Eye involvement in a series of 94 young patients with congenital ichthyosis: importance of early ophthalmological referral.
Description
Eye involvement in congenital ichthyosis, now reclassified as epidermal differentiation disorders (EDDs) is well recognized, but precise prevalence and risk factors remain unclear. Dry eye disease (72%) and meibomian gland dysfunction (62%) are highly prevalent. Ocular involvement varied by EDD subtype. Patients with STS-nonsyndromic EDD (nEDD) (formerly recessive X-linked ichthyosis) and KRT1/KRT10 nEDD (formerly keratinopathic ichthyosis) exhibited significantly fewer ocular findings, whereas those with severe involvement and syndromic forms showed higher rates of DED, MGD, and ectropion. In univariate analysis, age was the strongest predictor of DED. In multivariate modelling, EDD type, but not severity, remained associated with ocular involvement, while age showed a positive trend toward increasing risk over time. Causal inference analysis demonstrated a stepwise progression of eye disease: age-related MGD led to evaporative DED, which triggered conjunctival inflammation and keratopathy. Corneal opacities arose secondarily from chronic DED and exposure, and directly from ectropion. Astigmatism was strongly associated with DED and ectropion, likely due to progression of corneal surface irregularity. Importantly,this model suggests that ocular morbidity in EDD is not solely a function of severity, but reflects cumulative effects of time, eyelid changes, and tear film instability. Dry eye disease appears pivotal, driving conjunctival injection, keratopathy, and corneal opacities. Early ophthalmologic referral is crucial to prevent irreversible visual impairment.
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We performed a prospective cross-sectional study in a multidisciplinary dermatology–ophthalmology clinic between January 2019 and June 2023, following ethics approval (R-0053-19). Ninety-four patients with genetically confirmed epidermal differentiation disorders (EDDs) were included (median age 9 years). Data collected included EDD subtype, disease severity (Investigator Global Assessment [IGA] 1–4), and comprehensive ophthalmologic examinations. Demographic and clinical characteristics are summarized in supplementary Table 1S, and ocular findings in Table 1. Statistical analyses comprised univariate and multivariate logistic regression, as well as causal inference modeling, to explore associations between disease characteristics and ocular outcomes. Ophthalmologic assessment involved systematic evaluation of anterior and posterior segments. Ocular involvement was defined by the presence of meibomian gland dysfunction (MGD), dry eye disease (DED), conjunctival injection, keratopathy, corneal opacities, eyelid ectropion or retraction, and moderate-to-severe refractive errors (severe astigmatism or myopia). Hyperopia was excluded due to its frequency and spontaneous resolution in young children. Ectropion and DED were graded as absent, mild, moderate, or severe. DED diagnosis was based on slit-lamp findings, including tear film instability, ocular surface staining, and meibomian gland function; symptom questionnaires and Schirmer testing were not routinely used because of limited reliability in pediatric patients. Astigmatism was categorized as moderate (−1.00 to −2.00 D) or severe (> −2.00 D), and myopia as moderate (−3.00 to −5.75 D) or severe (≥ −5.75 D). For analysis, patients were grouped into: STS-related non-epidermolytic EDD (formerly recessive X-linked ichthyosis), other non-epidermolytic EDDs (including ARCI), KRT1/KRT10-related EDDs (formerly epidermolytic ichthyosis), and particularly severe EDDs (syndromic forms, desmosomal disorders, KRT10-nEDD revertant mosaic, and three undiagnosed cases with IGA 4). Statistical analyses were conducted in R. Logistic regression models evaluated associations between age, disease severity, EDD subtype, and ocular involvement. Additionally, causal inference analysis using directed acyclic graphs (DAGs) and the “dagitty” package was applied to examine potential causal pathways linking disease characteristics and specific ocular findings. This approach allowed differentiation between direct and indirect effects and identification of confounders and mediators, enhancing interpretation of observational data and improving understanding of mechanisms underlying ocular complications in EDDs.
Institutions
- Hospital Infantil Universitario Nino Jesus
- Hospital Clinico Universitario San Carlos
- Queen Victoria Hospital Eye Unit