This research protocol received approval from the Institutional Review Boards of the Bascom Palmer Eye Institute at the University of Miami Miller School of Medicine (Miami, Florida, USA), Rajavithi Hospital, and the Queen Sirikit National Institute of Child Health (Bangkok, Thailand). All procedures complied with the Health Insurance Portability and Accountability Act of 1996 and followed the ethical principles of the Declaration of Helsinki.

Patients with ARS diagnosed consecutively at these three tertiary centers between January 2004 and December 2023 were identified. The study population consisted of individuals younger than 18 years who attended the clinics and had a confirmed ARS diagnosis, documented in hospital registries using International Classification of Diseases (ICD)-9 code 743.44 or ICD-10 code Q13.81.

After compiling the patient list, glaucoma specialists reviewed medical records to verify the presence or absence of ARS-associated glaucoma according to the Childhood Glaucoma Research Network criteria. Exclusion criteria included eyes with other secondary glaucoma, prior ocular surgery, including glaucoma surgery, or less than 1 year of follow-up.

Demographic and clinical information was extracted, including age at diagnosis, sex, family history, laterality, systemic comorbidities, presenting symptoms, baseline best-corrected visual acuity (BCVA), intraocular pressure (IOP), cup-to-disc ratio, and refraction. Visual acuity (VA) was measured using age-appropriate methods and converted to the logMAR scale for consistency across modalities. Corneal clarity was evaluated on a four-point scale (0-3) using either a slit lamp or a portable slit lamp, where grade 0 indicated a completely clear cornea, grade 1 represented a fine haze with iris details easily visible, grade 2 denoted moderate haze with the iris visible only with difficulty, and grade 3 corresponded to severe haze in which the iris was not visible. Family history was considered positive if one or more first- or second-degree relatives has ARS, either diagnosed by an ophthalmologist or based on patient report, regardless of whether glaucoma was present. If any relative was found to carry a pathogenic FOXC1 variant, the case was classified as having a FOXC1 -positive family history.

IOP was primarily measured with Goldmann applanation tonometry. In cases where cooperation was limited, iCare rebound tonometry (Revenio Group, Vantaa, Finland) or the Tono-pen (Reichert, Depew, NY, USA) was used. Genetic testing results were included when available. The incidence of glaucoma was determined using data from the most recent follow-up visit.

Glaucoma surgical treatments included trabeculectomy with mitomycin C, ab externo Harms trabeculotomy, goniotomy, glaucoma drainage device implantation, and cyclophotocoagulation.

Visual disability was classified according to the World Health Organization International Classification of Diseases (2018) criteria for distance vision impairment (see Supplemental Table 1). Blindness was defined as a BCVA of 3/60 (equivalent to 20/400 or logMAR 1.30). Because visual field testing was either unavailable or unreliable in younger patients, this study relied solely on VA for assessment. Visual impairment was analyzed at both the eye level and the patient level. For patient-level analysis, categorization was based on the visual status of the better-seeing eye.

The primary outcome assessed was the extent of blindness and visual impairment, evaluated both at the initial presentation and at the final follow-up in patients with ARS, with and without glaucoma. Visual impairment was analyzed at the level of each eye as well as at the patient level (determined by the better-seeing eye). We also present the ARS family, highlighting its association with genetic testing and visual outcomes. Progression to blindness in eyes with ARS-associated glaucoma was defined as any eye that was not blind at presentation but subsequently met criteria for blindness during follow-up.

Baseline characteristics were described using means or medians for continuous variables and proportions for categorical variables. Group comparisons for categorical data were performed with either the Chi-square test or Fisher’s exact test, while continuous variables were analyzed using Student’s t test or the Mann–Whitney U test, depending on distribution. The cumulative risk of blindness in ARS eyes with glaucoma was estimated through Kaplan–Meier survival analysis was performed, and survival outcomes between glaucomatous and nonglaucomatous eyes were compared using the log-rank test. To identify risk factors associated with blindness, both univariable and multivariable regression models with Generalized Estimating Equations were applied, with results expressed as odds ratios and 95% CIs. All statistical tests were two-sided, and a P value below.05 was considered significant. Analyses were conducted using SPSS software, version 24.0, for Windows.

A total of 96 patients were included for analysis (72 from the USA site [75%]) and 24 from the Thailand site (25%), of whom 97% presented with bilateral involvement, resulting in 189 eyes analyzed. The mean age at ARS diagnosis was 4.05 ± 5.35 years, increasing to 5.26 ± 5.55 years when congenitally-diagnosed ARS cases were excluded. Males comprised the majority of the cohort (53.1%). The average follow-up duration was 8.72 ± 5.76 years, during which 55.5% of eyes developed glaucoma by the final visit. Among the eyes that developed glaucoma, 78.8% were diagnosed at the initial presentation with ARS.

At baseline, VA could be assessed in 77 eyes from the nonglaucoma group and 46 eyes from the glaucoma group. Among nonglaucoma eyes, 54.5% had no visual impairment, while 5.2% were blind at presentation. In contrast, only 34.8% of glaucoma eyes had no visual impairment, and 17.4% were blind at presentation. The distribution across categories is detailed in Table 1 .

At the final visit, VA was measurable in 96 nonglaucoma eyes and 81 glaucoma eyes. Of the nonglaucoma eyes, 71.6% remained without visual impairment. In the glaucoma group, however, only 27.1% retained normal vision, while 10.4%, 15.6%, and 5.2% had mild, moderate, and severe visual impairment, respectively, and 41.7% were blind.

For the patient-level analysis, we selected the better eye for each patient. Initially, 13% of patients were classified as blind in the better-seeing eye (eg, bilateral blindness) in those who presented with glaucoma. This number rose to 23.5% at the final visit.

For family-level analysis in ARS, the better eye of each patient was selected. Among the five families studied, two families (40%) had at least one member with a causative pathogenic FOXC1 variant, while the remaining families either had no such variant or no genetic testing performed. In the FOXC1 -positive families, all five affected members demonstrated a person-level final visual outcome of at least moderate visual impairment. In contrast, among the nine members from families with negative or absent genetic testing, 88.9% had no visual impairment at the final evaluation. The detailed distribution of visual outcomes across the five families is presented in Table 2 .

TABLE 2

Prevalence and Severity of Visual Impairment in Axenfeld–Rieger Syndrome By Family and Genetic Test Status.

			Level of Visual Impairment
Family Number	Number of Family Members	Genetic Test	No VI	Mild VI	Moderate VI	Severe VI	Blindness
1	3	No genetic test	3 (100%)
2	3	Negative genetic test	3 (100%)
3	3	FOXC1 variant			1 (33.3%)		2 (66.7%)
4	3	No genetic test	2 (66.7%)				1 (33.3%)
5	2	FOXC1 variant			1 (50%)	1 (50%)

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