Research progresses on pathogenic genes and related signal pathways of familial exudative vitreoretinopathy / 中华眼底病杂志

Familial exudative vitreoretinopathy (FEVR) is a serious hereditary retinal vascular disease. The clinical manifestations vary, and the severity of the patients' condition is different. In severe cases, it may lead to bilateral blindness. The pathogenic mechanism of FEVR is also complex. At present, more than ten classical and candidate pathogenic genes have been found: NDP, FZD4, LRP5, TSPAN12, CTNNB1, KIF11, ZNF408, RCBTB1, LRP6, CTNNA1, CTNND1, JAG1, ATOH7, DLG1, DOCK6, ARHGP31 and EVR3 region. These pathogenic genes are involved in Wnt/β-catenin signaling pathway, norrin/β-catenin pathway and Notch pathway. They regulate and affect the development of retinal blood vessels, hyaloid vascular system regression, endothelial cell connections, and blood retinal barrier homeostasis, ultimately leading to the occurrence and development of FEVR disease.

The macular structure and blood flow in familial exudative vitreoretinopathy with inner retinal layer persistence / 中华眼底病杂志

Objective:To compared the changes of macular microvascular architecture in early stage familial exudative vitreoretinopathy (FEVR) patients with inner retinal layer (IRL) persistence and without IRL persistence.Methods:A retrospective clinical study. From 2017 to 2022, 94 patients with stage 1 FEVR with or without IRL residue and 45 age- and sex-matched healthy volunteers with 45 eyes (normal control group) who were confirmed by ophthalmology examination in Hangzhou Hospital of Optometry Affiliated to Wenzhou Medical University and Zhejiang Provincial People's Hospital were included in the study. According to whether there was IRL residue, the patients were divided into IRL group and non-IRL group, with 22 patients (22 eyes) and 72 patients (72 eyes), respectively. Best corrected visual acuity (BCVA) and optical coherence tomography angiography (OCTA) were performed in all eyes. Superficial vessel density (SCP) and deep vessel density (DCP) of whole image, fovea and parafovea, the area and perimeter of fovea avascular area (FAZ), A-circularity index (AI, perimeter/standard circle perimeter with equal area) and vessel density around the 300 μm width of the FAZ (FD), central macular thickness (CMT) on macular 3 mm × 3 mm scan on OCTA were measured.Results:SCP and DCP of whole image ( F=10.774, 4.583) and parafovea ( F=10.433, 3.912), CMT ( F=171.940) in IRL group and non-IRL group on macular 3 mm × 3 mm scan on OCTA were significantly lower than that in normal persons ( P<0.05). There were significant differences among three groups of the area of FAZ ( F=4.315), AI ( F=3.413), FD-300 ( F=13.592) ( P<0.05). BCVA were worst in IRL group ( P<0.05). Conclusions:Blood flow density decreased in macular area of FEVR patients. CMT is significantly thicker than normal population. The FAZ area of the foveal IRL residual eyes is small and irregular, with worse BCVA and lower macular blood density.

Clinical features and treatment of glaucoma secondary to familial exudative vitreoretinopathy / 中华眼底病杂志

Objective:To investigate the etiology, clinical features and treatment of familial exudative vitreoretinopathy (FEVR) secondary glaucoma.Methods:A retrospective clinical study. From January 1, 2016 to January 1, 2022, 15 patients (17 eyes) were diagnosed with FEVR secondary glaucoma in Beijing Tongren Hospital, Capital Medical University were included in the study. All patients underwent systematic ophthalmological evaluation. According to the patient's age, visual acuity, intraocular pressure, anterior segment, vitreous body and retina condition, the choice of translimbal lensectomy combined with vitrectomy, goniectomy, cyclophotocoagulation, intravitreal injection of anti-vascular endothelial growth factor (VEGF) treatment were chosen. The follow-up time was 3 to 37 months. The clinical characteristics of the affected eye, and the changes of intraocular pressure, anterior chamber depth and complications after surgery were observed.Results:Among the 15 patients, there were 11 males with 13 eyes, and 4 females with 4 eyes. Age was 6.14±7.37 years old. FEVR stages 2B, 3B, 4A, 4B, 5A, and 5B were 1, 1, 5, 6, 3, and 1 eye, respectively. The intraocular pressure of the affected eye was 42.74±9.06 mm Hg (1 mm Hg=0.133 kPa). All eyes had shallow anterior chamber and angle closure, anterior or posterior iris adhesions, lens opacity, retinal detachment, iris neovascularization in 4 eyes, and vitreous hemorrhage in 2 eyes. Sixteen eyes were treated with translimbal lensectomy combined with vitrectomy and goniotomy, of which 8 eyes were treated with anti-VEGF treatment; 1 eye was treated with cyclophotocoagulation combined with anti-VEGF treatment. After operation, the intraocular pressure of 16 eyes returned to normal range, and the depth of anterior chamber of 16 eyes returned to normal, and no obvious complications occurred.Conclusions:The main etiology of secondary glaucoma in FEVR is the structural and functional abnormalities of the anterior chamber and angle, which are found in the 2B and above stages of FEVR. The lensectomy and vitrectomy via limbal approach can effectively control the intraocular pressure and restore the anterior chamber, with no serious complications.

Analysis of factors affecting the clinical features of familial exudative vitreoretinopathy / 中华眼底病杂志

Objective:To observe and investigate the related factors that might affect clinical features of familial exudative vitreoretinopaty (FEVR) patients.Methods:A retrospective chart study. From January 2012 and December 2021, 42 patients with 84 eyes with a diagnosis of FEVR from Department of Ophthalmology, Peking University People's Hospital were included in the study. The patients came from 42 separate families. There were 31 males and 11 females, with an average age of first diagnosis was 16.6±33.7 months. There were 21 patients referred from other hospitals for the fundus disease found in eye screening after birth, 21 patients were first seen in our hospital. There were 4 and 38 premature and full-term infants, respectively. Two patients with a positive family history of FEVR. All patients are FEVR stages 1-5. The wide-angle digital pediatric retinal imaging system after general anesthesia for fluorescein fundus angiography (FFA) examination were performed for patients aged <5 years. If patients ≥ 5 years old, routine FFA examination was performed. Sixty-eight first-degree relatives from 28 families undergo routine fundus examinations and FFA examination. Genetic examination was performed for 26 families, including 26 probands and 57 first-degree relatives. Genetic examination were performed on gene the coreceptor of low density lipoprotein receptor-associated protein 5 ( LRP5), Wnt receptor coiled protein 4 ( FZD4), Norrie disease ( NDP), tetraporin 12 ( TSPAN12), catenin β1 ( CTNNB1) genes known to be involved in FEVR. The clinical features and the genotype of FEVR were observed in relation to the clinical phenotype. Results:Among the 42 patients, 13 patients were first observed by strabismus and nystagmus, with the median age of 12 months. Eight patients were complained non-chasing or vision-related symptoms. Among the 84 eyes, FEVR stage 1 or 2, 3 or 4, and 5 were 50 (59.5%, 50/84), 31 (36.9%, 31/84), and 3 (3.6%, 3/84) eyes, respectively. Among the 23 patients who were > 3 months at first diagnosis, 16 patients had at least one eye severer than stage 3 (69.6%, 16/23). Of the 68 first-degree relatives, 22 (32.4%, 22/68) had FEVR-like changes. Among the 26 families that underwent genetic detection, 13 families (50%, 13/26) of 16 variants of FEVR-related genes were detected, of which 10 mutations of LRP5 gene were the most common. There were 10 families with single gene mutations, including 6, 2 and 2 families of LRP5, FZD4 and CTNNB1 genes, respectively. One family of LRP5 gene mutations were compound heterozygous mutations, 1 family with LRP5 gene mutaition combined with NDP gene mutation, and 1 family with LRP5 and TSPAN12 gene mutation. Among the proband with FEVR pathogenic genes, 6 cases with similiar stage of both eyes, and 7 cases with inconsistent disease stages, and there was no obvious correlation between gene mutations and clinical phenotypes. Conclusion:In addition to the age of first diagnosis, no exact factors affecting the clinical manifestations of FEVR are found, and the association between clinical phenotypic and genetic heterogeneity still needs to be further explored.

Efficacy of scleral buckling for retinal detachment secondary to familial exudative vitreoretinopathy / 中华实验眼科杂志

Objective:To evaluate the efficacy of scleral buckling in the treatment of retinal detachment (RD) secondary to familial exudative vitreoretinopathy (FEVR).Methods:An observational case series study was conducted.A total of 37 patients (42 eyes) of RD secondary to FEVR who were treated with scleral buckling in Beijing Tongren Hospital from July 2010 to March 2021 were enrolled.There were 30 males (35 eyes) and 7 females (7 eyes), with an average age of (15.21±5.42) years old.Scleral buckling under general anesthesia was performed in all patients.There were 22 eyes with rhegmatogenous RD (RRD), of which 21 eyes were treated with local external compression combined with cerclage, and 1 eye was treated with radial spinal compression.There were 13 eyes with tractive RD (TRD), of which 12 eyes were treated with local external compression combined with cerclage and subretinal fluid drainage, and 1 eye was treated with scleral buckling combined with vitrectomy.There were 7 eyes with RRD combined with TRD, of which 4 eyes were treated with local external compression combined with cerclage and subretinal fluid drainage, and 3 eyes were treated with scleral buckling combined with vitrectomy.The average follow-up time was (30.61±10.50) months.The main outcomes were best corrected visual acuity (BCVA) of the operated eye converted to the logarithm of the minimum angle of resolution, retinal reattachment rate, and incidence of complications.The study adhered to the Declaration of Helsinki and was approved by the Ethics Committee of Beijing Tongren Hospital, Capital Medical University (No.TRECKY2018-056-GZ[2022]-07). Written informed consent was obtained from each subject or their guardians before entering the cohort.Results:The average BCVA was 0.83±0.50 at last follow-up after surgery which was better than 1.10±0.39 before surgery, and the difference was statistically significant ( t=6.639, P<0.001). There were 39 eyes with retinal reattachment and 3 eyes without retinal reattachment.The reattachment rate was 95.45%(21/22) in RRD, 84.62%(11/13) in TRD, and 100%(7/7) in RRD combined with TRD.No serious complication occurred in any patients during postoperative follow-up. Conclusions:On the premise of optimized surgical strategy based on the indications of RD secondary to FEVR, scleral buckling has a high retinal reattachment rate in the treatment of RD secondary to FEVR.

Management and surgical outcomes of pediatric retinal detachment associated with familial exudative vitreoretinopathy – Our experience at a tertiary care ophthalmic center in North India

Purpose: To report the clinical profile, management, and long?term anatomical and visual acuity (VA) outcomes of pediatric macula?off rhegmatogenous retinal detachment (RRD) secondary to familial exudative vitreoretinopathy (FEVR). Methods: This was a prospective, interventional study of 14 eyes of 13 children aged ?18 years with macula?off FEVR?RRD. The primary outcomes were anatomical reattachment and VA changes. Results: The mean (±SD) age of the study population was 12.14 (±3.23) years (range 6–18 years) with a male preponderance (M:F – 10:3). Of the 14 eyes, 10 underwent vitrectomy with silicone oil injection, while four underwent scleral buckling surgery. Significant improvement in VA was noted at a mean (±SD) follow?up duration of 3.32 (±1.34) years, with the mean (±SD) LogMAR VA improving from 1.42 (±0.48) (Snellen equivalent 2/60; range from 6/36 to counting finger close to face [CFCF]) to 0.6 (±0.31) (Snellen equivalent 6/24; range 6/9–6/36) (P < 0.00001) at the final visit. Successful anatomical reattachment was achieved in 13/14 eyes (92.85%). Screening of the other eye and family members was performed for FEVR and treated with laser photocoagulation when deemed necessary (7/10 contralateral eye; 12/20 siblings; 0/24 parents). Conclusion: To conclude, RRD may arise in eyes with FEVR at a young age and with a male predilection in Indian population. Timely surgical intervention by scleral buckling procedure or vitrectomy, based on the patient profile, can achieve excellent anatomical and VA outcomes. Careful clinical and angiographic screening of the other eye and family members is vital.

Retinopatía del prematuro con presentación atípica / Retinopathy of prematurity with atypical presentation

La retinopatía de la prematuridad es una enfermedad dinámica vasoproliferativa de la retina inmadura postnatal que afecta a los bebés prematuros. Cuando aparecen signos de atipicidad en su diagnóstico o evolución deben descartarse otras entidades vasculares de la retina, que generalmente tienen un trasfondo genético y semejan o coexisten con dicha entidad. Se presenta un caso con características de Retinopatía del prematuro y algunos signos de atipicidad. Se describe su manejo y evolución, así como una breve descripción de las entidades que conforman el diagnóstico diferencial(AU)

Retinopathy of prematurity is a dynamic vasoproliferative disease of the immature postnatal retina that affects premature babies. When signs of atypicality appear in its diagnosis or evolution, other vascular entities of the retina must be ruled out, which generally have a genetic background and resemble or coexist with said entity. We present a case with characteristics of Retinopathy of prematurity and some signs of atypicality. Its management and evolution are described, as well as a brief description of the entities that make up the differential diagnosis(AU)

Research progress on pathogenic genes of familial exudative vitreoretinopathy / 国际眼科杂志(Guoji Yanke Zazhi)

@#Familial exudative vitreoretinopathy(FEVR)is a severe clinically and genetically heterogeneous retinal disease which characterized by abnormal development of the peripheral retinal vessels. FEVR presents many clinical phenotypes, the main and typical feature is retinal folds. There are various inheritance modes with high genetic heterogeneity of FEVR including autosomal recessive, X-recessive, autosomal dominant recessive, and other scattered inheritance modes. So far, nine FEVR pathogenic genes have been reported: NDP, FZD4, LRP5, CTNNA1, TSPAN12, ZNF408, KIF11, CTNNB1, and JAG1 genes. These genes are mainly involved in signaling pathways such as Wnt, Notch, and Norrin-β-catenin. This article reviews the above nine FEVR pathogenic genes and their signaling pathways.

Clinical characteristic of familial exudative vitreous retinopathy occurring in premature infants / 国际眼科杂志(Guoji Yanke Zazhi)

@#AIM: To describe the clinical characteristics of 6 premature infants diagnosed as familial exudative vitreoretinopathy(FEVR).<p>METHODS: From August 2018 to January 2019, the researchers collected six premature cases of FEVR from Xinhua Hospital Affiliated To Shanghai Jiao Tong University School of Medicine. All 6 infants born prematurely had examinations of fundus photography and fluorescein angiograms under anesthesia. Medical history and angiographic features were analyzed retrospectively.<p>RESULTS: Six infants born prematurely were initially misdiagnosed as retinopathy of prematurity ROP. All underwent injection anti-vascular endothelial growth factor(anti-VEGF)drug into vitreous body cavity subsequently, two of whom were treated with injection anti-VEGF drug into vitreous body cavity twice. Six infants born prematurely had follow-up examinations of fundus photography and fluorescein angiograms with the machine of Retcam digital imaging system under anesthesia, they were eventually diagnosed as FEVR. Then 2 cases were treated with laser photocoagulation, 1 case was treated with injection anti-VEGF drug into vitreous body cavity combined laser photocoagulation, 1 case was treated with injection anti-VEGF drug into vitreous body cavity, 2 cases maintain the follow-up visit. <p>CONCLUSION: Clinically, premature infants FEVR, tend to be misdiagnosed as ROP initially. If the demarcation line separating the avascular from the vascular retinal regions presents persistent or the condition turns to be worse, more examinations will be required to confirm the diagnosis such as fluorescein angiograms under anesthesia. FEVR is a lifelong disease, its symptoms, if present, typically take a progressive course during childhood and adolescence. Early diagnosis of FEVR is crucial due to its progressive nature and the genetic/familial underpinnings of the condition. The correct identification of those FEVR patients can help them receive timely treatment and genetic counseling for those of child-bearing age.

Screening and diagnosis of familial exudative vitreoretinopathy / 国际眼科杂志(Guoji Yanke Zazhi)

@#Familial exudative vitreoretinopathy(FEVR)is an inherited vitreoretinopathy characterized by vascular dysplasia of periphery retina. Typical fundus findings consist of avascular periphery retina, increasing branching and abnormal anastomosis of retinal vessels. Having diversified clinical phenotypes, FEVR patients can be asymptomatic, which can often be missed, or with severe complications including retinal detachment, retinal folds, vitreous hemorrhage, causing vision loss. While FEVR had been thought to be rare in previous studies, the incidence was found to reach up to 1% in recent studies of fundus screening in the newborn. Diagnosis is usually based on clinical features, fundus fluorescein angiography, and detection of pathogenic genes. Ultra-wide-field imaging is a noninvasive and convenient way for the screening and diagnosis of FEVR. In this review,clinical features and diagnostic approaches of FEVR are concluded, and application value of ultra-wide-field imaging in its screening is discussed.

Diversity of familial exudative vitreoretinopathy / 中华眼底病杂志

Familial exudative vitreoretinopathy (FEVR) is a hereditary retinal vascular dysplasia. So far, 6 genes have been found to be associated with FEVR: Wnt receptor Frizzled Protein 4, Norrie's disease, co-receptor low-density lipoprotein receptor-related protein 5, tetraspanin 12, zinc finger protein 408, and kinesin family members 11 genes. Its clinical manifestations, pathological processes and genetic patterns are diverse, and it shows the relationship between gene polymorphism and clinical manifestation diversity. It is characterized by different symptoms between the same individual, the same family, and the same gene mutation; different clinical stages and gene mutation types of parents or unilateral genetic children; different clinical characteristics and gene mutation patterns of full-term and premature infant; combined with other eye disease and systemic diseases;double gene mutations and single gene mutations have different clinical manifestations and gene mutation characteristics. A comprehensive understanding of the different clinical manifestations and diverse genetics of FEVR can provide better guidance for the treatment of FEVR.

NDP gene variants analysis and clinical features of Norrie disease and familial exudative vitreoretinopathy / 中华实验眼科杂志

Objective To analyze the clinical features and NDP gene variants in patients with Norrie disease and familial exudative vitreoretinopathy,(FEVR).Methods Sixteen patients who were diagnosed as FEVR and 3 patients who were diagnosed as Norrie disease underwent detailed ocular examinations in Beijing Tongren Hospital from 2012 to 2018.Peripheral venous blood was drawn from patients and their family members for extration of genomic DNA.All exons of NDP gene were analyzed by direct sequencing of PCR-amplified DNA fragments.This study was approved by Joint Committee on Clinical Investigation of Beijing Tongren Hospital,and patients information and venous blood collection were done after the informed consents were obtained.Results Four unreported NDP gene mutations were detected in one FEVR patient and 3 Norrie disease patients:c.217T＞C (p.S73P),c.2T＞C (p.M1),c.194G＞T (p.C65F) and c.384C＞G (p.C128W).One patient who was clinically diagnosed as FEVR had no symptom but the avascular zone on the bilateral peripheral retina.The three Norrie disease patients who were clinically diagnosed as Norrie disease all appearred to have bilateral congenital blindness,mass in the vitreous and retinal detachment,and one in the three Norrie disease patient had evident mental retardation.Conclusions The results of this paper extend NDP gene mutation spectrum,and NDP gene is further confirmed to be the casuse of Norrie disease.

Diagnosis and management of familial exudative vitreoretinopathy / 国际眼科杂志(Guoji Yanke Zazhi)

@#Familial exudative vitreoretinopathy(FEVR)is a rare inherited disorder of retinal angiogenesis. It is characterized by avascular peripheral retina. Mutations in FZD4, NDP, LRP5, TSPAN12, ZNF408, KIF11 have been found the causation genes of FEVR. The phenotypic features are variable, when some patients are asymptomatic while some may suffer from neovascularization, exudation, hemorrhage, retinal folds and retinal detachment. The use of FFA can help to identify the disease in the earlier stage, enabling timely treatment. The current treatments include laser photocoagulation, scleral buckling, vitrectomy and intravitreal anti-VEGF injections as an adjunctive therapy before surgery. With the development of genome research on this disease, the more effective diagnosis and treatments would be available.

Research advances in familial exudative vitreoretinopathy / 国际眼科杂志(Guoji Yanke Zazhi)

·Familial exudative vitreoretinopathy ( FEVR ) is a hereditary disease associated with abnormal angiogenesis in the pediatric period. The most prominent finding of the disease is avascularity in the peripheral retina. Whereas, the phenotypic features are variable. In some minor cases, missed diagnosis would happened due to asymptom, while, in severe FEVR, neovascularization, retinal exudation, retinal folds, macular heterotopy and retinal detachment may occur and give rise to extremely poor vision or even blindness. Mutations in the FZD4, LRP5, NDP, TSPAN12, ZNF408, and KIF11 genes have been reported to contribute to FEVR with X - linked recessive, autosomal dominant, and autosomal recessive inheritance manners. We have summarized aspects of pathogenesis, clinical features and classification, mutations genes as well as diagnosis and treatment of FEVR in this review.

How genetics works: An illustrative case report.

In this communication, we report the case of a four year old boy who presented with reduced vision in the right eye. He had visual acuity of light perception right eye and 6/12 in the left eye and anterior segment examination was normal. Fundus examination of the right eye showed a falciform retinal fold extending from the optic nerve temporally involving the entire retina with exudates within the falciform fold and dense pigmentation peripherally. The left eye showed mild macular temporal dragging of the vessels and 360° of peripheral laser scars. In addition he also had some characteristic systemic features such as developmental delay, obesity, dysmorphic facies and tapered fingers. Using this case as an example, we present a systematic, logical approach to a patient with a possible genetic disorder. The growing field of ocular genetics now allows for improved diagnosis using stepwise cost efficient testing as demonstrated herein.

Research progress on genetics of familial exudative vitreoretinopathy / 中华实验眼科杂志

Familial exudative vitreoretinopathy (FEVR) is an inherited retinal disorder characterized by abnormal vascularization of the peripheral retina with a variety of phenotypes.Genetic analyses have identified five causative genes,including FZD4,LRP5,NDP,TSPAN12 and ZNF408,which were associated with autosomal dominant (AD),autosomal recessive and X-linked recessive FEVR.FZD4,LRP5 and TSPAN12 are key genes in classical Wnt pathway,which plays an important role in retinal angiogenesis.FZD4 encodes FZD4 protein that forms a receptor complex with LRP5 and TSPAN12.The complex binds with Wnt ligand or Norrin,encoding by NDP,to active Wnt/Norrin signaling network.ZNF408 encodes zinc finger protein,which is associated with AD FEVR.The current review provided a comprehensive summary of the genes involved in FEVR.

Familial Exudative Vitreoretinopathy in 5 members of 3 generations

Familial Exudative Vitreoretinopathy is an autosomal dominant inherited congenital retinal disorder which is thought to be caused by abnormal development of retinal vascular system and characterized by avascularity of peripheral retina, temporally dragged retina and ectopia of macula. Fundus findings of this disorder are very similar to those of retinopathy of prematurity except for no history of prematurity and oxygen administration in perinatal period. So the perinatal history and careful examination of family members in suspicious patients are important in diagnosis. The authors examined a six year old girl with poor vision compatible to a familial exudative vitreoretinopathy and all of her family members. The examination revealed that five members of three generations in this family had familial exudative vitreoretinopathy. The inheritance pattern was an autosomal dominant based upon the pedigree.

Familial Exudative Vitreoretinopathy Involving One Family

The familial exudative vitreoretinopathy is an autosomal dominantly inherited disease and shows abnormalities of the retina and vitreous. It affects both eyes in most cases, but the involvement is often asymmetric. Thus it is important to screen familial members carefully, since they may have only mild, nonprogressive changes in the retinal periphery. It is important to know family history of the disorder and history of prematurity or oxygen supplementation, since the clinical features are most similar to retinopathy of prematurity. The authors experienced three cases of familial exudative vitreoretinopathy in a 2-year-old girl with cryotherapy and her father and her brother with asymptomatic familial exudative vitreoretinopathy that has retinal vascular avascular zone of peripheral retina.