Anterior Segment Dysgenesis Research Articles

Clinical features and results of surgical treatment of congenital corneal opacities in infants and children under 3 years of age

Congenital corneal opacities (CCO) are rare eye anomalies of various etiological causes. Given the heterogeneity of the clinical and morphological manifestations of CCO, its functional disorders are of the same type and significant, leading to visual disability. This anomaly occurs in 6 per 100,000 newborns.
 AIM: To study the clinical and anatomical features and treatment results of CCO in children aged under 3 years old, who were treated in the Department of Eye Pathology in Children of Helmholtz National Medical Research Center of Eye Diseases for the period from January 1, 2010, to December 31, 2022 (12 years).
 MATERIAL AND METHODS: The clinical and anatomical features and results of surgical treatment of 142 patients (172 eyes) with CCO aged 0–3 years were analyzed in the period from January 1, 2010, to December 31, 2022. According to the clinical picture, all CCOs were classified as congenital glaucoma, sclerocornea, Peters anomaly, anterior staphyloma, endothelial corneal dystrophy, dermoid, and Axenfeld–Rieger syndrome, and were idiopathic. Surgical methods included end-to-end keratoplasty, layered keratoplasty, limbokeratoplasty, and end-to-end reconstructive keratoplasty, including synechial excision, cataract removal, pupil formation, and anterior vitrectomy. The treatment results were evaluated based on the biological and functional results. The biological results of the operation (graft engraftment) were evaluated in the Kaplan–Meier model.
 RESULTS: Congenital glaucoma dominates among clinical diagnoses of CCO (40% of all cases), followed by Peters anomaly, sclerocornea, congenital hereditary endothelial corneal dystrophy, other hereditary corneal dystrophies and anterior staphyloma, Axenfeld–Rieger syndrome, and corneal dermoid. In 5 (3%) cases, the CCO was defined as idiopathic. Surgical treatment was performed on 78 (86 eyes) out of 142 (54.9%) patients. The 1-year survival rate following transplants in patients with high blood pressure was 75%; with Peters anomaly, 67%; and with sclerocornea, 54%, and the 2-year survival rates were 70%, 63%, and 36%, respectively. The 1 and 2 years urvival rates following transplants in patients with congenital endothelial hereditary dystrophy were 88 and 82%, respectively.
 CONCLUSION: The results show that CCO manifest heterogeneously in children aged under 3 years old. Careful anamnesis collection, thorough clinical examination, and additional studies such as UBM are crucial in obtaining accurate diagnosis and classification of CCO and provide recommendations on treatment strategies.

The Pkhd1del3-67 Deletion Disrupts Local Genomic Architecture Resulting in Reduced Expression of Tfap-2b in the Developing Eye and Peters Anomaly

The Pkhd1del3-67 Deletion Disrupts Local Genomic Architecture Resulting in Reduced Expression of Tfap-2b in the Developing Eye and Peters Anomaly

A Slc38a8 Mouse Model of FHONDA Syndrome Faithfully Recapitulates the Visual Deficits of Albinism Without Pigmentation Defects.

We aimed to generate and phenotype a mouse model of foveal hypoplasia, optic nerve decussation defects, and anterior segment dysgenesis (FHONDA), a rare disease associated with mutations in Slc38a8 that causes severe visual alterations similar to albinism without affecting pigmentation. The FHONDA mouse model was generated with clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 technology using an RNA guide targeting the Scl38a8 murine locus. The resulting mice were backcrossed to C57BL/6J. Melanin content was measured using spectrophotometry. Retinal cell architecture was analyzed through light and electron microscopy. Retinal projections to the brain were evaluated with anterograde labelling in embryos and adults. Visual function was assessed by electroretinography (ERG) and the optomotor test (OT). From numerous Slc38a8 mouse mutant alleles generated, we selected one that encodes a truncated protein (p.196Pro*, equivalent to p.199Pro* in the human protein) closely resembling a mutant allele described in patients (p.200Gln*). Slc38a8 mutant mice exhibit wild-type eye and coat pigmentation with comparable melanin content. Subcellular abnormalities were observed in retinal pigment epithelium cells of Slc38a8 mutant mice. Anterograde labeling experiments of retinal projections in embryos and adults showed a reduction of ipsilateral fibers. Functional visual analyses revealed a decreased ERG response in scotopic conditions and a reduction of visual acuity in mutant mice measured by OT. Slc38a8 mutant mice recapitulate the phenotype of patients with FHONDA concerning their normal pigmentation and their abnormal visual system, in the latter being a hallmark of all types of albinism. These mice will be helpful in better understanding the pathophysiology of this genetic condition.

Analysis of long-term outcomes of penetrating keratoplasty for congenital corneal opacity

Objective: To investigate the long-term outcomes of corneal grafts after penetrating keratoplasty(PK) for congenital corneal opacity(CCO) in children aged 0 to 5 years and the related influencing factors. Methods: It was a retrospective series case study. Data of 39 children (55 eyes) who underwent PK surgery due to CCO in the keratology Department of Beijing Tongren Hospital from April 2014 to April 2018 and were followed up for more than 30 months were collected. Among them, there were 17 males (43.6%) and 22 females (56.4%). The age at operation was (16.2±13.3) months, and the follow-up time was (46.4±13.8) months. Clinical data such as basic information, preoperative diagnosis, operation age, operation method and postoperative complications were recorded. The corneal graft transparency was analyzed according to preoperative diagnosis, corneal neovascularization area, age at surgery, monocular or binocular surgery interval, primary surgery type and further surgery, and postoperative complications were observed. Results: At 12 months, 24 months and the last follow-up after PK, 78.2% (43/55), 70.9% (39/55) and 58.2% (32/55) of the affected eyes had clear corneal grafts, respectively.There was no statistical significance between Peters anomaly and sclerocornea (P>0.05), while the extent of neovascularization in the limbus had a significant effect on corneal graft transparency, and graft opacity was more likely to occur in patients with vessel area exceeding 2 quadrants (P<0.05).The highest corneal graft transparency was found in children aged 1 to 3 years 80.8%(21/26) (P<0.05), followed by children younger than 6 months (7/15).The translucency rate of the corneal graft was higher in patients undergoing unilateral surgery than in those undergoing bilateral surgery (P<0.05).Translucency of corneal graft was higher in children with simple surgery than with combined surgery (P<0.05), however, cataract surgery after PK had no significant effect on corneal graft transparency (P>0.05).The postoperative complications mainly included immune rejection in 19 eyes (34.5%), complicated cataract in 13 eyes (23.6%), glaucoma in 7 eyes (13.2%), persistent corneal epithelial defect in 7 eyes (13.2%). Conclusions: After PK in children with CCO, the transparent rate of corneal grafts decreases gradually with time, but the long-term translucency of corneal grafts can still be obtained. The range of corneal neovascularization, age at the time of surgery, whether the surgery was binocular and whether the surgery was combined had an effect on the transparency of corneal graft.

Variable Phenotype of Congenital Corneal Opacities in Biallelic CYP1B1 Pathogenic Variants.

The aim of this study is to describe the variable phenotype of congenital corneal opacities occurring in patients with biallelic CYP1B1 pathogenic variants. A retrospective chart review was conducted to identify patients with congenital corneal opacities and CYP1B1 pathogenic variants seen at UPMC Children's Hospital of Pittsburgh. Ophthalmic examination, high-frequency ultrasound, anterior segment optical coherence tomography, histopathologic images, and details of genetic testing were reviewed. Three children were identified. All presented with raised intraocular pressure. Two patients showed bilateral limbus-to-limbus avascular corneal opacification that did not resolve with intraocular pressure control; 1 showed unilateral avascular corneal opacity with a crescent of clear cornea, iridocorneal adhesions, iridolenticular adhesions, and classical features of congenital glaucoma in the fellow eye (enlarged corneal diameter, Haab striae, and clearing of the corneal clouding with appropriate intraocular pressure control). The first 2 patients were visually rehabilitated with penetrating keratoplasty. Histopathology revealed distinct features: a variably keratinized epithelium; a thick but discontinuous Bowman-like layer with areas of disruption and abnormal cellularity; Descemet membrane, when observed, showed reduced endothelial cells; and no pathological changes of Haab striae were identified. Two patients had compound heterozygous pathogenic variants in CYP1B1 causing premature stop codons, whereas 1 was homozygous for a pathogenic missense variant. Congenital corneal opacities seen in biallelic CYP1B1 pathogenic variants have a variable phenotype. One is that commonly termed as Peters anomaly type 1 (with iridocorneal adhesions, with or without iridolenticular adhesions) and the other is a limbus-to-limbus opacity, termed CYP1B1 cytopathy. Clinicians should be aware of this phenotypic variability.

Risk and Prognostic Factors for Glaucoma Associated with Peters Anomaly.

Glaucoma secondary to Peters anomaly is an important factor affecting visual prognosis, but there are few reports on the condition. This study aimed to investigate the characteristics of glaucoma associated with Peters anomaly and glaucoma surgery outcomes. This retrospective study included 31 eyes of 20 patients with Peters anomaly. Peters anomaly was classified into three stages: Stage 1, with a posterior corneal defect only; Stage 2, a corneal defect with iridocorneal adhesion; and Stage 3, a corneal defect with lens abnormalities. The associations between glaucoma and anterior segment dysgenesis severity, visual prognosis, and glaucoma surgery outcomes were analyzed. Sixteen eyes of ten patients developed glaucoma. Stage 1 Peters anomaly had no glaucoma, 52% of Stage 2 had glaucoma, and 75% of Stage 3 had glaucoma. Of the 16 eyes with glaucoma, 11 underwent surgery. Eight of these eleven eyes achieved intraocular pressure (IOP) control. Five of the nine eyes that underwent trabeculotomy (TLO) succeeded, and none had corneal staphyloma. Three of the four eyes for which TLO was ineffective had corneal staphyloma (p = 0.0331). Patients with Peters anomaly are more likely to develop glaucoma as anterior segment dysgenesis progresses, and the effect of TLO is limited if corneal staphyloma is present.

A novel missense variant expands the phenotype and genotype of PAX6-associated foveal hypoplasia accompanied by various manifestations of anterior segment dysgenesis

BackgroundAccording to previous reports, PAX6-associated foveal hypoplasia (FH) could usually be accompanied by various anterior segment anomalies including variable iris changes. This study aims to exhibit unusual phenotypes of a novel missense variant of PAX6 from a Chinese pedigree.MethodsOphthalmic examinations including slit-lamp biomicroscopy, gonioscopy, ophthalmic ultrasound, ultrasonic biomicroscopy, optical coherence tomography, wide-field fundus imaging, and visual field test were performed to evaluate the clinical manifestations. Whole-exome sequencing (WES) and bioinformatics analysis were conducted in eight members from this pedigree to identify the causative mutation.ResultsWES revealed a novel heterozygous substitution of PAX6 (NM_000280.5:c.157G > A, p.(Val53Met) (chr11:31823309 C > T, hg19)), which cosegregated with the phenotype of this pedigree. All the three patients (a pair of fraternal twins and their mother) exhibited bilateral FH and anterior segment dysgenesis (ASD) including microcornea, sclerocornea, obvious symmetrical corectopia, iris stromal dysplasia, goniodysgenesis, and abnormal distribution of fundus blood vessels. The girl of the fraternal twins also demonstrated bilateral temporal deviation of lenses and abnormal tissue membrane connecting anterior chamber angle and lens anterior capsule in the right eye. The mother additionally showed apparent cataract bilaterally and cupping of the optic disc in her left eye.ConclusionA novel missense variant in PAX6 gene was detected in a Chinese pedigree demonstrating bilateral FH and ASD. It is really distinctive that the ASD involves almost all parts of the anterior segment, and bilateral symmetrical corectopia is the most perceptible sign. This study expands the phenotypic and genotypic spectrum of PAX6-associated ocular diseases, and facilitates the understanding of the crucial role that PAX6 plays in the development of the eye. Meanwhile, PAX6 could be considered as a candidate pathogenic gene of bilateral symmetrical corectopia.

Peters' anomaly in one premature twin following hydroxychloroquine exposure during pregnancy: A Case Report.

Peters' anomaly in one premature twin following hydroxychloroquine exposure during pregnancy: A Case Report.

Spectrum of white matter abnormalities associated with FOXC1-related disorders in two unrelated cases.

The purpose of this study is to document the wide spectrum of white matter abnormalities associated with FOXC1 pathogenic variants. We report two adult individuals-a 60-year-old individual and a 24-year-old one, presenting with hearing loss, anterior eye segment dysgenesis, and very different severity of cerebral small vessel disease. Molecular testing documented the presence of FOXC1 pathogenic variants in both individuals. Our paper documents the broad spectrum of radiological white matter involvement in adult individuals with FOXC1-related disorders. Mild forms of FOXC1-related small vessel disease, as we observed in individual 2, should be included in the list of genetic mimickers of MS.

Knockout of miR-184 in zebrafish leads to ocular abnormalities by elevating p21 levels.

miR-184 is one of the most abundant miRNAs expressed in the lens and corneal tissue. Mutations in the seed region of miR-184 are responsible for inherited anterior segment dysgenesis. Animal models recapitulating miR-184-related anterior segment dysgenesis are still lacking, and the molecular basis of ocular abnormalities caused by miR-184 dysfunction has not been well elucidated in vivo. In the present study, we constructed a miR-184-/- zebrafish line by destroying both two dre-mir-184 paralogs with CRISPR-Cas9 technology. Although there were no gross developmental defects, the miR-184-/- zebrafish displayed microphthalmia and cataract phenotypes. Cytoskeletal abnormalities, aggregation of γ-crystallin, and lens fibrosis were induced in miR-184-/- lenses. However, no obvious corneal abnormalities were observed in miR-184-/- zebrafish. Instead of apoptosis, deficiency of miR-184 led to aberrant cell proliferation and a robust increase in p21 levels in zebrafish eyes. Inhibition of p21 by UC2288 compromised the elevation of lens fibrosis markers in miR-184-/- lenses. RNA-seq demonstrated that levels of four transcriptional factors HSF4, Sox9a, CTCF, and Smad6a, all of which could suppress p21 expression, were reduced in miR-184-/- eyes. The predicted zebrafish miR-184 direct target genes (e.g., atp1a3a and nck2a) were identified and verified in miR-184-/- eye tissues. The miR-184-/- zebrafish is the first animal model mimicking miR-184-related anterior segment dysgenesis and could broaden our understanding of the roles of miR-184 in eye development.

A temporal single cell transcriptome atlas of zebrafish anterior segment development

Anterior segment dysgenesis (ASD), resulting in vision impairment, stems from maldevelopment of anterior segment (AS) tissues. Incidence of ASD has been linked to malfunction of periocular mesenchyme cells (POM). POM cells specify into anterior segment mesenchyme (ASM) cells which colonize and produce AS tissues. In this study we uncover ASM developmental trajectories associated with formation of the AS. Using a transgenic line of zebrafish that fluorescently labels the ASM throughout development, Tg[foxc1b:GFP], we isolated GFP+ ASM cells at several developmental timepoints (48–144 hpf) and performed single cell RNA sequencing. Clustering analysis indicates subdifferentiation of ASM as early as 48 hpf and subsequent diversification into corneal epithelium/endothelium/stroma, or annular ligament (AL) lineages. Tracking individual clusters reveals common developmental pathways, up to 72 hpf, for the AL and corneal endothelium/stroma and distinct pathways for corneal epithelium starting at 48 hpf. Spatiotemporal validation of over 80 genes found associated with AS development demonstrates a high degree of conservation with mammalian trabecular meshwork and corneal tissues. In addition, we characterize thirteen novel genes associated with annular ligament and seven with corneal development. Overall, the data provide a molecular verification of the long-standing hypothesis that POM derived ASM give rise to AS tissues and highlight the high degree of conservation between zebrafish and mammals.

Ocular Manifestations of Peters Plus-Like Syndrome in 8q21.11 Microdeletion Syndrome.

The aim of this study was to report a case of Peters plus-like syndrome, which revealed to have an 8q21.11 microdeletion by copy number variation analysis using exome data. A 6-month-old Japanese boy presented with bilateral corneal opacity since birth. The right eye maintained central corneal transparency with slightly inferior nasal and superior peripheral corneal opacities. The entire cornea was opacified in the left eye, particularly in the superior quadrants with vascularization, suggesting Peters anomaly. Identification of intraocular structures in the left eye was difficult; however, hypoplasia of the circumferential anterior iris stroma appeared bilaterally present, and no abnormalities were present in the posterior segment on funduscopic examination of the right eye and ultrasonography in the left eye. He had several facial malformations in addition to corneal opacity, but no other external abnormalities. General examination, including biochemical tests of blood and urine, physiological and imaging tests including abdominal echo, auditory brain stem response, brain computed tomography, and magnetic resonance imaging, showed no abnormalities. However, the patient showed intellectual disability and delayed motor development. Although his karyotype was normal, copy number variation analysis using exome data and subsequent quantitative polymerase chain reaction identified a de novo 4.6-Mb deletion at 8q21.11q21.13; thus, the patient was diagnosed with 8q21.11 microdeletion syndrome. We identified a de novo 4.6-Mb deletion at 8q21.11q21.13 in a patient with ophthalmic anterior segment dysgenesis and systemic complications, clinically diagnosed as Peters plus-like syndrome. Clinically, the 8q21.11 microdeletion syndrome shows a phenotype similar to that of Peters plus syndrome, and a genetic diagnosis is required.

Imbalanced symmetry of anterior segment dysgenesis – A novel case report and review of literature

Anterior segment dysgenesis (ASD) is a spectrum of disorders affecting the anterior chamber structures and is frequently associated with glaucoma and corneal opacity. It usually has bilateral presentation. We report a case of a 22-year-old male with unilateral Peters anomaly. However, on detailed examination, trabeculodysgenesis was noted in the fellow eye. This highlights the importance of a complete bilateral ocular examination with gonioscopy even in unilateral congenital ASD, which can aid in early diagnosis and management.

Современные методы диагностики аномалии Петерса

Peters anomaly is a rare disease, significant in its consequences and leading to disability. According to the literature, Peters anomaly was recorded in approximately 700 cases in Russia, and around the world about 35,000 people have various forms of this pathology. The main cause of occurrence is the presence of a genetic mutation. The disease has a variety of phenotypic manifestations, differently interpreted by the authors depending on the research methods used and clinical experience. An important step in determining the optimal tactics and timing of surgical intervention for Peters anomaly is a thorough diagnostic examination of the child. The data presented in the literature indicate that optical coherence tomography and ultrasound biomicroscopy are highly informative research methods for corneal opacity. Their data are indispensable in making the correct diagnosis of Peters anomaly, determining the subtype and severity of the process, as well as choosing further tactics for managing patients. An urgent direction for further research is the identification of informative signs of Peters anomaly using modern research methods, the development of a complex of multimodal algorithms for multifaceted diagnostics in establishing a diagnosis, as well as the development of a systematic approach in determining subtypes, choosing tactics for managing and treating this pathology. Key words: Peters anomaly, diagnostic methods, etiology, follow-up, surgical treatment

The phenotypic spectrum of terminal and subterminal 6p deletions based on a social media-derived cohort and literature review

BackgroundTerminal 6p deletions are rare, and information on their clinical consequences is scarce, which impedes optimal management and follow-up by clinicians. The parent-driven Chromosome 6 Project collaborates with families of affected children worldwide to better understand the clinical effects of chromosome 6 aberrations and to support clinical guidance. A microarray report is required for participation, and detailed phenotype information is collected directly from parents through a multilingual web-based questionnaire. Information collected from parents is then combined with case data from literature reports. Here, we present our findings on 13 newly identified patients and 46 literature cases with genotypically well-characterised terminal and subterminal 6p deletions. We provide phenotype descriptions for both the whole group and for subgroups based on deletion size and HI gene content.ResultsThe total group shared a common phenotype characterised by ocular anterior segment dysgenesis, vision problems, brain malformations, congenital defects of the cardiac septa and valves, mild to moderate hearing impairment, eye movement abnormalities, hypotonia, mild developmental delay and dysmorphic features. These characteristics were observed in all subgroups where FOXC1 was included in the deletion, confirming a dominant role for this gene. Additional characteristics were seen in individuals with terminal deletions exceeding 4.02 Mb, namely complex heart defects, corpus callosum abnormalities, kidney abnormalities and orofacial clefting. Some of these additional features may be related to the loss of other genes in the terminal 6p region, such as RREB1 for the cardiac phenotypes and TUBB2A and TUBB2B for the cerebral phenotypes. In the newly identified patients, we observed previously unreported features including gastrointestinal problems, neurological abnormalities, balance problems and sleep disturbances.ConclusionsWe present an overview of the phenotypic characteristics observed in terminal and subterminal 6p deletions. This reveals a common phenotype that can be highly attributable to haploinsufficiency of FOXC1, with a possible additional effect of other genes in the 6p25 region. We also delineate the developmental abilities of affected individuals and report on previously unrecognised features, showing the added benefit of collecting information directly from parents. Based on our overview, we provide recommendations for clinical surveillance to support clinicians, patients and families.

Commercial Gene Panels for Congenital Anterior Segment Anomalies: Are They All the Same?

We compared next generation sequencing multigene panels (NGS-MGP) from 5 commercial laboratories to inform ophthalmologists' decision making in diagnostic genetic testing for congenital anterior segment anomalies (CASAs). Comparison of commercial genetic testing panels. This observational study gathered publicly available information on NGS-MGP from 5 commercial laboratories for the following: cataracts, glaucoma, anterior segment dysgenesis (ASD), microphthalmia-anophthalmia-coloboma (MAC), corneal dystrophies, and Axenfeld-Rieger syndrome (ARS). We compared gene panel composition, consensus rate (genes covered by all the panels per condition, "concurrent"), dissensus rate (genes covered by only 1 panel per condition, "standalone"), and intronic variant coverage. For individual genes, we compared publication history and association with systemic conditions. Altogether, cataract, glaucoma, corneal dystrophies, MAC, ASD, and ARS panels tested 239, 60, 36, 292, and 10 discrete genes, respectively. The consensus rate varied between 16% and 50%, and the dissensus rate varied between 14% and 74%. After pooling concurrent genes from all conditions, 20% of these genes were concurrent in 2 or more conditions. For both cataract and glaucoma, concurrent genes had significantly stronger correlation with the condition than standalone genes. The genetic testing of CASAs using NGS-MGPs is complicated, owing to their number, variety, and phenotypic and genetic overlap. Although the inclusion of additional genes, such as the standalone ones, might increase diagnostic yield, these genes are also less well studied, indicating uncertainty over their role in CASA pathogenesis. Rigorous prospective diagnostic yield studies of NGS-MGPs will aid in making decisions of panel selection for the diagnosis of CASAs.

Missense Mutations in MAB21L1: Causation of Novel Autosomal Dominant Ocular BAMD Syndrome.

Biallelic MAB21L1 variants have been reported to cause autosomal recessive cerebellar, ocular, craniofacial, and genital syndrome (COFG), whereas only five heterozygous pathogenic variants have been suspected to cause autosomal dominant (AD) microphthalmia and aniridia in eight families. This study aimed to report an AD ocular syndrome (blepharophimosis plus anterior segment and macular dysgenesis [BAMD]) syndrome based on clinical and genetic findings from patients with monoallelic MAB21L1 pathogenic variants in our cohort and reported cases. Potential pathogenic variants in MAB21L1 were detected from a large in-house exome sequencing dataset. Ocular phenotypes of the patients with potential pathogenic variants in MAB21L1 were summarized, and the genotype-phenotype correlation was analyzed through a comprehensive literature review. Three heterozygous missense variants in MAB21L1, predicted to be damaging, were detected in 5 unrelated families, including c.152G>T in 2, c.152G>A in 2, and c.155T>G in one. All were absent from gnomAD. The variants were de novo in two families, transmitted from affected parents to offspring in two families, and with an unknown origin in the other family, demonstrating strong evidence of AD inheritance. All patients revealed similar BAMD phenotypes, including blepharophimosis, anterior segment dysgenesis, and macular dysgenesis. Genotype-phenotype analysis suggested that patients with monoallelic MAB21L1 missense variants had only ocular anomalies (BAMD), whereas patients with biallelic variants presented both ocular and extraocular symptoms. Heterozygous pathogenic variants in MAB21L1 account for a new AD BAMD syndrome, which is completely different from COFG caused by homozygous variants in MAB21L1. Nucleotide c.152 is likely a mutation hot spot, and the encoded residue of p.Arg51 might be critical for MAB21L1.

Spectrum of congenital and inherited ocular disorders seen in a genetic clinic: Experience of a developing ocular genetic service.

Hereditary causes are an important etiological category of childhood blindness. This study reports the real-world experience of a developing ocular genetic service. The study was carried out from Jan 2020 to Dec 2021 jointly by the Pediatric Genetic Clinic and the Department of Ophthalmology of a tertiary care hospital in North-West India. Children presenting to the genetic clinic with congenital or late-onset ocular disorder(s) and any individual (irrespective of age) suffering from an ophthalmic disorder and referred by an ophthalmologist for genetic counseling for himself/herself and/or his/her family member(s) were included. Genetic testing (exome sequencing/panel-based sequencing/chromosomal microarray) was outsourced to third-party laboratories with the cost of the test being borne by the patient. Exactly 8.6% of the registered patients in the genetic clinic had ocular disorders. Maximum number of patients belonged to the category of anterior segment dysgenesis, followed by microphthalmia anophthalmia coloboma spectrum, lens disorders, and inherited retinal disorders in decreasing numbers. The ratio of syndromic ocular to isolated ocular disorders seen was 1.8:1. Genetic testing was accepted by 55.5% of families. The genetic testing was clinically useful for ~35% of the tested cohort, with the opportunity for prenatal diagnosis being the most useful application of genetic testing. Syndromic ocular disorders are seen at a higher frequency compared to isolated ocular disorders in a genetic clinic. Opportunity for prenatal diagnosis is the most useful application of genetic testing in ocular disorders.

Clinical profile of Indonesian children with anterior segment dysgenesis as a contributor for childhood blindness

BackgroundAnterior segment dysgenesis (ASD) is an ocular malformation that can lead to childhood blindness. Although ASD prevalence is rare, it is potentially devastating for children and caretakers. We aim to report the clinical features of ASD patients in a tertiary referral center in Indonesia. MethodsWe conducted a retrospective review of medical records of ASD patients in the Pediatric Ophthalmology clinic in Cipto Mangunkusumo National Central Public Hospital, Jakarta, Indonesia between January 1, 2018, and December 31, 2021. ResultsA total of 172 eyes of 107 children with ASD were included in this study. Most of the patients were male, aged 3.4 years ±5.0 SD at first examination, 67.3% patients came from outside Jakarta, and 75.6% of eyes had bilateral ASD. Most common clinical manifestations was congenital corneal opacities (CCO), microcornea, and congenital glaucoma. The most common visual acuity (VA) was fixation and following light/object. Intraocular pressure (IOP) increased in 41% eyes. The most common surgery performed was glaucoma surgery, which was performed in 6.4% of eyes in the study. ConclusionASD has a devastating impact on children's VA, along with its poor prognosis despite surgery thus contributes largely to childhood blindness. ASD detection and management is highly challenging in children, and increased awareness on ASD is pivotal in earlier referral and treatment of ASD.

Diversity of clinical phenotypes in a cohort of Han Chinese patients with PAX6 variants.

The PAX6 gene plays an important role in ocular development. Mutations of the PAX6 gene may result in a series of ocular abnormalities, including congenital aniridia, anterior segment dysgenesis (ASD), progressive corneal opacification, glaucoma, and hypoplasia of the fovea and optic nerve, leading to reduced visual acuity and even blindness. This study aimed to describe the diversity of clinical features caused by PAX6 pathogenic variants in 45 Han Chinese patients from 23 unrelated families. All patients underwent detailed clinical assessment. Genetic testing was performed to identify pathogenic variations in the PAX6 gene by next-generation sequencing, minigene splicing assay, RT-qPCR, and long-range PCR. Twenty pathogenic variations were detected in the PAX6 gene from 12 pedigrees and 11 sporadic patients, of which 12 were previously reported and 8 were novel. The clinical phenotypes obtained as a result of the PAX6 gene mutations were complicated and vary among patients, even among those who carried the same variants. Genetic testing is helpful for differential diagnosis. Our genetic findings will expand the spectrum of pathogenic variations in the PAX6 gene. PAX6 pathogenic variants not only cause defects in ocular tissues, such as the iris and retina, but also lead to maldevelopment of the whole eye, resulting in microphthalmia.