Eczema in inborn errors of immunity with atopy: frequency, timing, phenotypic clustering

Abstract Background Inborn errors of immunity with atopy (IEIs-A) are an IEI subgroup with eczema as a prominent clinical feature that can mimic atopic dermatitis (AD). However, IEIs-A-associated eczema can differ from that of classic AD, and its frequency, genotype-specific clinical patterns and temporal relationships with other IEIs-A manifestations (infections, allergic manifestations, autoimmunity) remain poorly defined. Objectives To characterize eczema frequency, timing and phenotypes in IEIs-A patients, and explore eczema’s relationship with other clinical IEIs-A manifestations. Methods This retrospective study used data from the French national IEI (CEREDIH) Registry database, focusing on patients with genetically defined IEIs-A followed in three large CEREDIH-participating centers and available clinical data. Eczema frequency and onset in relationship to other clinical events, particularly severe-or-unusual infections, was assessed, as were eczema phenotypes, concomitant allergic manifestations, treatments and autoimmunity. Clustering analyses were computed to identify distinct IEI-A-eczema–associated clinical phenotypes. Results Among 373 IEIs-A patients, varying widely by genotype, 50.9% had eczema. All dedicator of cytokinesis-8 (DOCK8)-deficient patients were affected, followed by Forkhead box-P3 (FOXP3)-deficient patients (73.3%), and those with signal transducer and activator of transcription-1–loss-of-function (STAT3-LoF; 74.6%). Onset was usually early (median: 4 months). Eczema frequency and clinical presentation varied markedly across IEIs-A genotypes; four phenotypic clusters were identified, with particular localizations and severe pruritus being strongly associated with pathogenic STAT3 or DOCK8 variants. For children with isolated eczema at 24 months, the risk of developing IEI-related severe-or-unusual infections was lower than that of persistent isolated eczema until 6.8 years. Conclusion Eczema is a common, early IEIs-A feature, often preceding infections by years.While 38.4% of IEIs-A patients with eczema fulfilled the UK Working Party diagnostic criteria for AD, some clinical pictures may differ from that of classic AD. At a time when systemic AD treatments are rapidly advancing in pediatrics, recognizing these patterns to identify IEIs-A patients could refine diagnostic strategies, improve IEI detection among children with eczema, shorten the time to IEIs-A diagnosis, guide tailored management and ensure these patients receive the optimal care.