前眼部形成異常

Axenfeld-Rieger syndrome (ARS) is a rare genetic disorder characterised by a broad phenotypic spectrum and variable expressivity with characteristic ocular anterior segment dysgenesis, glaucoma and systemic manifestations. ARS is primarily associated with pathogenic variants in FOXC1 and PITX2, which both exhibit autosomal dominant inheritance with overlapping ocular findings but distinct systemic manifestations.Numerous different variants in FOXC1 and PITX2 have previously been described. Here we present a patient with heterozygosity for a previously unreported pathogenic variant in FOXC1 and a phenotype with significant ocular anterior segment dysgenesis, thereby contributing relevant clinical information about the genetic and phenotypic spectrum of ARS, reproductive considerations and importance of genetic counselling.

Glaucomas are heterogeneous optic neuropathies associated with extracellular matrix dysregulation, abnormal ocular morphogenesis, and inflammatory signaling. Targeted deep sequencing of 586 primary congenital glaucoma (PCG) cases and 1,757 controls identified rare pathogenic variants in multiple genes, including WT1 and MMP9. Notably, WT1 variants clustered within the nuclear export sequence. Further, functional analyses showed that combined wt1-pax6 suppression in zebrafish disrupted ocular morphogenesis, highlighting developmental interdependence. In human trabecular meshwork cells, WT1 acted as a transcriptional repressor of MMP9, while TNF-α signaling triggered nitric oxide-dependent nuclear export of WT1, resulting in delayed MMP9 upregulation. This effect was reversible by inhibiting nuclear export or nitric oxide synthase. A patient-derived mutation in the nuclear-export region of WT1, disrupted this regulatory switch, causing abnormal MMP9 expression. These findings position WT1 as an important regulator linking developmental and inflammatory mechanisms in glaucoma pathogenesis.

PURPOSE: To describe the novel clinical phenotypes and develop a three-dimensional (3D) primary myofibroblast culture model to investigate morphological alterations associated with CPAMD8 deficiency. METHODS: We identified novel CPAMD8 variants by exome sequencing. Primary myofibroblasts from human ciliary muscle were cultured in a Matrigel-based 3D system, and CPAMD8 was knocked down by siRNA to assess effects on aggregate growth, morphology, and gene expression. RESULTS: Two novel nonsense variants of the CPAMD8 gene were identified within the pedigree. We identified megalocornea, lentis ectopia, and iris hypoplasia in patients with ASGD8, whereas glaucoma was not observed. Notable alterations in corneal biometry were observed in patients with ASGD8 for the first time. Additionally, as a preliminary observation based on the two affected individuals, reduced retinal vascular density was noted. Upon knockdown of CPAMD8 expression, three-dimensional cultured myofibroblasts demonstrated restricted proliferation, as observed under a microscope and confirmed by CCK-8 assay. Furthermore, ACTA2 expression was downregulated, and the expression of certain TGF-β receptors (TGFBR2 and TGFBR3) was altered, while TGFBR1 and SMAD2 remained unchanged, suggesting a partial rather than global disruption of TGF-β signaling. These findings are consistent with structural abnormalities of the anterior segment in ASGD8. CONCLUSIONS: ASGD8 can cause abnormalities in both the anterior and posterior eye segments. Our newly developed three-dimensional myofibroblast model offers a straightforward, efficient, and cost-effective approach for investigating genetic eye disorders.

OBJECTIVE: To clarify the molecular and clinical characteristics of anterior-segment dysgenesis (ASD)/aniridia and microphthalmia/anophthalmia caused by monogenic variants. DESIGN: Clinical and genetic analyses of a large cohort of patients with bilateral ocular lesions. PARTICIPANTS: A total of 111 patients and their family members were recruited through a multicenter collaborative study in Japan. METHODS: Next-generation sequencing using custom-designed panels for 11 and 12 major causative genes for ASD/aniridia and microphthalmia/anophthalmia, respectively. We analyzed the clinical information of patients with pathogenic or likely pathogenic variants. MAIN OUTCOME MEASURES: Collated genetic results and clinical data. RESULTS: We achieved genetic diagnosis rates of 50.0% for ASD/aniridia and 37.5% for microphthalmia/anophthalmia. We identified 11 previously unreported variants. De novo variants in the PAX6, PITX2, or GJA8 genes and parentally derived variants in the FOXC1 and CYP1B1 genes were the major causes of ASD/aniridia. Microphthalmia/anophthalmia‑associated variants in the ABCB6, BMP4, and OTX2 genes were predominantly inherited from parents with no or different ocular phenotypes. We observed phenotypic diversity and variable ocular and systemic complications in variant-positive patients. Most importantly, this study showed a high incidence of glaucoma in patients with CYP1B1 and FOXC1 variants and frequent systemic abnormalities in patients with FOXC1 and PITX2 variants. In addition, BMP4 and RARB variants were associated with neurologic abnormalities. CONCLUSIONS: This study provides evidence that targeted gene panel approaches are useful for the clinical diagnosis of ASD/aniridia and microphthalmia/anophthalmia. Our data clarified the mutation spectrum and phenotypic characteristics of these disorders caused by monogenic variants. This study confirmed that various phenotypes classified as ASD, such as Peters anomaly and Axenfeld anomaly, constitute a group of disorders on the same spectrum, may overlap with aniridia, and exhibit genetic heterogeneity. The findings, which demonstrate an association between genotypes and complications, are expected to contribute to better management and care for children with these rare intractable eye diseases. FINANCIAL DISCLOSURES: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

OBJECTIVE: To describe the clinical findings and advanced in vivo imaging features of a bilateral case of peters anomaly type 2 in a dog. ANIMAL STUDIED: An 8-week-old male scottish terrier presented with bilateral central corneal leukomas and was followed clinically for 3 years. PROCEDURES: Complete ophthalmic examination was performed at multiple time points. Ocular ultrasonography, optical coherence tomography (OCT), and in vivo confocal microscopy (IVCM) were performed under sedation at 37 weeks of age to further evaluate anterior segment structures obscured by corneal opacity. RESULTS: Both eyes displayed central leukoma and iridocorneal adhesions consistent with anterior segment dysgenesis. The left eye had a keratolenticular adhesion, progressive cataract formation, microphthalmia, goniodysgenesis, and secondary glaucoma. A defect involving the posterior corneal stroma, descemet's membrane, and endothelium, with extension of the keratolenticular adhesion into the mid-stroma was demonstrated in detail with OCT. Endothelial cell loss, endothelial polymegathism and pleomorphism, stromal fibrosis, vascularization, and multiple highly refractile structures within the mid-stroma consistent with presumed lenticular material were visualized with IVCM. The right eye had a mild central corneal leukoma and incipient cataract, with spontaneous separation of the keratolenticular adhesion and no further clinically significant abnormalities. CONCLUSIONS: This report documents peters anomaly type 2 in a dog using OCT and IVCM. Advanced imaging allowed detailed evaluation of anterior segment abnormalities that were not fully appreciable on clinical examination and revealed presumed lenticular remnants within the corneal stroma, a finding not previously described in veterinary medicine.