Keratoconus (KC) is a progressive corneal ectasia and a leading cause of corneal transplantation in young adults. Once regarded as a biomechanical disorder, KC is now recognized as a complex disease driven by genetic predisposition, epigenetic modulation, and environmental triggers. Advances in genomics and transcriptomics have begun to elucidate the molecular mechanisms underlying corneal thinning and ectasia. This review synthesizes two decades of evidence on the genetic and epigenetic architecture of keratoconus, highlights key molecular pathways implicated by these findings, and discusses translational implications for early diagnosis, risk prediction, and novel therapeutic strategies. A narrative review was conducted of peer-reviewed human, animal, and in vitro studies published from 2000 to 2025, with emphasis on genome-wide association studies (GWAS), sequencing data, methylation profiling, and non-coding RNA analyses. Findings were integrated with functional studies linking genetic variation to molecular and biomechanical phenotypes. Genetic studies consistently implicate loci such as ZNF469, COL5A1, LOX, HGF, FOXO1, and WNT10A, alongside rare variants in Mendelian syndromes (e.g., brittle cornea syndrome, Ehlers-Danlos spectrum). Epigenetic research demonstrates altered DNA methylation, dysregulated microRNAs (e.g., MIR184, miR-143, miR-182), and aberrant lncRNA networks influencing extracellular matrix remodeling, collagen cross-linking, oxidative stress, and inflammatory signaling. Gene-environment interactions, particularly with eye rubbing and atopy, further shape disease expression. Translational progress includes polygenic risk scores, tear-based biomarkers, and early preclinical studies using RNA-based approaches (including siRNA and antisense oligonucleotides targeting matrix-degrading and profibrotic pathways) and proof-of-concept gene-editing strategies demonstrated in corneal cell and ex vivo models. Conclusions: Keratoconus arises from the convergence of inherited genomic risk, epigenetic dysregulation, and environmental stressors. Integrating multi-omic insights into clinical practice holds promise for earlier detection, precision risk stratification, and development of targeted therapies that move beyond biomechanical stabilization to disease modification.

Brittle cornea syndrome (BCS) is a connective tissue disorder with a vast majority of clinical presentations and prognostic outcomes. This case series highlights various ocular presentations, their responses to treatment strategies, and final visual outcomes. It was an observational case series at a tertiary eye care center. Three patients with BCS and different corneal pathologies were managed and studied. The first case presented with wound dehiscence, a shallow anterior chamber, and a disenclaved iris claw lens. He underwent intraocular lens (IOL) explantation and wound closure using cyanoacrylate glue and a bandage contact lens. The second case involved corneal ectasia with rupture and an intumescent cataract, along with lens-endothelial touch. He underwent lens aspiration with posterior chamber IOL implantation and epi-keratoplasty with a biosynthetic cornea. However, the biosynthetic cornea had to be removed due to a severe inflammatory reaction following the procedure. The patient was later rehabilitated with deep anterior lamellar keratoplasty. The third patient presented with bilateral tractional descemet membrane detachment resulting from multiple minor injuries. Refraction with prescription glasses was used for visual rehabilitation. In conclusion, the management of BCS requires individualized treatment strategies tailored to each patient's presentation and response.

The purpose of this study was to present two cases of brittle cornea syndrome (BCS) in siblings, one with severe corneal perforation and the other misdiagnosed as primary congenital glaucoma, emphasizing clinical, histopathological, and genetic findings. This was a case report involving a 4-year-old boy and his 8-year-old brother, both presenting with thin, steep corneas. Clinical examination, Pentacam imaging, genetic analysis, systemic evaluation, and corneal histopathology were performed. The younger sibling presented with corneal perforation after trauma, and histopathology revealed a markedly thinned corneal stroma with disrupted collagen architecture. Genetic testing confirmed a zinc finger protein (ZNF)469 mutation, consistent with brittle cornea syndrome type 1 (BCS1). Sanger sequencing of the older sibling, who was previously misdiagnosed with primary congenital glaucoma, identified the same ZNF469 mutation. He exhibited corneal thinning, bluish sclera, and healthy optic discs. These cases highlight the variability in BCS presentations, the risk of misdiagnosis as glaucoma, and the importance of early genetic testing and protective measures. Histopathological findings provide additional insights into the structural abnormalities in BCS corneas.

Background and Clinical Significance: Brittle cornea syndrome (BCS) is a rare, autosomal recessive connective tissue disorder characterized by extreme corneal thinning, high myopia, and increased risk of spontaneous or trauma-induced ocular rupture. It is primarily caused by mutations in the ZNF469 or PRDM5 genes, which regulate extracellular matrix integrity. Early recognition and diagnosis of BCS are crucial to prevent severe visual impairment. This report presents two genetically confirmed cases of BCS in Albanian siblings, emphasizing the diagnostic value of whole-exome sequencing and individualized surgical management strategies. Case Presentation: Two siblings-a 28-year-old male and a 25-year-old female-presented with progressive visual deterioration and marked corneal thinning (<200 µm). Both had a history of spontaneous ocular rupture following minor trauma in the contralateral eye. Detailed ophthalmologic evaluation revealed keratoglobus, high myopia, and irregular astigmatism. Genetic testing identified the homozygous pathogenic variant c.974delG (p.Cys325LeufsX2) in the PRDM5 gene in both cases. The male underwent penetrating keratoplasty (PKP), achieving a best-corrected visual acuity (BCVA) of 20/30. The female initially underwent deep anterior lamellar keratoplasty (DALK), which was converted to PKP intraoperatively due to central endothelial perforation, resulting in a BCVA of 20/25. Both patients remained complication-free over a 7-year follow-up period. Conclusions: These cases highlight the importance of early genetic diagnosis and a tailored surgical approach in managing BCS. Long-term monitoring and protective strategies are essential to prevent complications. Incorporating genetic testing into clinical practice can enhance diagnostic accuracy and guide personalized treatment plans in patients with hereditary corneal dystrophies.

Ehlers-Danlos syndrome (EDS) is a heterogeneous group of inherited connective tissue diseases characterized by abnormal collagen synthesis and affecting various organs, including the eyes. This review analyses the current data on this disease, focusing on EDS types associated with ophthalmological manifestations: brittle cornea syndrome, kyphoscoliotic, musculocontractural, spondylodysplastic, dermatosparaxis, vascular, and classical types. The article describes ophthalmological diagnostic criteria for the different types of EDS and lists other possible ocular symptoms. The review also emphasizes the need for molecular genetic testing for accurate diagnosis in view of the difficulty in identifying specific genes encoding collagen or collagen interacting proteins, highlights the importance of timely treatment and describes methods of correcting visual disturbances, which are important for preventing severe complications such as globe rupture and retinal detachment. Синдром Элерса—Данлоса (EDS) представляет собой гетерогенную группу наследственных заболеваний соединительной ткани, характеризующихся аномальным синтезом коллагена и поражающих различные органы, включая глаза. В настоящем обзоре проанализированы современные данные об этом заболевании, с акцентом на типы EDS, ассоциированные с офтальмологическими проявлениями: синдром хрупкой роговицы, кифосколиотический, мышечноконтрактурный, спондилодиспластический, дерматоспараксисный, сосудистый и классический типы. Описаны офтальмологические диагностические критерии для различных типов синдрома Элерса—Данлоса, а также перечислены другие возможные глазные симптомы. Учитывая сложность идентификации конкретных генов, кодирующих коллаген или взаимодействующие с ним белки, подчеркнута необходимость молекулярно-генетического тестирования для точной диагностики. Выделена значимость своевременного лечения и описаны методы коррекции нарушений со стороны органа зрения, которые важны для предотвращения таких серьезных последствий, как разрывы глазного яблока и отслойка сетчатки.