CARD11 is a component of the CBM complex, which plays a critical role in the antigen-dependent activation of B and T lymphocytes via the NF-κB. Mutations in CARD11 have been associated with three distinct inborn errors of immunity. One of these forms is caused by dominant-negative loss-of-function mutations, characterized by atopy, hyper-IgE, and hypogammaglobulinemia. However, clinical presentations could be heterogeneous, as reported in the literature. We describe the case of a female patient, born to non-consanguineous parents, who presented with early-onset severe atopic dermatitis occasionally associated with secondary bacterial skin infections beginning at two months of age. Laboratory evaluation revealed hyper-IgE syndrome and hypogammaglobulinemia, with reduced levels of IgM and IgG. Immunoglobulin replacement was initiated at 10 months of age. By this time, she had also been diagnosed with food allergy. Within one year, the patient underwent two procedures for the removal of disseminated molluscum contagiosum lesions, with one curettage involving more than 300 lesions. Despite no evidence of lymphopenia in blood count, immunophenotyping revealed mildly reduced levels of natural killer cells. Four months later, a primary immunodeficiency orientation tube (PIDOT) analysis identified lymphopenia in both naive and post-germinal center B cell, with or without rearrangement. Whole exome sequencing revealed a heterozygous loss-of-function variant in CARD11:c.C119A/p.A40D. This variant was classified as likely pathogenic following functional assay, in accordance with the American College of Medical Genetics and Genomics guidelines. Family segregation analysis showed that the patient’s mother also carries the same variant. She presented with a milder phenotype, including psoriasis, skin allergic manifestations, and asthma particularly during childhood. This family case highlights the phenotypic variability associated with loss-of-function dominant-negative CARD11 mutations. While the proband exhibited a severe atopic and infectious phenotype requiring early intervention, her mother displayed only mild symptoms.
