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Abstract Background Anterior segment dysgenesis (ASD) disorders comprises of spectrum of developmental conditions affecting the structures of angle of anterior chamber including cornea, iris, and lens. These conditions are characterized by both autosomal dominant and recessive patterns of inheritance often with incomplete penetrance/variable expressivity. A significant overlap among phenotypes attributed to mutations in different ASD genes is well recognized. Case presentation We present a case involving a 29-year-old pregnant woman referred for genetic screening and counseling. She had a 7-year-old male child with congenital bilateral corneal opacity, and his elder sister also exhibited similar findings. Exome sequencing identified a novel variant in the CYP1B1 gene in a homozygous state, which was associated with anterior segment dysgenesis. Both parents were found to be carriers of the same variant, while the sister had the same variant in a homozygous state. Genotype–phenotype correlation was performed, and it was concluded that the novel variant could be responsible for the eye changes in both siblings. The parents sought prenatal diagnosis for the current pregnancy, which was deemed possible. Conclusions This case underscores the importance of genetic testing in such rare diseases, as it can assist in early diagnosis, management, and prognosis. It also aids clinicians and parents in making decisions regarding the continuation of the pregnancy at the appropriate time.

Abstract Background According 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. Methods Ophthalmic 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. Results WES 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. Conclusion A 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.

Axenfeld-Rieger (AR) syndrome is an inherited Autosomal Dominant (AD) disorder with ocular, dental, and craniofacial defects, whereas AR anomaly presents only with ocular changes. Hereby, the authors present a case report of 40-year-old male patient who reported to the Outpatient Department (OPD) with complaints of diminution of vision in Both Eyes (BE) for three years. There was a significant family history. Visual acuity was limited to hand movements in both eyes. Both eyes showed prominent Schwalbe’s line, iris atrophic patches, and ectropion uvea. Intraocular Pressure (IOP) was high in the Right Eye (RE) and within normal limits in the Left Eye (LE). No craniofacial or dental anomalies were detected. Gonioscopy revealed a closed angle with broad peripheral anterior synechiae in both eyes. Fundus examination revealed a Cup Disc Ratio (CDR) of 0.5 in the RE and 0.9 in the LE. AR anomaly is a rare case. Long-term follow-up of these cases is as important as early diagnosis and treatment to prevent blindness.

Background: Anterior segment dysgenesis (ASD) is a developmental condition that affects the frontal part of the eyes. Genetic mutations in FORKHEAD BOX E3 can lead to a variety of ASD conditions. Case Presentation: Here, we report a 2-year-old female patient with ASD type 2 autosomal recessive linked disease. Whole exome sequencing test was conducted and resulted in a missense mutation at position 120 altering arginine to proline. To our knowledge, this is the first case reported in Oman. Conclusion: For patients with ASD, it is crucial to take the full family history and genetic work up to aid in the diagnosis and long-term management of the condition. [JBCGenetics 2023; 6(1.000): 75-79]

Purpose: To report a case of Axenfeld-Rieger and Stickler Syndrome in a pediatric patient. Observations: A 3-month-old male was referred to the glaucoma clinic after he was noted to have elevated intraocular pressures in both eyes. His family history was notable for infantile glaucoma on his maternal side and retinal detachment on his paternal side. He was found to have anterior segment dysgenesis with iris strands, iridocorneal adhesions, and corectopia, as well as veil-like vitreous in both eyes. He required trabeculotomy, goniotomy, and multiple Baerveldt glaucoma implants in both eyes to achieve intraocular pressure control. Furthermore, the patient later developed macula-involving retinal detachments in both eyes, requiring pars plana vitrectomy with silicone oil tamponade. Genetic analysis confirmed heterozygous pathogenic variants in both the FOXC1 and COL2A1 genes, leading to the concurrent diagnoses of Axenfeld-Rieger and Stickler syndromes. Conclusions and importance: This is a rare case of a patient with concurrent Axenfeld-Rieger and Stickler syndromes. The severity of pathology in both the anterior and posterior segments required a collaborative multidisciplinary approach. In the diagnostic evaluation of congenital eye diseases, if there is strong family history of atypical findings for a given diagnosis, concurrent syndromes should be considered and ruled out. A comprehensive eye genetics panel may be a useful tool in these cases.

PURPOSE: To describe three anterior segment dysgenesis disorders with infantile corneal opacities, namely, congenital hereditary endothelial dystrophy (CHED), primary congenital glaucoma (PCG), and Peters anomaly (PA) in terms of clinical characteristics, histopathology, genetic association, and diagnostic imaging profiles using imaging modalities such as ultrasound biomicroscopy (UBM) and microscope-integrated intraoperative optical coherence tomography (i-OCT). MATERIALS AND METHODS: Seventy-four eyes with 22 eyes of CHED, 28 eyes of PA, and 24 eyes of PCG were clinically evaluated and underwent imaging using UBM and i-OCT. Corneal buttons of 16 operated patients underwent histopathological analysis, while genetic analysis was done in 23 patients using whole-exome sequencing. RESULTS: Corneal diameters (CD) and UBM parameters like anterior chamber depth (ACD), iris thickness (IT), and ciliary body (CB) thickness revealed a statistically significant difference between the three categories. In PA, 9 eyes had a third rare phenotype with only a posterior corneal defect with no iris adhesions. Genetic mutations were seen in all tested patients with CHED, in 83.3% of patients with PCG, and in 80% of patients with the third type of PA. i-OCT helped in the characterization of corneal opacity, identification of posterior corneal defects, iridocorneal adhesions, and contour of Descemet's membrane. CONCLUSION: Overlapping phenotypes of the above disorders cause a diagnostic dilemma and parameters like CDs, UBM ACD, IT, and CB thickness help differentiate between them. i-OCT can help in classifying the diseases in a high resolution, non-contact manner, and can better delineate corneal characteristics. The rare third type of PA phenotype may have a genetic association.

Purpose: Hereditary causes are an important etiological category of childhood blindness. This study reports the real-world experience of a developing ocular genetic service. Methods: 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. Results: 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. Conclusion: 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.

Background: Anterior 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. Methods: We 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. Results: A 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. Conclusion: ASD 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.

Childhood glaucoma is a treatable cause of blindness, provided it is recognized, diagnosed, and treated in time. WHO has estimated that it is responsible for Blind Years second only to cataracts. The fundamental pathophysiology of all childhood glaucoma is impaired outflow through the trabecular meshwork. Anterior segment Dysgeneses (ASD) are a group of non-acquired ocular anomalies associated with glaucoma, characterized by developmental abnormalities of the tissues of the anterior segment. The cause is multifactorial, and many genes are involved in the development of the anterior segment. Over the last decade, molecular and developmental genetic research has transformed our understanding of the molecular basis of ASD and the developmental mechanisms underlying these conditions. Identifying the genetic changes underlying ASD has gradually led to the recognition that some of these conditions may be parts of a disease spectrum. The characterization of genes responsible for glaucoma is the critical first step toward developing diagnostic and screening tests, which could identify individuals at risk for disease before irreversible optic nerve damage occurs. It is also crucial for genetic counseling and risk stratification of later pregnancies. It also aids pre-natal testing by various methods allowing for effective genetic counseling. This review will summarize the known genetic variants associated with phenotypes of ASD and the possible significance and utility of genetic testing in the clinic.

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.

This study includes diagnostic efficacy of the antemortem, combined use of ultrasonography and magnetic resonance imaging (MRI) for the diagnosis of anterior segment dysgenesis. A 7-day-old male Holstein calf presented with progressive unilateral exophthalmos associated with enlargement of the right eyeball soon after birth. Ultrasonography of the enlarged right eyeball showed (1) a 2-cm-thick echogenic parenchymal lesion filling the anterior region of the right eyeball, (2) excess accumulation of the anechoic vitreous humor, and (3) absence of the lens structure. Antemortem examination using T2-weighted and fluid-attenuated inversion recovery MRI revealed a thickened, hyperintense anterior lesion and absence of the lens structure. These imaging findings were suggestive of anterior segment dysgenesis. Antemortem imaging showed no abnormalities other than the abnormal structure and size of the right eyeball; therefore, enucleation of the right eye was performed, which allowed intact healing without suppuration. Ocular ultrasonography enhanced the diagnostic accuracy due to the characteristic ultrasonographic findings of a thickened anterior lesion and absence of the lens structure in the eyeball, suggestive of anterior segment dysgenesis.

Abstract Background Severe congenital ophthalmological malformations and glaucoma might be an important occasional feature in patients with Coffin-Siris syndrome (CSS), especially Coffin-Siris syndrome 9 (CSS9, OMIM #615866) caused by SOX11 mutation. Recently, primary (open-angle) glaucoma was described in two children with the most common form of Coffin-Siris syndrome, CSS1 (OMIM #135900) by ARID1B (AT-rich interaction domain-containing protein 1B) gene mutation. In this article, we present the first report of glaucoma with Coffin-Siris syndrome 9 as well as the first report of secondary glaucoma with any form of Coffin-Siris syndrome. These findings indicate that secondary glaucoma is an occasional finding in patients with Coffin-Siris syndrome. Case presentation A child with secondary childhood glaucoma and additional ocular manifestations was evaluated and treated at the childhood glaucoma centre in Mainz, Germany. Examination under general anaesthesia revealed ocular anterior segment dysgenesis (ASD) (Peters type iridocorneal dysgenesis) in combination with congenital limbal stem cell deficiency (LSCD), aniridia, and cataract. The patient also had multiple other congenital anomalies and severe developmental delay. To explain his combination of anomalies, molecular genetic analysis from peripheral blood was performed in late 2018 and early 2019. Following normal findings with a panel diagnostic of 18 genes associated with congenital glaucoma, whole exome sequencing was performed and revealed a novel likely pathogenic heterozygous variant c.251G>T, p.(Gly84Val) in the SOX11 gene (SRY-related HMG-box gene 11). The variant had occurred de novo. Thus, the multiple congenital anomalies and developmental delay of the patient represented Coffin-Siris syndrome 9 (CSS9, OMIM #615866). Conclusions When eye diseases occur in combination with other systemic features, genetic analysis can be seminal. Results indicate that glaucoma is an occasional feature of patients with Coffin-Siris syndrome. As early treatment may improve the visual outcome of patients with glaucoma, we suggest that patients with Coffin-Siris syndrome should receive specific ophthalmological screening.

Abstract Background Mutations in CRYAA, which encodes the α-crystallin protein, are associated with a spectrum of congenital cataract–microcornea syndromes. Results In this study, we performed clinical examination and subsequent genetic analysis in two unrelated sporadic cases of different geographical origins presenting with a complex phenotype of ocular malformation. Both cases manifested bilateral microphthalmia and severe anterior segment dysgenesis, primarily characterized by congenital aphakia, microcornea, and iris hypoplasia/aniridia. NGS-based analysis revealed two novel single nucleotide variants occurring de novo and affecting the translation termination codon of the CRYAA gene, c.520T > C and c.521A > C. Both variants are predicted to elongate the C-terminal protein domain by one-third of the original length. Conclusions Our report not only expands the mutational spectrum of CRYAA but also identifies the genetic cause of the unusual ocular phenotype described in this report.

Abstract Background Peters plus syndrome (PPS) is a combination of congenital Peters anomaly and systemic abnormalities. It is inherited most commonly in an autosomal recessive pattern with homozygous B3GLCT mutations. Ocular findings consist predominantly anterior segment abnormalities without posterior segment involvement. Case presentation In this presentation, we report a case of PPS with homozygous pathogenic variant in B3GLCT who presented with classic anterior segment findings, systemic abnormalities, as well as atypical bilateral chorioretinal atrophy. The chorioretinal findings were characterized with spectral-domain optical coherence tomography. Conclusions Our report expands the phenotypic descriptions of PPS by characterizing posterior segment findings.

Purpose: To report the clinicopathological features of corneal buttons in patients with congenital primary aphakia. Methods: Five corneal specimens of five patients with congenital primary aphakia who underwent penetrating keratoplasty (PKP) were studied by light microscopy, and immunohistochemistry with anti-smooth muscle (SMA) antibody. Results: All patients were born from consanguineous parents. Of the five, two patients were identical twins. All eyes were microphthalmic. In four patients, congenital primary aphakia was bilateral and in one patient (Patient 3), it was unilateral. PKP failed in all eyes due to hypotony. Histologically, Bowman's layer was absent in all specimens. The corneal stroma was thin; however, the stromal collagen showed thick and irregularly arranged fibers with neovascularization in all eyes. Descemet's membrane and the corneal endothelium were absent in all specimens. In three specimens, atrophic iris tissue without dilator muscle was adherent to the posterior corneal surface. In addition, anteriorly displaced hypoplastic ciliary body and/or pigmented and non-pigmented ciliary epithelium were attached to the posterior corneal surface in three of the five specimens. SMA staining demonstrated disorganized ciliary muscle in one case. SMA-positive stromal keratocytes demonstrated their myofibroblast nature. Conclusion: The corneal findings in congenital primary aphakia are similar to that seen in other causes of congenital corneal opacification. The anteriorly displaced hypoplastic ciliary body that was partially excised during keratoplasty explains the ocular hypotony in these eyes.

We report the phenotype of a 15-year-old female patient with anterior segment dysgenesis (ASD) caused by a novel heterozygous loss-of-function FOXC1 variant. The proband underwent an ophthalmic examination as well as a molecular genetic investigation comprising exome sequencing, a single nucleotide polymorphism array to access copy number and Sanger sequencing to exclude non-coding causal variants. There was bilateral mild iris hypoplasia with pupil deformation and iridocorneal adhesions. In addition to these features of ASD, the corneas were flat, with mean keratometry readings of 38.8 diopters in the right eye and 39.5 diopters in the left eye. There was a snail track lesion of the left cornea at the level of the Descemet membrane. The central corneal endothelial cell density was reduced bilaterally at 1964 and 1373 cells/mm2 in the right and left eyes, respectively. Molecular genetic analysis revealed that the proband was a carrier of a novel heterozygous frameshifting variant in FOXC1, c.605del p.(Pro202Argfs*113). Neither parent had this change, suggesting a de novo origin which was supported by paternity testing. We found no possibly pathogenic variants in the other genes associated with posterior corneal dystrophies or ASD. Further studies are warranted to verify whether there is a true association between snail track lesions, corneal flattening, and pathogenic variants in FOXC1.

Peters’ anomaly (PA) is a rare form of anterior segment dysgenesis characterized by central corneal opacity accompanied by iridocorneal or lenticulo-corneal adhesions. Although genetic mutations, particularly those affecting transcription factors that function in eye development, are known to cause PA, the etiology of this disease remains poorly understood. In this study, 23 patients with PA were recruited for panel sequencing. Four out of 23 patients were found to carry variants in known PA causal genes, PITX2 and PITX3. More importantly, two homozygous mutations (NM_057164: p.Val86Ala and p.Arg689Cys) in the COL6A3 gene (collagen type VI alpha-3 chain) that correlated with the phenotype of type I PA were identified, and then validated by following whole-exome sequencing. The expression profile of the COL6A3 gene in the cornea and the impact of the mutations on protein physiological processing and cellular function were further explored. It was shown that COL6A3 presented relatively high expression in the cornea. The mutant COL6A3 protein was relatively retained intracellularly, and its expression reduced cellular resistance to oxidative stress through an enhanced endoplasmic reticulum stress response. Taken together, our findings expanded the known genetic spectrum of PA, and provided evidence for the involvement of COL6A3 or collagen VI in ocular anterior segment development, thereby offering new insight for future investigations targeting PA.

Anterior segment dysgenesis (ASD) encompasses a wide spectrum of developmental abnormalities of the anterior ocular segment, including congenital cataract, iris hypoplasia, aniridia, iridocorneal synechiae, as well as Peters, Axenfeld, and Rieger anomalies. Here, we report a large five-generation Caucasian family exhibiting atypical syndromic ASD segregating with a novel truncating variant of FOXC1. The family history is consistent with highly variable autosomal dominant symptoms including isolated glaucoma, iris hypoplasia, aniridia, cataract, hypothyroidism, and congenital heart anomalies. Whole-exome sequencing revealed a novel variant [c.313_314insA; p.(Tyr105*)] in FOXC1 that disrupts the α-helical region of the DNA-binding forkhead box domain. In vitro studies using a heterologous cell system revealed aberrant cytoplasmic localization of FOXC1 harboring the Tyr105* variant, likely precluding downstream transcription function. Meta-analysis of the literature highlighted the intrafamilial variability related to FOXC1 truncating alleles. This study highlights the clinical variability in ASD and signifies the importance of combining both clinical and molecular analysis approaches to establish a complete diagnosis.

Abstract Purpose Axenfeld‐Rieger syndrome (ARS) is a rare autosomal dominant disorder that affects the anterior segment of the eye. The aim of this study was to examine the PITX2 gene to identify possible novel mutations in Pakistani and Mexican families affected by the ARS phenotype. Methods Three unrelated probands with a diagnosis of ARS were recruited for this study. Genomic DNA was isolated from the peripheral blood of the probands and their family members. Polymerase chain reaction and Sanger sequencing were used for the analysis of coding exons and the flanking intronic regions of the PITX2 gene. Bioinformatics tools and database (VarSome, Provean, and MutationTaster, SIFT, PolyPhen‐2, and HOPE) were evaluated to explore missense variants. Results We identified novel heterozygous variations in the PITX2 gene that segregated with the ARS phenotype within the families. The variant NM_153426.2(PITX2):c.226G > T or p.(Ala76Ser) and the mutation NM_153426.2(PITX2):c.455G > A or p.(Cys152Tyr) were identified in two Pakistani pedigrees, and the mutation NM_153426.2(PITX2):c.242_265del or p.(Lys81_Gln88del), segregated in a Mexican family. Conclusion Our study extends the spectrum of PITX2 mutations in individuals with ARS, enabling an improved diagnosis of this rare but serious syndrome.

Assembly of the ocular anterior segment (AS) is a critical event during development of the vertebrate visual system. Failure in this process leads to anterior segment dysgenesis (ASD), which is characterized by congenital blindness and predisposition to glaucoma. The anterior segment is largely formed via a neural crest-derived population, the Periocular Mesenchyme (POM). In this study, we aimed to characterize POM behaviors and transcriptional identities during early establishment of the zebrafish AS. Two-color fluorescent in situ hybridization suggested that early AS associated POM comprise of a heterogenous population. In vivo and time-course imaging analysis of POM distribution and migratory dynamics analyzed using transgenic zebrafish embryos (Tg[foxc1b:GFP], Tg[foxd3:GFP], Tg[pitx2:GFP], Tg[lmx1b.1:GFP], and Tg[sox10:GFP]) revealed unique AS distribution and migratory behavior among the reporter lines. Based on fixed timepoint and real-time analysis of POM cell behavior a comprehensive model for colonization of the zebrafish AS was assembled. Furthermore, we generated single cell transcriptomic profiles (scRNA) from our POM reporter lines and characterized unique subpopulation expression patterns. Based on scRNA clustering analysis we observed cluster overlap between neural crest associated (sox10/foxd3), POM (pitx2) and finally AS specified cells (lmx1b, and foxc1b). scRNA clustering also revealed several novel markers potentially associated with AS development and/or function including lum, fmoda, adcyap1b, tgfbi, and hmng2. Taken together, our data indicates that AS-associated POM, or Anterior Segment Mesenchyme (ASM), is not homogeneous but rather comprised of several subpopulations with differing colonization patterns, migration behavior, and transcriptomic profiles.

A 3-year-old girl presented with a history of watering, haze and increase in the size of the right eye for two months. The child had bilateral preauricular skin tags, limbal dermoid and dermolipoma, consistant with the diagnosis of Goldenhad syndrome. In addition, her right eye manifested enlarged cornea, flat anterior chamber, atrophic iris and elevated intraocular pressure. This case report highlights a possible association of anterior segment dysgenesis and glaucoma with Goldenhar syndrome.

Ocular anterior segment dysgenesis (ASD) describes a spectrum of clinically and genetically heterogeneous congenital disorders affecting anterior structures that often lead to impaired vision. More importantly, 50-75% of patients with ASD develop early onset and aggressive glaucoma. Although several genes have been implicated in the etiology of ASD, the underlying mechanisms remain elusive. Type IV collagen alpha 1 (COL4A1) is an extracellular matrix protein and a critical component of nearly all basement membranes. COL4A1 mutations cause multi-system disorders in patients, including ASD (congenital cataracts, Axenfeld-Rieger's anomaly, Peter's anomaly and microphthalmia) and congenital or juvenile glaucoma. Here, we use a conditional Col4a1 mutation in mice to determine the location and timing of pathogenic events underlying COL4A1-related ocular dysgenesis. Our results suggest that selective expression of the Col4a1 mutation in neural crest cells and their derivatives is not sufficient to cause ocular dysgenesis and that selective expression of the Col4a1 mutation in vascular endothelial cells can lead to mild ASD and optic nerve hypoplasia but only on a sensitized background. In contrast, lens-specific expression of the conditional Col4a1 mutant allele led to cataracts, mild ASD and optic nerve hypoplasia, and age-related intraocular pressure dysregulation and optic nerve damage. Finally, ubiquitous expression of the conditional Col4a1 mutation at distinct developmental stages suggests that pathogenesis takes place before E12.5. Our results show that the lens and possibly vasculature play important roles in Col4a1-related ASD and that the pathogenic events occur at mid-embryogenesis in mice, during early stages of ocular development.

Development of the cornea, lens, ciliary body and iris within the anterior segment of the eye involves coordinated interaction between cells originating from the ciliary margin of the optic cup, the overlying periocular mesenchyme and the lens epithelium. Anterior segment dysgenesis (ASD) encompasses a spectrum of developmental syndromes that affect these anterior segment tissues. ASD conditions arise as a result of dominantly inherited genetic mutations and result in both ocular-specific and systemic forms of dysgenesis that are best exemplified by aniridia and Axenfeld–Rieger syndrome, respectively. Extensive clinical overlap in disease presentation amongst ASD syndromes creates challenges for correct diagnosis and classification. The use of animal models has therefore proved to be a robust approach for unravelling this complex genotypic and phenotypic heterogeneity. However, despite these successes, it is clear that additional genes that underlie several ASD syndromes remain unidentified. Here, we report the characterisation of a novel mouse model of ASD. Conditional deletion of Tsc1 during eye development leads to a premature upregulation of mTORC1 activity within the ciliary margin, periocular mesenchyme and lens epithelium. This aberrant mTORC1 signalling within the ciliary margin in particular leads to a reduction in the number of cells that express Pax6, Bmp4 and Msx1. Sustained mTORC1 signalling also induces a decrease in ciliary margin progenitor cell proliferation and a consequent failure of ciliary body and iris development in postnatal animals. Our study therefore identifies Tsc1 as a novel candidate ASD gene. Furthermore, the Tsc1-ablated mouse model also provides a valuable resource for future studies concerning the molecular mechanisms underlying ASD and acts as a platform for evaluating therapeutic approaches for the treatment of visual disorders.

Background: Developmental anomalies in congenital anomalies cause malformation, such as Anterior Segment Dysgenesis (ASD). Disorder in maturation of anterior segment of the eye occurs in ASD, associated with increased risk of glaucoma. This relation is not supported with enough data about characteristics pediatric patients with ASD in Indonesia. The aim of the study was to describe characteristics ASD in pediatric patient Cicendo Eye Hospital based on patients’ identity, clinical profile and obstetrics profile. Methods: This study used a descriptive method and conducted retrospectively. Data were collected from medical records of patient with ASD in Pediatric Ophthalmology and Strabismus Unit at Cicendo Eye Hospital, from January 2012 to December 2014. This study was conducted from July to November 2015. Total sampling based on inclusion criteria were used in this study. Statistic software was used to analyze data. Results: This study used a descriptive method and conducted retrospectively. Data were collected from medical records of patient with ASD in Pediatric Ophthalmology and Strabismus Unit at Cicendo Eye Hospital, from January 2012 to December 2014. This study was conducted from July to November 2015. Total sampling based on inclusion criteria were used in this study. Statistic software was used to analyze data. Conclusions: Characteristics pediatric patients with ASD at Cicendo Eye Hospital based on patients identity are mostly patients diagnosed in infant age group, from outside Bandung, and mostly boys. Based on clinical profile most diagnosis is congenital glaucoma, bilateral dominantly, and without complication. Based on obstetric profile most patients with ASD were born at term without difficulties.

Abstract Background Threonine Aspartase 1 (Taspase 1) is a highly conserved site‐specific protease whose substrates are broad‐acting nuclear transcription factors that govern diverse biological programs, such as organogenesis, oncogenesis, and tumor progression. To date, no single base pair mutations in Taspase 1 have been implicated in human disease. Methods A female infant with a new pattern of diagnostic abnormalities was identified, including severe craniofacial anomalies, anterior and posterior segment dysgenesis, immunodeficiency, and macrocytic anemia. Trio‐based whole exome sequencing was performed to identify disease‐causing variants. Results Whole exome sequencing revealed a normal female karyotype (46,XX) without increased regions of homozygosity. The proband was heterozygous for a de novo missense variant, c.1027G>A predicting p.(Val343Met), in the TASP1 gene (NM_017714.2). This variant has not been observed in population databases and is predicted to be deleterious. Conclusion One human patient has been reported previously with a large TASP1 deletion and substantial evidence exists regarding the role of several known Taspase 1 substrates in human craniofacial and hematopoietic disorders. Moreover, Taspase 1 deficiency in mice results in craniofacial, ophthalmological and structural brain defects. Taken together, there exists substantial evidence to conclude that the TASP1 variant, p.(Val343Met), is pathogenic in this patient.

Biallelic pathogenic variants in solute carrier family 38 member 8, SLC38A8, cause a pan-ocular autosomal recessive condition known as foveal hypoplasia 2, FVH2, characterised by foveal hypoplasia, nystagmus and optic nerve chiasmal misrouting. Patients are often clinically diagnosed with ocular albinism, but foveal hypoplasia can occur in several other ocular disorders. Here we describe nine patients from seven families who had molecularly confirmed biallelic recessive variants in SLC38A8 identified through whole genome sequencing or targeted gene panel testing. We identified four novel sequence variants (p.(Tyr88*), p.(Trp145*), p.(Glu233Gly) and c.632+1G>A). All patients presented with foveal hypoplasia, nystagmus and reduced visual acuity; however, one patient did not exhibit any signs of chiasmal misrouting, and three patients had features of anterior segment dysgenesis. We highlight these findings in the context of 30 other families reported to date. This study reinforces the importance of obtaining a molecular diagnosis in patients whose phenotype overlap with other inherited ocular conditions, in order to support genetic counselling, clinical prognosis and family planning. We expand the spectrum of SLC38A8 mutations which will be relevant for treatment through future genetic-based therapies.

Anterior segment dysgenesis (ASD) encompasses a group of developmental disorders in which a closed angle phenotype in the anterior chamber of the eye can occur and 50% of patients develop glaucoma. Many ASDs are thought to involve an inappropriate patterning and migration of the periocular mesenchyme (POM), which is derived from cranial neural crest cells (NCCs) and mesoderm. Although, the mechanism of this disruption is not well understood, a number of transcriptional regulatory molecules have previously been implicated in ASDs. Here, we investigate the function of the transcription factor AP-2β, encoded by Tfap2b, which is expressed in NCCs and their derivatives. Wnt1-Cre-mediated conditional deletion of Tfap2b in NCCs resulted in post-natal ocular defects typified by opacity. Histological data revealed that the conditional AP-2β NCC knockout (KO) mutants exhibited dysgenesis of multiple structures in the anterior segment of the eye including defects in the corneal endothelium, corneal stroma, ciliary body and disruption in the iridocorneal angle with adherence of the iris to the cornea. We further show that this phenotype leads to a significant increase in intraocular pressure and a subsequent loss of retinal ganglion cells and optic nerve degeneration, features indicative of glaucoma. Overall, our findings demonstrate that AP-2β is required in the POM for normal development of the anterior segment of the eye and that the AP-2β NCC KO mice might serve as a new and exciting model of ASD and glaucoma that is fully penetrant and with early post-natal onset.

Anterior segment dysgenesis (ASD) comprises a wide spectrum of developmental conditions affecting the cornea, iris, and lens, which may be associated with abnormalities of other organs. To identify disease-causing variants, we performed exome sequencing in 24 South Florida families with ASD. We identified 12 likely causative variants in 10 families (42%), including single nucleotide or small insertion−deletion variants in B3GLCT, BMP4, CYP1B1, FOXC1, FOXE3, GJA1, PXDN, and TP63, and a large copy number variant involving PAX6. Four variants were novel. Each variant was detected only in one family. Likely causative variants were detected in 1 out of 7 black and 9 out of 17 white families. In conclusion, exome sequencing for ASD allows us to identify a wide spectrum of rare DNA variants in South Florida. Further studies will explore missing variants, especially in the black communities.

Congenital heart diseases (CHDs) are still the leading cause of death in neonates. Anterior segment dysgenesis is a broad clinical phenotype that affects the normal development of the eye, leading in most of the cases to glaucoma which is still a major cause of blindness for children and adolescents. Despite tremendous insights gained from genetic studies, a clear genotype–phenotype correlation is still difficult to draw. In Lebanon, a small country with still a high rate of consanguineous marriages, there are little data on the epidemiology of glaucoma amongst children with or without CHD. We carried out whole exome sequencing (WES) on a family with anterior segment dysgenesis, and CHD composed of three affected children with glaucoma, two of them with structural cardiac defects and three healthy siblings. The results unravel a novel mutation in FOXC1 (p. R127H) segregating with the phenotype and inherited from the mother, who did not develop glaucoma. We propose a digenic model for glaucoma in this family by combining the FOXC1 variant with a missense variant inherited from the father in the dermatopontin (DPT) gene. We also unravel a novel NFATC1 missense mutation predicted to be deleterious and present only in the patient with a severe ocular and cardiac phenotype. This is the first report on FOXC1 using WES to genetically characterize a family with both ocular and cardiac malformations. Our results support the usage of such technology to have a better genotype–phenotype picture for Mendelian-inherited diseases for which expressivity and penetrance are still not answered.

Pellucid marginal degeneration (PMD) is an uncommon cause of inferior peripheral corneal thinning disorder, characterized by irregular astigmatism. We analyzed a case of bilateral PMD patient and treated one eye with corneal collagen cross-linking (CXL) therapy. Corneal topography was characteristic for PMD. Visual acuity, slitlamp examinations, tonometry, and corneal thickness were observed. Simulated keratometric and topographic index values were detected with corneal topography. Uncorrected, LogMAR visual acuity has improved from +0.8 to +0.55 during the 6 months and +0.3 during the 8 months follow-up after CXL. Pachymetry values and intraocular pressure showed no changes. Keratometric values and topografic indexes disclosed no progression of the disease. CXL may postpone or eliminate the need of corneal transplantation in cases with PMD.

A 65-year-old lady presented with decreased vision in left eye since seven months. Vision was 6/9 in right eye and 6/36 in left. Examination revealed idiopathic, full-thickness macular hole in left eye; confirmed by optical coherence tomography (OCT). Patient underwent phacoemulsification with intraocular lens (IOL) implantation, vitrectomy, internal limiting membrane (ILM) peeling and 14% C 3 F 8 gas injection. OCT repeated after six weeks revealed type II closure with cuff of subretinal fluid. Four weeks later, patient underwent fluid-gas exchange with 14% C 3 F 8 gas and postoperative positioning. OCT was repeated after two weeks, which showed complete closure of the macular hole. OCT can help in selection of eyes for re-surgery that stand a better chance for hole closure. Macular holes with cuff of subretinal fluid are probably more likely to close on re-surgery than those without. However, larger studies with longer follow-up are required to validate this finding.

Blepharophimosis ptosis epicanthus inversus syndrome (BPES) is a complex eyelid malformation characterized by the classical tetrad of blepharophimosis, telecanthus, ptosis, and epicanthus inversus. It has been reported to be associated with other ocular anomalies such as euryblepharon, strabismus, nystagmus, amblyopia, microphthalmos, lacrimal drainage apparatus abnormality, extra ocular muscle abnormalities, microcornea, trabecular dysgenesis, optic nerve hypoplasias, and colobomas of the optic disk. We describe a case of BPES with Axenfeld-Rieger syndrome, a neurocristopathy characterized by maldevelopment of the anterior segment with predisposition to development of glaucoma. Interestingly, both syndromes are caused by mutations in the same class of genes, namely the winged-helix/forked transcription factors (FOX) involved in a variety of developmental processes.

Annular elastolytic giant cell granuloma is a condition characterized histologically by damaged elastic fibers associated with preponderance of giant cells along with absence of necrobiosis, lipid, mucin, and pallisading granuloma. It usually occurs on sun-damaged skin and hence the previous name actinic granuloma. A similar process occurs on the conjunctiva. Over the past three decades only four cases of conjunctival actinic granuloma have been documented. All the previous patients were females with lesions in nasal or temporal bulbar conjunctiva varying 2-3 mm in size. We report a male patient aged 70 years presenting with a 14 mm × 7 mm fleshy mass on right lower bulbar conjunctiva. Clinical differential diagnoses were lymphoma, squamous cell carcinoma in situ and amyloidosis. Surgical excision followed by histopathology confirmed it to be a case of actinic granuloma. This is the first case of isolated conjunctival actinic granuloma of such a large size reported from India.

We are reporting an interesting case of ichthyosis follicularis with alopecia and photophobia syndrome in a daughter and father from the Indian subcontinent associated with Meibomian gland dysfunction. A three-year-old female child presented with pain, redness and severe photophobia in both eyes since one month. Cutaneous examination revealed ichthyosis, absence of hair all over the body including eyebrows, scalp and angular cheilosis. Ocular examination revealed bilateral severe meibomianitis, multiple superficial punctate keratitides in right eye and corneal epithelial defect in the left eye. Other systemic features were prominent high forehead and large ears. Her father had similar symptoms. Her symptoms improved after adequate treatment of meibomian gland dysfunction. She is asymptomatic at present.

This is a single case report of an elderly patient who had blunt trauma in an eye that had phacoemulsification and two trabeculectomies. She had good vision with a well-functioning bleb before the trauma. She presented during her routine follow-up visit for glaucoma with isolated aniridia and an intact globe. The capsular bag, zonules, and the intraocular lens were intact. The cupping was 0.8, and the rest of the fundus and macula were normal. Pigments were seen over the sclera extending posteriorly upto the fornix. Gonioscopy revealed only faint pigments at the fistula. Following the trauma, the intraocular pressure had increased to 26 mm Hg. The mechanism and the management of the glaucoma are discussed.

Implantation of iris-claw Artisan intraocular lens (IOL) is a surgical option for correction of aphakia; however, these IOLs have not been used in eyes with uveitis including Fuchs′ heterochromic iridocyclitis (FHI) due to possible risk of severe postoperative intraocular inflammation. In the case reported here, we secondarily implanted an Artisan IOL in a 28-year-old man with FHI who had aphakia with no capsular support due to a previous complicated cataract surgery. Enclavation was easily performed and no intraoperative complication was noted. Postoperative course was uneventful with no significant anterior chamber inflammation during 12 months of follow-up. Although there were few deposits on the IOL surface, the patient achieved a best-corrected visual acuity of 20/20 without developing glaucoma or other complications. Therefore, Artisan IOL may be considered for correction of aphakia in patients with FHI. However, studies on large number of patients are required to evaluate safety of the procedure.

Se describe un caso clínico con diagnóstico de anomalía de Rieger con embriotoxon posterior, adherencias iridocorneales, corectopia, atrofia sectorial del iris, goniodisgenesia y glaucoma bilateral no asociado a alteraciones sistémicas. Se decide realizar trabeculo-trabeculectomía con Mitomicina C. en ambos ojos manteniéndose compensado hasta el año de la cirugía con posterior adelgazamiento de la bula de filtración y salida de humor acuoso de ojo izquierdo con notable disminución de la presión intraocular, decidiéndose realizar reconstrucción de bula de filtración. Al mes de la cirugía las presiones intraoculares comenzaron a elevarse, encontrándose en estos momentos compensadas con dorzolamida colirio.