Stickler syndrome - lessons from a national cohort.
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ABSTRACT:
SUBMITTER: Snead MP
PROVIDER: S-EPMC8491173 | biostudies-literature | 2022 Oct
REPOSITORIES: biostudies-literature
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Stickler syndrome - lessons from a national cohort.
Snead M P MP Richards A J AJ McNinch A M AM Alexander P P Martin H H Nixon T R W TRW Bale P P Shenker N N Brown S S Blackwell A M AM Poulson A V AV
Eye (London, England) 20211005 10
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 molec ...[more]
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Project description:Stickler syndrome is a heterogeneous condition due to mutations in COL2A1, COL11A1, COL11A2, and COL9A1. To our knowledge, neither non-penetrance nor mosaicism for COL2A1 mutations has been reported for Stickler syndrome. We report on a family with two clinically affected sibs with Stickler syndrome who have clinically unaffected parents. Both sibs have a novel heterozygous mutation in exon 26 of COL2A1 (c.1525delT); this results in a premature termination codon downstream of the mutation site. One parent was found to have low level mosaicism in DNA extracted from whole blood. This scenario encourages consideration of molecular testing in seemingly unaffected parents for recurrence risks and potential screening for mild age-related manifestations.
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Project description: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 general population has a high success rate, outcomes from surgical repair in Stickler syndrome patients are notoriously poor, providing a strong argument for prophylactic intervention. Variable case selection, absence of molecular genetic sub-typing and inconsistent treatment strategies have all contributed to the historic uncertainty regarding the safety and efficacy of prophylactic treatment. This paper reviews the major published clinical studies that have evaluated different methods and strategies for prophylaxis. Based on the current body of literature, there is extremely strong evidence from cohort comparison studies demonstrating the efficacy and safety of prophylactic retinopexy to reduce, but not eliminate, the risk of retinal detachment in Stickler syndrome patients. It is vital that this body of evidence is provided to Stickler syndrome patients, to enable them to make their own fully informed choice about whether to receive prophylaxis for themselves and particularly on behalf of their affected children, to reduce the risk of retinal detachment.
| S-EPMC9318672 | biostudies-literature
Project description:Stickler syndrome is an autosomal dominant disorder with characteristic ophthalmological and orofacial features, deafness, and arthritis. Abnormalities of vitreous gel architecture are a pathognomonic feature, usually associated with high myopia which is congenital and non-progressive. There is a substantial risk of retinal detachment. Less common ophthalmological features include paravascular pigmented lattice degeneration and cataracts. Non-ocular features show great variation in expression. Children with Stickler syndrome typically have a flat midface with depressed nasal bridge, short nose, anteverted nares, and micrognathia. These features can become less pronounced with age. Midline clefting, if present, ranges in severity from a cleft of the soft palate to Pierre-Robin sequence. There is joint hypermobility which declines with age. Osteoarthritis develops typically in the third or fourth decade. Mild spondyloepiphyseal dysplasia is often apparent radiologically. Sensorineural deafness with high tone loss may be asymptomatic or mild. Occasional findings include slender extremities and long fingers. Stature and intellect are usually normal. Mitral valve prolapse was reported to be a common finding in one series but not in our experience. The majority of families with Stickler syndrome have mutations in the COL2A1 gene and show the characteristic type 1 vitreous phenotype. The remainder with the type 2 vitreous phenotype have mutations in COL11A1 or other loci yet to be identified. Mutations in COL111A2 can give rise to a syndrome with the systemic features of Stickler syndrome but no ophthalmological abnormality.
| S-EPMC1734362 | biostudies-other
Project description: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 summaryTreatment 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).
| S-EPMC10032448 | biostudies-literature
Project description:BackgroundStickler syndrome is a collagen disorder that can affect multiple organ systems. It is characterized by ocular abnormalities, hearing loss, midfacial hypoplasia, hypermobility, and joint abnormalities. The phenotypic expression of Stickler syndrome can vary among those affected. Since Stickler syndrome is a collagen disorder, it is possible to expect pregnancy complications similar to those reported in other collagen disorders. To our knowledge, there is only one case report in the literature on the management of pregnancy and delivery of a patient with Stickler syndrome.Methods/case reportA 37-year-old primigravid woman with a diagnosis of Stickler syndrome presented at 9 weeks gestation for prenatal genetic consultation. At 26, the patient had prophylactic laser therapy for lattice degeneration of the retina. At 32, she was found to be heterozygous for the c.1527 G>T variant in the COL2A1 gene, which is associated with ocular abnormalities and autosomal dominant form of Stickler syndrome. Subsequently, she desired to pursue prenatal diagnostic testing for the familial variant. The patient voiced that the results would impact pregnancy management. Amniocentesis was performed at 16 weeks gestation. Results were negative for the maternal COL2A1 variant. Karyotype was normal (46, XX).ResultsA multidisciplinary team using a patient-centered approach including obstetrics, ophthalmology, maternal-fetal medicine, and genetics determined that there were no contraindications for vaginal delivery. At 39 weeks, the patient underwent spontaneous vaginal delivery with no complications.ConclusionThere is a paucity of data available regarding the maternal outcomes of women affected with collagen disorders, especially Stickler Syndrome. This case highlights the importance of accurate genetic diagnosis in the prenatal period and provides information to physicians caring for patients with Stickler syndrome.
| S-EPMC7434740 | biostudies-literature
Project description:BackgroundStickler syndrome is a connective tissue disorder characterized by ocular, skeletal, orofacial and auditory defects. It is caused by mutations in different collagen genes, namely COL2A1, COL11A1 and COL11A2 (autosomal dominant inheritance), and COL9A1 and COL9A2 (autosomal recessive inheritance). The auditory phenotype in Stickler syndrome is inconsistently reported. Therefore we performed a systematic review of the literature to give an up-to-date overview of hearing loss in Stickler syndrome, and correlated it with the genotype.MethodsEnglish-language literature was reviewed through searches of PubMed and Web of Science, in order to find relevant articles describing auditory features in Stickler patients, along with genotype. Prevalences of hearing loss are calculated and correlated with the different affected genes and type of mutation.Results313 patients (102 families) individually described in 46 articles were included. Hearing loss was found in 62.9%, mostly mild to moderate when reported. Hearing impairment was predominantly sensorineural (67.8%). Conductive (14.1%) and mixed (18.1%) hearing loss was primarily found in young patients or patients with a palatal defect. Overall, mutations in COL11A1 (82.5%) and COL11A2 (94.1%) seem to be more frequently associated with hearing impairment than mutations in COL2A1 (52.2%).ConclusionsHearing impairment in patients with Stickler syndrome is common. Sensorineural hearing loss predominates, but also conductive hearing loss, especially in children and patients with a palatal defect, may occur. The distinct disease-causing collagen genes are associated with a different prevalence of hearing impairment, but still large phenotypic variation exists. Regular auditory follow-up is strongly advised, particularly because many Stickler patients are visually impaired.
| S-EPMC3551705 | biostudies-literature
Project description:Stickler syndrome is a connective tissue disorder characterized by hearing loss, ocular anomalies, palatal defects, and skeletal abnormalities. The autosomal dominant form is the most common, but autosomal recessive forms have also been described. We report the second case of autosomal recessive Stickler syndrome due to homozygosity for a loss of function mutation in COL9A3, which encodes the α3 chain of type IX procollagen. The clinical features were similar to the previously described COL9A3 Stickler syndrome family, including moderate to severe sensorineural hearing loss, high myopia, and both tibial and femoral bowing at birth. Radiographs demonstrated abnormal capital femoral epiphyses and mild irregularities of the vertebral endplates. This case further establishes the phenotype associated with mutations in this gene. We suggest that loss of the α3 chain of type IX collagen results in a Stickler syndrome phenotype similar to that of the other autosomal recessive forms caused by mutations in genes encoding the α1 and α2 chains of type IX collagen.
| S-EPMC7608529 | biostudies-literature
Project description:PurposeStickler 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.MethodsThe 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.ResultsTwenty 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.ConclusionNGS 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.
| S-EPMC9426114 | biostudies-literature
Project description:BackgroundIn a four-generation Caucasian family variably diagnosed with autosomal dominant (AD) Stickler or Wagner disease, commercial gene screening failed to identify a mutation in COL2A1 or VCAN. We utilized linkage mapping and exome sequencing to identify the causal variant.Materials and methodsGenomic DNA samples collected from 40 family members were analyzed. A whole-genome linkage scan was performed using Illumina HumanLinkage-24 BeadChip followed by two-point and multipoint linkage analyses using FASTLINK and MERLIN. Exome sequencing was performed on two affected individuals, followed by co-segregation analysis.ResultsParametric multipoint linkage analysis using an AD inheritance model demonstrated HLOD scores > 2.00 at chromosomes 1p36.13-1p36.11 and 12q12-12q14.1. SIMWALK multipoint analysis replicated the peak in chromosome 12q (peak LOD = 1.975). FASTLINK two-point analysis highlighted several clustered chromosome 12q SNPs with HLOD > 1.0. Exome sequencing revealed a novel nonsense mutation (c.115C>T, p.Gln39*) in exon 2 of COL2A1 that is expected to result in nonsense-mediated decay of the RNA transcript. This mutation co-segregated with all clinically affected individuals and seven individuals who were clinically unaffected.ConclusionsThe utility of combining traditional linkage mapping and exome sequencing is highlighted to identify gene mutations in large families displaying a Mendelian inheritance of disease. Historically, nonsense mutations in exon 2 of COL2A1 have been reported to cause a fully penetrant ocular-only Stickler phenotype with few or no systemic manifestations. We report a novel nonsense mutation in exon 2 of COL2A1 that displays incomplete penetrance and/or variable age of onset with extraocular manifestations.
| S-EPMC6680000 | biostudies-literature
Project description:BackgroundPatients 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 complications in a nonselected series of Stickler syndrome cases. To our knowledge, this is the largest such series in the published literature.MethodsWe retrospectively identified patients with genetically confirmed Stickler syndrome who had undergone general anesthesia in a major teaching hospital, seeking to identify factors that predicted patients who would require more than 1 attempt to correctly site an endotracheal tube (ETT) or supraglottic airway device (SAD). Patient demographics, associated factors, and anesthetic complications were collected. Descriptive statistical analysis and logistic regression modeling were performed.ResultsFive hundred and twoanesthetic events were analyzed. Three hundred ninety-five (92.7%) type 1 Stickler and 63 (96.9%) type 2 Stickler patients could be managed with a single attempt of passing an ETT or SAD. Advanced airway techniques were required on 4 occasions, and we report no major complications. On logistic regression, modeling receding mandible (P = .0004) and history of cleft palate (P = .0004) were significantly associated with the need for more than 1 attempt at airway manipulation.ConclusionsThe majority of Stickler patients can be anesthetized safely with standard management. If patients have a receding mandible or history of cleft, an experienced anesthetist familiar with Stickler syndrome should manage the patient. We recommend that patients identified to have a difficult airway wear an alert bracelet.
| S-EPMC7717475 | biostudies-literature