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Congenital quadrantic lamellar cataract. Typical of Stickler syndrome, but does not differentiate between subtypes.
Source publication
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...
Context in source publication
Context 1
... association with congenital cataract is well recognised, 21,22 and some patients may exhibit a characteristic quadrantic lamellar cortical lens opacity, which, if present, can be a useful diagnostic sign ( Figure 3). It does not, however, differentiate between subgroups, being present in both type 1 and type 2 Stickler syndrome. ...
Similar publications
Purpose
Our previous study reported that 5.5% of probands with early-onset high myopia (eoHM) had mutations in COL2A1 or COL11A1. Why were the probands initially considered to have eoHM but not Stickler syndrome (STL)?
Methods
Probands and family members with eoHM and mutations in COL2A1 or COL11A1 were followed up and reexamined based on the crit...
Citations
... 1 The condition is frequently diagnosed in late childhood to early adolescence, but the onset of symptoms can occur anywhere from birth to over 50 years of age. 1 Stickler Syndromes affects collagen proteins that are principally and collectively expressed in the eye and articular and hyaline cartilage, and is associated with a spectrum of ocular, auditory, orofacial and musculoskeletal manifestations, with variable phenotypic expression. 1 Key clinical features of Stickler Syndromes are congenital high myopia, retinal detachment, hearing loss (conductive or sensorineural), and premature arthropathy. 2,3 Ocular manifestations, which could also include glaucoma and presenile cataracts, are found in about 95% of affected cases. 1,2,4 Characteristic craniofacial features of Stickler Syndromes include a flattened facial profile with a depressed nasal bridge, epicanthal folds, cleft palate, and Pierre Robin sequence, which is a triad of micrognathia, glossoptosis, and airway obstruction. ...
... 2,3 Ocular manifestations, which could also include glaucoma and presenile cataracts, are found in about 95% of affected cases. 1,2,4 Characteristic craniofacial features of Stickler Syndromes include a flattened facial profile with a depressed nasal bridge, epicanthal folds, cleft palate, and Pierre Robin sequence, which is a triad of micrognathia, glossoptosis, and airway obstruction. 1,2,4 Understanding clinical features associated with Stickler Syndromes can assist with diagnosis, but given the phenotypic heterogeneity, genetic testing remains the gold standard. ...
... 1,2,4 Characteristic craniofacial features of Stickler Syndromes include a flattened facial profile with a depressed nasal bridge, epicanthal folds, cleft palate, and Pierre Robin sequence, which is a triad of micrognathia, glossoptosis, and airway obstruction. 1,2,4 Understanding clinical features associated with Stickler Syndromes can assist with diagnosis, but given the phenotypic heterogeneity, genetic testing remains the gold standard. 5,6 At least six Stickler Syndrome subgroups have been characterised according to the genetic abnormalities of collagen types affected, including COL2A1 (type 1), COL11A1 (type 2), and COL11A2 (type 3) Stickler Syndrome, associated with autosomal dominant inheritance, and COL9A1 (type 4), COL9A2 (type 5), and COL9A3 (type 6) Stickler Syndrome, associated with autosomal recessive inheritance. ...
Purpose
Stickler Syndromes are multisystem collagenopathies affecting 1 in 7500–9000 individuals and are associated with craniofacial, ocular, auditory, and musculoskeletal complications. Prophylactic retinopexy treatment reduces the risk of retinal detachment, emphasising the need for early detection and multidisciplinary referral. This study evaluated knowledge and awareness of Stickler Syndromes among allied health professionals and their perceived needs for targeted education to improve multidisciplinary care.
Methods
A cross-sectional survey was undertaken among audiologists, speech pathologists, optometrists, orthoptists, and physiotherapists in Australia. Survey questions included practitioner demographics, awareness and knowledge of Stickler Syndromes, confidence managing Stickler Syndromes, and perception of multidisciplinary care needs for Stickler Syndromes.
Results
Of 180 healthcare professions who participated (79% female; 78% aged between 25 and 44 years), 55% indicated that they had heard of Stickler Syndrome, and 14% had directly worked with patients known to have Stickler Syndromes. Practitioners who had were either optometrists, orthoptists, or audiologists. The most recognised clinical sign of Stickler Syndromes was retinal detachment (selected by 66% of optometrists and orthoptists and 16% of other professions), but only 41% of optometrists and orthoptists (27% all respondents) selected cryopexy as a potential management strategy. Vitreous anomaly was recognised as a clinical feature by 20% of all respondents. Overall, 69% of allied health professionals did not feel confident managing Stickler Syndromes, and a similar number of practitioners (69%) indicated that they were willing to attend professional development courses for complex conditions such as Stickler Syndromes.
Conclusion
This study provides meaningful insights on awareness and knowledge of Stickler Syndromes among allied healthcare professionals. Targeted clinician education, enhanced communication between healthcare entities, and multidisciplinary care programs can significantly improve the integrated care of Stickler Syndromes leading to better patient outcomes.
... Stickler syndrome is a hereditary connective tissue disorder leading to joint problems, hearing difficulties, ocular abnormalities and midfacial hypoplasia (1). Typical ocular manifestations include progressive myopia, degeneration of the vitreous body, and secondary rhegmatogenous retinal detachment (RRD) (1,2). ...
... Stickler syndrome is a hereditary connective tissue disorder leading to joint problems, hearing difficulties, ocular abnormalities and midfacial hypoplasia (1). Typical ocular manifestations include progressive myopia, degeneration of the vitreous body, and secondary rhegmatogenous retinal detachment (RRD) (1,2). Patients with Stickler syndrome, owing to collagen synthesis disorder, are at high risk to develop RRD (3). ...
Background
Stickler syndrome is a hereditary connective tissue disorder associated with ocular, orofacial, musculoskeletal, and auditory impairments. Its main clinical characteristics include retinal detachment, hearing loss, and midface underdevelopment. In clinical practice, macrocyst is rarely reported in retinal detachment cases with Stickler syndrome.
Case presentation
We report the case of a 7-year-old child who developed a rhegmatogenous retinal detachment (RRD) in the right eye, accompanied by multiple peripheral macrocysts. The detachment was successfully surgically repaired with vitrectomy, retinal laser photocoagulation, cryotherapy and silicone oil tamponade. During the operation, a mini-retinectomy in the outer layer of each macrocyst was made for vesicular drainage and retinal reattachment. Genetic testing identified a pathogenic point mutation variant (c.1693C>T; p.Arg565Cys) in exon 26 of the COL2A1 gene. Six-months after the operation, the retina remained attached with improvement of best corrected visual acuity to 20/200.
Conclusion
Patients with Stickler syndrome may develop RRD of different severity. Macrocyst is rarely reported in previous literature of Stickler syndrome. In this case report, we share our experience in treating with multiple macrocysts in RRD and emphasize the importance of periodic follow-up for patients with Stickler syndrome.
... Correlation between genetic analyses and patient phenotypes shows that most SS exhibits autosomal dominant inheritance, 4 with the most prevalent sub-group Type 1 SS associated with heterozygous COL2A1 loss-of-function variants leading to deformities in Type II collagen. 5 These patients exhibit a pathognomonic membranous vitreous anomaly, congenital megalophthalmos and a very high up to 78% risk of retinal detachment. 1 Palate abnormalities are seen in 45% of patients 6 and hearing loss in 52%. ...
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 pathogenic variants of genes encoding type-IX collagen (COL9A1-3), but there is limited published data on patients’ phenotype or RD risk. Our study aimed to investigate the RD risk in recessive SS, primarily to determine whether patients would benefit from prophylactic retinopexy. A secondary objective was to explore patient phenotypes, identifying key features which clinicians should identify, leading to genetic testing and early diagnosis.
Methods
We report 13 cases from 11 families with Type-IX collagen recessive SS, identified from the cohort attending the National Stickler Syndrome Service at Addenbrooke’s Hospital, Cambridge, between 1/1/15–31/12/22. Patients underwent multidisciplinary assessment by ophthalmology, rheumatology and audiology.
Results
6/11 families exhibited previously undescribed genetic variants, and 7 had consanguineous parents. Clinical findings included abnormal vitreous architecture and high myopia. 15.4% of patients developed RD secondary to horseshoe retinal tears, with no cases of bilateral RD or Giant Retinal Tears. No patients had cleft palate, 30.8% had midfacial hypoplasia. Hearing loss was more prevalent (91.7%) than that reported for dominant SS. Arthropathy was uncommon but highly variable in manifestation.
Conclusions
There is currently insufficient evidence to suggest that all patients with recessive Stickler Syndrome require prophylactic retinopexy, and it should only be offered case-by-case according to individual risk assessment.
... This is the first variant to be reported for MOD in the dog and appears to segregate exclusively in this breed. The variant is a SNP located in a collagen type XI gene (COL11A1) in which pathogenic variants are known to cause syndromic conditions in humans; Stickler Syndrome Type II being the most analogous to the OES MOD phenotype described here [13,20]. The clinical presentation of MOD in the OES in this study shares similar phenotypes with previous reports of the condition in other breeds, such as cataract, microphakia and retinal dysplasia [1][2][3][4][5]. ...
... Collagen type XI is a heterotrimeric construct of α chains encoded by the COL11A1, COL11A2 and COL2A1 genes, with COL11A1 expressed in ocular and connective tissue [20,41,42]. Differentiation between STL1 and STL2 can be made by the causal genetic variants for each type, which occur in the collagen type genes COL2A1 and COL11A1, respectively. ...
... The ocular-only subgroup of Stickler syndrome has to date only been reported to be caused by variants located in the COL2A1 gene, largely as a consequence of missplicing of exon 2, which is excluded in the protein in mature cartilage but included within ocular tissue [13,20,59]. COL11A1 is also an alternatively spliced gene, however, pathogenic variants in humans result in additional systemic anomalies that can include cleft palate, deafness, hypermobility and arthropathy [13,20]. ...
Multiocular defect has been described in different canine breeds, including the Old English Sheepdog. Affected dogs typically present with multiple and various ocular abnormalities. We carried out whole genome sequencing on an Old English Sheepdog that had been diagnosed with hereditary cataracts at the age of five and then referred to a board-certified veterinary ophthalmologist due to owner-reported visual deterioration. An ophthalmic assessment revealed that there was bilateral vitreal degeneration, macrophthalmos, and spherophakia in addition to cataracts. Follow-up consultations revealed cataract progression, retinal detachment, uveitis and secondary glaucoma. Whole genome sequence filtered variants private to the case, shared with another Old English Sheepdog genome and predicted to be deleterious were genotyped in an initial cohort of six Old English Sheepdogs (three affected by multiocular defect and three control dogs without evidence of inherited eye disease). Only one of the twenty-two variants segregated correctly with multiocular defect. The variant is a single nucleotide substitution, located in the collagen-type gene COL11A1 , c.1775T>C, that causes an amino acid change, p.Phe1592Ser. Genotyping of an additional 14 Old English Sheepdogs affected by multiocular defect revealed a dominant mode of inheritance with four cases heterozygous for the variant. Further genotyping of hereditary cataract-affected Old English Sheepdogs revealed segregation of the variant in eight out of nine dogs. In humans, variants in the COL11A1 gene are associated with Stickler syndrome type II, also dominantly inherited.
... Stickler syndrome was named by Gunnar B. Stickler et al., who first described this systemic connective tissue disorder (Stickler et al., 1965). Stickler syndrome is characterized by ophthalmologic, orofacial, auditory, and musculoskeletal manifestations, including high myopia, congenital cataracts, glaucoma, vitreous abnormalities, retinal detachment, midfacial hypoplasia, hearing loss, hypermobile joints, arthritis, and spinal deformation (Snead et al., 2011;Stickler et al., 2001). The prevalence of Stickler syndrome among neonates is approximately 1/7500-1/9000 (Robin et al., 1993). ...
Background
Stickler syndrome is a multisystemic disorder characterized by ophthalmological and non‐ophthalmological abnormalities, frequently misdiagnosed due to high clinical heterogeneity. Stickler syndrome type I (STL1) is predominantly caused by mutations in the COL2A1 gene.
Methods
Exome sequencing and co‐segregation analysis were utilized to scrutinize 35 families with high myopia, and pathogenic mutations were identified. Mutant COL2A1 was overexpressed in cells for mechanistic study. A retrospective genotype–phenotype correlation analysis was further conducted.
Results
Two novel pathogenic mutations (c.2895+1G>C and c.3505G>A (p.Val1169Ile)) and two reported mutations (c.1597C>T (p.Arg533*) and c.1693C>T (p.Arg565Cys)) in COL2A1 were identified causing STL1. These mutations are all in the G‐X‐Y triplet, and c.2895+1G>C contributed to aberrant RNA splicing. COL2A1 mutants tended to form large aggregates in the endoplasmic reticulum (ER) and elevated ER stress. Additionally, mutations c.550G>A (p.Ala184Thr) and c.2806G>A (p.Gly936Ser) in COL2A1 were found in high myopia families, but were likely benign, although c.2806G>A (p.Gly936Ser) is on G‐X‐Y triplet. Moreover, genotype–phenotype correlation analysis revealed that mutations in exon 2 mainly contribute to retinal detachment, whereas mutations in the collagen alpha‐1 chain region of COL2A1 tend to cause non‐ophthalmologic symptoms.
Conclusion
This study broadens the COL2A1 gene mutation spectrum, provides evidence for ER stress caused by pathogenic COL2A1 mutations and highlights the importance of non‐ophthalmological examination in clinical diagnosis of high myopia.
... Additionally, three out of four patients from family 1 were found to have retinal breaks, which could progress to retinal detachment if they had not been treated. Although the majority of patients with type 1 Stickler syndrome exhibit congenital myopia, 15% of affected patients have no significant refractive error (Snead et al., 2011) and notably, 7 out of 11 patients reported here had no significant refractive error or unaided visual deficit. Importantly, these patients with good visual acuity are still at risk of retinal detachment and giant retinal tears. ...
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 findings have been reported in patients with Czech dysplasia even though COL2A1 has been implicated in other ocular conditions such as type 1 Stickler syndrome. For the first time, we report the ocular findings in four families with Czech dysplasia, including type 1 vitreous anomaly, hypoplastic vitreous, retinal tears, and significant refractive error. These novel ocular findings expand the phenotype associated with Czech dysplasia and may aid clinicians as an additional diagnostic feature. Patients with congenital abnormalities of vitreous gel architecture have an increased risk of retinal detachment, and as such, patients may benefit from prophylaxis. Considering that many of the patients did not report any ocular symptoms, vitreous phenotyping is of key importance in identifying the need for counseling with regard to prophylaxis.
... STL was initially considered as a monogenic disorder. Mutations in various collagen genes were reported [3] , including COL2A1, COL11A1, COL11A2 [4] , COL9A1 [5] , COL9A2 [6] , and COL9A3 [7] , which can cause Stickler syndrome type I (STL1) to Stickler syndrome type Ⅵ (STL6), respectively [7] . Studies of the mechanism in STL suggest the mutations of collagen genes affect collagen production and lead to abnormalities in tissues and organs that contain corresponding collagens. ...
AIM: To report the myopia-controlling effect of repeated low-level red-light (RLRL) therapy in patients with Stickler syndrome (STL), an inherited collagenic disease typically presenting with early onset myopia. METHODS: Three STL children, aged 3, 7, and 11y, received RLRL therapy throughout the follow-up period of 17, 3, and 6mo, respectively after exclusion of fundus anomalies. Data on best-corrected visual acuity (BCVA), intraocular pressure, cycloplegic subjective refraction, ocular biometrics, scanning laser ophthalmoscope, optical coherence tomography, genetic testing, systemic disease history, and family history were recorded. RESULTS: At the initiation of the RLRL therapy, the spherical equivalent (SE) of 6 eyes from 3 patients ranged from -3.75 to -20.38 D, axial length (AL) were from 23.88 to 30.68 mm, and BCVA were from 0.4 to 1.0 (decimal notation). Myopia progression of all six eyes slowed down after RLRL therapy. AL in five out of the six eyes shortened -0.07 to -0.63 mm. No side effects were observed. CONCLUSION: Three cases of STL whose progression of myopic shift and AL elongation are successfully reduced and even reversed after RLRL therapy.
... 11 Ocular manifestations commonly include vitreous abnormalities (40%) and high myopia (90%). 12,13 Repair of RRDs among patients with Stickler syndrome is often technically challenging because of vitreous abnormalities and early age of presentation. 14 Therefore, multiple surgeries are often required to achieve anatomical success. ...
Purpose:
To determine the treatment patterns and outcomes of pediatric retinal detachments (RDs) associated with hereditary vitreoretinopathies.
Design:
Retrospective cohort analysis using IRIS® Registry (Intelligent Research in Sight) database.
Participants:
Patients < 18 years old with a rhegmatogenous RD and a systemic disorder associated with vitreoretinal degeneration (e.g., Stickler syndrome) or other malformation of the vitreous from 2013-2019.
Methods:
Cases were identified using International Classification of Diseases, Ninth and Tenth Revisions (ICD-9, ICD-10) diagnostic codes from the IRIS® Registry cohort. Other hereditary vitreoretinopathies that are not encoded by specific ICD code(s) were captured by text search. Nonspecific vitreous abnormality ICD codes were also included. Exclusion criteria included traumatic retinal detachments using ICD codes for ocular trauma and serous or exudative retinal detachment. Surgical procedures were identified using Current Procedural Terminology (CPT) codes for repair of retinal detachment. Baseline demographic information collected included age, gender, race/ethnicity, geographic region of the provider location, and health insurance status.
Main outcome measures:
Main outcomes measured in this study were average time to first surgery, number of eyes presenting with bilateral detachments, and choice of initial surgical procedure.
Results:
A total of 2115 eyes of 1722 patients were identified (mean age, 10.4 years; 58% male). The median time to first surgery was 7 days (interquartile range, 40 days). One thousand four hundred seven eyes of 1134 patients had ≥ 1 year of follow-up, with 506 eyes (36%) developing a fellow eye RD. Thirty-three percent of patients presenting with bilateral detachments, and 349 eyes had initial RD surgery within 1 year of the index date documented by CPT code. Fellow eye detachment occurred a mean of 32 days after initial presentation. The mean number of surgeries per eye within 1 year was 1.68. Best-corrected visual acuity did not improve from a baseline 20/54 to 20/62. The initial procedure was most commonly complex RD repair (n = 176), followed by scleral buckle (n = 102), pars plana vitrectomy (n = 89), laser (n = 59), cryotherapy (n = 5), and pneumatic retinopexy (n = 5). There were 51 new diagnoses of glaucoma and 37 new diagnoses of aphakia within 1 year after the surgical procedure.
Conclusions:
IRIS Registry data provide insight into rare pediatric vitreoretinopathy-associated RDs, which have a high rate of reoperation and fellow eye involvement.
Financial disclosures:
Proprietary or commercial disclosure may be found after the references.
... We also found three previously unreported stop-gained variants (c.3299C>G, c.1447G>T, and c.1030C>T) and three splice-donor variants (c.2208+2T>C, c.898-972G>A, and c.897+696G>A) in COL11A1. Stickler syndrome is caused by variants of two genes 64 , and is clinically characterized by HM, which is the most common cause of inherited retinal detachment 65 . These results indicated that WES could find potential pathogenic variants and provide new genetic evidence for HM candidate genes in our study. ...
Importance
High myopia (HM) is one of the leading causes of visual impairment and blindness worldwide. It is well-known that genetic factors play a significant role in the development of HM. Early school-aged population-based genetic screening and treatment should be performed to reduce HM complications.
Objective
To identify risk variants in a large HM cohort and to examine the implications of universal genetic testing of individuals with HM with respect to clinical decision-making.
Design, setting, and participants
In this cross-sectional study, we retrospectively reviewed whole-exome sequencing(WES) results for myopia-related genes in 6,215 school-aged students with HM who underwent germline genetic testing between September 2019 and July 2020. The study setting was a commercial genetic testing laboratory and a multicenter census of elementary and high schools from different educational systems. Participants were aged 6 to 20 years, including 355 primary school students, 1970 junior high school students, and 3890 senior high school students.
Main outcomes and measures
The frequency and distribution of positive germline variants and the percentage of individuals with HM (spherical equivalent refraction, SER ≤ -6.00D) in both eyes were detected using the whole-exome sequencing (WES) genetic testing approach.
Results
Among individuals with HM, molecular testing yielded 15.52% diagnoses based on systematic analysis of variants in 75 candidate myopic genes. We found 36 known variants in 490 (7.88%) HM cases and 235 protein-truncating variants (PTVs) in 506 (8.14%) HM cases. We found that diagnostic yield was significantly positively associated with SER (P = 0.0108), which ranged from 7.66% in the common High Myopia group (HM, -8.00D ≤ SER ≤ -6.00D) to 11.90% in Extreme Myopia group (EM, SER < -10.00D). We also found that primary school students (≤ 11 years) with EM had the highest diagnostic rate of PTV variants (22.86%), which was 1.77 and 4.78 times that of the Ultra Myopia (UM, -10.00D ≤ SER < -8.00D) and HM, respectively.
Conclusions and relevance
Using whole-exome sequencing, multiple previously discovered mutations and PTVs which have not been reported to be associated with HM were identified in a substantial number of school-age students with HM. The high mutation frequency in younger students with EM can provide clues for genetic screening and further specific clinical examinations of HM to promote long-term follow-up assessment.
... COL11A2 is the coding gene for the α2 (XI) chain (Bruckner and van der Rest, 1994). Hence, defects in COL11A2 will only affect osteoarthritis with the normal ocular phenotype (Snead et al., 2011). ...
... The majority of -X-Y-consists of prolines and hydroxyprolines that are essential for the formation and stabilization of the triple helix. The mutation sites in this region may lead to changes in the structure of the triple helix and corresponding functional changes (Snead et al., 2011;Chakchouk et al., 2015). ...
Background: Stickler syndrome (SS) is a group of hereditary collagenopathies caused by a variety of collagen and non-collagen genes. Affected patients have characteristic manifestations involving ophthalmic, articular, craniofacial and auditory disorders. SS is classified into several subtypes according to clinical and molecular features. Type 3 SS is an ultra-rare disease, known as non-ocular SS or otospondylomegaepiphyseal dysplasia (OSMED) with only a few pathogenic COL11A2 variants reported to date.
Case presentation: A 29-year-old Chinese male was referred to our hospital for hearing loss and multiple joint pain. He presented a phenotype highly suggestive of OSMED, including progressive sensorineural deafness, spondyloepiphyseal dysplasia with large epiphyses, platyspondyly, degenerative osteoarthritis, and sunken nasal bridge. We detected compound heterozygous mutations in COL11A2, both of which were predicted to be splicing mutations. One is synonymous mutation c.3774C>T (p.Gly1258Gly) supposed to be a splice site mutation, the other is a novel intron mutation c.4750 + 5 G>A, which is a highly conservative site across several species. We also present a review of the current known pathogenic mutation spectrum of COL11A2 in patients with type 3 SS.
Conclusion: Both synonymous extonic and intronic variants are easily overlooked by whole-exome sequencing. For patients with clinical manifestations suspected of SS syndrome, next-generation whole-genome sequencing is necessary for precision diagnosis and genetic counseling.
