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Carroll C, Papaioannou D, Rees A, et al. The Clinical Effectiveness and Safety of Prophylactic Retinal Interventions to Reduce the Risk of Retinal Detachment and Subsequent Vision Loss in Adults and Children with Stickler Syndrome: A Systematic Review. Southampton (UK): NIHR Evaluation, Trials and Studies Coordinating Centre (UK); 2011 Apr. (Health Technology Assessment, No. 15.16.)

Cover of The Clinical Effectiveness and Safety of Prophylactic Retinal Interventions to Reduce the Risk of Retinal Detachment and Subsequent Vision Loss in Adults and Children with Stickler Syndrome: A Systematic Review

The Clinical Effectiveness and Safety of Prophylactic Retinal Interventions to Reduce the Risk of Retinal Detachment and Subsequent Vision Loss in Adults and Children with Stickler Syndrome: A Systematic Review.

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Description of health problem

Stickler syndrome, also known as hereditary progressive arthro-ophthalmopathy, is an inherited progressive disorder of the collagen connective tissues which was first described in 1965.13 It is indicated by a variety of symptoms and can affect the formation of the eyes, ears, palate, jaw and joints.1,2,49 Manifestations can include short-sightedness, cataracts, retinal problems leading to retinal detachment (RD) and possible blindness, hearing loss, facial abnormalities including cleft palate and joint problems.1,2,8 Stickler syndrome is the most commonly identified, inherited cause of RD in childhood.1 RD is a separation of the sensory retina from the retinal pigment epithelium, with an accumulation of vitreous fluid in the potential space between them.

There are no agreed diagnostic criteria for Stickler syndrome,1 but diagnosis can be confirmed by genetic analysis. Stickler syndrome is genetically heterogeneous with at least five subgroups, some with a high risk of ocular complications, others with no ocular involvement at all. The majority of patients have type 1 Stickler syndrome (MIM 108300), which is caused by mutation in the single gene which encodes type II collagen and has ocular, auditory, oro-facial and skeletal manifestations.10,11 This gene is called COL2A1. Types 2 and 3 Stickler syndrome are caused by mutations in the genes encoding type XI collagen.6,12,13 Unlike type II collagen there are three genes encoding type XI collagen and they are COL11A1, COL11A2 and COL2A1. Type 2 Stickler syndrome (MIM 604841) is due to mutations in the COL11A1 gene and has ocular, auditory, oro-facial and skeletal manifestations.6,1214 The COL11A2 gene (mutations of which are responsible for type 3 Stickler syndrome – MIM 104840) is not expressed in the eye and therefore this group of patients do not suffer eye problems and are more properly referred to as suffering from otospondylomegaepiphyseal dysplasia.14 Given that these patients have no ocular involvement, they are not considered further in this review. Both type 1 and type 2 Stickler syndrome are autosomal dominant disorders, but recently a fourth recessive variety of Stickler syndrome has been identified due to mutations affecting both alleles of the gene encoding the α1 chain of type IX collagen (COL9A1) (MIM 120210). In other families, all known candidate genes have been excluded, so that there is at least a fifth genetic variation, and further heterogeneity remains to be resolved.

About 75% of people diagnosed with Stickler syndrome suffer from type 1. Types 1 and 2 both indicate ‘full’ Stickler syndrome.11 ‘Full’ Stickler syndrome affects the eyes, joints and hearing; patients with type 1 have an increased incidence of cleft abnormalities and those with type 2 an increased incidence of deafness.15 Type 2 may also have a reduced risk of RD.2,5,6 There can be a great deal of variability in the number and type of systemic or non-ocular symptoms in Stickler syndrome patients.2,8,16 A subgroup of individuals have been identified who have type 1 Stickler syndrome, confirmed by genetic analysis, but with no or very few systemic features.1720 In the absence of genetic testing, the diagnosis of Stickler syndrome can therefore be problematic. Diagnosis may also be delayed (e.g. until the first RD has occurred), especially in children, who may not report symptoms.2,8,21,22 Clinical advice also suggests that a diagnosis of Stickler syndrome may not even be considered for adults experiencing an RD. Consequently, the number of individuals with Stickler syndrome may be higher than currently diagnosed or reported. No figures on prevalence are available for the UK, but it has been reported previously to be approximately one case in 10,000 people for types 1 and 2 in the USA.8,23 However, given the difficulties with diagnosis, this figure may not be reliable: for these reasons prevalence is estimated to be higher by the UK Genetic Testing Network (

The rate of RD, potentially leading to loss of vision, in patients with Stickler syndrome has been found in adults to be as high as 57%,20 60%2 or 61%8 in one eye or 40% in both eyes.2 RD is ‘a separation of the sensory retina from the retinal pigment epithelium, with an accumulation of fluid in the potential space between them’.24 Whereas RD can occur at any age and the risk is life-long,2,25,26 the first RD has been found to occur most commonly in adolescence or early adulthood, between the ages of 10 and 30 years.2,27 For example, the mean age of those presenting with a first RD (and therefore being diagnosed as having Stickler syndrome) has been reported by one study to be between 21 and 25 years.27 However, clinical advice also suggests that a diagnosis of Stickler's syndrome is not always considered for adults presenting with an RD, so the mean age of first RD may be higher still. Children may therefore be more likely to be diagnosed with Stickler syndrome but represent a different problem as they may be unlikely to report symptoms and so are diagnosed only after the first RD or other irreparable damage has occurred. Given the more likely diagnosis of Stickler syndrome in children, there is therefore a potential case for early prophylactic intervention in type 1 and type 2 Stickler syndrome patients, especially as the treatment of RD in this population is complex and difficult to manage: success rates for reattachment have been reported to be 78.57% (22/28 patients), but with an average time to redetachment of < 4 months in 73% of cases.27 The risk of RD progressing to blindness, i.e. the loss of sight in both eyes, in Stickler syndrome is also uncertain as there are very little published data. A survey of members of Stickler syndrome support groups from the UK and the USA reported that 11% and 8% respectively were registered as legally blind (i.e. both eyes).2 Sixteen per cent of the UK sample was also categorised as ‘partially sighted’, i.e. complete loss of sight in one eye and reduced vision in the fellow eye. However, this sample was composed of individuals diagnosed with various types of Stickler syndrome, and it is known that the risk of RD, and therefore blindness, is higher for those with type 1. The proportion of this published sample with type 1 is unknown. It is also unclear how many of this sample had suffered and been treated for an RD prior to blindness or how many who received treatment for RD were not classified as legally blind. The long-term success of RD surgery is therefore unknown for this population and the risk of subsequent blindness is uncertain.

Current service provision

Current service provision in the UK in terms of prophylaxis for RD in Stickler syndrome populations consists of no treatment, with or without monitoring; prophylaxis using 360° cryotherapy; or prophylaxis using laser treatment. In both cases the procedure forms a scar with the aim of increasing adhesion and reducing the likelihood of tears or holes leading to a detachment. There is currently a lack of certainty regarding best practice. There are no current guidelines on prophylactic interventions for this population either in the UK or elsewhere.

Description of technology under assessment

The technologies under assessment are primary prophylactic interventions to reduce the risk of RD in eyes that have not previously had a detachment, and, thus, to reduce the potential for loss of vision. The possible interventions include cryotherapy, laser photocoagulation and scleral buckling. Cryotherapy uses intense cold, applied via a freezing probe at the peripheral retina throughout 360°, to destroy choroidal and retinal tissue in order to form a chorioretinal scar. The scar increases adhesion between the neurosensory retina and the retinal pigment epithelium.28

Different areas of the eye can be treated in this way: at the post-oral retina and at the equator. Laser photocoagulation involves applying multiple small laser burns to the peripheral retina throughout 360° to create a chorioretinal scar and thus increase retinal adhesion. As with cryotherapy, this treatment can be applied to different areas of the eye.29 Scleral buckling involves the application of a 360° silicone band around the eyeball at the equator or over affected areas. However, these prophylactic interventions are not without the possibility of unwanted side effects or adverse events, such as discomfort, lid swelling or epiphora.

A possible relevant subgroup for primary prophylactic intervention may be children, because the risk of a first RD has been reported to be highest in Stickler syndrome populations between the ages of 10 and 30 years: the percentage of individuals with Stickler syndrome experiencing RD increases from 8% (aged 0–9 years) to 26% (aged 10–19 years) to 61% (aged 20–29 years), then it levels out (57%–65% for those aged ≥ 30 years).2 Given that children are also arguably the most likely to be diagnosed with Stickler syndrome, albeit perhaps only after an RD has already occurred, it therefore makes sense to perform prophylaxis at an earlier rather than a later age. There are currently no data publicly available on the current levels of use of each or any of these technologies in the NHS.

© 2011, Crown Copyright.

Included under terms of UK Non-commercial Government License.

Bookshelf ID: NBK99342
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