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 – lessons from a national cohort

In 2011 NHS England commissioned a new national specialist MDT service for patients and families affected by Stickler syndrome. The Stickler syndromes form part of the spectrum of inherited vitreoretinopathies and are the most common cause of retinal detachment in childhood and the most common cause of familial retinal detachment. Now in its 10th year, the Stickler Highly Specialised Service (HSS) has assessed 1673 patients from 785 families. Using a combination of accurate phenotyping and molecular genetic analysis it is possible to identify the underlying genetic mutation in over 95% of cases including those with deep intronic mutations likely to be missed by conventional exome panel analysis and which require whole gene sequencing and supplementary functional analysis to confirm pathogenicity. The vast majority that presents to ophthalmologists will be from one of three autosomal dominant sub-groups with a high associated risk of retinal detachment but the diagnosis is often overlooked, especially in adults. In contrast to many other blinding retinal conditions, blindness through giant retinal tear detachment particularly in children is largely preventable provided these high-risk groups are identified and appropriate evidence-based prophylaxis offered. This article summarises ten selected briefcase histories from the national dataset with key learning points from each.Subject terms: Risk factors, Mutation     

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...     

影响孔源性视网膜脱离术后视功能的因素分析

孔源性视网膜脱离(RRD)是最常见的视网膜脱离,最有效的治疗方法为手术治疗。目前主要通过间接检眼镜、OCT、眼部超声等手段,辅助确诊RRD,以及观察术后视网膜解剖复位的情况。最佳矫正视力是最常用于评估术后视功能恢复的指标。然而部分患者术后未达最佳矫正视力。本文主要对影响RRD复位术后视功能的因素进行总结归纳,并分析其可能的影响机制。     

Molecular genetics of rhegmatogenous retinal detachment

Rhegmatogenous retinal detachment (RRD) most commonly occurs as a spontaneous event resulting from posterior vitreous detachment, typically between the ages of 40-70 yrs. It is also a feature in some inherited disorders, most commonly Stickler syndrome. The relationship between these inherited disorders and the spontaneous cases is unclear. Here in particular we review Stickler syndrome, and discuss the differential diagnosis of Stickler, Wagner and Marshall syndromes. Other rare inherited disorders associated with RRD are also briefly reviewed.     

The Stickler syndrome: case reports and literature review.

BACKGROUND: Stickler syndrome is a progressive autosomal-dominant connective tissue disorder with numerous ocular and systemic manifestations. Ocular abnormalities include: retinal detachment, glaucoma, premature cataracts, high myopia, optically empty vitreous cavities, and retinal pigmentary changes. Systemic signs include premature osteoarthritis and hearing loss, as well as numerous skeletal and facial malformations, such as maxillofacial hypoplasia and cleft palate. While many affected patients are diagnosed as children who exhibit obvious skeletal abnormalities, diagnosis can be delayed due to variable expressivity. In some cases, systemic problems may be mild or nonexistent. Thus, Stickler syndrome should be considered in the differential diagnosis of any patient who manifests a strong family history of premature cataracts, glaucoma, or retinal detachment. CASE REPORTS: Three patients representing three different generations within the same family manifested severe ocular manifestations of Stickler syndrome, and minimal systemic involvement: a 56-year-old woman, her 25-year-old son, and the first patient's 8-year-old grandson. CONCLUSIONS: Our cases highlight the need for appropriate vigilance in examining patients with a strong family history of common ocular disorders such as cataract, glaucoma, and retinal detachment. By recognizing the ocular and sometimes subtle systemic signs of Stickler syndrome, optometrists can play a vital role in limiting vision loss and improving the quality of life of affected patients and family members.     

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.     

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.     

COL2A1 exon 2 mutations: relevance to the Stickler and Wagner syndromes

AIMS: To compare the clinical and molecular genetic features of two phenotypically distinct subgroups of families with type 1 Stickler syndrome. BACKGROUND: Stickler syndrome (hereditary arthro-ophthalmopathy, McKusick Nos 108300 and 184840) is a dominantly inherited disorder of collagen connective tissue, resulting in an abnormal vitreous, myopia, and a variable degree of orofacial abnormality, deafness, and arthropathy. Stickler syndrome is the commonest inherited cause of rhegmatogenous retinal detachment in childhood with a risk of giant retinal tear (GRT) which is commonly bilateral and a frequent cause of blindness. METHOD: Pedigrees were identified from the vitreoretinal service database and subclassified according to vitreoretinal phenotype. Ophthalmic, skeletal, auditory, and orofacial features were assessed. Linkage analysis was carried out with markers for the candidate genes COL2A1, COL11A1, and COL11A2. The COL2A1 gene was amplified as five overlapping PCR products. Direct sequencing of individual exons identified mutations. RESULTS: Eight families exhibiting the type 1 vitreous phenotype were studied. Seven were consistent for linkage to COL2A1, with lod scores ranging from 2.1 to 0.3. In most instances linkage to COL11A1 and COL11A2 could be excluded. One family was analysed without prior linkage analysis. Three of the families exhibited a predominantly ocular phenotype with minimal or absent systemic involvement and were found to have mutations in exon 2 of COL2A1. Five other pedigrees with an identical ocular phenotype plus orofacial, auditory, and articular involvement had mutations in others regions of the COL2A1 gene. None of the pedigrees exhibited the characteristic lenticular, retinal pigment epithelial, or choroidal changes seen in Wagner syndrome. CONCLUSIONS: These data confirm that type 1 Stickler syndrome is caused by mutations in the gene encoding type II collagen (COL2A1). In addition, data are submitted showing that mutations involving exon 2 of COL2A1 are characterised by a predominantly ocular variant of this disorder, consistent with the major form of type II procollagen in non-ocular tissues having exon 2 spliced out. Such patients are all at high risk of retinal detachment. This has important implications for counselling patients with regard to the development of systemic complications. It also emphasises the importance and reliability of the ophthalmic examination in the differential diagnosis of this predominantly ocular form of Stickler syndrome from Wagner's vitreoretinopathy.     

Familial retinal detachment associated with COL2A1 exon 2 and FZD4 mutations

Background: To characterize the clinical and genetic abnormalities within two Australian pedigrees with high incidences of retinal detachment and visual disability. Design: Prospective review of two extended Australian pedigrees with high rates of retinal detachment. Participants: Twenty‐two family members from two extended Australian pedigrees with high rates of retinal detachment were examined. Methods: A full ophthalmic history and examination were performed, and DNA was analysed by linkage analysis and mutation screening. Main Outcome Measures: Characterization of a causative hereditary gene mutation in each family. Results: All affected family members of one pedigree carried a C192A COL2A1 exon 2 mutation. None of the affected family members had early‐onset arthritis, hearing abnormalities, abnormal clefting or facial features characteristic of classical Stickler syndrome. All affected members of the familial exudative vitreoretinopathy pedigree carried a 957delG FZD4 mutation. Conclusions: Patients with retinal detachment and a positive family history should be investigated for heritable conditions associated with retinal detachment such as Stickler syndrome and familial exudative vitreoretinopathy. The absence of non‐ocular features of Stickler syndrome should raise the possibility of mutations in exon 2 of COL2A1. Similarly, late‐onset familial exudative vitreoretinopathy may appear more like a rhegmatogenous detachment and not be correctly diagnosed. When a causative gene mutation is identified, cascade genetic screening of the family will facilitate genetic counselling and screening of high‐risk relatives, allowing targeted management of the pre‐detachment changes in affected patients.     

Retinal detachment in identical twins with Stickler syndrome type 1.

BACKGROUND: The high incidence of retinal detachment and its poor surgical prognosis in patients with Stickler syndrome are well known. However, the vitreoretinal relation to retinal detachment in this syndrome is uncertain. METHODS: Vitreoretinal examination with a binocular indirect ophthalmoscope and a Goldmann three mirror contact lens was performed on identical twin boys with Stickler syndrome. Each had retinal detachment in the left eye, and many aspects of their fundus findings were similar. The vitreous showed distinct abnormalities consistent with congenital vitreous anomaly of type 1 Stickler syndrome. The twins were followed up for 4 years after undergoing a successful operation to reattach their left retinas. RESULTS: Rhegmatogenous detachment with multiple tears occurred in the right eye of only one twin during the follow up period, despite the similar condition of their fundi. Although vitreous body was not present in most parts, slightly opaque vitreous cortex was attached to the retina near the ora serrata, and neither twin had posterior vitreous detachment during the follow up period. CONCLUSION: Multiple retinal tears appeared simultaneously in the right eye of one twin, indicating some tractional force had acted on the retina. It is believed that this force was caused by very thin vestigial vitreous cortex attached to the retina. Although these observations have been limited, vitreoretinal findings of the twins and their father were consistent and suggested presence of thin vitreous cortex attached to the retina without posterior vitreous detachment.     

Variante genética del síndrome de Stickler

Cases reports

Three myopic components of a same family came for study because presented severely degraded vitreous, equatorial membranes, retinal pigment epithelium hyperplasia, vascular sheathed and sclerosis of peripheral predominance. A genetic study confirmed the diagnosis of Stickler syndrome with a variant in the mutation of the COL2A1 gene.

Causes of vitreous hemorrhage

It is often a challenge for the ophthalmologist to find the underlying cause of a vitreous hemorrhage. Unless clinical signs clearly point in another direction, the first suspicion should always be a posterior vitreous detachment causing a retinal tear. The other two major causes, diabetic retinopathy and retinal vein occlusion, remain common complications in spite of recent years' improvement in retinal treatment. Macroaneurysm is one of the most often overlooked causes of vitreous hemorrhage. An ocular tumor sometimes presents with a vitreous hemorrhage. In all cases of dense vitreous hemorrhages, the use of diagnostic ultrasonography is mandatory.     

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。     

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.     

Retinal detachment in children: differential diagnosis and current therapy

The number of retinal detachments in children is very low in comparison to the number of retinal detachments in adults, only 3.2 - 6.6% occur in children. The main predisposing factors are trauma, associated conditions, myopia and retinopathy of prematurity (ROP) i. e., stage 4 and 5 and late stage of ROP. Furthermore, retinal detachment in children can be idiopathic. These eyes are not associated with any identified ocular or systemic comorbidity. Associated conditions include hereditary vitreoretinal disorders (e. g., morbus Stickler, X-linked juvenile retinoschisis, Marfan syndrome, famili?r exsudative vitreoretinopathy), malformations (e. g., persistent hyperplastic primary vitreous, coloboma) and retinal detachment following cataract surgery. In a few cases retinal detachment is caused by uveitis and by Coats disease. Delayed presentation and proliferative vitreoretinopathy are a common problem and in most eyes primary pars plana vitrectomy is necessary. It is important to perform consequent postoperative follow-up. The functional and anatomic outcomes of retinal detachment in children are less successful than in adults. Further surgical innovations and aetiology-specific treatment strategies are required to improve the outcome in this group. Recent results show that the intravitreal use of VEGF inhibitors to treat proliferative retinopathy (ROP) in children is effective, but we need further information about safety and side-effects.     

Hereditary progressive arthro-ophthalmopathy of Stickler

The ocular histopathologic findings in three patients with the Stickler syndrome from two families included the following: total retinal detachment with marked folding, disorganization of the retina, and a preretinal membrane. The progression of the fundus lesions was followed up in two patients during the course of 30 and 24 years. Many cases variously reported as Wagner's disease, familial retinal detachment, hyaloideoretinopathy with cleft palate, and the Pierre Robin syndrome probably were the Stickler syndrome.     

Current Understanding of the Genetic Architecture of Rhegmatogenous Retinal Detachment

Rhegmatogenous retinal detachment (RRD) is a common and potentially blinding surgical retinal disease. While the precise molecular mechanisms leading to RRD are poorly understood, there is an increasing body of literature supporting the role of heritable factors in the pathogenesis of the condition. Much work has been undertaken investigating genes important in syndromic forms of RRD (e.g., Stickler, Wagner Syndrome, etc.) and research pertaining to genetic investigations of idiopathic or non-syndromic RRD has also recently been reported. To date, at least 12 genetic loci have been implicated in the development of syndromes of which RRD is a feature. A recent GWAS identified five loci implicated in the development of idiopathic RRD.This article provides an overview of the genetic mechanisms of both syndromic and idiopathic RRD. The genetics of predisposing conditions, such as myopia and lattice degeneration, are also discussed.     

Examination of premature infants

The efficacy of cryotherapy for acute ROP was recently demonstrated [Multicenter trial of cryotherapy for retinopathy of prematurity, Arch. Ophthalmol. 196 (1988) 471-479]. This is a challenge for the ophthalmologist to contribute to the prevention of retinal detachment by adequate examination of premature infants. For this purpose any ophthalmologist involved in the care of premature infants care must be familiar with the timing, frequency, and technique of ophthalmologic examination as well as with the new International Classification of ROP, which is described in detail.     

Just another metastatic carcinoid tumour to the uveal tract

We describe the clinic, image, and histopathologic features of a well differentiated neuroendocrine carcinoma (carcinoid tumour) metastatic to choroid and ciliary body in a 52-year-old Mexican Mestizo man. The ophthalmologic examination showed an inferior choroidal mass accompanied by exudative retinal detachment. Ultrasound B-Scan study revealed a diffuse thickened choroid with overlying serous retinal detachment, ultrasound A-Scan revealed a high internal reflectivity solid lesion. Ultrasound biomicroscopy (UBM) evidenced a dome shaped ciliary body mass, presumptive diagnosis was uveal tract metastatic disease. Scleral flap choroidal incisional biopsy was performed. Microscopic evaluation demonstrated a hypercellular lesion replacing choroid, composed by cohesive oval-round cells with finely granular chromatin arranged in organoid pattern. Immunohistochemical reactions were Pankeratin AE1/AE3 (+), Cytokeratin CK5/6 (+), Chromogranin A (+), Ki67 (20%), typical well differentiated neuroendocrine carcinoma (carcinoid tumour) was diagnosed. Patient had a mediastinal carcinoid diagnosed 3?years earlier. Metastatic cancer to the eye is perhaps the leading cause of intraocular tumour, despite this fact metastases are rarely seen by the ophthalmologist while the patient is alive. Intraocular metastasis should be considered in the presence of ciliary body or/and choroidal amelanotic or pigmented mass and serous retinal detachment in a patient with history of carcinoid tumor, althought its low frequency (2.2%).