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BACKGROUND Familial exudative vitreoretinopathy (FEVR) is a group of inherited eye diseases characterized by premature arrest of retinal vessel development. The purpose of our study was to characterize the genetic causes and clinical features in eight Chinese families with FEVR using next-generation sequencing (NGS) technology. MATERIALS AND METHODS Eight families with FEVR were included in genetic and clinical analyses. We screened the proband and the parents in eight pedigrees with FEVR using targeted NGS approach and in silico analysis to determine the causative mutation for their family's phenotype. RESULTS Four cases (4/8, 50.0%) were confirmed to harbor mutations in known genes, including 3 novel mutations and one previously reported mutation. Among the detected mutations, TSPAN12 accounted for 75% (3/4). We identified a novel stop codon of TSPAN12, a heterozygous missense mutation NM_012338.4:c.633T>A, NP_036470.1:p.Tyr211Ter involved in highly conserved residues in the proband. Retrospective analysis of its clinical manifestation showed that the mutant carrier presented mild clinical features. CONCLUSIONS We found the novel stop codon mutation p.Tyr211Ter in the TSPAN12, which creates a milder phenotype. Discovery of this novel mutation expands the mutation spectrum of TSPAN12, and would be valuable for future genetic disease diagnosis.

PURPOSE To present the scope of prenatal diagnosis and early treatment of patients with clinically heterogeneous phenotypic retinal dysplasia associated with NDP gene variants. METHODS Retrospective. Review of electronic medical records. RESULTS Twenty-nine-year-old woman known to carry a NDP gene variant presented to the eye clinic for consultation and risk assessment at her second pregnancy. Her 11-year-old son had bilateral retinal detachment, despite surgical treatment. The family declined prenatal testing. The patient was born full term, was examined, and underwent genetic testing after birth. He was found to have bilateral retinal avascular periphery abnormalities and preretinal hemorrhages on the left eye. The patient received bilateral laser treatment at 2 months of age. He was found to be doing well at 16 months after treatment with adequate visual acuity and flat maculae. The asymptomatic mother and maternal grandfather of the proband were found to have retinal periphery abnormalities with unremarkable posterior pole and excellent visual acuity. CONCLUSION NDP gene variants associated with X-linked familial exudative vitreoretinopathy phenotype benefit from early treatment. Providers who take care of these patients need to monitor closely the pregnancy and delivery of a male child born to a female carrier to offer appropriate and timely treatment.

The pathogenic variants in TSPAN12 could lead to familial exudative vitreoretinopathy (FEVR), which has high clinical variability. This study aims to assess the pathogenicity of TSPAN12 variants and their phenotypic spectrum based on exome sequencing from 7092 probands with different eye conditions. The variants in TSPAN12 were selected from exome sequencing data of samples from 7092 probands with different forms of eye conditions. Potentially pathogenic variants were evaluated through the annotation of types, locations, population frequencies, and in silico predictions of variants from in-house data, gnomAD, and published literature. The clinical features of patients with potentially pathogenic variants in TSPAN12 were assessed. A total of 45 variants in TSPAN12 with coding effects were detected based on the exome data from 7092 probands, among which 31 were classified as pathogenic variants including 15 novels. The 31 variants were identified in 34 probands with various initial diagnoses, including FEVR in 21 probands and diseases other than FEVR in the remaining 13 probands. Biallelic pathogenic variants were identified in one proband with initial diagnosis of high myopia. Truncating variants and the missense variants that are predicted as deleterious are likely pathogenic variants of TSPAN12. Approximately 61.8% of patients with pathogenic variants in this gene had an initial diagnosis of FEVR, and the remaining 38.2% of patients had various initial diagnoses. These findings expand the understanding about variant evaluation of TSPAN12 and phenotypic spectrum of TSPAN12-associated FEVR.

Familial exudative vitreoretinopathy (FEVR) is a rare inherited disorder affecting retinal angiogenesis that may present with a wide range of phenotypic characteristics. In this report, the authors describe an atypical presentation of FEVR in a healthy 9-year-old male with progressive decreased visual acuity in the left eye. Fundus examination showed an avascular retina in the temporal periphery bilaterally. The left eye also revealed serpiginous hypopigmented lesions in the superior quadrant, which showed intraretinal location on optical coherence tomography and hyperautofluorescence. Genetic testing revealed LRP5 mutation, confirming a diagnosis of FEVR. The serpiginous lesions represent an unusual finding associated with FEVR not previously described in the literature. [ Ophthalmic Surg Lasers Imaging Retina . 2021;52:155–159.]

Background Familial exudative vitreoretinopathy (FEVR, OMIM 133780) is a severe hereditary retinal disease characterized by incomplete retinal vascular development and pathological neovascularization. It has been reported that variants in nine genes are associated with FEVR, but they can only explain approximately 50% of FEVR patients, suggesting that other FEVR-associated variants or genes remain to be discovered. Methods Whole-exome sequencing (WES) was carried out to analyse genomic DNA samples from the probands of 68 families with FEVR. Sanger sequencing was used to verify all identified variants. Western blot analysis was utilized to detect the expression of the variant mutant proteins. A luciferase assay was conducted to test the receptor activity of the mutant FZD4 proteins in Norrin-β-catenin signaling. Results Seven heterozygous FZD4 variants were found to cause FEVR in seven families, including six missense variants and one deletion variant: c.182C>T (p.T61I), c.205C>T (p.H69Y), c.217_234del (p.73T_78Qdel), c.264C>A (p.Y88X), c.344G>T (p.G115V), c.678G>A (p.W226X) and c.1310T>C (p.I437T). Among these variants, c.205C>T (p.H69Y) and c.678G>A (p.W226X) are known FEVR-causing variants, while the other five variants are novel pathogenic variants. Conclusion Our study revealed the cause of FEVR in seven Chinese families and identified five novel pathogenic variants in FZD4, which expanded the mutation spectrum of FEVR in the Chinese population. These findings also provided further support for using WES in the clinical diagnosis of FEVR.

Purpose: To characterize the lens morphology and to measure the clinical features of familial exudative vitreoretinopathy (FEVR) in children. Methods: Unique lens changes were observed in a cohort of children with FEVR from March 2015 to November 2017 using slit lamp examination and all the patients underwent cycloplegic refraction, ultrasound A and B, keratometry and fundus fluorescein angiography. Results: Twelve eyes of eight children with FEVR had unique lens changes. The contraction of the posterior capsule caused unique lens changes resulting in myopia in nine eyes of six children and astigmatism in eight eyes of five children. Retinal lesions in the affected eyes were all stage 1 to 2. Six eyes of three patients underwent lensectomy and intraocular lens implantation due to high anisometropia which could not be corrected by conventional optical correction. During lensectomy, the opacification in the posterior capsule was found to be due to the fibrous membrane that protruded into the anterior vitreous and not due to lens opacification. Three patients had bilateral lensectomy, in two of whom significant macular involvement was observed in one eye and in one of whom significant macular involvement was observed in both eyes. After surgery visual acuity (VA) improved obviously in two eyes without significant macular involvement and did not improve in the four eyes which had significant macular involvement. Among the five patients who did not have lensectomy, one patient was lost to follow-up and one patient had VA improved in both eyes without significant macular involvement. The other three patients did not have much change in VA. Conclusions: Clinicians should be aware that when a high myopia or astigmatism does not match the corneal curvature and the length of the eye, one should check carefully the changes of lens and fundus after dilating the pupil, to avoid misdiagnosis and missed diagnosis.

Purpose We report a patient with CTNNB1-associated vitreoretinopathy. We discuss imaging findings and surgical management. Methods Case report. Results An 18-month-old girl with microcephaly, failure to thrive, developmental delay, and chronic rhinitis presented with bilateral central and peripheral tractional retinal detachments and an anomalous retinal vasculature. She underwent multimodal imaging and genetic testing, and we discuss successful surgical management. Conclusion CTNNB1 mutations can cause a vision-threatening vitreoretinopathy. We recommend CTNNB1 to be considered as part of the workup of patients presenting with familial exudative vitreoretinopathy-like clinical findings, especially if there are systemic manifestations.

To describe the surgical procedures, outcomes, and complications of a novel technique of subretinal injection of ranibizumab (SRR). Between September 2012 and September 2018, 37 eyes of 26 consecutive children with vascularly active total retinal detachments in 1 or both eyes treated with SRR as primary treatment were included in this retrospective study. All included eyes received subretinal injection of ranibizumab (0.25 mg/ 0.025 ml). Data included demographics, ocular examination, and anatomic outcomes, following treatment and complications of eyes after SRR were collected. Eleven patients had bilateral SRR injections and 15 had monocular SRR injection. Thirteen patients were diagnosed as retinopathy of prematurity. Of all patients, the mean gestational age was 34.5 ± 5.1 weeks (range: 29.6~40.7 weeks), and birth weight was 2328.1 ± 1083.9 g (range: 940~3900 g). On 1-week postoperative follow-up, vascular activity decreased in all 37 eyes (100%). On the 1-month postoperative follow-up, vascular activity decreased but remained in 24 eyes (24/35, 68.6%) of 16 patients and vanished in 11 eyes (11/35, 31.4%) of 9 patients. No eye needed a secondary anti-VEGF therapy. Local subconjunctival hemorrhage was noted in two eyes (2/37, 5.4%). Localized wound leakage of subretinal fluid was also noted in one eye (1/37, 2.7%). In this very limited study, we showed that SRR in vascularly active advanced pediatric vasoproliferative disorders with total retinal detachments is effective and promising, although more extensive controlled trials will be needed to confirm its safety and efficacy.

To describe the incidence, clinical features, and long-term outcomes of photodynamic therapy (PDT)-induced acute exudative maculopathy (PAEM) in patients who underwent PDT for various indications.This retrospective observational case series included all cases who developed massive serofibrinous macular exudation within a week after PDT. Medical records of patients with post-PDT exudative events were reviewed for relevant data and imaging abstraction including optical coherence tomography and indocyanine green angiography features and were subjected to analysis.The incidence rate of PAEM was 4.52%, being noted in 8 eyes (out of 177 PDT sessions in 155 eyes) with a mean age of 70.25 ± 6.65 years. Pre-PDT factors commonly associated with PAEM included age ≥65 years (87.5%), clinical diagnosis of polypoidal choroidal vasculopathy (75%), spot size ≥3,500 µm (100%), best-corrected visual acuity of 20/40 or better (87.5%), low-fluence PDT (87.5%), and the first exposure to PDT (75%). Photodynamic therapy-induced acute exudative maculopathy was noted at a mean interval of 2.9 ± 1.7 days (2-7 days) after PDT. Photodynamic therapy-induced acute exudative maculopathy resulted in significant decrease in mean best-corrected visual acuity from logMAR 0.29 ± 0.21 (approximate Snellen equivalent 20/39) to logMAR 0.91 ± 0.37 (approximate Snellen equivalent 20/163) [P = 0.0018], and significant increase in mean central macular thickness from 228.1 ± 71.8 µm to 481.4 ± 154.8 µm (P = 0.0029). Photodynamic therapy-induced acute exudative maculopathy resolved to baseline or even better tomographic status at a mean interval of 4.6 ± 1.2 weeks, resulting in complete visual recovery compared with baseline. During mean follow-up of 77.8 ± 46.4 weeks after PDT, no activity was noted for a mean duration of 26.3 ± 42.5 weeks after resolution. At final visit, mean best-corrected visual acuity and central macular thickness was logMAR 0.49 ± 0.28 (approximate Snellen equivalent 20/62) and 153.6 ± 40.0 µm, respectively, with underlying pathology being stable in 50% of the eyes.Photodynamic therapy-induced acute exudative maculopathy is an uncommon complication with self-resolving course and favorable prognosis. Patients undergoing PDT should be warned of the possibility of PAEM. The factors frequently associated with PAEM include elderly age (65 years), clinical diagnosis of polypoidal choroidal vasculopathy, larger spot size (≥3,500 µm), pre-PDT best-corrected visual acuity of 20/40 or better, low-fluence PDT, and the first exposure to PDT.

Purpose: To evaluate the heterogeneity of both the clinical features and genetics of familial exudative vitreoretinopathy (FEVR) in a Northern Irish population. Methods: A retrospective trawl of a secure pediatric database was completed, as well as communication with all Northern Ireland ophthalmologists to identify adult cases. Cases were cross-referenced with a regional genetics database. Data on patient demographics, clinical findings, genetic testing, and patient treatment were collected. Results: Sixteen patients were identified. Average age at presentation was 11.8 years (range: 4 months to 38 years). Earlier age at presentation was associated with more advanced disease and those presenting later had more subtle signs such as retinal tear or vitreous hemorrhage. Four types of gene mutations were identified in 7 patients ( NDP , TSPAN12 , FZD4 , and KIF11 ). Thirteen patients had complications associated with FEVR and associated systemic conditions were found in 5 patients. Twelve eyes received active treatment to control disease. Conclusions: FEVR is a sight-threatening disease affecting prenatal retinal angiogenesis with a spectrum of disease and diverse genetic basis. Clinicians should look for signs of systemic and other ophthalmic sequelae in patients with FEVR because this could point to a genetic cause. Vigilance should also be exercised in older patients with unexplained vitreous hemorrhage or retinal tear with consideration of widefield angiography if FEVR is suspected. [ J Pediatr Ophthalmol Strabismus . 2022;59(2):102–109.]

Supplemental Digital Content is Available in the Text. The retrospective interventional case study demonstrated the efficacy of intravitreal injection of ranibizumab for advanced familial exudative vitreoretinopathy with high vascular activity, in patients with varying clinical and genetic backgrounds., Purpose: To determine the efficacy of intravitreal ranibizumab (IVR) treatment for advanced familial exudative vitreoretinopathy with high vascular activity. Methods: The retrospective interventional case series included 28 eyes (20 patients) that had IVR in combination or not with other treatment, for Stage 3 to 5 familial exudative vitreoretinopathy with active fibrovascular proliferation and prominent subretinal exudation. Outcome measures were fundus features after treatment, associated clinical variables, and genetic mutations. Results: The age of patients at the first IVR ranged from 0.2 to 36 months. An average of 1.3 IVR injections per eye were given. Familial exudative vitreoretinopathy regressed in 16 (57%) eyes and progressed in 12 eyes (43%) after IVR. Laser and/or vitrectomy was performed on 13 eyes. The retina was reattached in 22 eyes (78%) after 24 to 58 months follow-up. Clinical variables associated with progression after IVR were preexisting fibrovascular proliferation over one quadrant and persistent vascular activity after the initial injection (P < 0.05). Familial exudative vitreoretinopathy-causative genetic mutations in 11 patients were related to variable response to IVR treatment. Conclusion: Intravitreal ranibizumab treatment may effectively regress advanced familial exudative vitreoretinopathy with high vascular activity in selected cases. Different treatment outcomes may be relevant to variable presentation and genetic heterogeneity of familial exudative vitreoretinopathy.

CTNNB1-related disorder is an autosomal dominant neurodevelopmental disorder characterized by a variable degree of cognitive impairment, microcephaly, truncal hypotonia, peripheral spasticity, visual defects, and dysmorphic features. In this case series, we report the clinical and molecular findings of nine Chinese patients affected by CTNNB1-related disorders. The facial features of these affected individuals appear to resemble what had been previously described, with thin upper lip (77.8%) and hypoplastic alae nasi (77.8%) being the most common. Frequently reported clinical characteristics in our cohort include developmental delay (100%), peripheral spasticity (88.9%), truncal hypotonia (66.7%), microcephaly (66.7%), and dystonia (44.4%). While various eye manifestations were reported, two affected individuals (22.2%) in our cohort had familial exudative vitreoretinopathy. One of the affected individuals had craniosynostosis, a feature not reported in the literature before. To our knowledge, this is the first reported Chinese case series of CTNNB1-related neurodevelopmental disorders. Further studies are required to look into whether ethnic differences play a role in phenotypic variations.

Familial exudative vitreoretinopathy (FEVR) is a human disease characterized by defective retinal angiogenesis and associated complications that can result in vision loss. Defective Wnt/β-catenin signaling is an established cause of FEVR, whereas other molecular alterations contributing to the disease remain insufficiently understood. Here, we show that integrin-linked kinase (ILK), a mediator of cell-matrix interactions, is indispensable for retinal angiogenesis. Inactivation of the murine Ilk gene in postnatal endothelial cells results in sprouting defects, reduced endothelial proliferation and disruption of the blood-retina barrier, resembling phenotypes seen in established mouse models of FEVR. Retinal vascularization defects are phenocopied by inducible inactivation of the gene for α-parvin (Parva), an interactor of ILK. Screening genomic DNA samples from exudative vitreoretinopathy patients identifies three distinct mutations in human ILK, which compromise the function of the gene product in vitro. Together, our data suggest that defective cell-matrix interactions are linked to Wnt signaling and FEVR., Integrin-linked kinase (ILK) is an important mediator of integrin signaling. Here Park et al. show that mice with endothelial-specific deletion of Ilk develop vascular defects that resemble familial exudative vitreoretinopathy, and identify mutations in ILK in patients with exudative vitreoretinopathy suggesting a potential role in human pathogenesis.

Background: Septo-optic dysplasia, also known as de Morsier syndrome, is a disorder of brain development characterized by optic nerve hypoplasia, hypopituitarism, and midline brain defects.Materials and Methods: Single retrospective case report.Results: An infant born at 38 5/7 weeks gestation age weighing 3125 g developed respiratory distress shortly after birth. Systemic findings included myocardial dysfunction, hypopituitarism, feeding intolerance, microphallus, and dysmorphic features. Eye examination revealed tractional retinal detachments and optic nerve hypoplasia. In addition, peripheral non-perfusion and peripheral neovascularization were consistent with Familial Exudative Vitreoretinopathy (FEVR) phenotype. MRI showed hypoplastic optic nerves, ectopic posterior pituitary with hypoplastic pituitary infundibulum, and slightly thin corpus callosum, diagnostic of septo-optic dysplasia. Genetic testing revealed no pathogenic variants and two variants of uncertain significance.Conclusion: FEVR findings can be associated with septo-optic dysplasia and may point to an etiologic connection between neural development and subsequent vascular development.

The mammalian CNS is capable of tolerating chronic hypoxia, but cell type-specific responses to this stress have not been systematically characterized. In the Norrin KO ( Ndp KO ) mouse, a model of familial exudative vitreoretinopathy (FEVR), developmental hypovascularization of the retina produces chronic hypoxia of inner nuclear-layer (INL) neurons and Muller glia. We used single-cell RNA sequencing, untargeted metabolomics, and metabolite labeling from 13 C-glucose to compare WT and Ndp KO retinas. In Ndp KO retinas, we observe gene expression responses consistent with hypoxia in Muller glia and retinal neurons, and we find a metabolic shift that combines reduced flux through the TCA cycle with increased synthesis of serine, glycine, and glutathione. We also used single-cell RNA sequencing to compare the responses of individual cell types in Ndp KO retinas with those in the hypoxic cerebral cortex of mice that were housed for 1 week in a reduced oxygen environment (7.5% oxygen). In the hypoxic cerebral cortex, glial transcriptome responses most closely resemble the response of Muller glia in the Ndp KO retina. In both retina and brain, vascular endothelial cells activate a previously dormant tip cell gene expression program, which likely underlies the adaptive neoangiogenic response to chronic hypoxia. These analyses of retina and brain transcriptomes at single-cell resolution reveal both shared and cell type-specific changes in gene expression in response to chronic hypoxia, implying both shared and distinct cell type-specific physiologic responses.

Familial exudative vitreoretinopathy (FEVR) is a rare hereditary ocular disorder characterized by incomplete or abnormal development of peripheral retinal vasculature. The genes responsible for this disorder are associated with the wingless-related integration site (Wnt) signaling pathway, a critical pathway for the development of normal retinal vasculature. A pathogenic variant in any one of these genes may disrupt retinal vasculogenesis. Furthermore, the type and number of pathogenic variants may influence the severity of disease and clinical course. Here, the authors identify a novel pathogenic variant in the NDP gene, not previously described in the literature. [ Ophthalmic Surg Lasers Imaging Retina. 2019;50:120–124.]

To the Editor:We read with interest the article by Yang and colleagues.1 The authors argued that in their series of 29 families with RCBTB1 variants, none had FEVR syndrome, in contrast to what we ...

Familial exudative vitreoretinopathy (FEVR) is a severe retinal vascular disease that causes blindness. FEVR has been linked to mutations in several genes associated with inactivation of the Norrin/β-catenin signaling pathway, but these account for only approximately 50% of cases. We report that mutations in CTNNA1 (α-catenin) cause FEVR by overactivating the β-catenin pathway and disrupting cell adherens junctions. Three heterozygous mutations in CTNNA1 (p.F72S, p.R376Cfs*27 and p.P893L) were identified by exome-sequencing. We further demon-strated that FEVR-associated mutations led to overactivation of Norrin/β-catenin signaling due to impaired protein interactions within the cadherin/catenin complex. The clinical features of FEVR were reproduced in mice lacking Ctnna1 in vascular endothelial cells (ECs) or with overactivat-ed β-catenin signaling by an EC-specific gain-of-function allele of Ctnnb1. In isolated mouse lung endothelial cells, both CTNNA1-P893L and F72S mutants failed to rescue either the dis-rupted F-ACTIN arrangement or VE-Cadherin and CTNNB1 distribution. Moreover, we discov-ered that compound heterozygous Ctnna1 F72S and a deletion allele could cause similar pheno-type. Furthermore, a LRP5 mutation, which activates Norrin/β-catenin signaling, was identified in a FEVR family and the corresponding knock-in mice exhibited partial FEVR-like phenotype. Our study demonstrates that precise regulation of β-catenin activation is critical for retinal vascu-lar development and provides new insights into the pathogenesis of FEVR.

Purpose This study aims to analyze the Norrie disease gene (NDP) variants in patients with familial exudative vitreoretinopathy (FEVR) and their clinical features. Methods Thirty-three Chinese patients (22 familial and 11 simplex) who were diagnosed as FEVR underwent detailed ocular examinations in Beijing Tongren Hospital. Peripheral venous blood was drawn from the patients and their family members for the extraction of genomic DNA. All exons of NDP gene were analyzed by direct sequencing of PCR-amplified DNA fragments. Results Four novel mutations in NDP gene were identified in four X-linked FEVR families: a C → T transversion, c. 625C → T, in exon 3, resulting in a serine-to-proline change in codon 73 (S73P); a C → G transition, c. 751C → G, in exon 3, resulting in an arginine-to-glycine change in codon 115 (R115G); a T → C transversion of nucleotide 331 at 5’UTR in exon 2 (c.331 T → C); and a C → T transversion of the nucleotide 5 in intron 1 (IVS1 + 5C → T). The mutations were not present in the control group (n = 100). Conclusions Our results extend the spectrum of NDP gene mutations. The mutations in the non-coding region of NDP may play a crucial role in the pathogenesis of FEVR.

Familial exudative vitreoretinopathy (FEVR) is a hereditary vitreoretinal disorder characterized by incomplete vascular development in the peripheral retina. The secondary pathological processes le...

Background CTNNB1 (MIM 116806) encodes beta‐catenin, an adherens junction protein that supports the integrity between layers of epithelial tissue and mediates intercellular signaling. Recently, various heterozygous germline variants in CTNNB1 have been associated with human disease, including neurodevelopmental disorder with spastic diplegia and visual defects (MIM 615075) as well as isolated familial exudative vitreoretinopathy without developmental delays or other organ system involvement (MIM 617572). From over 40 previously reported patients with CTNNB1‐related neurodevelopmental disorder, many have had ocular anomalies including strabismus, hyperopia, and astigmatism. More recently, multiple reports indicate that these abnormalities are associated with the presence of vitreoretinopathy. Methods We gathered a cohort of three patients with CTNNB1‐related neurodevelopmental disorder, recruited from both our own clinic and referred from outside providers. We then searched for a clinical database comprised of over 12,000 exome sequencing studies to identify and recruit four additional patients. Results Here, we report seven new cases of CTNNB1‐related neurodevelopmental disorder, all harboring de novo variants, six of which were previously unreported. All patients but one presented with a spectrum of ocular abnormalities and one patient, who was found to carry a missense variant in CTNNB1, had notable vitreoretinopathy. Conclusions Our findings suggest ophthalmologic screening should be performed in all patients with CTNNB1 variants., Here, we report seven new cases of CTNNB1‐related neurodevelopmental disorder, all harboring de novo variants, six of which were previously unreported. All patients but one presented with a spectrum of ocular abnormalities and one patient, who was found to carry a missense variant in CTNNB1, had notable vitreoretinopathy. Our findings suggest that ophthalmologic screening should be performed in all patients with CTNNB1 variants.

Loss-of-function mutations in the Wnt co-receptor, low-density lipoprotein receptor-related protein 5 (LRP5), result in familial exudative vitreoretinopathy (FEVR), osteoporosis-pseudoglioma syndrome (OPPG), and Norrie disease. CRISPR/Cas9 gene editing was used to produce rat strains deficient in Lrp5. The purpose of this study was to validate this rat model for studies of hypovascular, exudative retinopathies. The retinal vasculature of wildtype and Lrp5 knockout rats was stained with Giffonia simplifolia isolectin B4 and imaged by fluorescence microscopy. Effects on retinal structure were investigated by histology. The integrity of the blood-retina barrier was analyzed by staining for claudin-5 and measurement of permeability to Evans blue dye. Retinas were imaged by fundus photography and SD-OCT, and electroretinograms were recorded. Lrp5 gene deletion led to sparse superficial retinal capillaries and loss of the deep and intermediate plexuses. Autofluorescent exudates were observed, correlated with absence of claudin-5 expression in superficial vessels and increased Evans blue permeability. OCT images show pathology similar to OCT of humans with FEVR, and retinal thickness is reduced by 50% compared to wild-type rats. Histology and OCT reveal that photoreceptor and outer plexiform layers are absent. The retina failed to demonstrate an ERG response. CRISPR/Cas9 gene-editing produced a predictable rat Lrp5 knockout model with extensive defects in the retinal vascular and neural structure and function. This rat model should be useful for studies of exudative retinal vascular diseases involving the Wnt and norrin pathways.

The vasa hyaloidea propria, a component of the fetal hyaloidal vasculature, is characterized by multiple persistent fetal vasculatures branching into the vitreous. We present a 4-month-old girl with stage 4 familial exudative vitreoretinopathy, with multiple ectopic retinal vessels extending into the vitreous, confirmed with fluorescein angiography, which was consistent with persistent vasa hyaloidea propia/retinae making contact with the retina. The patient underwent vitreoretinal surgery to address the retinal detachment, during which the patent stalks of the persistent vasa hyaloidea propia/retinae were transected.

Purpose To determine the incidence of worsening vitreoretinal traction after laser treatment for familial exudative vitreoretinopathy (FEVR) and to determine whether any baseline clinical features are associated with worsening. Design Retrospective cohort comparison study in a university tertiary referral center. Methods: All patients 0-21 years of age treated with laser from January 1, 2001, to June 1, 2018, were studied. Worsening traction after treatment was defined as the occurrence within 6 months of worsening or development of tractional retinal detachment, folds, dragging, breaks, rhegmatogenous detachment, or worsening tractional membranes. Comparisons of baseline features between groups with and without worsening were performed to determine features associated with higher risk. Results A total of 46 eyes from 28 patients met inclusion criteria. Of the 46 eyes, 6 (13%) had worsening after treatment. There were no significant differences in age or other baseline demographics between the cohorts with and those without worsening traction. The presence of proliferative tissue in contact with the lens was found in 2 of 6 patients with worsening compared to 1 of 40 (3%) without worsening (P = .04). Mean follow-up was 57.8 months (range, 6.6-134 months). At the 6-month follow-up, median logMAR visual acuity in the cohorts with and without worsening was 1.7 (Snellen 20/1002; n = 5) and 0.24 (Snellen 20/35; n = 16), respectively. Conclusions Laser treatment resulted in worsening traction in a substantial proportion of eyes with FEVR. Children with proliferative tissue in contact with the lens may be at higher risk of worsening after laser. Potential measures to reduce risk will require further study to establish efficacy.

Mutations in NDP and FZD4 have been closely related to a series of retinal diseases including familial exudative vitreoretinopathy (FEVR). Our study was designed to identify novel NDP and FZD4 mutations by whole exome sequencing (WES) in a cohort of patients with a definitive diagnosis of FEVR and explore the underlying molecular mechanism. During 2016, we investigated fifty nonconsanguineous families with affected individuals exhibiting FEVR phenotype and WES identified one recently reported mutation: NDP c.127C>A (p.H43N), and five novel mutations: NDP c.129_131del (p.44del), NDP c.320_353del (p.R107Pfs), NDP c.321delG (p.L108Cfs), NDP c.377G>T (p.C126F), and FZD4 c.314T>G (p.M105R) that cosegragated with the abnormal fundus vascular manifestations in six families. All the mutations were perceived to be pathogenic or likely pathogenic according to the standards and guidelines from the American College of Medical Genetics and Genomics (ACMG) and predicted to be deleterious by a series of bioinformatics analyses. We systematically performed functional analyses on the six mutations utilizing the Topflash reporter assay, where all NDP and FZD4 mutants revealed at least 50% loss of wild-type activity. Immunoprecipitation finally demonstrated that the six mutations could degrade the Norrin-Frizzled-4 pair-binding effect to varying degrees. Finally, our study underscores the correlation between the FEVR phenotype and genotype in NDP and FZD4, extending the mutation spectrum, allowing a reliable assessment of FEVR recurrence and improving genetic counseling. Further, our findings provide essential evidence for the follow-up study of animal models and drug targets by Topflash assays and immunoprecipitation.

Background/Aims To describe some novel vitreoretinal microstructural findings in patients with mild familial exudative vitreoretinopathy (FEVR) on ultra-wide-field scanning laser ophthalmoscopy (UWF-SLO) and UWF optical coherence tomography (UWF-OCT) and to evaluate their clinical significance.MethodsA total of 32 patients and 32 healthy controls were studied. An additional independent 40 FEVR patients, 44 patients with non-FEVR retinopathies and 40 healthy controls participated in a diagnostic test to validate the abilities of novel findings in FEVR screening.ResultsA novel anatomic change, named Temporal Mid-Peripheral Vitreoretinal Interface Abnormality (TEMPVIA), was found on UWF-SLO in 88.3% of FEVR patients and in none of the healthy controls. The clinical significance of TEMPVIA was further validated by a diagnostic test in new independent cases, with satisfying sensitivity (91.5%) and specificity (98.8%) and Youden Index 0.90. In addition to foveal hypoplasia, some previously unrecognised, novel clinical changes in FEVR, for instance, retinoschisis, focal retinal thickening, sudden thinning of the retina and retinal ridge, were identified using UWF-OCT.ConclusionThe results of this study have led to an update of the clinical spectrum of FEVR and have improved our understanding of its pathogenesis. TEMPVIA is therefore suggested to be a useful biomarker in the screening strategy for mild FEVR.

Familial exudative vitreoretinopathy (FEVR) is an inherited disease characterized by abnormal development of retinal vasculature. KIF11 mutations were identified to be associated with FEVR in recent years. The purpose of this study was to investigate novel variants and describe associated ocular and extraocular phenotypes in FEVR patients with KIF11 mutations. Herein, 417 probands with clinical diagnosis of FEVR were enrolled. Genetic testing and ophthalmic examinations were performed in all subjects, and the genotype-phenotype correlation was analyzed. Overall, KIF11 mutation was identified in nine probands (9/417, 2.2%) among the patients with FEVR phenotype. There were six males and three females whose median age was six months (range: four months to six years old) at first visit. Among the detected mutations, five (55.6%) were frameshift, two (22.2%) were missense, one (11.1%) nonsense, and one (11.1%) splicing. Seven of these KIF11 mutations were detected as novel. Four (4/9, 44.4%) of the mutations were de novo. Clinical examinations showed that: four probands presented with bilateral falciform retinal fold; two with bilateral tractional retinal detachment; one was observed tractional retinal detachment in one eye and retinal fold in the other eye; one had falciform retinal fold in one eye and chorioretinal atrophy in the other eye; one exhibited rhegmatogenous retinal detachment in the left eye. Six of the probands were detected to have microcephaly. In conclusion: Most (5/9,55.6%) of the causative mutations were frameshift, and nearly half (4/9, 44.4%) of the mutations were de novo. Most (8/9, 88.9%) patients with KIF11 mutations showed typical ocular manifestations of severe FEVR. Majority (6/9, 66.7%) of the probands had a KIF11 mutation and were detected to have microcephaly. Seven of these harbored KIF11 mutations detected to be novel.

PURPOSE. Familial exudative vitreoretinopathy (FEVR) is an inherited retinal disease in which the retinal vasculature is affected. Patients with FEVR typically lack or have abnormal vasculature in the peripheral retina, the outcome of which can range from mild visual impairment to complete blindness. A missense mutation (p.His455Tyr) in ZNF408 was identified in an autosomal dominant FEVR family. Little, however, is known about the molecular role of ZNF408 and how its defect leads to the clinical features of FEVR. METHODS. Using CRISPR/Cas9 technology, two homozygous mutant zebrafish models with truncated znf408 were generated, as well as one heterozygous and one homozygous missense znf408 model in which the human p.His455Tyr mutation is mimicked. RESULTS. Intriguingly, all three znf408-mutant zebrafish strains demonstrated progressive retinal vascular pathology, initially characterized by a deficient hyaloid vessel development at 5 days postfertilization (dpf) leading to vascular insufficiency in the retina. The generation of stable mutant lines allowed long-term follow up studies, which showed ectopic retinal vascular hyper-sprouting at 90 dpf and extensive vascular leakage at 180 dpf. CONCLUSIONS. Together, our data demonstrate an important role for znf408 in the development and maintenance of the vascular system within the retina. Funding Agencies|Radboudumc PhD grant; Svenska Sallskapet for Medicinsk Forskning; Linkoping University; Loo och Hans Ostermans Stiftelse; Eva och Oscar Ahrens Stiftelse; Stiftelsen Sigurd och Elsa Goljes Minne; Magnus Bergvalls Stiftelse; Ogonfonden; Jeanssons Stiftelser; VetenskapsradetSwedish Research Council

To evaluate the clinical outcome of 25-gauge lens-sparing vitrectomy with dissection of retrolental adhesions on the peripheral retina for familial exudative vitreoretinopathy in infants. Fifty-one eyes of 39 infants with familial exudative vitreoretinopathy associated with retrolental adhesions on the peripheral retina, retinal fold with macular detachment, and partial lens opacity. A 25-gauge lens-sparing vitrectomy was performed, and retrolental adhesions between the peripheral retina and the posterior lens capsule were surgically dissected. Lens opacification, as assessed or graded by Lens Opacities Classification System III, and the retinal reattachment rate were observed and recorded monthly for up to 7 months postoperatively. After 7 months, the detached retina along the retinal fold was reattached in 42/51 (82.4%) eyes; the macula was reattached completely in 26/51 (51.0%) eyes and partially in 15/51 (29.4%) eyes. There was no statistically significant change in the lens opacity of the posterior capsule or cortex before or after surgery (P > 0.05, paired t test) or in postoperative progression of lens opacity (P > 0.05, modified McNemar’s test) according to Lens Opacities Classification System III scores. A 25-gauge lens-sparing vitrectomy with dissection of peripheral retinal retrolental adhesions is helpful for preservation of the lens and reattachment of the macula in infants with FEVR.

Background/Aims: Familial exudative vitreoretinopathy (FEVR) is a complex hereditary eye disorder characterized by incomplete development of the retinal vasculature, thereby affecting retinal angiogenesis. Methods: In this study, a Chinese autosomal dominant FEVR pedigree was recruited. Ophthalmic examinations were performed, targeted next-generation sequencing was used to identify the causative gene, and Sanger sequencing was conducted to verify the candidate mutation. Co-segregation analysis was performed to evaluate pathogenicity. Semi-quantitative reverse transcription-PCR was applied to investigate the spatial and temporal expression patterns of the frizzled class receptor 4 (FZD4) gene in the mouse. Results: A novel heterozygous, deleterious variant of the FZD4 gene, c.A749G (p.Y250C), was identified in this FEVR pedigree, which co-segregated with the clinical phenotype. The amino acid tyrosine (Y) is highly conserved both orthologously and paralogously. The FZD4 gene was highly expressed in the retina, sclera of the eye, ovary, kidney, and liver; ubiquitously expressed in other tissues; and highly expressed in 6 different developmental stages/times of retinal tissue. Conclusion: Our study is the first to identify that the novel heterozygous variant c.A749G (p.Y250C) in the FZD4 gene may be the disease-causing mutation in this FEVR family, extending its mutation spectrum. These findings further our understanding of the molecular pathogenesis of FEVR and will facilitate the development of methods for the diagnosis, prevention, and genetic counseling of this disease.

We report two cases of bilateral severe familial exudative vitreoretinopathy (FEVR) presenting with bilateral angle closure glaucoma, with evidence of neovascularization in one eye of each case. Both cases displayed bilateral disc dragging with evidence of avascular retinae on fundus fluorescein angiography. Retinal laser photocoagulation and antivascular endothelial growth factor injections provided satisfactory regression of the neovascularization. Medical management of glaucoma was administered to both patients. Lens aspiration with posterior chamber intraocular lens implantation was performed for one eye of each patient. It helped in clearing media as well as in increasing anterior chamber depth, helping in indirect control of intraocular pressure. Although the primary pathology of FEVR lies in the retina, a comprehensive glaucoma screening is essential. We conclude that neovascular glaucoma albeit uncommon in FEVR, may be the presenting feature in advanced unlasered cases, and should be specifically looked for.

Familial exudative vitreoretinopathy (FEVR) is a rare hereditary retinal disorder characterized by the premature arrest of vascularization in the peripheral retina. The aim of the present study was to characterize the clinical presentations of a Chinese family affected by bilateral severe FEVR, and to identify the underlying genetic variations. One family that presented with bilateral FEVR was recruited for this study. Comprehensive ophthalmic examinations, including best‑corrected visual acuity, slit‑lamp examination, fundus photography, fundus fluorescein angiography imaging and electroretinogram were performed. Genomic DNA was extracted from leukocytes of the peripheral blood collected from the affected and unaffected family members, as well as 200 unrelated control subjects from the same population. Next‑generation sequencing of the candidate genes associated with ocular diseases was performed, and the identified mutations were validated by conventional polymerase chain reaction‑based sequencing. The functional effects of the mutations were analyzed by polymorphism phenotyping (PolyPhen) and sorting intolerant from tolerant (SIFT). One heterozygous ATP binding cassette subfamily A member 4 (ABCA4) c.5693G>A (p.R1898H) mutation in exon 40 and one heterozygous LDL receptor related protein 5 (LRP5) c.260T>G (p.I87S) mutation in exon 2 were identified in this family. To the best of our knowledge, the ABCA4 c.5693G>A (p.R1898H) mutation has not been reported in FEVR, and the LRP5 c.260T>G (p.I87S) mutation is a novel mutation. PolyPhen and SIFT predicted that the amino acid substitution R1898H in protein ABCA4 is benign, whereas the amino acid substitution I87S in protein LRP5 is damaging. A single nucleotide polymorphism c.266A>G (p.Q89R, rs41494349) was identified in exon 2 of LRP5. These findings expand the mutation spectrums of ABCA4 and LRP5, and will be valuable for genetic counseling and development of therapeutic interventions for patients with FEVR.

To describe the clinical features and surgical outcomes of macular dragging or tractional retinal detachment that occurred as a result of fibrovascular tissue (FT) progression toward the posterior retina in eyes with familial exudative vitreoretinopathy (FEVR). The medical records of 4 patients (2 girls, 2 boys) with FEVR were reviewed retrospectively. All 4 patients had retinal dragging or radial retinal folds with FT in the peripheral retina in at least 1 eye at the initial visit. During the follow-up period, all the patients had FT that progressed toward the posterior pole and developed from the peripheral FT, resulting in macular dragging or posterior tractional retinal detachment. Vitrectomy with or without scleral buckling and laser photocoagulation were performed in all 4 cases, with removal of the FT in the posterior pole and segmentation of the FT between the posterior and peripheral FT. The traction resolved postoperatively and the retina extended in all 4 cases. In 4 cases with FEVR, the FT developed from the peripheral FT, progressed toward the posterior retina, and generated traction. Vitrectomy with focal removal and segmentation of the FT in the posterior pole might be a good surgical option in such eyes.

Purpose: To report a family affected by familial exudative vitreoretinopathy (FEVR) in which more severe disease phenotypes segregated with digenic rather than monogenic variants in FEVR-related genes. Methods: Phenotype was documented with high-resolution imaging of retinal structure and wide-field fundus photography. Next-generation sequencing (NGS) of known genes involved in FEVR was performed. Results: Three affected individuals within a family with FEVR presented with variable disease severity. All three affected family members harboured mutation c.349T>C (p.Cys117Arg) in FZD4. In addition, the youngest family member, a 9-year-old boy, who presented with bilateral tractional retinal detachment, and his mother, who presented with retinal pigmentary alterations and bilateral dragging of the macula and atrophy, both harboured the variant c.565T>C (p.Cys189Arg) in TSPAN12. Both suffered from bilateral severe visual loss. On the other hand, the older sister who presented with mild visual loss, temporal avascularity in the right eye and dragging of the blood vessels over the disc and macula in the left eye did not harbour the variant p.Cys189Arg in TSPAN12. Conclusion: These data suggest variants in more than one FEVR-related gene can underlie variable expressivity for FEVR phenotypes in a single family. Further studies of phenotype-genotype correlation, including next-generation sequencing, in larger cohorts of patients with FEVR are needed to investigate whether changes in more than one gene coding for proteins in the Norrin-β-catenin pathway are a recurrent cause for variable expressivity in the disease. (Less)

Purpose To report a novel presentation of dyskeratosis congenita masquerading as familial exudative vitreoretinopathy. Methods Observational case series involving single family and literature review. Results A brother and sister were diagnosed with familial exudative vitreoretinopathy at ages 4 and 2, respectively. Both patients were managed with laser photocoagulation. Eight years after the initial presentation, both siblings developed pancytopenia secondary to bone marrow failure. Laboratory work-up revealed severely shortened telomere length in both patients, and genetic testing revealed a missense mutation in the gene that encodes the reverse transcriptase component of telomerase, confirming the diagnosis of dyskeratosis congenita. The father of both children was a carrier of the same mutation, who exhibited marked retinal vascular tortuosity of the second-order vessels. Conclusion Dyskeratosis congenita is a severe multisystem disorder, which should be considered in cases of pediatric exudative retinopathies with concurrent signs and/or symptoms of bone marrow failure.

Contains fulltext : 174538.pdf (Publisher’s version ) (Closed access) Familial exudative vitreoretinopathy (FEVR) is an inherited blinding disorder characterized by the abnormal development of the retinal vasculature. The majority of mutations identified in FEVR are found within four genes that encode the receptor complex (FZD4, LRP5, and TSPAN12) and ligand (NDP) of a molecular pathway that controls angiogenesis, the Norrin-beta-catenin signaling pathway. However, half of all FEVR-affected case subjects do not harbor mutations in these genes, indicating that further mutated genes remain to be identified. Here we report the identification of mutations in CTNNB1, the gene encoding beta-catenin, as a cause of FEVR. We describe heterozygous mutations (c.2142_2157dup [p.His720 *] and c.2128C>T [p.Arg710Cys]) in two dominant FEVR-affected families and a de novo mutation (c.1434_1435insC [p.Glu479Argfs *18]) in a simplex case subject. Previous studies have reported heterozygous de novo CTNNB1 mutations as a cause of syndromic intellectual disability (ID) and autism spectrum disorder, and somatic mutations are linked to many cancers. However, in this study we show that Mendelian inherited CTNNB1 mutations can cause non-syndromic FEVR and that FEVR can be a part of the syndromic ID phenotype, further establishing the role that beta-catenin signaling plays in the development of the retinal vasculature.

AimsTo explore the clinical and genetical features of families with strictly confirmed familial exudative vitreoretinopathy (FEVR) in a large Chinese cohort.MethodsA retrospective chart review study was conducted on the FEVR families diagnosed by both angiography and targeted next-generation sequencing in six FEVR known genes (FZD4, LRP5, TSPAN12, NDP, KIF11, ZNF408) in the probands and at least one first-degree family member. Variation in expressivity and severity was evaluated in different gene groups.Results105 FEVR families (223 FEVR affected subjects with 434 eyes) met the inclusion criteria. There were 105 probands with mean age of 3.8 years old and 118 affected family members of 32.7 years old averagely. Mutations in FZD4 were most prevalent (33.33%), followed by LRP5 (29.52%), TSPAN12 (22.86%), NDP (5.71%), KIF11 (1.9%) and ZNF408 (0.95%). 81% of the probands were classified as stage 4 or worse which most prevalently contributed to FZD4 mutations. All of the three affected family members with stage 4 or worse carried FZD4 variants. More than half (51.43%) of the probands in FZD4 group showed asymmetry. Unilateral FEVR was detected in 11 (10.5%) families consisting of six probands and six affected relatives, and FZD4 mutations accounted for 63.64% of all the cases with variant (c.1282_1285del, p. D428fs) identified in three families.ConclusionsGenotype-phenotype correlation in FEVR was complex with family dependent. Mutations in FZD4 might initiate the most diverse and asymmetric phenotypes.

PURPOSE: Familial exudative vitreoretinopathy (FEVR) is a rare finding in patients with genetic forms of microcephaly. This study documents the detailed phenotype and expands the range of genetic heterogeneity. Design; Retrospective case-series METHODS: Twelve patients (ten families) with a diagnosis of FEVR and microcephaly were ascertained from pediatric genetic eye clinics and underwent full clinical assessment including retinal imaging. Molecular investigations included candidate gene Sanger sequencing, whole-exome sequencing (WES) and whole-genome sequencing (WGS).RESULTS: All patients had reduced vision and nystagmus. Six were legally blind. Two probands carried bi-allelic LRP5 variants, both presenting with bilateral retinal folds. A novel homozygous splice variant, and two missense variants were identified. Subsequent bone density measurement, identified osteoporosis in one proband.Four families had heterozygous KIF11 variants. Two probands had a retinal fold in one eye and chorioretinal atrophy in the other; the other two had bilateral retinal folds. Four heterozygous variants were found, including two large deletions not identified on Sanger sequencing or WES.Finally, a family of two children with learning difficulties, abnormal peripheral retinal vasculogenesis and rod-cone dystrophy were investigated. They were found to have bi-allelic splicing variants in TUBGCP6.Three families remain unsolved following WES and WGS.CONCLUSIONS: Molecular diagnosis has been achieved in seven of ten families investigated including a previously unrecognized association with LRP5. WGS enabled molecular diagnosis in three families after prior negative Sanger sequencing of the causative gene. This has enabled patient-specific care with targeted investigations and accurate family counseling.

Purpose The purpose of this study was to investigate the etiology and clinical features of nontraumatic rhegmatogenous retinal detachment (RRD) in children. Design Consecutive, cross-sectional study. Methods In this study, 112 operative eyes of 102 patients ≤18 years of age with nontraumatic RRD were included. Comprehensive ophthalmic examinations were performed in all patients. Genetic testing was performed in 34 patients with hereditary congenital/developmental diseases. The etiology of RRD was analyzed. Results The average age was 12.2 ± 4.5 years (range, 1-18 years). The percentages of male and female patients were 74.5% (76/102) and 25.5% (26/102), respectively. The most common etiologic factors were congenital/developmental anomalies (51/102, 50%), followed by simple myopia (34/102, 33.3%) and previous intraocular surgery (6/102, 5.9%). More than half (31/51, 60.8%) of the patients with congenital/developmental anomalies had familial exudative vitreoretinopathy. Further analysis of the underlying etiologic factors based on age revealed that the most common etiology of RRD in patients ≤12 years of age was congenital/developmental anomalies (28/48, 58.3%); however, simple myopia was the major etiologic factor in patients >12 years of age (27/54, 50%). Conclusions Congenital/developmental diseases were the most common etiologies of pediatric nontraumatic RRD in China. Familial exudative vitreoretinopathy accounted for most of the congenital/developmental anomalies.

Background Familial exudative vitreoretinopathy (FEVR) is a severe clinically and genetically heterogeneous retinal disorder characterized with failure of vascular development of the peripheral retina. The symptoms of FEVR vary widely among patients in the same family, and even between the two eyes of a given patient. The purpose of this study was to investigate the molecular mechanisms by which the start codon mutation of the TSPAN12 causes difference in clinical manifestations between individuals in the same family. Methods Next‐generation sequencing (NGS)‐based target capture sequencing was performed in proband with a diagnosis of FEVR and their normal visual acuity family members. Cosegregation analysis of the candidate causative variant was performed in additional family members by using Sanger sequencing. Complete fundus examination, fundus fluorescein angiography (FFA), and family history collection were performed in all family members. Potential candidate causative variants were verified with reference to guidelines and standards from the American College of Medical Genetics and Genomics. Results We identified a novel heterozygous missense mutation (c.1A>G, p.M1V) localized in the start codon of the TSPAN12 and was detected as a potentially disease‐causing variant for the proband. Retrospective analysis of clinical data, fundus examination, and FFA showed that the mutant carrier presented peripheral retinal vascular anomalies in early stages, and visual acuity did not show significant effects. However, the proband who carried this mutation and his cousin showed typical high‐stage FEVR fundus changes coupled with a sharp decline in vision. Conclusions We report a novel start codon mutation (c.1A>G, p.M1V) in the TSPAN12 that causes clinically heterogeneous manifestations. Our results expand the mutation spectrums of TSPAN12, and will be valuable for disease diagnosis, prognosis, genetic counseling, and enriching our understanding of the role of the tetraspanin‐12 protein in the pathogenesis of FEVR.

To describe the etiology and clinical characteristics of macular edema (ME) in patients with familial exudative vitreoretinopathy.Observational, retrospective case series of 30 patients (34 eyes) with ME and familial exudative vitreoretinopathy who underwent spectral-domain optical coherence tomography imaging between 2009 and 2016. Baseline and follow-up optical coherence tomographies were correlated with color fundus photography and fluorescein angiography.The average age was 20.6 years (6.6-68.7). Eighteen eyes exhibited cystoid ME (52.9%), 14 noncystoid ME (41.2%), and 2 eyes (5.9%) with both. Macular edema was foveal in 52.9% (n = 18). Eighteen of 24 eyes (64.3%) with an available fluorescein angiography showed leakage from ME. The most common structural feature was posterior hyaloidal organization/contraction (n = 15). Sixteen eyes were treated with topical or intravitreal steroids (n = 6), intravitreal anti-vascular endothelial growth factor (n = 3), or pars plana vitrectomy with membrane stripping (n = 7). There was no difference between mean preoperative and postoperative LogMAR visual acuity (0.63 [20/85] vs. 0.87 [20/148], P = 0.35) after vitrectomy despite a statistical improvement in the mean central foveal thickness (596 mm vs. 303 mm, P = 0.04).Macular edema in familial exudative vitreoretinopathy occurs most commonly because of traction. Vitrectomy is effective for relieving tractional forces with anatomical improvement.

Background To delineate the characteristics of complicated familial exudative vitreoretinopathy (FEVR) patients diagnosed before surgery or intra−/post-operatively and to analyze the risk factors for the diagnostic timing. Methods Forty-eight patients who underwent surgery and were diagnosed as FEVR in our department were retrospectively reviewed. Data were collected including the demographic and clinical characteristics of these patients. FEVR patients were divided into 2 groups according to the diagnostic timing: FEVR diagnosed pre-operatively (23 patients), FEVR diagnosed intra−/post-operatively (25 patients). Multivariable analysis was applied for analyzing the risk factors for diagnostic timing. Results The clinical characteristics of the FEVR patients were of great variability, including retinal detachment (RD), disappear of anterior chamber, retrolental membrane, epiretinal membrane (ERM), vitreous hemorrhage (VH), myopic foveoschisis (MF), lamellar macular hole (LMH), high myopia (HM). And the referral diagnosis or pre-operative diagnosis were always non-specific. The majority of the referral or preoperative diagnosis were unilateral RD (52.1%), bilateral RD (8.3%), unilateral persistent fetal vasculature (PFV) (8.3%), bilateral PFV (4.2%). There are two risk factors for the complicated FEVR cases diagnosed as FEVR preoperatively: pre-operative ocular manifestations with RD only (OR, 0.104; p-value, 0.022), positive parent’s fluorescein angiography (FA) (OR, 0.105; p-value, 0.035). Conclusions The phenotypes of FEVR were greatly variable, they can mimic many non-specific vitreoretinal disorders. The most non-specific referral diagnosis/pre-operative diagnosis was unilateral RD, bilateral RD, unilateral PFV, bilateral PFV. A positive family history or a simple ocular presentation with RD only could contribute to diagnose FEVR preoperatively.

Familial exudative vitreoretinopathy (FEVR) is a rare congenital disorder characterized by a lack of blood vessel growth to the periphery of the retina with secondary fibrovascular proliferation at the vascular-avascular junction. These structurally abnormal vessels cause leakage and hemorrhage, while the fibroproliferative scarring results in retinal dragging, detachment and blindness. Mutations in the FZD4 gene represent one of the most common causes of FEVR. A loss of function mutation resulting from a 10-nucleotide insertion into exon 1 of the zebrafish fzd4 gene was generated using transcription activator-like effector nucleases (TALENs). Structural and functional integrity of the retinal vasculature was examined by fluorescent microscopy and optokinetic responses. Zebrafish retinal vasculature is asymmetrically distributed along the dorsoventral axis, with active vascular remodeling on the ventral surface of the retina throughout development. fzd4 mutants exhibit disorganized ventral retinal vasculature with discernable tubular fusion by week 8 of development. Furthermore, fzd4 mutants have impaired optokinetic responses requiring increased illumination. We have generated a visually impaired zebrafish FEVR model exhibiting abnormal retinal vasculature. These fish provide a tractable system for studying vascular biology in retinovascular disorders, and demonstrate the feasibility of using zebrafish for evaluating future FEVR genes identified in humans. This article is protected by copyright. All rights reserved.

PURPOSE To quantitatively detect the macular microvascular alterations of eyes with familial exudative vitreoretinopathy (FEVR) and analyze their associations with the severity and visual acuity of FEVR. METHODS A case-control study comprising 62 patients (62 eyes) with FEVR and 21 age-matched healthy individuals (21 eyes) with normal vision was conducted. Parafoveal vascular density (VD) was measured using optical coherence tomography angiography. Visual acuity, intraocular pressure, and axial length were recorded. RESULTS Parafoveal VD of eyes with FEVR was lower than that of the controls (P < 0.05). Parafoveal VD decreased with increasing FEVR stages (P < 0.05), and decreased VD in superficial capillary plexus (SCP) was independently correlated with FEVR severity (odds ratio: 1.558, P < 0.001) after controlling for other confounding variables. Vascular density in eyes with FEVR and decreased visual acuity was lower than eyes with FEVR and normal visual acuity (SCP, P < 0.001; deep capillary plexus, P = 0.001). Moreover, VD loss had independent association with visual loss in FEVR (SCP: odds ratio: 0.817, P = 0.019; deep capillary plexus: odds ratio: 0.763, P = 0.016). CONCLUSION There may be parafoveal microvascular defects in FEVR and that VD loss in SCP may be correlated with the severity of FEVR. In addition, VD loss in SCP and deep capillary plexus may be associated with the visual loss in FEVR.

Background Frizzled family members belong to G-protein coupled receptors and encode proteins accountable for cell signal transduction, cell proliferation and cell death. Members of Frizzled receptor family are considered to have critical roles in causing various forms of cancer, cardiac hypertrophy, familial exudative vitreoretinopathy (FEVR) and schizophrenia. Results This study investigates the evolutionary and structural aspects of Frizzled receptors, with particular focus on FEVR associated FZD4 gene. The phylogenetic tree topology suggests the diversification of Frizzled receptors at the root of metazoans history. Moreover, comparative structural data reveals that FEVR associated missense mutations in FZD4 effect the common protein region (amino acids 495–537) through a well-known phenomenon called epistasis. This critical protein region is present at the carboxyl-terminal domain and encompasses the K-T/S-XXX-W, a PDZ binding motif and S/T-X-V PDZ recognition motif. Conclusion Taken together these results demonstrate that during the course of evolution, FZD4 has acquired new functions or epistasis via complex patter of gene duplications, sequence divergence and conformational remodeling. In particular, amino acids 495–537 at the C-terminus region of FZD4 protein might be crucial in its normal function and/or pathophysiology. This critical region of FZD4 protein may offer opportunities for the development of novel therapeutics approaches for human retinal vascular disease. Electronic supplementary material The online version of this article (10.1186/s12862-019-1400-9) contains supplementary material, which is available to authorized users.

Familial exudative vitreoretinopathy (FEVR) is a hereditary retinal vascular disorder. Among the various clinical phenotypes of this disease, retinal folds are the primary and typical feature of FEVR. However, little is known about the clinical characteristics, genetic spectrum, or potential phenotype-genotype correlation of retinal folds. Herein, we describe and analyze the clinical and genetic characteristics of retinal folds in FEVR. Eighty-nine patients with unilateral or bilateral retinal folds were included in this study. Clinical examinations showed that the retinal folds were bilateral in 37 patients (41.6%). Various retinal abnormalities were noted in the fellow eyes in the remaining 52 patients with unilateral folds. Most of the folds were located temporally (98.4%, 124/126), and were complete (97.6%, 123/126). 67.5% (60/89) probands were genetic confirmed FEVR. 25 novel pathogenic mutations (7 in FZD4, 7 in LRP5, 1 in NDP, 4 in TSPAN12, and 6 in KIF11) were identified in 25 families. Overall, 87.5% (14/16) and 73.7%(14/19) patients with LRP5 and FZD4 mutations were with unilateral folds, respectively.Nevertheless, only 25% (2/8), 36.4%(4/11) and 16.7%(1/6) patients with NDP, TSPAN12, and KIF11 mutations were with unilateral folds. Moreover, 85.7%(12/14),100% (6/6) and 100%(8/8) of the patients with mutated TSPAN12, KIF11, and NDP genes presented with symmetry in disease staging, while 55% and 64.7% of patients with FZD4 and LRP5 mutation displayed symmetry in staging. In conclusion, the majority of retinal folds extended completely and radially in the temporal peripheral retina. Patients with causative mutations in NDP, TSPAN12, or KIF11 were more likely to have bilaterally symmetrical severe retinopathy. In contrast, patients with LRP5 and FZD4 mutations displayed a relatively milder but broader spectrum of phenotypes and a higher frequency of asymmetry.