Early-Onset Ocular Presentation in Stickler Syndrome Type 1 Due to a COL2A1 Frameshift Variant

Introduction

Stickler syndrome, also known as hereditary progressive arthro-ophthalmodystrophy, is a very common inherited connective tissue disorder, with an estimated incidence of 1: 7500 live births. It is also the leading cause of inherited retinal detachment in childhood [1,2]. The disorder involves pathogenic variants in type II, IX, or XI collagen and is characterized by a distinctive craniofacial appearance, high myopia, vitreoretinal degeneration, hearing loss, and early-onset arthritis.

Stickler syndrome is genetically heterogeneous and classified into 4 principal subtypes according to the underlying gene defect. Type 1, the most common autosomal dominant form, is associated with mutations in COL2A1; type 2 with mutations in COL11A1; type 3 with mutations in COL11A2; and type 4 with mutations in COL9A1 or COL9A2 [2,3]. Disease pathogenesis is primarily linked to vitreous degeneration caused by COL2A1 mutations, which encode type II procollagen located on chromosome 12 [4,5]. Pathogenic variants mainly act through 2 mechanisms: missense mutations within the triple-helical domain exert a dominant-negative effect, whereas truncating variants (eg, frameshift or nonsense mutations) result in haploinsufficiency via nonsense-mediated decay. Both mechanisms lead to defective or reduced type II collagen, resulting in vitreous degeneration and connective tissue fragility. COL2A1-related Stickler syndrome demonstrates high penetrance with pronounced inter- and intrafamilial variability in age at onset and disease severity, particularly with respect to ocular manifestations [1,6,7]. Structural and molecular abnormalities of type II collagen give rise to a membranous vitreous phenotype in Stickler syndrome type 1, whereas mutations in COL11A1 (type 2) produce a fibrillar vitreous appearance [1]. Type 3 typically lacks ocular manifestations and predominantly presents with auditory and skeletal abnormalities, whereas type 4 generally lacks systemic involvement. Ocular-only variants, most often associated with COL2A1 mutations, exhibit minimal or absent systemic features [8].

In the differential diagnosis of pediatric vitreoretinal degeneration with early retinal detachment, conditions such as Wagner syndrome and Knobloch syndrome may mimic Stickler syndrome but typically differ in vitreous morphology and systemic associations. Wagner syndrome is characterized by an optically empty vitreous with avascular vitreous veils, high myopia, presenile cataract, and night-vision manifestations secondary to progressive chorioretinal atrophy, in the absence of systemic abnormalities. Knobloch syndrome is characterized by severe high myopia, vitreoretinal degeneration, macular chorioretinal atrophy, smooth cryptless irides, cataract, and glaucoma, with the hallmark finding of an occipital skull encephalocele [1,9]. Clinically, Stickler and Marshall syndromes share overlapping craniofacial and auditory features because both may involve COL11A1 mutations; however, Marshall syndrome often demonstrates more pronounced midfacial hypoplasia and nasal flattening. Stickler syndrome type 1 is strongly associated with ocular complications, particularly retinal detachment, which remains a major cause of vision loss. Retinal manifestations include radial perivascular pigmentation, lattice degeneration, giant anterior retinal tears, and posterior retinal breaks. Retinal detachment typically occurs between 10 and 30 years of age, with 8% of cases presenting before 10 years of age and 26% arising between ages 10 and 19 [7,8]. Overall, approximately 60% to 70% of affected individuals develop retinal detachment, most commonly during childhood and adolescence [1,7,10,11]. These findings underscore the importance of early detection and prophylactic measures to reduce retinal detachment risk in Stickler syndrome type 1 [12,13]. Here, we describe a novel COL2A1 frameshift mutation in a pediatric patient who exhibited high myopia and retinal detachment consistent with Stickler syndrome type 1.

Case Report

An 8-year-old Saudi girl presented to the ophthalmic emergency department with a 2-day history of sudden vision loss in the right eye. High myopia was present, with refractive errors of −17.00 diopters in the right eye and −15.00 diopters in the left eye. No prior history of ocular trauma, flashes, floaters, or retinal detachment was reported. General health was unremarkable, and academic performance was appropriate for age. Craniofacial examination revealed midfacial hypoplasia; no cleft palate, uvular anomaly, or clinically evident micrognathia was observed. No joint complaints or auditory symptoms were reported; however, formal audiologic evaluation, rheumatologic assessment, and range-of-motion or hyperextensibility testing were not performed. Anthropometric measurements (height, weight, arm span, and sitting-height ratio) and detailed dysmorphologic assessment findings (orbital configuration, nasal morphology, mandibular position, and auricular morphology) were not recorded. Skeletal radiographs to assess spondyloepiphyseal dysplasia, karyotype analysis, and echocardiography were not obtained. The patient was born to nonconsanguineous parents and had 3 sisters, all with high myopia. Her father, who had short stature and a flat midface, reported a history of retinal detachment that had been surgically repaired during childhood (Figure 1).

Ophthalmic examination demonstrated best-corrected visual acuities of 20/80 in the right eye and 20/20 in the left eye. Intraocular pressures were within normal limits in both eyes. The anterior segment was unremarkable, except for pigmented cells (Shafer’s sign) in the anterior vitreous and anterior chamber of the right eye. The vitreous exhibited a membranous, sheet-like configuration with beaded folds, reflecting the classic type 1–related vitreous phenotype. Dilated fundus examination revealed inferior rhegmatogenous retinal detachment caused by a round inferior retinal break in the right eye, with partial macular involvement (Figure 2). Posterior vitreous detachment was absent. The left eye demonstrated myopic fundus changes with peripheral retinal holes.

The following day, the patient underwent chandelier-assisted scleral buckle (SB) surgery with cryotherapy. This approach was selected because the retinal detachment was relatively shallow, originated inferiorly from a single round atrophic hole, and was associated with neither vitreoretinal traction nor posterior vitreous detachment. These features favored external support while minimizing intraocular manipulation and preserving the crystalline lens in an 8-year-old patient. A recent comparative study of pars plana vitrectomy (PPV), SB, and combined PPV–SB in syndromes with an optically empty vitreous demonstrated that primary SB was associated with superior visual acuity and anatomic outcomes [4]. The use of chandelier illumination, based on surgeon preference, provided enhanced visualization of the peripheral retina during the procedure [14]. Two peripheral retinal holes at the 7 o’clock position were treated with cryopexy. A #240 encircling band was placed beneath the rectus muscles; a #70 sleeve was positioned in the inferotemporal quadrant to support the inferior break. The buckle was secured with 5-0 Mersilene sutures. After tightening, optic disc pulsations were observed, and anterior chamber paracentesis was performed. Prophylactic laser photocoagulation was applied to the fellow eye.

At the 4-month follow-up, recurrent inferior retinal detachment was detected intraoperatively. The SB was encapsulated, and the encircling band had shifted anteriorly, leaving the inferior break unsupported. These findings were consistent with mechanical underindentation, rather than proliferative vitreoretinopathy, as the cause of failure. Revision surgery was performed, during which cryopexy was reapplied and a #506 sponge was sutured posteriorly to the sclera at the site of the break to provide additional support. After revision, the retina remained attached. At the final follow-up, 3 years post-revision, best-corrected visual acuity in the right eye had improved to 20/30.

Given the strong family history and clinical features, Stickler syndrome was suspected. Clinical whole-exome sequencing (Bioscientia) – using an exome capture method that targeted more than 20 000 protein-coding genes – identified a heterozygous COL2A1 frameshift variant, c.3642delT (p.Gly1215Alafs*12), in exon 51 (Figure 3). This deletion introduces a premature stop codon, consistent with loss of function via nonsense-mediated decay or protein truncation. The variant was confirmed by Sanger sequencing in the proband and segregated with disease in the affected father, who was heterozygous; the mother showed negative test results. The variant was absent from population databases, including gnomAD, and had not been reported in the Human Gene Mutation Database (version 2025.3) at the time of initial analysis. ClinVar (accessed October 2025) lists COL2A1 NM_001844.5: c.3642del (p.Gly1215fs) (Variation ID VCV000635549.5), corresponding to the present case (submitter: Bioscientia; SCV000925932.1; GRCh37 chr12: 48369344). Missense prediction tools, such as PolyPhen-2 and SIFT, are not applicable to frameshift variants. Notably, previously published Saudi and regional cohorts did not identify a COL2A1 variant at this position or involving exon 51, supporting the interpretation that the present variant represents a newly observed pathogenic allele in this population. The single-base deletion introduces a premature termination codon and is predicted to undergo nonsense-mediated mRNA decay, consistent with a loss-of-function mechanism in COL2A1. In addition to pathogenic very strong 1 (PVS1), 2 additional American College of Medical Genetics and Genomics/Association for Molecular Pathology criteria support pathogenicity: pathogenic moderate 2 (PM2; absence from population databases, including gnomAD) and pathogenic supporting 1 (PP1; segregation in the affected father). Collectively, these criteria support classification of c.3642delT as a pathogenic loss-of-function COL2A1 variant [15].

Discussion

Only a limited number of studies have reported treatment outcomes in patients with Stickler syndrome involving rhegmatogenous retinal detachment. Al Rashaed et al reported a primary reattachment success rate of 60% following scleral buckling, which increased to 93% after a second procedure; visual acuity improvement was observed in 54% of eyes [16]. Similarly, in the present case, complete retinal reattachment was achieved after a second SB procedure, with a final best-corrected visual acuity of 20/30. In our case, the decision to perform chandelier-assisted scleral buckling (rather than PPV) was guided by several anatomic and clinical factors. The retinal detachment was relatively shallow, originated from a single inferior round atrophic hole without vitreoretinal traction, and occurred in the absence of posterior vitreous detachment. These features indicated that an external support procedure would be sufficient to achieve retinal reattachment while avoiding unnecessary intraocular intervention. PPV in pediatric patients with Stickler syndrome is linked to additional concerns, including increased risks of lens injury, accelerated cataract formation, iatrogenic retinal breaks, and postoperative proliferative vitreoretinopathy. The use of silicone oil may introduce further complications, such as emulsification, secondary glaucoma, and keratopathy. The chandelier-assisted technique, selected based on surgeon preference, provided enhanced intraoperative visualization of the retinal periphery and improved surgical ergonomics. A recent comparative study evaluating primary scleral buckling, PPV, and combined PPV–SB for retinal detachment in syndromes characterized by an optically empty vitreous demonstrated that initial scleral buckling achieved anatomic and visual outcomes superior to those of PPV alone or the combined approach [4]. The presence of high myopia and a strong family history of retinal detachment further supported the diagnosis of Stickler syndrome. Although recognizable craniofacial features were present in this patient, diagnosis may be challenging in cases where such findings are absent. Huang et al described 2 novel COL2A1 mutations associated with bilateral retinal detachment in Chinese families, located in exons 21–22 and 33–34, respectively [17]. Similarly, Al Rashaed et al reported that 22.6% of patients with Stickler syndrome type 1 had a family history of rhegmatogenous retinal detachment, underscoring the heritable nature of the disorder [16].

Genetic studies indicate that approximately 10% of pathogenic variants are missense mutations within the triple-helical domain, some of which retain partial function, such as arginine-to-cysteine substitutions. Vitreoretinal complications, including retinal tears and retinal detachment, are observed more frequently in patients harboring COL2A1 mutations than in those without such variants. Together with cleft palate and a positive family history, these findings serve as strong indicators of type II collagen defects, in contrast to features such as severe sensorineural hearing loss [7]. Most pathogenic COL2A1 variants involve substitution of glycine within the repeating Gly–X–Y sequence of the type II collagen triple helix. Glycine replacement disrupts helix folding and collagen fibril assembly, explaining the phenotypic variability observed in Stickler syndrome and related type II collagenopathies. Recent multigenerational series continue to emphasize the substantial variability of COL2A1-related Stickler phenotypes within families, even among individuals carrying the same variant [7,18]. The clinical overlap with Marshall syndrome reflects shared involvement of collagen genes, although distinct mutations result in differing craniofacial and auditory manifestations.

Conclusions

The identification of a novel COL2A1 frameshift mutation (c.3642delT, p.Gly1215Alafs*12) introducing a premature stop codon provided molecular confirmation of Stickler syndrome type 1 in our patient. The truncating mutation may be associated with the early-onset, ocular-predominant presentation observed in the present case. This variant expands the known COL2A1 mutational spectrum and underscores the importance of genetic testing for diagnostic confirmation and family counseling. Recognition of genotype–phenotype correlations is essential to anticipate disease course and refine therapeutic strategies in pediatric collagenopathies.