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

Inborn errors of immunity (IEI) with atopy (IEI-A) are a subgroup of IEIs with eczema as a prominent clinical feature that can mimic atopic dermatitis (AD). However, IEI-A-associated eczema can differ from that of classic AD, and its frequency, genotype-specific clinical patterns and temporal relationships with other manifestations of IEI-A (infections, allergic manifestations, autoimmunity) remain poorly defined.

To characterize the frequency of eczema, timing and phenotypes in patients with IEI-A, and to explore the relationship of eczema with other clinical manifestations of IEI-A.

This retrospective study used data from the French National Referral Center for Primary Immunodeficiency Diseases (CEREDIH), focusing on patients with genetically defined IEI-A followed in three large CEREDIH-participating centres 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.

Among 373 patients with IEI-A, varying widely by genotype, 50.9% (n = 190) had eczema. All patients deficient in DOCK8 (dedicator of cytokinesis-8) were affected, followed by those deficient in FOXP3 (n = 22/30; 73%) and those with STAT3 loss of function (n = 44/59; 75%). Onset was usually early (median 4 months). Eczema frequency and clinical presentation varied markedly across IEI-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 the age of 6.8 years.

Eczema is a common, early feature of IEI-A, often preceding infections by years. While 38.4% (n = 73/190) of patients with IEI-A 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 paediatrics, recognizing these patterns to identify patients with IEI-A could refine diagnostic strategies, improve IEI detection among children with eczema, shorten the time to IEI-A diagnosis, guide tailored management and ensure patients receive the optimal care.