Retinal detachment and infantile-onset glaucoma in Stickler syndrome associated with known and novel COL2A1 mutations

Background: Few reports on surgical outcomes after retinal detachment in Stickler syndrome exist. Also, infantile-onset glaucoma associated with Stickler syndrome has been rarely reported and no reports exist that examine outcomes after glaucoma surgery. This study describes the clinical and genetic associations and the long-term outcomes of retinal detachment repair or glaucoma surgery in patients with Stickler syndrome.

Materials and Methods: Retrospective, single-center, case series of patients with Stickler syndrome. Demographics, clinical features, genetic mutations, and long-term surgical outcomes of eyes that experienced retinal detachment or diagnosed with infantile-onset glaucoma were assessed.

Results: Fifteen patients were identified with a mean age of 13 years at presentation and followed for a mean of 6 years. Two-thirds were male. Genetic analysis was performed as part of routine examination in nine patients from eight families. All were identified as having variants in COL2A1, three of which were novel. Six eyes of six patients experienced retinal detachment. Fifty percent of eyes without prophylactic laser treatment experienced retinal detachment, whereas only 5% of eyes that underwent prophylactic therapy detached. Despite surgical intervention for retinal detachment, five eyes became phthisical. Five eyes of three patients were diagnosed with infantile-onset glaucoma. All five eyes required multiple glaucoma surgeries, and three eyes became phthisical.

Conclusions: This study illustrates the surgical challenges encountered in patients with Stickler syndrome. Additionally, infantile-onset glaucoma may be more prevalent than previously reported and presents a challenge in terms of management. A multidisciplinary approach is recommended to provide optimal care to these patients.     

Stickler syndrome

Stickler syndrome is a relatively rare condition (approximately 1 in 10,000), caused by a defective collagen gene and characterised by high myopia, high risk of retinal detachment and flattened facial features. An outline of the condition, its systemic and ocular manifestations and optometric management are described.     

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.     

I型Stickler综合征家系临床和基因突变研究

背景Stickler综合征是一种遗传性结缔组织病,主要以眼部、关节、口面部及听力损伤为特征。确定Stickler综合征的基因突变位点能够为该综合征的基因诊断和治疗提供依据。目的研究一个I型Stickler综合征家系的临床特征并确定致病基因突变。方法对一个患I型Stickler综合征的家系进行临床研究和系谱分析。采集Stickler综合征家系中3例患者和6位表型正常者的外周血标本,采用PCR法扩增COL2A1基因的全部外显子及其侧翼,对扩增产物进行直接测序,结果与Genbank中相应序列进行比对。同时检测100位无亲缘关系的正常人外周血标本进行对照。结果该家系共4代11位成员,2位成员去世,其中包括1例患病者。现存的9位成员中共3例患者,调查显示该家系符合常染色显性遗传方式。3例患者的临床特点包括高度近视、膜型玻璃体异常及面中部扁平、短鼻、腭裂等,符合I型Stickler综合征的临床诊断。COL2A1基因突变筛查结果显示,该家系中3例患者COL2A1基因内含子12的第～个碱基发生了单个碱基缺失（IVSl2＋1Gde1）的杂合性剪接位点突变,核苷酸序列分析结果证实该突变致提前形成终止密码子,形成一种包括306个氨基酸在内的截短蛋白,导致该基因的功能异常,而家系中表型正常者及无亲缘关系的正常对照者均未发现该基因突变。结论本研究确定了一个I型Stickler家系,并在该家系确定了一个新的COL2A1基因突变,这是中国首次报道Stickler综合征家系的基因突变。     

Clinical Variability of Stickler Syndrome : Role of Exon 2 of the Collagen COL2A1 Gene

Stickler syndrome (progressive arthro-ophthalmopathy) is a genetically heterogeneous disorder resulting from mutations in at least three collagen genes. The most common disease-causing gene is COL2A1, a 54-exon-containing gene coding for type II collagen. At least 17 different mutations causing Stickler syndrome have been reported in this gene. Phenotypically, it is also a variably expressed disorder in which most patients present with a wide range of eye and extraocular manifestations including auditory, skeletal, and orofacial manifestations. Some patients, however, present without clinically apparent systemic findings. This observation has led to difficulty distinguishing this Stickler phenotype from other hereditary vitreoretinal degenerations, such as Wagner syndrome and Snowflake vitreoretinal degeneration. In this regard, review of the literature indicates type II collagen exists in two forms resulting from alternative splicing of exon 2 of the COL2A1 gene. One form, designated as type IIB (short form), is preferentially expressed in adult cartilage tissue. The other form, designated as type IIA (long form), is preferentially expressed in the vitreous body of the eye. Because of this selective tissue expression, mutations in exon 2 of the COL2A1 gene have been hypothesized to produce this Stickler syndrome phenotype with minimal or absent extraocular findings. We review the evidence for families with exon 2 mutations of the collagen COL2A1 gene presenting in a distinct manner from families with mutations in the remaining 53 exons, as well as other hereditary vitreoretinal degenerations without significant systemic manifestations.     

Analysis of the vitreous membrane in a case of type 1 Stickler syndrome

Background  Stickler syndrome causes ocular abnormalities, including retinal detachment and vitreoretinal degeneration, and systemic anomalies such as arthritis and deafness. Although retinal detachment is characteristic of this syndrome, the pathogenesis is unknown. Case report  A 10-year-old boy reported decreased vision and presented 5 days after visual loss. Results  Ophthalmoscopy showed a retinal detachment with a giant tear in the right eye, and a nonpigmented epithelial detachment with pars plicata breaks in the left eye. Bilateral findings included an empty vitreous and a vitreous membrane at the equator. The systemic abnormalities included short stature and joint hypermobility. The diagnosis was type 1 Stickler syndrome, and the eyes were treated surgically. Immunohistochemistry showed that the vitreous membrane resected intraoperatively was comprised primarily of Müller cells. Electron microscopy showed dense collagen fibers around the cells in the membrane that were identical to the vitreous collagen inserted into the basement membrane of the cells, which was similar to the ultrastructure of the vitreous base. Conclusion  Müller cells might be primary components of the vitreous membrane in type 1 Stickler syndrome. The vitreoretinal interface, which resembled the ectopic vitreous base, in the vitreous membrane may be related to the pathogenesis of the retinal detachment.     

一Stickler综合征家系的临床特征及分子遗传学分析

目的：:研究一Stickler综合征家系的临床表型及分子遗传学特点,并确定致病基因及其突变。方法：:实验研究。对一Stickler综合征家系4代11例患者进行临床特征及系谱分析。采集该家系先证者及其他成员（患者及正常人）的外周静脉血标本,并利用高通量二代测序技术对先证者及正常对照样本行全外显子组测序（WES）分析。针对...     

非典型Stickler综合征I型三个家系的遗传分析及产前诊断

目的：:分析非典型Stickler综合征I型患者的临床表现和遗传学病因,为患者基因诊断、遗传咨询、产前诊断提供理论依据。方法：:实验研究。收集3个典型Stickler综合征I型家系患者的临床表型资料,采集患者及家系其他成员的外周血提取基因组DNA。应用全外显子组测序筛查可疑基因变异,对候选变异进行Sanger测序验证并...     

The uncommon occurrence of two common inherited disorders in a single patient: a mini case series

Background: Inherited eye disorders are genetically determined conditions that are present from birth and usually manifest early, although some may develop later in life. Despite their low incidence, they are a common etiology of pediatric blindness. The occurrence of more than one such disease in a patient is very rare.

Material and Methods: Case series of two unrelated patients with simultaneous Stargardt disease (STGD1) as well as Stickler’s Syndrome (SS), both genetically confirmed.

Results: Patient 1: 13-year-old girl was referred for unexplained bilateral decreased vision for 6 months. She had a clinical diagnosis of SS, same as her mother. Her visual acuity was 20/200 with high myopia in both eyes. Her fundus showed foveal/perifoveal atrophy, retinal pigment epithelium (RPE) changes and beaded vitreous. Goldman visual fields (GVF) revealed enlarged blind spots with central depression. A macular dystrophy was suspected. Genetic testing revealed SS, COL11A1 gene mutation; and STGD1, ABCA4 gene mutation.

Patient 2: 67-year-old female with a history of hearing loss, cleft palate, strabismus and myopia, same as her daughter and granddaughters. Her visual acuity was 20/400 and 20/250 with high myopia in both eyes. Her fundus showed macular pigment clumping and RPE atrophy with no vitreous abnormality. GVF revealed a relative central scotoma with generalized constriction. Genetic testing revealed SS, COL11A2 gene mutation; and STGD1, ABCA4 gene mutation.

Conclusions: If a patient’s signs/symptoms cannot be explained by the working/known diagnosis, additional work up should be pursued for concomitant diseases. SS and STGD1 are commonly diagnosed inherited eye disorders and can coexist in one patient on rare occasions.     

Outcomes of surgery for retinal detachment in patients with Stickler syndrome: a comparison of two sequential 20-year cohorts

Background Stickler syndrome is a hereditary oculo-systemic disorder where patients are predisposed to retinal detachments which are often complex and challenging to manage. Significant progress has been made regarding the molecular genetics of the condition; however, there is little recent literature on surgery for retinal detachment in Stickler syndrome. Our aim is to describe a population of Stickler patients presenting to Moorfields Eye Hospital with detachment from 1986 to 2003. We looked at patient characteristics, characteristics of detachment, management and anatomical and functional outcomes. We also aim to compare this group from 1986 to 2003 with a past group of Stickler patients treated at Moorfields between 1965 and 1985, reported by (Billington et al. in Trans Ophthalmol Soc UK 104:875–879, 1985). This comparison of 20-year matched cohorts examined patient characteristics, features of detachment, management and anatomical outcome in the two groups using the same definitions as the earlier authors. Results In the Stickler group from 1986 to 2003, complete re-attachment rate was 67% for primary scleral-buckle surgery, 84.2% for primary vitrectomy and 78.57% for all surgery in 30 eyes of 23 patients. Overall in this group there was an average increase in Logmar visual acuity of 0.33 and 0.32 in patients undergoing primary cryo-buckle and primary vitrectomy surgery respectively. When comparing the two groups using Fisher’s exact test, we found that the group from 1986 to 2003 had significant improvement in re-attachment for detachments with multiple tears and for vitrectomy surgery, compared with the group from 1965 to 1985. Conclusions This study shows that despite complicated surgery and often multiple procedures, good anatomical outcomes were achieved as well as useful functional visual results after retinal detachment surgery in Stickler patients. It would also appear that when comparing the group of Stickler patients from 1986 to 2003 with the group from 1965 to 1985 improvements were seen in outcome from vitrectomy surgery and surgery for multiple breaks probably due to advances in technique and technology in vitreoretinal surgery, over the past 4 decades.     

The avulsed retinal vessel syndrome and its variants

The course of 18 patients (19 eyes) with the avulsed retinal vessel syndrome and its variants was followed up for an average of 54 months. This syndrome consists of recurrent vitreous hemorrhages from an avulsed retinal vessel caused by retinal tear formation. Even after the retinal tears are closed by various techniques, vitreous hemorrhages may recur until the retinal vessel ruptures. The visual prognosis is generally good.     

A mouse model for Stickler's syndrome: ocular phenotype of mice carrying a targeted heterozygous inactivation of type II (pro)collagen gene (Col2a1)

The influences of targeted heterozygous inactivation of type II (pro)collagen gene (Col2a1) on eye structures in the 15-month-old C57BL/6JOlaHsd mouse was studied. The eyes were collected from C57BL mice heterozygous for a targeted inactivation of one allele of the Col2a1 gene (Col2a1(+/-) mice). The eyes of C57BL mice with normal gene alleles were used as controls (Col2a1(+/+) mice). Ocular histology was analyzed from tissue sections, stained with hematoxylin and eosin, toluidine blue and alcian blue. Type II collagen was localized by immunohistochemistry. Hyaluronan (HA) was stained utilizing the biotinylated complex of the hyaluronan-binding region of aggrecan and link protein (bHABC). The anterior segment of the eye was well-formed in both genotypes, but typical folding of ciliary processes was decreased, while increased stromal extracellular matrix vacuolization was seen in the Col2a1(+/-) mice. In the lens of these mice, subcapsular extracellular matrix changes were observed. Differences in retinal structures or the number of the eyes with retinal detachment were not detected between the genotypes. In Col2a1(+/-) mice, staining for type II collagen was weaker in cornea, ciliary body, iris, lens, vitreous, retina, choroid and sclera than in the control mice. HA staining was detected in the extraocular tissues, ciliary body, iris and the choroid of both genotypes. HA staining was observed only in the vitreous body of the control animals. Heterozygous inactivation of Col2a1 gene causes structural defects in the murine eye. The observed structural changes in the ciliary body, lens and vitreous of the Col2a1(+/-) mice may represent ocular features found in the human Stickler syndrome, where the abnormalities result from COL2A1 gene mutations which lead to functional haploinsufficiency.     

Knobloch syndrome caused by homozygous frameshift mutation of the COL18A1 gene in a Chinese pedigree

AIM: To explore the clinical feature and genetic etiology of a Chinese Knobloch syndrome family. METHODS: Ocular examinations and magnetic resonance imagings (MRIs) were performed on the family. Whole exome sequencing was conducted on the two patients. Sanger sequencing was utilized to validate the presence of variation in the family as well as in 100 normal controls. Real-time quantitative polymerase chain reaction (PCR) was used to detect the expression level of COL18A1 in peripheral blood lymphocytes of the patients and normal carriers. RESULTS: The affected subjects presented with vision loss, exotropia, cataracts, retinal detachment, and other complications. A homozygous c.4759_4760delCT (p.Leu1587ValfsX72) mutation (rs398122391) in COL18A1 was identified in the two patients, cosegregating with the phenotypes, and did not be detected in 100 normal controls. This mutation caused significant decreased expression of COL18A1 mRNA in the patients. CONCLUSION: The findings strongly indicate that this mutation is the disease-causing mutation. Moreover, this is the first Knobloch syndrome pedigree reported in the Chinese population.     

Surgical and visual outcome following 20-gauge vitrectomy in proliferative diabetic retinopathy over a 10-year period, evidence for change in practice

Introduction

The study reports 10-year anatomical and visual outcome in patients who underwent pars plana vitrectomy (PPV) for complications due to proliferative diabetic retinopathy (PDR).

Methods

Retrospective analysis of patients undergoing 20G PPV from January 1999 to May 2010 for tractional retinal detachment (TRD) and non-clearing vitreous hemorrhage (NCVH) secondary to PDR recorded prospectively on an electronic patient record. The primary aim was to study anatomical success and eyes with visual acuity (VA) of ≤0.3 logMAR at last follow-up.

Results

There were 346 eyes of 249 patients with mean age of 55.63 years and follow-up of 1.44 years. In all, 95.3% of eyes had a flat retina at final follow-up. Overall 136/346 (39.4%) eyes had final VA of logMAR ≤0.3 (Snellen 6/12) and 129 (37.3%) had logMAR ≥1.0 (Snellen 6/60). In all, 50/181 (27.6%) eyes with TRD and 84/165 (50.9%) with NCVH achieved final VA of ≤0.3 logMAR (Snellen 6/12). A total of 218 (63.1%) showed ≥0.3 logMAR improvement from baseline to last follow-up. Both preoperative VA and final postoperative (post-op) VA (P<0.001) improved significantly with each year from 1999 to 2010. The commonest peroperative complication was iatrogenic retinal tear formation (28.4%). This was a risk factor for the development of post-op retinal detachment, odds ratio: 3.90 (95% confidence interval: 1.91–7.97, P=0.0002). Silicone oil was used in 5.2% of patients at the primary procedure. In all, 9.2% required removal of non clearing post vitrectomy hemorrhage.

Conclusions

Outcomes from vitreoretinal surgery for complications of diabetic retinopathy have improved. In addition, the visual outcome after diabetic vitrectomy steadily improved over the 10-year period, which may in part be due to the move to operate on patients with better vision.     

Longterm follow‐up of pars plana vitrectomy for vitreous floaters: complications,outcomes and patient satisfaction

Purpose: Floaters caused by degenerative or postoperative changes in the vitreous can interfere with all aspects of visual functioning. The aim of this study is to report the longterm outcome of pars plana vitrectomy (PPV) for persistent vitreous opacities. Methods: In a retrospective, non‐randomized, interventional case study we reviewed all cases of vitreous floaters that were vitrectomized at our department between 1997 and 2006. Patient complaints and satisfaction were assessed by a questionnaire administered at the end of follow‐up. Results: Seventy‐three consecutive cases were included (61 patients). Mean Snellen best corrected visual acuity (BCVA) before surgery was 0.81. Overall, 85% of patients complained of severe or very severe difficulty caused by floaters. A total of 42% of eyes were pseudophakic, four of which were operated with combined PPV and phacoemulsification. Mean follow‐up time was 37 months. Of the phakic eyes, 60% were operated for cataract during follow‐up. One retinal detachment (RD) occurred immediately postoperatively (1.3%) and another four eyes developed RD during longterm follow‐up 24–44 months after PPV (5.5% of cases). Postoperative BCVA remained mostly unchanged. Overall, 88% of patients were satisfied with the results of the operation. Conclusions: Some patients make considerable complaints as a result of vitreous opacities and their distress does not correlate with visual acuity. Vitrectomy is a safe and effective procedure with which to help these patients. Patients should be informed about the risk of cataract progression, unexpected inflammatory reaction and an increased risk for RD several years after PPV (5.5%).     

Visual and anatomical outcomes following vitrectomy for complications of diabetic retinopathy: the DRIVE UK study

Introduction

End-stage diabetic eye disease is an important cause of severe visual impairment in the working-age group. With the increasing availability of refined surgical techniques as well as the early diagnosis of disease because of screening, one would predict that the prevalence of this condition is decreasing and the visual outcome is improving.

Aim

To study the prevalence and visual outcome following vitrectomy for complications of diabetic retinopathy.

Materials and methods

This study identified the patients who underwent vitrectomy from January 2007 to December 2009 because of diabetes-related complications in South East London. Data collected included baseline demographics, best-corrected visual acuity, indication for the vitrectomy, complication, outcome, and duration of follow-up.

Results

The prevalence of people requiring vitrectomy who are registered in the diabetes register of this region was 2 per 1000 people with diabetes. Vitrectomy was required in 185 eyes of 158 patients during this period. These included 83 Caucasians, 51 Afro-Caribbeans, 17 South Asians, and 7 from other ethnic groups. There were 58 patients with type I diabetes and 100 with type II, with a mean duration of diabetes of 23 and 16.5 years, respectively. The reason for vitrectomy included tractional retinal detachment (TRD) in 109 eyes, non-clearing vitreous haemorrhage (NCVH) in 68 eyes, and other causes in 8 eyes. In all, 50% of the eyes with TRD and NCVH, and 87% of the eyes with NCVH improved by at least three ETDRS lines at 12 months. Poor predictors of visual success included longer duration of diabetes (OR: 0.69), use of insulin (OR: 0.04), presence of ischaemic heart disease (OR: 0.04), delay in surgery (OR: 0.59), and the failure to attend clinic appointments (OR: 0.58). Preoperative use of intravitreal bevacizumab in eyes with TRD undergoing vitrectomy showed a marginal beneficial effect on co-existent maculopathy (P=0.08) and required less laser intervention post procedure, but did not affect the number of episodes of late-onset vitreous haemorrhage post vitrectomy (P=0.81).

Conclusion

Visual outcome has improved significantly in eyes with complications due to diabetic retinopathy compared with the previously reported Diabetic Vitrectomy Study.     

Tilted disc syndrome (TDS): New hypotheses for posterior segment complications and their implications in other retinal diseases

Tilted disc syndrome (TDS) is considered a congenital anomaly due to a delayed closure of the embryonic fissure. It is characterized by an oblique orientation of the axis of the optic disc, associated with other posterior pole anomalies such as inferior crescent, situs inversus and inferior staphyloma. The aim of this review was to summarize the data supporting the current hypotheses for the pathogenesis of TDS, and its anatomical and functional clinical consequences. Recent imaging techniques, such as magnetic resonance imaging, wide-field fundus imaging, and 2- and 3-D optical coherence tomography have provided a new perspective on TDS and its complications. Different abnormalities have previously been reported, both in the anterior and posterior segments. The focus was on vision-threatening chorioretinal changes or complications, including choroidal neovascularization and serous retinal detachments and their therapeutic options. Based on clinical observations, assumptions were proposed to understand the occurrence of complications such as chorioretinal degenerative changes, choroidal neovascularization and polypoidal choroidal vasculopathy, macular serous retinal detachment, myopic foveoschisis and chorioretinal folds. These hypotheses could be referred to as the curvature “breaking point” hypothesis, the uneven growth “tractional” hypothesis, the “container-content” imbalance hypothesis, and the “choroidal funnel” hypothesis. Because these complications could also occur in other contexts, understanding the pathogenesis of TDS complications could help to understand their pathophysiology.