Uveal Coloboma Research Articles

Increased Netrin downstream of overactive Hedgehog signaling disrupts optic fissure formation.

Uveal coloboma, a developmental eye defect, is caused by failed development of the optic fissure, a ventral structure in the optic stalk and cup where axons exit the eye and vasculature enters. The Hedgehog (Hh) signaling pathway regulates optic fissure development: loss-of-function mutations in the Hh receptor ptch2 produce overactive Hh signaling and can result in coloboma. We previously proposed a model where overactive Hh signaling disrupts optic fissure formation by upregulating transcriptional targets acting both cell- and non-cell-autonomously. Here, we examine the Netrin family of secreted ligands as candidate Hh target genes. We find multiple Netrin ligands upregulated in the zebrafish ptch2 mutant during optic fissure development. Using a gain-of-function approach to overexpress Netrin in a spatiotemporally specific manner, we find that netrin1a or netrin1b overexpression is sufficient to cause coloboma and disrupt wild-type optic fissure formation. We used loss-of-function alleles, CRISPR/Cas9 mutagenesis, and morpholino knockdown to test if loss of Netrin can rescue coloboma in the ptch2 mutant: loss of netrin genes does not rescue the ptch2 mutant phenotype. These results suggest that Netrin is sufficient but not required to disrupt optic fissure formation downstream of overactive Hh signaling in the ptch2 mutant.

Uveal colobomas with pseudo-duplication of the optic disc in both eyes: imaging by ultra-widefield swept-source optical coherence tomography angiography: a case report

BackgroundDuplication of the optic disc is a rare phenomenon. Differentiating between true duplication and pseudo-duplication requires a comprehensive set of diagnostic procedures. Advancements in imaging provide new insights into this condition.Case presentationThis report details a unique case involving an 8-year-old Han Chinese girl diagnosed with uveal colobomas and pseudo-duplication of the optic disc in both eyes. The extensive multimodal examination included assessments of vision, fundus examination, fundus photography, B-scan ultrasonography, ultra-widefield swept-source optical coherence tomography angiography, fundus fluorescein angiography, fundus autofluorescence, and magnetic resonance imaging.ConclusionUltra-widefield swept-source optical coherence tomography angiography proves to be a vital tool for examining and monitoring uveal colobomas with pseudo-duplication of the optic disc.

Increased Netrin downstream of overactive Hedgehog signaling disrupts optic fissure formation.

Uveal coloboma, a developmental eye defect, is caused by failed development of the optic fissure, a ventral structure in the optic stalk and cup where axons exit the eye and vasculature enters. The Hedgehog (Hh) signaling pathway regulates optic fissure development: loss-of-function mutations in the Hh receptor ptch2 produce overactive Hh signaling and can result in coloboma. We previously proposed a model where overactive Hh signaling disrupts optic fissure formation by upregulating transcriptional targets acting both cell- and non-cell-autonomously. Here, we examine the Netrin family of secreted ligands as candidate Hh target genes. We find multiple Netrin ligands upregulated in the zebrafish ptch2 mutant during optic fissure development. Using a gain-of-function approach to overexpress Netrin in a spatiotemporally specific manner, we find that netrin1a or netrin1b overexpression is sufficient to cause coloboma and disrupt wild-type optic fissure formation. We used loss-of-function alleles, CRISPR/Cas9 mutagenesis, and morpholino knockdown to test if loss of Netrin can rescue coloboma in the ptch2 mutant: loss of netrin genes does not rescue the ptch2 mutant phenotype. These results suggest that Netrin is sufficient but not required to disrupt optic fissure formation downstream of overactive Hh signaling in the ptch2 mutant.

Therapeutic approach to ocular coloboma - a case report of a 37-year-old patient with high myopia and choroidal coloboma of the right eye

Introduction: Coloboma is a congenital malformation caused by a defect of optic fissure closure. We report a rare case of choroidal coloboma and management of possible complications. Clinical case: A 37-year-old patient presented for the current evaluation of uveal coloboma located in the inferior-nasal quadrant with the involvement of the optic disc and advanced high myopia. Conclusions: The management of coloboma includes follow-up of visual acuity level, anterior segment and fundus evaluations. Retinal detachment, cataract and choroidal neovascularization may occur secondary to the defect. Pars plana vitrectomy, autologous neurosensory retinal transplantation and laser therapy are considered methods in present case.

Outcomes of "Complex" Cataract Surgeries Performed by Long-Term Glaucoma Fellows in a Tertiary Eye Centre from Eastern India.

To evaluate the outcomes of operating on "complex cataracts" by the glaucoma fellows. This was a retrospective study done at a tertiary referral eye care centre in eastern India. After obtaining IRB approval, a retrospective chart review of all patients who underwent "complex" cataract surgery by one of four long-term (2 years) glaucoma fellows between January 2016 and November 2020 was conducted. 'Complex' was defined as cataracts complicated with pseudoexfoliation syndrome, phacodonesis with or without blunt ocular trauma, posterior polar cataract, small pupil, co-existent corneal opacity or uveal coloboma, post-glaucoma filtering surgery, post-vitreoretinal surgery, co-existent glaucoma or post-laser iridotomy and monocular patients. Out of a total of 677 eyes done by the glaucoma fellows during the study period, 83 eyes had complex cataract surgery and completed the six-week post-operative follow-up. Intraoperative surgical complications like posterior capsular rent or vitreous loss were noted in 36 of the cases. Thirty of the eyes were left aphakic. Despite a high rate of complications, the LogMAR best-corrected visual acuity (mean ± standard deviation) improved from the preoperative level of 1.7 (±0.5) to 1.0 (± 0.8) at post-operative six weeks, significant at p < 0.001. As far as the surgeon's experience was concerned-less than or more than a year since joining the fellowship-there was statistically no difference in the final visual acuity. The group with greater experience had shorter surgical time and lesser complications though this difference was not statistically significant. This is the first study in the literature reporting the outcomes of "complex" cataract surgery performed by glaucoma fellows. Though high rates of postoperative complications were noted in this study, the mean best-corrected visual acuity improved significantly in all eyes after the surgery.

Zfp503/Nlz2 Is Required for RPE Differentiation and Optic Fissure Closure.

Uveal coloboma is a congenital eye malformation caused by failure of the optic fissure to close in early human development. Despite significant progress in identifying genes whose regulation is important for executing this closure, mutations are detected in a minority of cases using known gene panels, implying additional genetic complexity. We have previously shown knockdown of znf503 (the ortholog of mouse Zfp503) in zebrafish causes coloboma. Here we characterize Zfp503 knockout (KO) mice and evaluate transcriptomic profiling of mutant versus wild-type (WT) retinal pigment epithelium (RPE)/choroid. Zfp503 KO mice were generated by gene targeting using homologous recombination. Embryos were characterized grossly and histologically. Patterns and level of developmentally relevant proteins/genes were examined with immunostaining/in situ hybridization. The transcriptomic profile of E11.5 KO RPE/choroid was compared to that of WT. Zfp503 is dynamically expressed in developing mouse eyes, and loss of its expression results in uveal coloboma. KO embryos exhibit altered mRNA levels and expression patterns of several key transcription factors involved in eye development, including Otx2, Mitf, Pax6, Pax2, Vax1, and Vax2, resulting in a failure to maintain the presumptive RPE, as evidenced by reduced melanin pigmentation and its differentiation into a neural retina-like lineage. Comparison of RNA sequencing data from WT and KO E11.5 embryos demonstrated reduced expression of melanin-related genes and significant overlap with genes known to be dynamically regulated at the optic fissure. These results demonstrate a critical role of Zfp503 in maintaining RPE fate and optic fissure closure.

Clinical and Demographic Profile of Uveal Coloboma: A Hospital-Based Study of 14,371 Eyes of 9557 Indian Patients

To describe the demographics and clinical profile of uveal coloboma in patients presenting to a multi-tier ophthalmology hospital network in India. Cross-sectional hospital-based study. This cross-sectional, hospital-based study included 2,817,766 new patients presenting between August 2010 and May 2021. Patients with a clinical diagnosis of uveal coloboma in at least 1 eye were included as cases. Data were collected using an electronic medical record system. Overall, 9557 patients (0.34%) were diagnosed with uveal coloboma. Just over half of the patients were male (51.82%) and were affected bilaterally (50.37%). The most common age group at presentation was individuals in the second decade of life, comprising 2198 patients (23%). The overall prevalence was higher in patients of lower socio-economic status (0.53%) and from rural areas (0.39%). The most common type was retino-choroidal coloboma in 8049 patients (84.22%), followed by iris coloboma in 2129 patients (22.28%). The most common Ida Mann classification in the eyes with retino-choroidal coloboma was type 4 in 7049 eyes (57.23%), followed by type 2 in 3685 eyes (29.92%). Of the 14,371 eyes, 5696 eyes (39.64%) had a visual impairment of blindness (>20/400), followed by mild or no visual impairment (<20/70) in 2875 eyes (20.01%). In the 2228 eyes (15.5%) that required a surgical/ laser intervention, cataract surgery was performed in 951 eyes (6.62%), vitreo-retinal surgery in 661 eyes (4.6%), followed by laser photocoagulation in 357 eyes (2.48%). Uveal coloboma is more common in male individuals and is predominantly bilateral in the population studied. It is more commonly found in patients from lower socio-economic strata and from a rural background. The most common type is retino-choroidal coloboma, and more than one-third of the eyes are affected by blindness.

Microphthalmos with Orbital Cyst: Case series with a review of literature

Microphthalmos with orbital cyst is a rare congenital abnormality of fetal fissure closure leading to a small eyeball associated with an orbital cyst. In this case series, we describe six such cases and discuss the clinical features, differential diagnosis, diagnostic modalities, and management in accordance with the existing literature. Out of the six cases, four were male and two were females. All the cases presented with a swelling in the lower eyelid of the involved eye, which was the right eye in all the male patients and the left eye in all the female cases. Other eye showed uveal coloboma in 50% of the cases. Microphthalmos with orbital cyst was diagnosed based on the clinical features and radiological findings (ultrasonography B-scan and/or Computed Tomography scan). Two patients from our case series underwent surgery (cyst excision with enucleation of microphthalmic eye with orbital implant and conformer) and, histopathology confirmed the diagnosis of microphthalmos with orbital cyst. Microphthalmos with orbital cyst presents as a swelling of the lower eyelid since birth in which a careful examination often reveals a microphthalmic eye. Two such cases in our case series were managed with orbital cyst excision and enucleation of microphthalmic eye followed by orbital implant and conformer, leading to good cosmetic results.

Bilateral congenital uveal coloboma concurrent with retinal detachment.

Bilateral congenital uveal coloboma concurrent with retinal detachment.

Imaging the pediatric retina: An overview.

Recent decade has seen a shift in the causes of childhood blinding diseases from anterior segment to retinal disease in both developed and developing countries. The common retinal disorders are retinopathy of prematurity and vitreoretinal infections in neonates, congenital anomalies in infants, and vascular retinopathies including type 1 diabetes, tumors, and inherited retinal diseases in children (up to 12 years). Retinal imaging helps in diagnosis, management, follow up and prognostication in all these disorders. These imaging modalities include fundus photography, fluorescein angiography, ultrasonography, retinal vascular and structural studies, and electrodiagnosis. Over the decades there has been tremendous advances both in design (compact, multifunctional, tele-consult capable) and technology (wide- and ultra-wide field and noninvasive retinal angiography). These new advances have application in most of the pediatric retinal diseases though at most times the designs of new devices have remained confined to use in adults. Poor patient cooperation and insufficient attention span in children demand careful crafting of the devices. The newer attempts of hand-held retinal diagnostic devices are welcome additions in this direction. While much has been done, there is still much to do in the coming years. One of the compelling and immediate needs is the pediatric version of optical coherence tomography angiography. These needs and demands would increase many folds in future. A sound policy could be the simultaneous development of adult and pediatric version of all ophthalmic diagnostic devices, coupled with capacity building of trained medical personnel.

Asymmetric diabetic retinopathy.

Increasing prevalence of diabetes mellitus warrants recognition of factors related to asymmetric diabetic retinopathy (DR). This thematic synthesis based on an iterative literature review conducted in Medline and Google Scholar pertaining to diabetes with coexistent asymmetry of retinopathy included 45 original articles, 21 case reports and series, and 18 review articles from 1965 to 2020. Asymmetric DR is defined as proliferative DR (PDR) in one eye and nonproliferative, preproliferative, background, or no DR in the other eye lasting for at least 2 years. It is observed in 5%–10% of patients with PDR. Associated factors can be divided into (i) vascular: carotid obstructive disease, ocular ischemic syndrome, and retinal vascular diseases; (ii) Inflammatory: uveitis, endophthalmitis, and Fuchs’ heterochromic cyclitis; (iii) degenerative: posterior vitreous detachment, high myopia and anisometropia, uveal coloboma, retinal detachment, retinitis pigmentosa, and chorioretinal atrophy and scarring; (iv) cataract surgery and vitrectomy; and (v) miscellaneous: elevated intraocular pressure, glaucoma, amblyopia, retinal detachment, and optic atrophy. The gamut of diagnostic modalities for asymmetric DR includes thorough ocular examination, slit-lamp biomicroscopy, fundus photography, fundus fluorescein angiography, optical coherence tomography, and newer modalities such as ultra-widefield fluorescein angiography and optical coherence tomography angiography, along with a complete systemic evaluation and carotid Doppler studies. The differential diagnosis includes other causes of retinal neovascularization that may present in an asymmetric manner, such as sickle cell retinopathy, retinal vein occlusions, and featureless retina. This review discusses in detail the aforementioned considerations and draws a comprehensive picture of asymmetric DR in order to sensitize ophthalmologists to this important condition.

Nf2 fine-tunes proliferation and tissue alignment during closure of the optic fissure in the embryonic mouse eye.

Uveal coloboma represents one of the most common congenital ocular malformations accounting for up to 10% of childhood blindness (~1 in 5000 live birth). Coloboma originates from defective fusion of the optic fissure (OF), a transient gap that forms during eye morphogenesis by asymmetric, ventral invagination. Genetic heterogeneity combined with the activity of developmentally regulated genes suggests multiple mechanisms regulating OF closure. The tumor suppressor and FERM domain protein Neurofibromin 2 (NF2) controls diverse processes in cancer, development and regeneration, via Hippo pathway and cytoskeleton regulation. In humans, NF2 mutations can cause ocular abnormalities, including coloboma, however, its actual role in OF closure is unknown. Using conditional inactivation in the embryonic mouse eye, our data indicate that loss of Nf2 function results in a novel underlying cause for coloboma. In particular, mutant eyes show substantially increased retinal pigmented epithelium (RPE) proliferation in the fissure region with concomitant acquisition of RPE cell fate. Cells lining the OF margin can maintain RPE fate ectopically and fail to transition from neuroepithelial to cuboidal shape. In the dorsal RPE of the optic cup, Nf2 inactivation leads to a robust increase in cell number, with local disorganization of the cytoskeleton components F-actin and pMLC2. We propose that RPE hyperproliferation is the primary cause for the observed defects causing insufficient alignment of the OF margins in Nf2 mutants and failure to fuse properly, resulting in persistent coloboma. Our findings indicate that limiting proliferation particularly in the RPE layer is a critical mechanism during OF closure.

Cataract surgery in eyes with congenital ocular coloboma.

To assess the safety, efficacy, and complication rate of phacoemulsification and intraocular lens (IOL) implantation in patients with congenital uveal coloboma and to evaluate the role of pupilloplasty. A retrospective review of 41 eyes (31 patients) with congenital coloboma that underwent phacoemulsification and IOL implantation between September 2012 and September 2018. Preoperative, intraoperative, and postoperative data were collected for analysis. The mean patient age at surgery was 53.9years (range 15-82). The primary indication for surgery was cataract removal for visual improvement, and lens subluxation was additionally present in two eyes (5%) preoperatively. The mean preoperative corrected distance visual acuity (CDVA) was 0.90 LogMAR. Phacoemulsification surgery was performed in all cases and nine eyes (22%) had pupilloplasty for pupil reconstitution at the time of the procedure. Surgeon grade varied from trainee surgeon under supervision to consultant. Eight patients (19.5%) had posterior capsular rupture (PCR) with or without vitreous loss requiring anterior vitrectomy. Of these, 2 cases (5%) had dropped nuclear fragments requiring subsequent pars plana vitrectomy and lens fragment removal. The mean postoperative CDVA was 0.62 LogMAR (p = 0.0003). Patients with iridolenticular choroidal coloboma appear to be more at risk of complications, as were cases performed by non-consultant surgeons. Contrary, patients with phakodonesis, preoperative anterior chamber vitreous, dense cataracts, and cases were iris hooks used had no significant difference at PCR rate. The risk of postoperative glare and pupilloplasty needs to be considered in cases with good visual potential to avoid a possible second procedure.

Ocular and Systemic Findings in Adults with Uveal Coloboma

Although visual acuity is largely stable in adults with coloboma, they are at risk of being labelled as glaucoma suspects and developing early-onset cataracts. Broad systemic screening may identify previously unnoticed comorbidities.

High-throughput custom capture sequencing identifies novel mutations in coloboma-associated genes: Mutation in DNA-binding domain of retinoic acid receptor beta affects nuclear localization causing ocular coloboma.

Uveal coloboma is a potentially blinding congenital ocular malformation caused by the failure of optic fissure closure during the fifth week of human gestation. We performed custom capture high‐throughput screening of 38 known coloboma‐associated genes in 66 families. Suspected causative novel variants were identified in TFAP2A and CHD7, as well as two previously reported variants of uncertain significance in RARB and BMP7. The variant in RARB, unlike previously reported disease mutations in the ligand‐binding domain, was a missense change in the highly conserved DNA‐binding domain predicted to affect the protein's DNA‐binding ability. In vitro studies revealed lower steady‐state protein levels, reduced transcriptional activity, and incomplete nuclear localization of the mutant RARB protein compared with wild‐type. Zebrafish studies showed that human RARB messenger RNA partially reduced the ocular phenotype caused by morpholino knockdown of rarga gene, a zebrafish homolog of human RARB. Our study indicates that sequence alterations in known coloboma genes account for a small percentage of coloboma cases and that mutations in the RARB DNA‐binding domain could result in human disease.

Childhood blindness - Etiological risk factors as evaluated by blind schools survey in Prayagraj and surrounding districts

Aim: The purpose of our study is to examine and evaluate avoidable i.e. preventable or treatable causes and etiological risk factors responsible for childhood blindness. Materials and Methods: The study was conducted by examining total 159 Students in four schools for blinds and four accelerated learning camps situated in Prayagraj and three neighbouring districts - Fatehpur, Koushambi and Pratapgarh. Basic informations including time, duration and mode of vision loss, was obtained. Careful prenatal, natal and postnatal history was also gathered. Vision assessment was done by snellen’s, Echarts or broken rings, student’s behaviour while walking, talking, moving head etc. Anterior segment and fundus examination was also done. We tried to evaluate causes and it aetiogolical risk factors responsible for childhood blindness in every blind student. Results: In about 80% of blind children cause was, microphthalmos, Anophthalmos, Buphthalmos, Corneal Conditions as staphyloma or scarring, uveal coloboma. Although R.O.P., R.D. and optic nerve diseases also contributed. Four students were not requiring admission, yet admitted. Specialized teachers were not available. Conclusion: Approximately 80% of childhood blindness may be avoidable i.e. preventable or treatable. Meticulous prenatal, natal and post natal care as avoiding medicines and x-rays during Ist trimesters, harmful traditional medications, nutritional & anti infective measures, safe delivery and effective immunization may reduce childhood blindness considerably. Keywords: Severe visual impairment, Microphthalmos, Anopthalmos, Buphthalmos.

Localisation atypique d’un colobome cristallinien

Nous rapportons le cas d'un patient âgé de 37 ans, sans antécédents pathologiques particuliers, se présentant à la consultation d'ophtalmologie pour changement de correction optique. L'examen de l'œil droit retrouve une acuité visuelle corrigée à 6/10ème, une réfraction automatique à -1,50 (-6,25 à 56°), l'examen du segment antérieur retrouve un colobome cristallinien en supéro-temporal avec défect zonulaire allant de 8h à 11h et une opacité cristallinienne en regard. L'examen de l'iris et du fond d'œil sont normaux. L'examen de l'œil gauche est sans particularité. Les colobomes sont des malformations congénitales de l'œil secondaires à une anomalie de fermeture de la fente fœtale. Le colobome cristallinien reste une localisation rare de cette malformation; secondaire à un colobome uvéal entraîne un aspect d'indentation de la périphérie du cristallin, sa localisation est classiquement inféro-nasale. La particularité de notre cas est la localisation du colobome cristallinien en supéro-temporale. Il faut rechercher une opacité cristallinienne en regard d'autres anomalies colobomateuses, et des malformations oculaires associées comme la cataracte, la microphtalmie ou l'ectopie cristallinienne.

“Two's company, three's a crowd”: Retinal vein occlusion in an eye with optic disc pit and uveal coloboma

“Two's company, three's a crowd”: Retinal vein occlusion in an eye with optic disc pit and uveal coloboma

Corneal Endothelial Cell Density in Uveal Coloboma Associated With Microcornea.

To evaluate the relationship between endothelial cell density (ECD) and mean corneal diameter (MCD) in eyes with uveal coloboma associated with microcornea. Corneal endothelial cell imaging was performed using specular microscopy on 22 eyes of 18 subjects diagnosed with uveal coloboma associated with microcornea. The MCD was noted as the average of horizontal and vertical corneal diameters, which were measured using the ruler tool of the slit-lamp biomicroscope and Castroviejo calipers. Mean age of the study subjects was 29.7 ± 10.4 years (range, 14-46 years). The MCD was 7.3 ± 1.1 mm (range, 4.9-9 mm). Mean ECD (3436 ± 316.2 cells/mm) of the study subjects was significantly (P < 0.0001) higher than the mean ECD (2761.8 ± 140.9 cells/mm) of age-matched (range, 10-40 years) normal eyes with no ocular pathology. The pleomorphism and polymegathism were comparable between the 2 groups. Regression analysis showed that MCD had a significant negative (R = -0.55; P = 0.02) relationship with ECD. Eyes with congenital uveal coloboma associated with microcornea have increased ECD. Increased ECD may be partly due to a reduced posterior corneal surface area in microcornea.

Emerging trends in childhood blindness and ocular morbidity in India: the Pavagada Pediatric Eye Disease Study 2

To discuss the aims, methods, and results of a population-based cross-sectional prevalence survey of children ≤15 years, in South India and compare it with a study conducted earlier, in the same area. We also discuss the changing trends in the domain of childhood blindness in India. A population-based cross-sectional prevalence survey of children ≤15 years, in Pavagada and Madhugiri taluks of Tumkur district in Karnataka state in south India, was conducted in 2 phases. One trained medical-social-worker and one field-investigator identified eligible children and brought them to a makeshift clinic in the village school, where they were examined by an ophthalmologist. Children with minor problems were treated on the field and those with major conditions were referred to the pediatric ophthalmologist in the tertiary hospital. The prevalence of specific diseases were calculated in percentages. The prevalence of childhood ocular morbidity (COM) was 6.54%. Refractive errors (2.77%) constituted the major cause of COM. The prevalence of blindness (best corrected visual acuity of <3/60 in the better eye) was 0.09%. Whole-globe anomalies (25%) and uveal coloboma (25%) constituted the main cause of blindness. A major proportion of the blindness was due to unavoidable causes. Unlike several earlier studies, corneal blindness is no longer the main cause of blindness. This shows that there is a changing trend in the pattern of childhood blindness in India. The current data demonstrate the need for low vision rehabilitative services and a review of public health strategy in India.