Therapeutic and diagnostic advances in Stickler syndrome

Abstract

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, diagnosis and prevention of blindness in the increasingly widely recognised sub-groups with ocular-only (or minimal systemic) involvement. Without diagnosis and prophylaxis in such high-risk subgroups, these patients are at high risk of Giant Retinal Tear detachment and blindness, especially in the paediatric population, where late or second eye involvement is common. Initially considered a monogenic disorder, there are now known to be at least 11 distinct phenotypic subgroups in addition to allied connective tissue disorders that can present to the clinician as part of the differential diagnosis. Plain language summary Treatment and diagnostic advances in Stickler syndrome The Stickler syndromes are a group of related connective tissue disorders that are associated with short-sight and a very high risk of blindness from detachment of the retina – the light sensitive film at the back of the eye. Other features include cleft palate, deafness and premature arthritis. It is the most common cause of retinal detachment in children and the most common cause of familial or inherited retinal detachment. In contrast to most other forms of blinding genetic eye disease, blindness from retinal detachment in Stickler syndrome is largely avoidable with accurate diagnosis and prophylactic (preventive) surgery. Recent advances in the understanding of the genetic causes of Stickler syndrome mean that the diagnosis can now be confirmed in over 95% of cases and, most importantly, the patient’s individual risk of retinal detachment can be graded. Preventative surgery is hugely effective in reducing the incidence of retinal detachment in those patients shown to be at high risk. NHS England have led the way in the multidisciplinary care for patients with Stickler syndrome by launching a highly specialist service that has been free at point of care to all NHS patients in England since 2011 ( https://www.england.nhs.uk/commissioning/spec-services/highly-spec-services , www.vitreoretinalservice.org )

Stickler syndrome – lessons from a national cohort

“…Schematic and slit-lamp illustration: Beaded congenital vitreous anomaly [COL11A1 dominant-negative mutations]. Reproduced with permission from [ 1 ]. …”

“… Affected adults, as well as children, are susceptible to GRT and prophylaxis should be considered in confirmed high risk cases irrespective of age. Facial phenotype is unreliable for diagnosis exclusion–especially in adults and the ocular-only variants [ 1 , 12 , 13 ]. Examination of both parents may be valuable for any infant in whom Stickler syndrome is suspected but in whom vitreous examination is not possible.…”

“…Facial phenotype is unreliable for diagnosis exclusion–especially in adults and the ocular-only variants [ 1 , 12 , 13 ].…”

“…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. Initially considered a mono-genic disorder, at least 10 clinically and genetically distinct sub-groups of Stickler syndrome are now recognised (Table 1 ) [ 1 ]. The principal clinical features are congenital myopia, retinal detachment, deafness, cleft palate and premature arthropathy.…”

“…Using a combination of accurate phenotyping and molecular genetic analysis it is possible to identify the underlying genetic mutation in over 95% of cases so that prophylactic retinopexy can be offered to the high-risk sub-groups and reduce the risk of blindness [Table 1 ]. The last 10 years have also seen the emergence of an increasing array of sub-groups including ocular-only and autosomal recessive variants through a variety of molecular mechanisms [ 1 ].…”