Identification and functional characteristics of a novel splicing heterozygote variant of COL2A1 associated with Stickler syndrome type I.

Background: Stickler syndrome type I (STL1) is an autosomal dominant disorder characterized by ocular, auditory, orofacial, and skeletal anomalies. The main causes of STL1 are variants in the COL2A1 gene, which encodes a type II collagen precursor protein. The specific focus of this study was on a newborn from China diagnosed with STL1, with the aim of providing novel insights into the effects of a newly identified intronic variant in the COL2A1 gene on pre-mRNA splicing. Methods: Trio whole exome sequencing was used to identify the causative variant in the family. The identified variant was validated using Sanger sequencing. Bioinformatics programs were used to predict the pathogenicity of the candidate variant. Additionally, an in vitro minigene assay was used to investigate the effects of the identified variant on RNA splicing. Results: The proband with STL1 had a novel heterozygous splicing variant in the intron nine acceptor donor site of COL2A1 (c.655-2A>G). This splice junction variant resulted in aberrant COL2A1 mRNA splicing, leading to the skipping of exon 10 and the production of a shorter protein that may lack the last 18 native amino acids. Conclusion: The c.655-2A>G variant in the COL2A1 gene leads to STL1 through abnormal splicing. By expanding the spectrum of variants in the COL2A1 gene, this finding improves the clinical understanding of STL1 and provides guidance for early diagnosis and disease counseling.

Novel LOXL3-associated stickler syndrome-like phenotype: a case report.

PURPOSE: To report the case of a young boy with early onset high myopia (eoHM), foveal hypoplasia and skeletal dysplasia due to a homozygous LOXL3 pathogenic variant. Atypically, this was from a paternal uniparental isodisomy (UPiD) of chromosome 2. CLINICAL CASE: Four-year-old boy with several months history of holding items close to his face was found to have reduced visual acuity 6/30 in both eyes, bilateral vitreous syneresis, foveal hypoplasia and bilateral high myopia (-8.50D). A skeletal survey showed spondylo-epi-metaphyseal dysplasia. Whole-exome sequencing (WES) revealed a homozygous LOXL3 variant c.1448_1449del, p.(Thr483Argfs*13), inherited through paternal UPiD of chromosome 2. CONCLUSION: To our knowledge, this is the first reported case of LOXL3-associated eoHM, foveal hypoplasia and mild skeletal dysplasia due to the rare phenomenon of paternal UPiD of chromosome 2. This case further delineates the phenotype associated with LOXL3 pathogenic variants and supports truncating LOXL3 pathogenic variants being associated with a phenotypic spectrum; from isolated eoHM through to a Stickler syndrome-like phenotype.

Posterior Precortical Vitreous Pocket in Stickler Syndrome: A Report of Two Cases.

Stickler syndrome is a genetic disorder characterized by collagen abnormalities leading to various ocular manifestations, such as retinal detachment. We present two cases of siblings clinically diagnosed with Stickler syndrome who exhibited retinal detachment. Case 1, a seven-year-old girl, and case 2, her 14-year-old brother, both displayed severe myopia and other clinical signs consistent with Stickler syndrome. Despite their ages, neither case showed evidence of posterior precortical vitreous pocket (PPVP) on imaging or during surgical intervention. These findings suggest a potential relationship between collagen abnormalities and PPVP dysplasia in Stickler syndrome.

Nonperfusion of the Far Peripheral Retina in Highly Myopic Stickler Syndrome.

Purpose: To describe the clinical course of 3 patients with Stickler syndrome found on fluorescein angiography (FA) to have nonperfusion of the peripheral retina. Methods: Three patients with confirmed Stickler syndrome were examined under anesthesia. Genetic testing and FA were performed. Results: Each patient had characteristic ocular findings of Stickler syndrome, including high myopia with vitreoretinal degeneration. FA was performed on each patient and showed 360 degrees of nonperfusion of the retinal periphery in all eyes, with mild leakage in Case 3. Conclusions: The current series presents evidence of peripheral retinal nonperfusion in 3 consecutive patients with Stickler syndrome. Based on these findings, the authors recommend adopting FA as a standard imaging modality and using laser photocoagulation to treat the areas of retinal nonperfusion for all patients with Stickler syndrome.

Peripapillary Hyperreflective Ovoid Mass-Like Structures in Stickler Syndrome.

PURPOSE: To report a previously undescribed finding of peripapillary hyperreflective ovoid mass-like structures (PHOMS) in Stickler syndrome. DESIGN: Noncomparative case series. SUBJECTS: Twenty-two eyes with anomalous optic disc from 11 Stickler syndrome patients were identified and imaged. METHODS: Peripapillary hyperreflective ovoid mass-like structures were graded using enhanced-depth imaging OCT (EDI-OCT) according to the consensus recommendations of the Optic Disc Drusen Studies Consortium. All EDI-OCT scans were obtained using the Heidelberg Spectralis (Heidelberg Engineering) with a dense horizontal raster (15 × 10°, 97 sections) centered on the optic nerve head and graded by 2 independent assessors. In case of disagreement, the image was graded by a third assessor. The presence of any coexisting optic disc drusen was also assessed using EDI-OCT and autofluorescence. MAIN OUTCOME MEASURES: The presence of PHOMS, clinical characteristics and genetic mutations. RESULTS: A pilot sample of 22 eyes with phenotypic optic disc abnormalities from 11 Stickler syndrome patients were identified and imaged. Eight patients were female and 3 were male. The mean age was 31 years (13-58 years). Peripapillary hyperreflective ovoid mass-like structures were present in 91% (n = 20) of imaged eyes. Seventy percent (n = 14) were type 1 Stickler syndrome and 30% (n = 6) were type 2 Stickler syndrome. All eyes were myopic and the degree of myopia did not seem to affect whether or not PHOMS was present in this cohort. One eye with PHOMS had retinal detachment, and 77.3% (n = 17) of eyes had undergone 360o prophylactic retinopexy. Thirty-two percent (n = 7) of eyes with PHOMS were present in patients with coexisting hearing loss and 22.7% (n = 5) had orofacial manifestation of Stickler syndrome in the form of a cleft palate. Seventy-seven percent (n = 15) of eyes with PHOMS were present in patients who reported joint laxity or symptoms of arthritis. No coexisting optic disc drusen were identified and raised intracranial pressure was also excluded after neurological investigation. CONCLUSIONS: These data suggest that PHOMS are a novel finding in Stickler syndrome patients and should be considered when evaluating the optic nerves of these patients. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Clinician Awareness of Stickler Syndromes Among Australian Allied Health Care Professionals.

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.

Unraveling the genetic collagen connection: clinical and therapeutic insights on genetic connective tissue disorders.

Hereditary connective tissue disorders include more than 200 conditions affecting different organs and tissues, compromising the biological role of the extracellular matrix through interference in the synthesis, development, or secretion of collagen and/or its associated proteins. The clinical phenotype includes multiple signs and symptoms, usually nonspecific but of interest to rheumatologists because of musculoskeletal involvement. The patient´s journey to diagnosis is long, and physicians should include these disorders in their differential diagnoses of diseases with systemic involvement. In this review, insights for the diagnosis and treatment of osteogenesis imperfecta, hypermobility spectrum disorder/Ehlers-Danlos syndrome, Marfan, Loeys-Dietz, and Stickler syndromes are presented.

Retinal detachment with multiple macrocysts in Stickler syndrome: case report and review of the literature.

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.

Syndromic Piere Robbin Sequence- A Rare Presentation in Association with Multiple Heart Defects and Type III Stickler Syndrome.

Pierre Robin Sequence (PRS), a rare congenital disorder, is a triad of micrognathia, glossoptosis, and tongue based airway obstruction (TBSO). It may occur as isolated anomaly (iPRS) or as a part of a syndrome (sPRS), like that seen in association with Stickler Syndrome. Approximately 20% of children with PRS have congenital heart diseases. To the best of our knowledge this case of a one-day old infant is the first one to be reported as having two heart defects; patent ductus arteriosus and patent foramen ovale in Pierre Robbin Sequence child.

Outcomes of rhegmatogenous retinal detachment surgery in patients with Stickler syndrome.

PURPOSE: Despite recent developments in vitrectomy technology and instrumentation, rhegmatogenous retinal detachment in Stickler syndrome (RDS) remains a challenge for surgeons. RDSs are associated with a higher rate of complications and surgical failures than those not associated with Stickler syndrome. This study is a report about anatomic and visual outcomes of RDS surgery and describes the surgical techniques associated with the treatment of this specific condition. METHODS: This is a retrospective, interventional, consecutive case series of patients with RDS undergoing retinal reattachment surgery from 1990 to 2020 at the Institute of Ocular Microsurgery (IMO) in Barcelona, Spain. RESULTS: Twenty-four eyes of 18 patients with genetically confirmed Stickler syndrome were included in the study. Ten eyes (41.6%) presented a giant retinal tear. Retinal reattachment was achieved in all cases after an average of 1.21 (range 1-6) surgical interventions. Nineteen eyes (79%) required only one operation to achieve complete retinal reattachment. The most common first surgical procedure was a 4-mm scleral buckle with posterior pars plana vitrectomy and silicone oil endotamponade, performed on 16 (66.6%) of the eyes. The mean follow-up period was 10.2 years. Mean preoperative visual acuity LogMar was 1.10 (Snellen equivalent 20/252), which improved to 0.50 (Snellen equivalent 20/63) at final follow-up (p < 0.05). CONCLUSION: In most RDS cases, anatomic success and visual acuity improvement can be achieved with the first surgical procedure, using a combination of silicone oil tamponade and a 4-mm scleral encircling band. In some early cases of RDS, other less invasive surgical techniques can be used.

Microphthalmia and congenital cataract in two patients with Stickler syndrome type II: a case report.

BACKGROUND: Stickler syndrome (STL) is a collagenopathy caused by pathogenic variants in collagen-coding genes, mainly COL2A1 or COL11A1 associated with Stickler syndrome type 1 (STL1) or type 2 (STL2), respectively. Affected individuals manifest ocular, auditory, articular, and craniofacial findings in varying degrees. Previous literature and case reports describe high variability in clinical findings for patients with STL. With this case report, we broaden the clinical spectrum of the phenotype. MATERIALS AND METHODS: Case report on two members of a family (mother and son) including clinical examination and genetic testing using targeted trio whole exome sequencing (trio-WES). RESULTS: A boy and his mother presented with microphthalmia, congenital cataract, ptosis, and moderate-to-severe sensorineural hearing loss. Trio-WES found a novel heterozygote missense variant, c.4526A>G; p(Gln1509Arg) in COL11A1 in both affected individuals. CONCLUSIONS: We report a previously undescribed phenotype associated with a COL11A1-variant in a mother and son, expanding the spectrum for phenotype-genotype correlation in STL2, presenting with microphthalmia, congenital cataract, and ptosis not normally associated with Stickler syndrome.

The molecular complexity of COL2A1 splicing variants and their significance in phenotype severity.

Pathogenic single nucleotide variants (SNVs) found in the COL2A1 gene are associated with a broad range of skeletal dysplasias due to their impact on the structure and function of the Col2a1 protein. However, the molecular mechanisms of some nucleotide variants detected during diagnostic testing remain unclear. The interpretation of missense and splicing variants caused by SNVs poses a significant challenge for clinicians. In this work, we analyzed 22 splicing variants in the COL2A1 gene which have been found in patients with COL2A1-associated skeletal dysplasias. Using a minigene system, we investigated the impact of these SNVs on splicing and gained insights into their molecular mechanisms and genotype-phenotype correlations for each patient. The results of our study are very useful for improving the accuracy of diagnosis and the management of patients with skeletal dysplasias caused by SNVs in the COL2A1 gene.

Use of vitreous phenotype as a key clinical marker to identify Ocular-only Stickler syndrome in a family with Marfan syndrome.

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 solely based on clinical presentation. Vitreous phenotyping allows for the identification of vitreous anomalies pathognomonic of Stickler syndrome, which can guide future gene sequencing. Having the accurate diagnosis of Marfan or type 1 Stickler syndrome is important, as patients with type 1 Stickler syndrome have higher rates of retinal detachment and will benefit from prophylaxis.

Exome sequencing-aided precise diagnosis of four families with type I Stickler syndrome.

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.

Axial length shortening in myopic children with Stickler syndrome after repeated low-level red-light therapy.

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.

Developmental outcome of children with Robin sequence treated with the current Paris protocol.

AIM: We aimed to investigate the developmental outcome of children with Robin sequence (RS) for whom continuous positive airway pressure was the main strategy to release upper airway obstruction. METHODS: We included children with isolated RS or RS associated with Stickler syndrome who were aged 15 months to 6 years. We used the French version of the Child Development Inventory and calculated the developmental quotient (DQ) for eight different domains and the global DQ (DQ-global). We searched for determinants of risk of delay. RESULTS: Of the 87 children, for 71%, the developmental evolution was within the norm (DQ-global ≥86 or ≥-1 SD), 29% were at high risk of delay (DQ-global <86 or <-1 SD), and only 3% were at very high risk of delay (DQ-global <70 or <-2 SD). The DQs for expressive language and language comprehension were lower in our study population than the general population, but an improvement was noticed with the children's growth. CONCLUSION: Risk of a developmental delay was not greater for children with the most severe respiratory phenotype than the others. Children whose mothers had low education levels were more at risk than the others.

A patient with concurrent Axenfeld-Rieger and Stickler syndromes verified by molecular genetics.

Purpose: To report a case of Axenfeld-Rieger and Stickler Syndrome in a pediatric patient. Observations: A 3-month-old male was referred to the glaucoma clinic after he was noted to have elevated intraocular pressures in both eyes. His family history was notable for infantile glaucoma on his maternal side and retinal detachment on his paternal side. He was found to have anterior segment dysgenesis with iris strands, iridocorneal adhesions, and corectopia, as well as veil-like vitreous in both eyes. He required trabeculotomy, goniotomy, and multiple Baerveldt glaucoma implants in both eyes to achieve intraocular pressure control. Furthermore, the patient later developed macula-involving retinal detachments in both eyes, requiring pars plana vitrectomy with silicone oil tamponade. Genetic analysis confirmed heterozygous pathogenic variants in both the FOXC1 and COL2A1 genes, leading to the concurrent diagnoses of Axenfeld-Rieger and Stickler syndromes. Conclusions and importance: This is a rare case of a patient with concurrent Axenfeld-Rieger and Stickler syndromes. The severity of pathology in both the anterior and posterior segments required a collaborative multidisciplinary approach. In the diagnostic evaluation of congenital eye diseases, if there is strong family history of atypical findings for a given diagnosis, concurrent syndromes should be considered and ruled out. A comprehensive eye genetics panel may be a useful tool in these cases.

Pattern of choroidal thickness in early-onset high myopia.

Purpose: To explore the etiology and choroidal thickness (ChT) pattern in children with early-onset high myopia (eoHM). Methods: Sixty children with eoHM and 20 healthy controls were enrolled in this study between January 2019 and December 2021. All children underwent comprehensive ophthalmologic examinations including swept-source optical coherence tomography. ChT was measured in the subfoveal region and at 1000 µm and 2,500 µm nasal, temporal, superior, and inferior to the fovea. Results: Overall, 120 eyes of 60 children with eoHM were examined (mean spherical equivalent, -8.88 ± 3.05 D; mean axial length, 26.07 ± 1.59 mm). Simple high myopia (SHM), familial exudative vitreoretinopathy (FEVR), and Stickler syndrome (STL) were the most frequent etiologies of eoHM and were included in further ChT analysis. Adjusted the effect of SE, multivariate regression analysis showed that children with SHM had thinnest ChT at N2500 and I2500 among the subgroups (p = 0.039, p = 0.013). FEVR group showed thinner ChT at T2500 (p = 0.023), while STL patients exhibited thin ChT at all locations. Conclusion: This study revealed that SHM, STL and FEVR was the most frequent etiology, and showed a distinctive pattern of ChT. Asymmetric nasal ChT thinning is a distinctive biomarker for SHM, asymmetric temporal ChT thinning might serve as a biomarker for FEVR, and symmetric diffuse thinning is more common in STL. These ChT patterns may provide a convenient, fast, and noninvasive strategy to differentiate the potential etiology of eoHM.

Preventing Retinal Detachment: The Encircling Laser Retinopexy Technique.

Encircling (360 degree) retinal detachment prophylaxis using indirect ophthalmoscope laser delivery recently achieved strong proof of safety and effectiveness by preventing the development of peripheral retinal tears and detachments in the eyes of patients with Stickler syndrome (syndromic eyes). Untreated, Stickler syndrome patients have a 65% lifetime risk of retinal detachment (half by age 20, 80% bilateral). This report describes an optimal technique of encircling laser retinopexy to also prevent the more common retinal detachments seen in aging (non-syndromic) eyes that share with Stickler syndrome the common pathogenesis of peripheral retinal tears caused by vitreous traction.

Streptococcal pyomyositis in asplenia and underlying connective tissue disease.

Pyomyositis is an infection of skeletal muscles, commonly affecting deep longitudinal muscles of the lower extremities. Primary pyomyositis is uncommon in the United States. Staphylococcus aureus is the most common cause of pyomyositis, but Streptococcus pneumoniae is the most common cause of life-threatening bacterial infection in asplenic patients. Most cases of S. pneumoniae pyomyositis occur in immunocompromised patients. We describe a 31-year-old man with S. pneumoniae pyomyositis whose diagnosis and hospital course were complicated by an immunocompromised state from asplenia and an underlying connective tissue disease, Stickler syndrome. Underlying connective tissue diseases such as systemic lupus erythematosus and polymyositis can predispose patients to infection, but susceptibility with Stickler syndrome is less known. While pyomyositis is only seen in up to 0.2% of US hospital admissions, it remains a pertinent differential for patients with asplenia and connective tissue disease.