Two patients with Knobloch syndrome due to mutation in COL8A1 gene: case report and review of the literature.

BACKGROUND: Knobloch syndrome (KNO, OMIM # 267,750) is a rare ciliopathy group sydrome characterized by a collagen synthesis disorder. It represents an uncommon cause of pediatric retinal detachment. This report presents two cases with different COL18A1 gene mutations, complicated by retinal detachment. CASE PRESENTATION: Both cases exhibited high myopia and various degrees of occipital skull defect. The first case, a female, had bilateral congenital retinal detachment, posterior embryotoxon, and strabismus. The second case, a male, had unilateral congenital retinal detachment and neuromotor developmental delay. The first case, diagnosed in the early months of life, underwent successful retinal reattachment surgery. However, surgery was not performed on the second case, who presented with late-stage unilateral retinal detachment and pre-phthisis. CONCLUSIONS: The report describes two patients with Knobloch syndrome, one of whom responded favorably to surgery for retinal detachment in both eyes. Successful anatomical results were achieved with early surgical interventions. It is essential to recognize the phenotypic and genetic heterogeneity within KNO.

Comprehensive exploration of hub genes involved in oxidative stress in rhegmatogenous retinal detachment based on bioinformatics analysis.

Rhegmatogenous retinal detachment (RRD) is a type of ophthalmologic emergency, if left untreated, the blindness rate approaches 100 %. The RRD patient postoperative recovery of visual function is unsatisfactory, most notably due to photoreceptor death. We conducted to identify the key genes for oxidative stress (OS) in RRD through bioinformatics analysis and clinical validation, thus providing new ideas for the recovery of visual function in RRD patients after surgery. A gene database for RRD was obtained from the Gene Expression Omnibus (GEO) database (GSE28133). Then we screened differentially expressed OS genes (DEOSGs) from the database and assessed the critical pathways in RRD with Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. Protein-protein interaction (PPI) networks and hub genes among the common DEOSGs were identified. In addition, we collected general information and vitreous fluid from 42 patients with RRD and 22 controls [11 each of epiretinal membrane (EM) and macular hole (MH)], examined the expression levels of proteins encoded by hub genes in vitreous fluid by enzyme-linked immunosorbent assay (ELISA) to further assess the relationship between the ELISA data and the clinical characteristics of patients with RRD. Ten hub genes (CCL2, ICAM1, STAT3, CD4, ITGAM, PTPRC, CCL5, IL18, TLR2, VCAM1) were finally screened out from the dataset. The ELISA results showed that, compared with the control group, patients with RRD: TLR2 and ICAM-1 were significantly elevated, and CCL2 had a tendency to be elevated, but no statistically significant; RRD patients and MH patients compared with EM patients: STAT3 and VCAM-1 were significantly elevated. We found affected eyes of RRD patients compared with healthy eyes: temporal and nasal retinal nerve fiber layer (RNFL) were significantly thickened. By correlation analysis, we found that: STAT3 was negatively correlated with ocular perfusion pressure (OPP); temporal RNFL was not only significantly positively correlated with CCL2, but also negatively correlated with Scotopic b-wave amplitude. These findings help us to further explore the mechanism of RRD development and provide new ideas for finding postoperative visual function recovery.

Ophthalmic manifestations of Czech dysplasia.

Czech dysplasia is an autosomal dominant type 2 collagenopathy that is caused by heterozygosity for the recurrent p.(Arg275Cys) COL2A1 variant. Affected individuals usually present with skeletal abnormalities such as metatarsal hypoplasia of the third and fourth toes and early-onset arthropathy, as well as hearing loss. To date, no ophthalmic findings have been reported in patients with Czech dysplasia even though COL2A1 has been implicated in other ocular conditions such as type 1 Stickler syndrome. For the first time, we report the ocular findings in four families with Czech dysplasia, including type 1 vitreous anomaly, hypoplastic vitreous, retinal tears, and significant refractive error. These novel ocular findings expand the phenotype associated with Czech dysplasia and may aid clinicians as an additional diagnostic feature. Patients with congenital abnormalities of vitreous gel architecture have an increased risk of retinal detachment, and as such, patients may benefit from prophylaxis. Considering that many of the patients did not report any ocular symptoms, vitreous phenotyping is of key importance in identifying the need for counseling with regard to prophylaxis.

Molecular Signatures Integral to Natural Reprogramming in the Pigment Epithelium Cells after Retinal Detachment in Pleurodeles waltl.

The reprogramming of retinal pigment epithelium (RPE) cells into retinal cells (transdifferentiation) lies in the bases of retinal regeneration in several Urodela. The identification of the key genes involved in this process helps with looking for approaches to the prevention and treatment of RPE-related degenerative diseases of the human retina. The purpose of our study was to examine the transcriptome changes at initial stages of RPE cell reprogramming in adult newt Pleurodeles waltl. RPE was isolated from the eye samples of day 0, 4, and 7 after experimental surgical detachment of the neural retina and was used for a de novo transcriptome assembly through the RNA-Seq method. A total of 1019 transcripts corresponding to the differently expressed genes have been revealed in silico: the 83 increased the expression at an early stage, and 168 increased the expression at a late stage of RPE reprogramming. We have identified up-regulation of classical early response genes, chaperones and co-chaperones, genes involved in the regulation of protein biosynthesis, suppressors of oncogenes, and EMT-related genes. We revealed the growth in the proportion of down-regulated ribosomal and translation-associated genes. Our findings contribute to revealing the molecular mechanism of RPE reprogramming in Urodela.

Transcriptomic Analysis of Retinal Gene in Experimental Retinal Detachment Rats and Exploration of S100A9 and TLR4 in Human Vitreous.

PURPOSE: To screen for the differentially expressed genes in experimental retinal detachment rats, and to explore the expression of S100 calcium-binding protein A9 and Toll-like receptor 4 in the vitreous of rhegmatogenous retinal detachment patients. METHODS: Three rats of experimental retinal detachment and three normal rats were enrolled in the study. Transcriptomics (RNAseq) sequencing technology was used to screen differentially expressed genes in the retinas of the experimental retinal detachment group and the normal group. The selected differentially expressed genes for gene ontology and Kyoto Encyclopedia of Genes and Genomes functional enrichment analysis were performed. In addition, the vitreous of 15 patients with rhegmatogenous retinal detachment and six patients with the control group were collected. The expressions of S100 calcium-binding protein A9 and Toll-like receptor 4 were detected by Elisa, and the differences in expression levels were analyzed statistically. RESULTS: A total of 198 differentially expressed genes were screened by RNAseq sequencing, including 118 upregulated genes and 80 downregulated genes. Kyoto Encyclopedia of Genes and Genomes analysis confirmed that the most enriched pathway was the mitogen-activated protein kinase signaling pathway. Compared to the normal group, the expressions of suppressor of cytokine signaling-3, Storkhead box-2, S100 calcium-binding protein A9, Spi-1 proto-oncogene, phosphodiesterase 1B, and kinesin-light chain 1 mRNA in the retinas of the experimental retinal detachment rats were up-regulated, and the expressions of Max interacting protein 1 and the voltage-gated sodium 1 were down-regulated. Compared to the control group, the expressions of S100 calcium-binding protein A9 and Toll-like receptor 4 were upregulated by Elisa in the vitreous humor of rhegmatogenous retinal detachment patients with a statistically significant difference (p all <.05). CONCLUSION: The differentially expressed genes of experimental retinal detachment rats were suppressor of cytokine signaling-3, Storkhead box-2, S100 calcium-binding protein A9, Spi-1 proto-oncogene, phosphodiesterase 1B, kinesin-light chain 1, Max interacting protein 1, voltage-gated sodium 1, etc. The differences of S100 calcium-binding protein A9 and Toll-like receptor 4 expressions between the rhegmatogenous retinal detachment patients and the control group were statistically significant, indicating that they may play a potential role in the inflammatory process of rhegmatogenous retinal detachment.

Inflammation and Oxidative Stress Gene Variability in Retinal Detachment Patients with and without Proliferative Vitreoretinopathy.

This study investigated the association between certain genetic variations and the risk of developing proliferative vitreoretinopathy (PVR) after surgery. The study was conducted on 192 patients with primary rhegmatogenous retinal detachment (RRD) who underwent 3-port pars plana vitrectomy (PPV). The distribution of single nucleotide polymorphisms (SNPs) located in genes involved in inflammation and oxidative stress associated with PVR pathways were analyzed among patients with and without postoperative PVR grade C1 or higher. A total of 7 defined SNPs of 5 genes were selected for genotyping: rs4880 (SOD2); rs1001179 (CAT); rs1050450 (GPX1); rs1143623, rs16944, rs1071676 (IL1B); rs2910164 (MIR146A) using competitive allele-specific polymerase chain reaction. The association of SNPs with PVR risk was evaluated using logistic regression. Furthermore, the possible association of SNPs with postoperative clinical parameters was evaluated using non-parametric tests. The difference between two genotype frequencies between patients with or without PVR grade C1 or higher was found to be statistically significant: SOD2 rs4880 and IL1B rs1071676. Carriers of at least one polymorphic IL1B rs1071676 GG allele appeared to have better postoperative best-corrected visual acuity only in patients without PVR (p = 0.070). Our study suggests that certain genetic variations may play a role in the development of PVR after surgery. These findings may have important implications for identifying patients at higher risk for PVR and developing new treatments.

18p Deletion Syndrome With Concurrent Frizzled-4 Mutation: Surgical Management of Bilateral Stage 5 Traction Retinal Detachment.

We report a case of a patient with 18p deletion syndrome and concurrent FZD4 (frizzled-4) mutation. A 6-month-old boy with known 18p deletion syndrome presented with abnormal eye movements in both eyes and an inability to track objects. The patient had a history of laryngomalacia, hypotonia, and developmental delay. Examination showed bilateral total exudative and traction retinal detachment with anomalous retinal vascular development noted on widefield fluorescein angiography. Genetic analysis identified a concurrent FZD4 mutation (c.205C>T [p.H69Y]). Both eyes underwent 25-gauge limbal vitrectomy, lensectomy, and membrane peeling, and the posterior pole successfully reattached with improvement in visual function. The 18p region contains the LAMA1, TGIF1, and APCDD1 genes, which are involved in the vascular basement membrane and Wnt/ß-catenin signaling, which may have potentiated the particularly severe familial exudative vitreoretinopathy phenotype. We present the clinical findings, imaging analyses, and surgical management of concurrent 18p deletion syndrome and FDZ4 mutation. The overlap in molecular mechanisms of the multiple gene products may potentiate the severe phenotype. [Ophthalmic Surg Lasers Imaging Retina 2023;54:284-290.].

Stickler and Wagner Syndrome in African Americans.

BACKGROUND: Stickler (STL) and Wagner (WGN) syndromes are rare inherited vitreoretinopathies associated with retinal detachments (RD). There is a paucity of case reports describing these diseases in African American patients. METHODS: An IRB-approved, retrospective chart review of African American patients with genetically proven ocular-only STL or WGN was performed, and 6 patients were identified. RESULTS: Three patients had a COL2A1 mutation, two had a COL11A1 mutation, and one had a VCAN mutation. None had Pierre Robin facies. All were myopes with lattice degeneration and five had RD. Three underwent RD repair with vitrectomy (PPV), scleral buckle (SB), endolaser (EL), and silicone oil (SO). Two received laser retinopexy for localized RD and one received a prophylactic SB with 360° peripheral laser retinopexy. CONCLUSION: STL and WGN should be considered in myopic African American patients with lattice degeneration, giant retinal tears, abnormal vitreous, or spontaneous RD. Prophylactic laser treatment and aggressive surgical treatment of RD should be considered. [Ophthalmic Surg Lasers Imaging Retina 2023;54:97-101.].

Progressive degeneration of the retina in Loxl3 mutant mouse model of Stickler syndrome.

Stickler syndrome is a multisystem collagenopathy with affected individuals exhibiting a high rate of ocular complications. Lysyl oxidase-like 3 (LOXL3) is a human disease gene candidate with a critical role in catalyzing collagen crosslinking. A homozygous missense variant of LOXL3 was reported in Stickler syndrome with severe myopia. However, the underlying mechanisms of the LOXL3 missense mutation that causes Stickler syndrome are unknown. In this study, a mouse model of Stickler syndrome induced by LOXL3 mutation (c.2027G â€‹> â€‹A, p.Cys676Try) was obtained using CRISPR/Cas9 gene editing techniques. The Loxl3 mutant mice exhibited perinatal death, spinal deformity, and cleft palate, and Loxl3 mutation also induced skeletal dysplasia and progressive visual degeneration. Furthermore, we observed the damage of the bruch's membrane (BrM) and an increase in the levels of glial fibrillary acidic protein (GFAP) and Rpe65 in the Loxl3 mutant mice. Thus, we provided the critical in vivo evidence that Loxl3 possibly has a pivotal role in maintaining the eye function.

Hearing Loss in Stickler Syndrome: An Update.

Stickler syndrome is a connective tissue disorder characterized by ocular, skeletal, orofacial and auditory manifestations. Its main symptoms are high myopia, retinal detachment, joint hypermobility, early osteoarthritis, cleft palate, midfacial hypoplasia, micrognathia and hearing loss. Large phenotypical variability is apparent and partly explained by the underlying genetic heterogeneity, including collagen genes (COL2A1, COL11A1, COL11A2, COL9A1, COL9A2, COL9A3) and non-collagen genes (BMP4, LRP2, LOXL3). The most frequent type of Stickler syndrome (COL2A1) is characterized by a rather mild high-frequency sensorineural hearing loss in about half of the patients. COL11A1- and COL11A2-related Stickler syndrome results in more frequent hearing loss, being moderate and involving all frequencies. Hearing loss in the rarer types of Stickler syndrome depends on the gene expression in the cochlea, with moderate to severe downsloping hearing loss for Stickler syndrome caused by biallelic type IX collagen gene mutations and none or mild hearing loss for the non-collagen genes. Inherent to the orofacial manifestations, middle ear problems and temporary conductive hearing loss, especially at young age, are also prevalent. Consequently, hearing loss should be actively sought for and adequately treated in Stickler syndrome patients given its high prevalence and the concomitant visual impairment in most patients.

Autosomal Recessive Stickler Syndrome.

Stickler syndrome (SS) is a genetic disorder with manifestations in the eye, ear, joints, face and palate. Usually inherited in a dominant fashion due to heterozygous pathogenic variants in the collagen genes COL2A1 and COL11A1, it can rarely be inherited in a recessive fashion from variants in COL9A1, COL9A2, and COL9A3, COL11A1, as well as the non-collagen genes LRP2, LOXL3 and GZF1. We review the published cases of recessive SS, which comprise 40 patients from 23 families. Both homozygous and compound heterozygous pathogenic variants are found. High myopia is near-universal, and sensorineural hearing loss is very common in patients with variants in genes for type IX or XI collagen, although hearing appears spared in the LRP2 and LOXL3 patients and is variable in GZF1. Cleft palate is associated with type XI collagen variants, as well as the non-collagen genes, but is so far unreported with type IX collagen variants. Retinal detachment has occurred in 18% of all cases, and joint pain in 15%. However, the mean age of this cohort is 11 years old, so the lifetime incidence of both problems may be underestimated. This paper reinforces the importance of screening for SS in congenital sensorineural hearing loss, particularly when associated with myopia, and the need to warn patients and parents of the warning signs of retinal detachment, with regular ophthalmic review.

Prevention of Blindness in Stickler Syndrome.

Stickler syndromes are inherited conditions caused by abnormalities of structural proteins in the eye, inner ear and cartilage. The risk of retinal detachment, particularly due to the development of giant retinal tears, is high. Stickler syndrome is the most common cause of childhood retinal detachment. Although retinal detachment surgery in the general population has a high success rate, outcomes from surgical repair in Stickler syndrome patients are notoriously poor, providing a strong argument for prophylactic intervention. Variable case selection, absence of molecular genetic sub-typing and inconsistent treatment strategies have all contributed to the historic uncertainty regarding the safety and efficacy of prophylactic treatment. This paper reviews the major published clinical studies that have evaluated different methods and strategies for prophylaxis. Based on the current body of literature, there is extremely strong evidence from cohort comparison studies demonstrating the efficacy and safety of prophylactic retinopexy to reduce, but not eliminate, the risk of retinal detachment in Stickler syndrome patients. It is vital that this body of evidence is provided to Stickler syndrome patients, to enable them to make their own fully informed choice about whether to receive prophylaxis for themselves and particularly on behalf of their affected children, to reduce the risk of retinal detachment.

Genetic testing in four Indian families with suspected Stickler syndrome.

Purpose: Stickler syndrome is associated with the development of rhegmatogenous retinal detachment (RRD), and often presents with ocular, auditory, skeletal, and orofacial abnormalities. Molecular analysis has proven effective in diagnosis, confirmation and classification of the disease. We aimed to describe the utility of next-generation sequencing (NGS) in genetic analysis of four Indian families with suspected Stickler syndrome. Methods: The index cases presented with retinal detachment with family history. Genetic analysis in the index case was performed by next-generation sequencing of inherited retinal degeneration genes, and validated by Sanger sequencing followed by co-segregation analysis in the other family members. Results: Twenty patients were included for the genetic analysis (15 males and 5 females from four families). Clinical details were available for 15 patients (30 eyes). Fourteen eyes (11 patients) developed RRD. In the 16 eyes without RRD, 8 underwent barrage laser to lattice degeneration and 8 were under observation. Disease segregating heterozygous mutations with pathogenic/likely pathogenic effect was identified in COL2A1 (c.4318-1G>A, c.141G>A, c.1221+1G>A for 3 families) and COL11A1 (c.1737+1 G>A for 1 family) gene. In addition to the mutation in the COL2A1 gene, a pathogenic heterozygous variant associated with risk for arrhythmogenic right ventricular cardiomyopathy (ARVC) was identified in one member. Conclusion: NGS testing confirmed the presence of the causative gene for Stickler syndrome in the index case followed by evaluation of family members and confirmation of genetic and ocular findings. We believe that this may be the first such report of families with RRD from India.

[Ultrasonographic manifestation and genetic analysis of a fetus with Stickler syndrome].

OBJECTIVE: To carry out genetic analysis for a family with a fetus manifesting micrognathia and a previous history for fetal micromandibular deformity. METHODS: Systematic ultrasound examination was carried out for the fetus, and the prenatal and postnatal phenotype of the first fetus were retrospectively analyzed. The fetus and his parents were subjected to whole exome sequencing (WES) to identify potential pathogenic variants. Candidate variants were verified by Sanger sequencing. RESULTS: Fetal ultrasound has indicated micrognathia. The first fetus was found to have micrognathia by prenatal ultrasonography and have featured macrosomia and dyspnea due to with tongue retraction, high palatal arch and small mandibular deformity. WES revealed that the fetus has a harbored a c.3G>C (p.Met1?) variant of the COL2A1 gene, which was inherited from the father who had myopia and retinal detachment. CONCLUSION: Stickler syndrome is mainly characterized prenatally by micrognathia, in addition with a variety of postnatal anomalies. The c.3G>C (p.Met1?) variant probably underlay the Stickler syndrome in this pedigree.

Retinal Detachment Present at Birth in an Infant With a Novel CTNNB1 Mutation.

A full-term neonate was diagnosed on birth with a unilateral total retinal detachment. The contralateral eye had extensive fibrovascular proliferation, temporal dragging, and peripheral nonvascularized retina. Genetic testing confirmed a mutation in the CTNNB1 gene, which has been associated with familiar exudative vitreoretinopathy and phenotypic features including intellectual disability and spastic diplegia. This novel mutation and its associated syndrome should be considered as a cause of retinal detachment presenting in the neonatal period. [Ophthalmic Surg Lasers Imaging Retina 2022; 53:403-405.].

Dominant Stickler Syndrome.

The Stickler syndromes are a group of genetic connective tissue disorders associated with an increased risk of rhegmatogenous retinal detachment, deafness, cleft palate, and premature arthritis. This review article focuses on the molecular genetics of the autosomal dominant forms of the disease. Pathogenic variants in COL2A1 causing Stickler syndrome usually result in haploinsufficiency of the protein, whereas pathogenic variants of type XI collagen more usually exert dominant negative effects. The severity of the disease phenotype is thus dependent on the location and nature of the mutation, as well as the normal developmental role of the respective protein.

Pediatric Retinal Detachment in Homozygous Protein C Deficiency: Genetic and Phenotypic Description of a Single Family.

Homozygous protein C deficiency is a rare hypercoagulability disorder. This study describes the ocular manifestations and the genetic background in a family with two affected children. This is a retrospective review of ophthalmic examinations, investigations, genetic testing, and blood work-up of two children with homozygous protein C deficiency from a single family. A family with a positive history of consanguineous marriage was found to have two affected children with homozygous protein C deficiency. Abnormal visual behavior was the presenting symptom. Both children had bilateral total tractional retinal detachments at presentation. Skin manifestations included episodes of discoloration and bruising. Laboratory work-up revealed absent protein C activity. Genetic testing confirmed the presence of a homozygous pathogenic mutation in protein C gene (NM_000312.3: c.1297G>A: p.Gly433Ser). Homozygous protein C deficiency should be considered in the differential diagnosis of early-onset tractional retinal detachment in infancy. Although rare, the ophthalmologist may be the first to encounter the condition, and treatment with protein C replacement or anticoagulants may be life-saving. Examination under anesthesia with fluorescein angiography and laser treatment early in life may be warranted to preserve vision. [Ophthalmic Surg Lasers Imaging Retina. 2022;53:293-296.].

Severe foveal hypoplasia and macular degeneration in Stickler syndrome caused by missense mutation in COL2A1 gene.

BACKGROUND: The aim is to determine the retinal changes in patients with Stickler syndrome caused by a p.R565C missense mutation of the COL2A1 gene. METHODS: We reviewed the clinical records of 10 eyes of six patients from two families with the Stickler syndrome. The members of both families were heterozygous for the p.R565C mutation. The clinical features including the visual acuity, fundus appearances, fundus autofluorescence (FAF), optical coherence tomographic (OCT) images, and electroretinograms were examined. RESULTS: Myopia of -12 diopters (D) to -24 D with an average of -16.8 D was observed in 9 eyes of the 5 patients. The FAF images showed different degrees of hyper and hypoautofluorescent patterns in the macula in all but the two youngest patients (7 of 9 eyes, 78%). The OCT images showed the absence of a foveal pit and destruction of the outer retinal layers in the macular area in all patients. The ellipsoid zone (EZ) in the macular region was disrupted in eight eyes (80%) of which seven were fovea sparing. CONCLUSION: Two families with Stickler syndrome with the p.R565C mutation showed more severe foveal hypoplasia, macular degeneration, and extensive retinal degeneration. A correlation of the OCT and FAF images with the genotype is helpful in determining the prognosis of Stickler syndrome.

Identification of three novel homozygous variants in COL9A3 causing autosomal recessive Stickler syndrome.

BACKGROUND: Stickler syndrome (STL) is a rare, clinically and molecularly heterogeneous connective tissue disorder. Pathogenic variants occurring in a variety of genes cause STL, mainly inherited in an autosomal dominant fashion. Autosomal recessive STL is ultra-rare with only four families with biallelic COL9A3 variants reported to date. RESULTS: Here, we report three unrelated families clinically diagnosed with STL carrying different novel biallelic loss of function variants in COL9A3. Further, we have collected COL9A3 genotype-phenotype associations from the literature. CONCLUSION: Our report substantially expands the molecular genetics and clinical basis of autosomal recessive STL and provides an overview about allelic COL9A3 disorders.