Stickler syndrome [Online Mendelian Inheritance in Man (OMIM) nos. 108300, 609508, 604841,184840, 614134 and 614284], first reported in 1965 by Stickler et al (1), is a group of inherited connective tissue disorders, with an incidence of 1 in 10,000 (2,3). Stickler syndrome is frequently misdiagnosed due to its widely varied clinical manifestations, which may resemble other diseases (4,5). It commonly involves distinctive ocular and facial abnormalities, hearing loss and joint problems (3,6-8). Patients with Stickler syndrome typically present with shallow supraorbital ridges, hypoplastic short nose with anteverted nares, buphthalmic eyes, a flat hypoplastic midface with a depressed nasal bridge, long philtrum and micrognathia (9).

Stickler syndrome is caused by mutations in collagen genes during fetal development, and can be divided into various subtypes based on the clinical manifestations and underlying genetic mutations (10). The most common form, Type 1 Stickler syndrome, is caused by a collagen type II α1 chain (COL2A1) mutation (OMIM no. 120140), and is characterized by membranous vitreous anomaly and megalophthalmos (11,12). Type 2 Stickler syndrome with an underlying collagen type XI α1 chain (COL11A1) mutation (OMIM no. 120280) accounts for a minority of patients and presents with a typical beaded vitreous phenotype (13). Type 3 or non-ocular Stickler syndrome, caused by collagen type XI α2 chain (COL11A2) mutation (OMIM no. 120290), often manifests as systemic malformations, including midface hypoplasia and osteoarthritis (14,15). Type 4 Stickler syndrome, caused by collagen type IX α1 chain (COL9A1) or collagen type IX α2 chain (COL9A2) mutation (OMIM no. 120210), is associated with sensorineural deafness, myopia, vitreoretinopathy and epiphyseal dysplasia (16).

Stickler syndrome can lead to a variety of ocular abnormalities, including vitreoretinal degeneration, retinal detachment, cataract, ocular hypertension and high myopia (17). The development of Stickler syndrome is progressive and can ultimately lead to blindness (3). The molecular mechanism of Stickler syndrome is not fully characterized. However, type 1 Stickler syndrome arises from aberrant type II collagen, which is the major collagen type synthesized in the adult human vitreous (18). Under physiological conditions, the strongly adherent collagen fibrils (typically types II, XI and IX) are interspersed in the extracellular matrix, which is predominantly composed of water and glycosaminoglycans. The interaction between collagen and hyaluronan, the most prevalent glycosaminoglycan in the vitreous, provides swelling pressure required to maintain the ocular structure (19). Mutation in the COL2A1 gene can result in an abnormal fibrillar lamellar structure of the vitreous gel (20), disrupt collagen helices, alter fibrillogenesis and reduce collagen secretion (20,21).

Characterizing the Stickler syndrome phenotypes and identifying the underlying genetic mutations are initial steps to understand the disease pathogenesis and will be useful for future genetic counseling. The current study aimed to characterize the clinical presentation of two young patients with Stickler syndrome and bilateral retinal detachment, and to identify the genetic changes in these patients using targeted next-generation sequencing (NGS).

The clinical manifestation of Stickler syndrome is heterogeneous (3-5). Retinal detachment is the most severe consequence of Stickler syndrome (34), and there is a high incidence of blindness. Approximately 55-73% of Caucasian patients with a clinical diagnosis of Stickler syndrome exhibit retinal detachment (35,36). Thus, Stickler syndrome should be considered and excluded if a patient presents with multiple peripheral degeneration spots in both eyes (37-40). In the current report, both patients exhibited sequential bilateral retinal detachment and multiple peripheral retinal degeneration at a young age. In Patient 1, the localized retinal detachment of the right eye did not extend to the macular area; thus, the visual impairment was less severe.

The diagnostic criteria for Stickler syndrome have not been well-established (5,10). Adult patients diagnosed with Stickler syndrome typically do not present with typical facial anomalies as children (41). In Family 2, the patient and his mother had cleft palate, which is an important clinical indicator of Stickler syndrome (6,37,42,43). Other typical extraocular collagenopathies include achondrogenesis, hypochondrogenesis and early onset osteoarthritis (44). However, diagnosing Stickler syndrome only based on clinical manifestations is often challenging. Genetic analysis, therefore, is an important tool for the diagnosis of Stickler syndrome, particularly in patients with myopia and peripheral retinal degeneration (12,39,45-47). Early diagnosis and close-follow up will help to decrease the incidence of the retinal detachment (3,38). Currently, the Cambridge prophylactic cryotherapy protocol has been demonstrated to be a safe intervention and can markedly reduce the risk of retinal detachment in patients with Stickler syndrome (48).

Although the affected patients in the present study had different genetic mutations, they exhibited similar clinical presentations of retinal detachment and degeneration. Previous studies have also reported that different mutations in COL2A1 can lead to similar phenotypes, with various degrees of expressivity (42,49). The majority of COL2A1 mutations identified in Stickler syndrome are loss-of-function mutations, as they are predicted to result in nonsense-mediated decay of transcripts (42). Splice site mutations, as identified in Family 2 in the current study, are commonly identified in Stickler syndrome, and are likely to cause unusual RNA isoforms with premature stop codons (42). Additionally, silent mutations in COL2A1 can also result in splicing defects and reading frame shifts (50).

In summary, the present study characterized the clinical presentation of two Chinese families with Stickler syndrome, and identified two novel mutations in the COL2A1 gene in the affected family members. These findings expand the known mutation spectrums of COL2A1, and may facilitate genetic counseling and development of therapeutic strategies for patients with Stickler syndrome.