The main protocol for this project is in active recruitment and accrual stages now. We continue to enroll a cohort of patients with severe atopic dermatitis (AD) alone, and those with AD in the context of immune deficiency. We have a substantial cohort of patients with genetic disorders, which include atopy as a part of the syndrome (now numbering over 400 patients total). The main findings that have occurred in this project within the past year are described in detail below. Finding 1: Severe atopic dermatitis in the absence of other syndromic features can be difficult to explain pathophysiologically. We had recently identified heterozygous, hypomorphic, dominant interfering CARD11 mutations in four unrelated families with severe atopic dermatitis, with and without comorbid conditions including infection. Since the publication, in collaboration with Bodo Grimbacher, Matthew Cook and Andrew Snow, we identified more than 20 new families with rare or novel mutations in CARD11, from whom 10 new dominant negative mutations were confirmed. The analysis of these families showed a more broad picture of the phenotype associated with the dominant negative mutations, including allergy and viral skin infections of all sorts, but also neutropenia, oral ulcers, autoimmunity, lymphoma, CVID-like and IPEX-like presentation. Penetrance was variable and not allele specific. In addition, our system provides a workflow for characterizing newly found CARD11 mutations to establish their pathogenicity, since a number of patients with presentations not terribly different from the rest of the cohort had CARD11 mutations which ultimately did not prove to be pathogenic. This process can serve as a model for what will likely be many more genes in which mutations of unknown significance will be found in patients whose clinical presentation are at least consistent with having a pathogenic mutation in the particular gene. The results were published in the Journal of Allergic and Clinical Immunology Finding 2: In collaboration with Pam Guerrerio within the Laboratory of Allergic Diseases, our cohort of moderate to severe atopic dermatitis patients was analyzed for growth trajectory based on food allergy diagnosis. Those with food allergy, in particular to milk, had surprisingly low BMI, while those without food allergy actually had a high BMI. These findings have significant implications for nutritional management of patients with atopic dermatitis and also highlight the importance of accuracy in diagnosing such populations with food allergies given the difficulty in such patients to make the diagnosis, yet the substantial effects food avoidance can cause. The results were published in the Journal of Allergy and Clinical Immunology
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