LTBP2 variants in childhood glaucoma: Phenotypic expansion and clinical experience

Purpose: This study describes a distinct spectrum of latent transforming growth factor-beta-binding protein 2 (LTBP2)-re- lated ocular phenotypes in pediatric glaucoma with supporting genetic evidence and highlights our clinical experiences in its management. Methods: A total of 189 children with childhood glaucoma underwent whole-exome sequencing-based genetic testing. Of these, 24 children displayed LTBP2-related phenotypes, among whom 18 cases who tested positive for LTBP2 variants were included in the study. The identified variants were confirmed through Sanger sequencing whenever possible and analyzed using in silico tools. The clinical presentation, genetic variants, and management of these 18 cases were thoroughly reviewed and presented. Results: All 36 eyes of the 18 children with biallelic LTBP2 variants exhibited megalocornea without Descemet break, iridodonesis, and ectopia lentis. Pupillary changes were noted in all eyes, with persistent pupillary membrane in 78% (28/36) and ectropion uveae in 19% (7/36) eyes. Secondary glaucoma was observed in 72% (26/36) eyes, requiring surgery in 13 of these. Retinal pathology was noted in 47% (17/36) eyes. Lensectomy was performed in 94% (34/36) eyes with a mean age of 4.09 +/- 3.5 years. Logistic regression analysis suggested that older age at lensectomy increased the risk of secondary glaucoma (hazard ratio, 1.69; [95% Confidence Interval: 1.00, 2.86], p < 0.05). The identified LTBP2 variants included five stop-gain variations, six frameshift variations, and one substitution variation, with five being novel and seven classified as rare variants. Conclusions: The study expands the classic LTBP2-related phenotype spectrum in an Indian pediatric glaucoma cohort, highlighting additional features such as persistent pupillary membrane, ectropion uveae, and associated retinal pathology. These ocular manifestations were predominantly linked to nonsense LTBP2 variants. From a management standpoint, early lensectomy can help prevent secondary glaucoma, while timely identification and treatment of peripheral retinal pathology can reduce the risk of sight-threatening complications.