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Introduction
I have a special interest in all aspects of retinal and vitreous surgery.I lead the Vitreoretinal Research Group at the van Geest Brain Repair Centre, University of Cambridge investigating the molecular pathology of retinal detachment, particularly familial retinal detachment and the Stickler syndromes. I am the service lead for the NHS England nationally commissioned Highly Specialised Services diagnostic service for patients and families with this disorder.
Current institution
Publications
Publications (163)
Background
Separation of the posterior hyaloid membrane (PHM) from the retina in posterior vitreous detachment (PVD) is a fundamental, but poorly understood, process underlying vitreoretinal disorders including retinal detachment and macular hole. We performed electron microscopy studies of the PHM after PVD to investigate its ultrastructure, assoc...
Objective
Stickler Syndrome (SS) is associated with eye, joint and orofacial abnormalities. Most cases are dominantly inherited through COL2A1/COL11A1 variants encoding type-II/XI collagen, with patients having up to 78% retinal detachment (RD) risk. Rarer cases of recessive SS have also been identified, associated with pathogenic variants of genes...
It is over 60 years since Paul Cibis et al. reported the experimental use of liquid silicone in the surgical management of retinal detachment. Initial experiences were complicated by significant side-effects associated with the impurities in the non-medical grade commercial silicone oils deployed at the time. These were substantially reduced (but n...
Objective
Stickler Syndrome (SS) is associated with eye, joint and orofacial abnormalities. Most cases are dominantly inherited through variants in genes encoding type-II/XI collagen (COL2A1/COL11A1), with patients having up to 78% retinal detachment (RD) risk.¹ More recently, rarer cases of recessive SS have been identified, associated with pathog...
Literature discussing fellow eye risk in patients with rhegmatogenous retinal detachment secondary to posterior vitreous detachment (PVD) is limited, particularly in subgroups where this risk may be greater than the general population. In this retrospective consecutive case series with 107 study patients, the risk of retinal tears in fellow eyes of...
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 findi...
Background
Retinal tears (RT) from posterior vitreous detachment (PVD) are an important and treatable cause of rhegmatogenous retinal detachment (RRD). Better understanding of the risk of RT from PVD will help plan urgent eye care.
Methods
Prospective observational case series over two years. Patients presenting to their optometrist, family doctor...
Purpose:
The purpose of this study was to evaluate the epidemiology, etiology, clinical assessment, investigation, management, and visual consequences of high myopia (≤-6 diopters [D]) in infants and young children.
Findings:
High myopia is rare in pre-school children with a prevalence less than 1%. The etiology of myopia in such children is dif...
This clinical report describes a family with both Marfan and ocular-only Stickler syndromes. We report 2 cases of ocular-only Stickler syndrome and 2 cases of Marfan syndrome concurrent with ocular-only Stickler syndrome. Type 1 Stickler syndrome and Marfan syndrome share many clinical similarities, and it can be difficult to differentiate them sol...
Legg-Calve-Perthes’ disease (LCP) is defined as avascular necrosis of the femoral head in a child and may present to a variety of disciplines from general practice to orthopaedics, paediatrics, rheumatology and more. The Stickler syndromes are a group of disorders of type II, IX and XI collagen associated with hip dysplasia, retinal detachment, dea...
Loeys–Dietz syndrome (LDS) is an autosomal‐dominant connective‐tissue disorder with vascular and musculoskeletal abnormalities similar to Marfan syndrome. However, unlike Marfan, retinal detachment (RD) is rarely reported, and screening protocols do not currently feature ophthalmic assessment or RD counseling. We report a 5‐generation family affect...
Retinal detachment (RD) is one of the most common, sight-threatening ocular conditions requiring emergency intervention. Posterior vitreous detachment (PVD) occurs in the majority of an aging population whereby the vitreous body separates from the retina. It is well established that PVD is the common precursor to the most common forms of RD; howeve...
The fibrillar collagen family is comprised of the quantitatively major types I, II and III collagens and the quantitatively minor types V and XI. These form heterotypic collagen fibrils (composed of more than a single collagen type) where the minor collagens have a regulatory role in controlling fibril formation and diameter. The structural pre-req...
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 ge...
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 no...
Diagnostic genetics within the United Kingdom National Health Service (NHS) has undergone many stepwise improvements in technology since the completion of the human genome project in 2003. Although Sanger sequencing has remained a cornerstone of the diagnostic sequencing arena, the human genome reference sequence has enabled next-generation sequenc...
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 syndro...
The interface between silicone oil and saline layers in a 3D model of the eye chamber was studied under different eye-like saccadic motions in order to determine the stability of the interface and propensity for emulsification in the bulk. The effect of level of fill; saccade amplitude, angular velocity, latency time; and orientation were investiga...
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 y...
Purpose:
To present the extent and site of lesion of auditory dysfunction in a large cohort of individuals with type 2 Stickler Syndrome. Type 2 Stickler Syndrome results from a mutation in the gene coding for α-1 type XI pro-collagen, which has been identified in the human vitreous, cartilage and the cochlea of the mouse. The condition is charact...
Recent reports suggest that the use of an outpatient-based procedure (pneumatic retinopexy, PR) for retinal detachment repair should be encouraged within the UK, especially in light of Covid-19 and possible restrictions/competing demands on access to operating theatres. It is therefore essential that patients receive comprehensive information about...
The Stickler syndromes are the leading cause of inherited retinal detachment and the most common cause of rhegmatogenous retinal detachment in childhood. The clinical and molecular genetic spectrum of this connective tissue disorder is discussed in this article, emphasising the key role the ophthalmologist has to play in the identification, diagnos...
Purpose
Emulsification of silicone oil (SiOil) in a vitrectomized eye was investigated using a 3D model of the vitreous cavity to test the hypothesis that oil droplet formation arises from the breakdown of the bulk SiOil‐aqueous interface during eye saccadic movement.
Methods
Round bottom flasks filled with SiOil and a saline phase modelled the vi...
Background
Type 2 Stickler syndrome is usually a dominant disorder resulting from pathogenic variants in COL11A1 encoding the alpha 1 chain of type XI collagen. Typical molecular changes result in either substitution of an obligate glycine within the Gly‐Xaa‐Yaa amino acid sequence repeat region of the molecule, mRNA missplicing or deletions/duplic...
The key to successful management of rhegmatogenous retinal detachment (RRD) is to find and seal all of the retinal breaks, and the two main surgical techniques used to achieve this are scleral bucking (SB) or pars plana vitrectomy (PPV). Techniques for SB have remained mostly unchanged for the last 60 years, whilst PPV techniques and instruments ha...
Background:
Patients with Stickler syndrome often require emergency surgery and are often anesthetized in nonspecialist units, typically for retinal detachment repair. Despite the occurrence of cleft palate and Pierre-Robin sequence, there is little published literature on airway complications. Our aim was to describe anesthetic practice and compl...
Stickler syndrome (SS) is characterized by ophthalmic, articular, orofacial, and auditory manifestations. SS is usually autosomal dominantly inherited with variants in COL2A1 or COL11A1. Recessive forms are rare but have been described with homozygous variants in COL9A1, COL9A2, and COL9A3 and compound heterozygous COL11A1 variants. This article ex...
Stickler syndrome is a genetic disorder that can lead to joint problems, hearing difficulties and retinal detachment. Genes encoding collagen types II, IX and XI are usually responsible, but some families have no causal variant identified. We investigate a variant in the gene encoding growth factor BMP4 in a family with Stickler syndrome with assoc...
Stickler syndrome is a genetic disorder that can lead to joint problems, hearing difficulties and retinal detachment. Genes encoding collagen types II, IX and XI are usually responsible, but some families have no causal variant identified. We investigate a variant in the gene encoding growth factor BMP4 in a family with Stickler syndrome with assoc...
Aim:
To review the radiological findings of the largest cohort to date of paediatric patients with Stickler syndrome, all with confirmed molecular genetic analysis and sub-typing.
Patients and methods:
It is understood that the National Health Service (NHS) commissioned service at Addenbrookes Hospital, Cambridge, UK has the largest cohort of St...
Osteogenesis imperfecta (OI) is a rare primarily autosomal dominant condition in which the connective tissues of bones, ligaments and sclerae do not form properly. Typically, mutations in COL1A1 and COL1A2 genes lead to the defective formation or quantity of type I collagen, the principle matrix in these tissues. Molecular genetic studies have now...
Background:
Osteogenesis imperfecta (OI) is a rare primarily autosomal dominant condition in which the connective tissues of bones, ligaments and sclerae do not form properly. Typically, mutations in COL1A1 and COL1A2 genes lead to the defective formation or quantity of type I collagen, the principle matrix in these tissues. Molecular genetic stud...
Background Osteogenesis imperfecta (OI) is a rare primarily autosomal dominant condition in which the connective tissues of bones, ligaments and sclerae do not form properly. Typically, mutations in COL1A1 and COL1A2 genes lead to the defective formation or quantity of type I collagen, the principle matrix in these tissues. Molecular genetic studie...
Purpose:
Despite posterior vitreous detachment being a common ocular event affecting most individuals in an aging population, there is little consensus regarding its precise anatomic definition. We investigated the morphologic appearance and molecular composition of the posterior hyaloid membrane to determine whether the structure clinically obser...
Anterior segment dysgeneses (ASDs) comprise a spectrum of developmental disorders affecting the anterior segment of the eye. Here, we describe three unrelated families affected by a previously unclassified form of ASD. Shared ocular manifestations include bilateral iris hypoplasia, ectopia lentis, corectopia, ectropion uveae, and cataracts. Whole-e...
Purpose:
To report a case of bilateral intraocular hemorrhage secondary to cerebral venous sinus thrombosis with no associated intracranial hemorrhage.
Methods:
Case report.
Results:
A 32-year-old Asian gentleman presented with left reduced vision as a result of a left subhyaloid macular hemorrhage associated with severe headache. Right retina...
COL2A1 mutations causing haploinsufficiency of type II collagen, cause type 1 Stickler syndrome which has a high risk of retinal detachment and failure of the vitreous to develop normally. Exon 2 of COL2A1 is alternatively spliced, expressed in the eye but not in mature cartilage and encodes a region that binds growth factors TGFβ1 and BMP-2. We in...
Importance:
In-the-bag intraocular lens dislocation is an uncommon but serious complication of cataract surgery in patients with previous repair of retinal detachment. The causative mechanism is currently unknown. We report histologic findings from a retrospective case series from 1993 to 2010 and suggest a possible mechanism to explain this assoc...
PurposeTo study the variability of the ophthalmic phenotype in Kniest dysplasia. Kniest dysplasia is an inherited disorder associated with defects in type II collagen and characterised by short-trunked dwarfism, kyphoscoliosis, and enlarged joints with restricted mobility. Other features include marked hand arthropathy, cleft palate, hearing loss,...
Inherited vitreoretinopathies mostly result from genetic abnormalities of types II, IX, or V/XI collagen [see chapter I. A. Vitreous proteins] and proteoglycans, [see chapters I.B. Vitreous GAGs and I. F. Vitreous biochemistry and artificial vitreous] expressed principally and collectively in the eye but also in articular and hyaline cartilage. The...
Purpose
The Stickler syndromes are the most common causes of inherited and childhood retinal detachment; however, no consensus exists regarding the effectiveness of prophylactic intervention. We evaluate the long-term safety and efficacy of the Cambridge prophylactic cryotherapy protocol, a standardized retinal prophylactic treatment developed to p...
Inherited Vitreoretinopathies and molecular genetic analysis
Stickler syndromes types 1, 2 and 3 are usually dominant disorders caused by mutations in the genes COL2A1, COL11A1 and COL11A2 that encode the fibrillar collagens types II and XI present in cartilage and vitreous. Rare recessive forms of Stickler syndrome exist that are due to mutations in genes encoding type IX collagen (COL9A1 type 4 Stickler sy...
Background
COL11A1 is a large complex gene around 250 kb in length and consisting of 68 exons. Pathogenic mutations in the gene can result in Stickler syndrome, Marshall syndrome or Fibrochondrogenesis. Many of the mutations resulting in either Stickler or Marshall syndrome alter splice sites and result in exon skipping, which because of the exon s...
Rhegmatogenous retinal detachment (RRD) is an important cause of vision loss and can potentially lead to blindness. The underlying pathogenesis is complex and incompletely understood. We applied a two-stage genetic association discovery phase followed by a replication phase in a combined total of 2,833 RRD cases and 7,871 controls. The discovery ph...
Mutations in COL2A1, the gene for type II-collagen, can result in a wide variety of phenotypes depending upon the nature of the mutation. Dominant negative mutations tend to result in severe and often lethal skeletal dysplasias such as achondrogenesis type 2, Kniest dysplasia, and spondyloepiphyseal dysplasia congenita. Stickler syndrome, a conditi...
UK NHS diagnostic service sequence analysis of genes generally examines and reports on variations within a designated region 5' and 3' of each exon, typically 30 bp up and downstream. However, because of the degenerate nature of the splice sites, intronic variants outside the AG and GT dinucleotides of the acceptor and donor splice sites (ASS and D...
The entity described by Gunnar Stickler, which included hereditary arthro-ophthalmopathy associated with retinal detachment, has recently been recognised to consist of a number of subgroups, which might now more correctly be referred to as the Stickler syndromes. They are the most common clinical manifestation of the type II/XI collagenopathies and...
Stickler syndrome is a dominantly inherited disorder affecting the fibrillar type II/XI collagen molecules expressed in vitreous and cartilage. Mutations have been found in COL2A1, COL11A1 and COL11A2. It has a highly variable phenotype that can include midline clefting, hearing loss, premature osteoarthritis, congenital high myopia and blindness t...
Isolated motor third, fourth or sixth nerve palsies are a well recognized complication following botulinum toxin injection for hemifacial spasm or essential blepharospasm. A case of hemifacial spasm secondary to giant aneurysm of the internal carotid artery is reported, stressing the importance of further investigation if such neurological sequelae...
Eye is the official journal of the Royal College of Ophthalmologists. It aims to provide the practising ophthalmologist with information on the latest clinical and laboratory-based research.
For rhegmatogenous retinal detachment, reattachment with a single procedure is associated with better visual outcomes. In the past, silicone oil has been used mostly as a last resort following failed primary surgery. This study evaluates a novel approach to patients at high risk of primary failure, using silicone tamponade as the primary stage of a...
Separation of the vitreous and posterior hyaloid membrane (PHM) or posterior vitreous detachment (PVD) typically occurs between the ages of 45 and 65 years in the general population, but may occur earlier in myopic or otherwise predisposed individuals. Age-related synergetic changes occurring within the cortical and central gel must be distinguishe...
Purpose/background:
Epiretinal membrane (ERM) formation is a common change resulting in disturbance of macular vision and predisposing to rhegmatogenous retinal detachment. Current treatment strategies rely chiefly on surgical removal of the membranes from the surface of the retina, allowing the retina to remodel and reattach. Improved knowledge o...
This paper will illustrate how variation in the processing of mutant pre-mRNA can affect the phenotypic outcome of inherited disorders of type II collagen.
Type 1 Stickler's syndrome is one of the different phenotypes resulting from mutations in COL2A1 (the type II collagenopathies). It is also the commonest, but often goes undiagnosed due to the v...
The use of adjunctive scleral buckling during vitrectomy for retinal detachment associated with inferior breaks has been the recent focus of some debate. It has been suggested that any benefit might be outweighed by potential complications associated with buckling surgery. The purpose of this study was to compare the success rate of vitrectomy, gas...
To report the prevalence of retinal detachment (RD) and results of prophylaxis against detachment from a giant retinal tear in a large cohort of patients with type 1 Stickler syndrome.
Retrospective study.
Two hundred four type 1 Stickler syndrome patients.
Pedigrees and individuals with type 1 Stickler syndrome were identified from the vitreous re...
The type II collagenopathies are a phenotypically diverse group of genetic skeletal disorders caused by a mutation in the gene coding for type II collagen. Reports published before the causative mutations were discovered suggest heritable bone dysplasias with skeletal malformations may be associated with a vitreoretinopathy.
A retrospective notes s...
Stickler syndrome due to mutations in COL2A1 is usually the result of premature termination codons and nonsense mediated decay resulting in haploinsufficiency of type II collagen. Here we present two missense mutations and one apparently silent mutation that each result in Stickler syndrome, but via different molecular mechanisms. One alters the tr...
To detail the clinical findings in a British family with molecularly characterised Wagner syndrome.
Only in the last year has the specific genetic defect in Wagner syndrome been identified, and the background literature of the molecular genetics is outlined. Clinical and laboratory findings in a second case of Wagner syndrome are included to highli...
