI such as CD28, MAGT1 and CARMIL2 deficiencies, and affected patients have been documented with HPV-driven warts (1, 16, 17). In a cohort of 44 individuals with CADINS disease, cutaneous infections were the second most common manifestation (68%) after AD (73%). Viral skin infections included common HPV-driven warts in over 25% of patients with CARD11 DN variants (1). HPV is known to cause malignancies like cervical cancer and is linked to more than 90% of all anal carcinomas (18) e.g. in HIV positive individuals. These findings highlight a possible relationship between this germline CARD11 variant and the HPV18 positive anal carcinoma in the index patient’s mother. HPV16 has been identified as the predominant HPV type in anal squamous cell carcinoma, followed to a lesser extent by HPV18, HPV33, HPV31, HPV6, HPV58 and HPV35 (19). HPV vaccination which is 9-valent (HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58) may offer an option for primary prevention of HPV induced carcinomas in patients with CADINS in analogy to HIV patients. Likewise, routine screening including anoscopy and anal cytology may be warranted in CADINS patients (16, 18).

Somatic CARD11 variants have been associated with several lymphoid malignancies (20). Somatic GOF CARD11 mutations were initially described in ~10% of diffuse large B-cell lymphomas associated with constitutive NF-κB activity (21). Moreover, hypermorphic/GOF variants in CARD11 and other non-canonical NF-κB genes were also reported in patients with MF, Sézary Syndrome, and HTLV-1-driven adult T-cell lymphoma (20, 22, 23). More recently, somatic variants in CARD11 were found to be associated with solid tumors such as human sinonasal tumors (24). Watt et al. showed that in cutaneous squamous cell carcinomas, CARD11 protein expression is increased, and novel CARD11 variants outside the coiled-coil domain led to constitutively activated NF-κB signaling (25). By contrast, germline CARD11 LOF/DN variants were previously discovered in 2 patients with peripheral T-cell lymphoma (p.Glu57Asp) and MF (p.Arg187Trp) (11). Our findings further underscore a perplexing connection between attenuated CBM signaling and malignancy, perhaps linked to infectious triggers (e.g. HSV-1) and/or impaired T-cell surveillance in the skin. More work is required to decipher how defects in distinct CARD11-dependent signaling pathways may explain this surprising phenomenon.

Dupilumab, a humanized monoclonal antibody against IL-4Rα, is increasingly being used in treatment-refractory AD, including in children from the age of 6 years. The imbalance towards Th2 cytokine production in CARD11 DN patients suggests that this biological may be useful in controlling AD in IEI with atopy. Recently, it has been successfully administered in the treatment of AD in monogenic forms of HIES, such as STAT3 LOF (3) and also in one individual with a DN CARD11 variant (26). Moreover, a recent meeting report described three patients with CADINS disease and severe AD ameliorated by treatment with dupilumab or omalizumab (27).

In summary, we describe a multi-generation family with CADINS disease caused by a novel CARD11 DN variant. The clinical phenotype is not only characterized by severe atopy (AD, asthma, food allergies) and recurrent infections in the context of both hypogammaglobulinemia and reduced T-cell responses to specific antigens, but also through the occurrence of 2 different malignancies: an HPV-driven anal squamous cell carcinoma and skin infiltrating T-cell lymphoma in one family member each. Dupilumab is likely helpful in alleviating AD in some CADINS patients.

Patients were enrolled on protocols approved by ethics review committees and thereupon provided written informed consent.

Patients with CARD11-associated atopy and dominant interference of NF-κB signaling (CADINS) disease, were first described in 2017. They usually present with varying degrees of atopy and cutaneous viral and respiratory infections with or without hypogammaglobulinemia. Our study expands the clinical spectrum of CADINS patients by reporting a multi-generation family with Hyper-IgE, disturbed T-cell function in response to IL-2, MLC and specific antigens, hypogammaglobulinemia and malignancies. Poor CD28 signaling may explain predisposition to HPV infection. An HPV triggered squamous cell carcinoma has, however, not been reported in CARD11 deficiency before. This finding underscores a perplexing connection between attenuated CBM signaling and malignancy, perhaps linked to infectious triggers and/or impaired T-cell surveillance. Further investigation is warranted to elucidate how defects in distinct CARD11-dependent signaling pathways may explain this surprising phenomenon. Dupilumab is likely helpful in alleviating severe AD in some CADINS patients.

The datasets for this article are not publicly available due to concerns regarding participant/patient anonymity. Requests to access the datasets should be directed to the corresponding author.

The studies involving human participants were reviewed and approved by Ethikkommission an der TU Dresden. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

LP and JK, conceptualization, data collection, writing, and editing. FB, formal analysis (interpretation of exome data), software, and visualization. MS, methodology and HPV sequencing. DP, technical assistance and methodology. EK, patient care, methodology, and photodocumentation. CK, ML, and RB, patient care and editing. EJ, data curation and investigation. JR, methodology, writing, editing, and treatment of the index patient. BD, DY, and AS, investigation, functional testing of the variant, and editing. DA, methodology, data interpretation, and editing. VG and ML-K, Sanger sequencing, editing, and funding acquisition. CS, conceptualization, data curation, writing-editing, supervision, and funding acquisition. All authors contributed to the article and approved the submitted version.

This work was supported by a grant from the Deutsche Forschungsgemeinschaft (CRC237 369799452/B21) to ML-K, by the Rosemarie-Germscheid Stiftung to CS, by a grant from the Else-Kröner Fresenius clinician-scientist program to JK, and a Specific Defect Research Program grant from the Jeffrey Modell Foundation to AS.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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