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

Abstract

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.CARD11 encodes a membrane-associated protein that partners with BCL10 and MALT1 to form the CBM complex responsible for integrating antigenreceptor engagement with downstream activation of NF-κB. Recently, heterozygous hypomorphic mutations in CARD11 have been discovered in patients with severe atopic manifestations, otherwise known as CARD11-associated atopy with dominant interference of NF-κB signaling (CADINS). Our case highlights the need for genetic testing in the evaluation of patients with severe and/or unusual atopy. We discovered a novel CADINS variant (p.G74D) in an infant presenting with extensive atopic dermatitis, seborrheic dermatitis, and hypogammaglobulinemia. Curiously, our patient also developed B cell lymphocytosis in the first year of life which is typically associated with BENTA disease. However, no gain-of-function activity was detected on in vitro testing. Further studies are needed to elucidate if modulation of CARD11 signaling by this variant can explain both gain-of-function and loss-of-function phenotypic features, as noted in prior cases.