A heterozygous CARD11 variant in a patient with infantile atopic disease, humoral deficiency and lymphocytosis

The etiology of a vast majority of allergic diseases is presumed to be multifactorial, with environmental and nutritional exposures playing a causal role in polygenically susceptible individuals. The expanding availability of sequencing has allowed the identification of monogenic causes in patients presenting with severe atopic disease with or without other co-morbidities. Here, we describe a case of severe atopic dermatitis and hypogammaglobinemia associated with a CARD11 loss-of-function. Patient is an otherwise healthy 7-month male who presented with severe atopic dermatitis and seborrheic dermatitis. Eczematous lesions developed at 3 months of age and progressed despite standard treatment with topical steroids. There was no history of immunodeficiency or atopy in the family. Physical exam was notable for extensive scaly and xerotic plaques with lichenification. Workup revealed hypereosinophilia, high IgE (179 kIU/L), normal IgA (10 mg/dL), low IgM (6 mg/dL) and IgG (41 mg/dL). Lymphocyte analysis was significant for mild B-cell lymphocytosis (1,063 cells/cm2) with appropriate subsets. Patient was initiated on subcutaneous replacement immunoglobulin. Whole exome trio sequencing identified a de novo CARD11 variant (c.221G>A, p.G74D). Confirmatory testing in a CARD11 deficient Jurkat T-cell line demonstrated loss-of-function and dominant interference of wild-type CARD11 signaling.