Stickler Syndrome

Literature and regulatory information updated: 6 October 2026.

Stickler syndrome (hereditary progressive arthro-ophthalmopathy): autosomal dominant forms due to COL2A1, COL11A1 and COL11A2 (the latter without ocular involvement), autosomal recessive forms due to COL9A1, COL9A2, COL9A3 and COL11A1, phenocopies due to LOXL3, LRP2, GZF1 and BMP4, and relationship with Pierre Robin sequence

0. Initial Reference Table

1. Introduction

Stickler syndrome is a hereditary connective tissue disorder resulting from alterations in fibrillar collagens II and XI and collagen IX, which associates with the fibrils of the first two, in the three structures where these collagens coexist: the vitreous body, hyaline and articular cartilage, and the inner ear [4, 22]. This produces the defining combination of congenital myopia with abnormal vitreous gel architecture and high retinal detachment risk, hearing loss, midface hypoplasia with cleft palate or Pierre Robin sequence, and mild spondyloepiphyseal dysplasia with early arthropathy [4, 5]. The syndrome's severity lies mainly in the risk of blindness from retinal detachment, frequently bilateral and occurring in childhood, which can be reduced by prophylactic intervention when diagnosis is timely [9, 12].

In 1965, Gunnar B. Stickler, a paediatrician at the Mayo Clinic in Rochester, United States, described under the designation “hereditary progressive arthro-ophthalmopathy” a family with five affected generations, autosomal dominant transmission, high myopia, retinal detachment with blindness, joint hypermobility, abnormalities in development of articular surfaces and early joint degeneration [1, 23]. Two years later, a second paper on the same family added mild epiphyseal changes and sensorineural hearing loss [22, 23]. Spranger documented the skeletal aspects in 1968 and Herrmann and colleagues delineated the malformation pattern in 1975 [22]. Molecular confirmation in the original pedigree came decades later with identification of the splicing variant COL2A1 c.1222-2A>G, a description valid in the MANE reference transcript NM_001844.5 according to VariantValidator [24, 25].

Genetic heterogeneity was demonstrated by the Cambridge group through the observation that different families had distinct vitreous phenotypes, leading to association of the membranous phenotype with COL2A1 and the beaded phenotype with COL11A1, and description of the form without ocular involvement due to COL11A2 [24, 26–28]. Autosomal recessive forms due to loss of function of collagen IX genes were recognised from 2006, beginning with a family of Moroccan origin with a homozygous COL9A1 variant [29–31]. The English group now describes at least ten clinically and genetically distinct subgroups, hence its proposed designation “Stickler syndromes” [7, 12]. Classification based on the vitreous phenotype has proved reliable in guiding molecular investigation [5, 24].

In this article, allelic and related entities (severe COL2A1 dysplasias, multiple epiphyseal dysplasia due to collagen IX genes, COL2A1-associated Legg-Calvé-Perthes disease and isolated Robin sequence) are addressed only insofar as they are relevant to differential diagnosis and recognition of Stickler syndrome. Marshall syndrome, caused by COL11A1 variants, is described as an allelic entity and close differential diagnosis [4, 32].

2. Molecular Genetics and Pathophysiology

2.1. The heterotypic II/XI/IX fibril

Type II collagen is a homotrimer of three α1(II) chains, encoded by COL2A1 (12q13.11), and constitutes the main fibrillar collagen of hyaline cartilage, the nucleus pulposus and vitreous [4, 33]. Type XI collagen is a quantitatively minor heterotrimer composed of α1(XI) (COL11A1, 1p21.1), α2(XI) (COL11A2, 6p21.32) and an α1(II) chain produced by COL2A1 itself; it forms the core of composite fibrils and regulates nucleation, diameter and spacing of type II collagen fibrils [4, 9, 24]. Type IX collagen, a heterotrimer of α1(IX), α2(IX) and α3(IX) encoded by COL9A1 (6q13), COL9A2 (1p34.2) and COL9A3 (20q13.33), belongs to the group of FACIT collagens (fibril-associated collagens with interrupted triple helices), is deposited on the II/XI fibril surface and acts as a bridge between it and other matrix components [4, 8]. In the vitreous, some α2(XI) chains are replaced by the α2(V) chain, and COL11A2 is virtually not expressed in the eye, explaining the absence of an ocular phenotype with variants in this gene [4, 23, 24]. Clinical overlap between subtypes arises because collagens II, IX and XI coexist in the vitreous, inner ear and articular cartilage [2, 22].

2.2. COL2A1 and type 1: haploinsufficiency

The pro-α1(II) chain contains a central helical region (codons 201–1214) formed by the Gly-X-Y repeat, essential to the triple helix [5]. Variants causing type 1 Stickler syndrome are overwhelmingly loss-of-function variants: nonsense variants, small frameshift insertions or deletions and splicing variants producing a premature termination codon, whose mRNA is degraded by NMD (nonsense-mediated decay), halving production of structurally normal chains [4, 5, 24]. In the European series of Hoornaert and colleagues, 77 different COL2A1 variants were identified in 100 patients and more than 90% were predicted to undergo NMD [34]. Apparently silent variants, particularly in glycines at exon ends, may create a cryptic donor site and likewise lead to haploinsufficiency [5, 24]. Conversely, variants preserving the reading frame (glycine substitutions, in-frame exon skipping) produce abnormal chains incorporated into the trimer; because collagen II is homotrimeric, in a heterozygote seven of every eight molecules contain at least one mutant chain, and this dominant-negative effect is associated with more severe type II collagenopathies such as spondyloepiphyseal dysplasia congenita and Kniest dysplasia [4, 24, 35]. Glycine substitutions have nevertheless been described in Stickler syndrome and tend to cluster at the protein's amino terminus [4]. It is thought that a critical mass of collagen II is required for secondary vitreous development, completed between 8 and 14 weeks of gestation; haploinsufficiency would leave only a vestigial retrolental gel, corresponding to the type 1 membranous phenotype [24].

COL2A1 exon 2 undergoes alternative splicing: the long IIA isoform, which includes it, is expressed in the vitreous and developing chondrogenic tissue, whereas the short IIB isoform predominates in adult cartilage [5, 36]. Exon 2 variants therefore cause a predominantly ocular form, with optically empty vitreous, perivascular pigmentary changes and early retinal detachment, with minimal or absent systemic manifestations, in which diagnosis may be missed without vitreous examination [4, 9, 37]. The isolated ocular form has its own Orphanet entry (ORPHA:209867) [6]. The ocular form is not restricted to exon 2, because variants elsewhere may cause abnormal tissue-specific splicing, and the vitreous, with its rapid embryogenesis, would be more sensitive to reduced collagen II quantity [24]. The Cambridge group also described a subgroup of COL2A1 variants with hypoplastic vitreous, optically empty or containing sparse irregular lamellae, and two complete gene deletions detected by MLPA (multiplex ligation-dependent probe amplification) [38]. Intragenic and whole-gene deletions, as well as mosaicism, have been described [4].

2.3. COL11A1 and type 2: dominant-negative effect

Unlike COL2A1, COL11A1 variants associated with the dominant form are mainly splice-site alterations causing in-frame skipping and glycine substitutions in the helix; the transcript escapes NMD and the abnormal chain enters the type XI heterotrimer, with a dominant-negative effect [4, 5, 24]. The intron 50 donor site is a mutational hotspot: in the series of Majava and colleagues, variant c.3816+1G>A occurred in three of ten patients, and all patients classified as Marshall syndrome had intron 50 splicing variants [39]; this description is valid in the MANE transcript NM_001854.4 [25]. Splicing variants in the 54-base-pair exons of the C-terminal region are associated with the Marshall phenotype, although intermediate Marshall/Stickler phenotypes exist [2, 40]. Heterozygous loss-of-function COL11A1 variants are rare in Stickler syndrome and associated with milder phenotypes such as non-syndromic hearing loss; null-allele carriers in fibrochondrogenesis families had early-onset hearing loss and carriers of glycine-substitution alleles had myopia [4, 41]. Reference transcript NM_001854.4 has 68 exons, with alternative splicing of exons 6, 7 and 9 [5]. Dysregulation of fibril diameter and spacing would explain the beaded vitreous appearance, with irregular, thickened lamellae [24].

The recessive type 2 form results from biallelic COL11A1 variants in which at least one allele affects alternatively spliced exon 9: this exon is expressed in the vitreous and immature chondrocytes, but not mature chondrocytes, except in Meckel's cartilage, which gives rise to the malleus and incus [8, 42]. Variants affecting it are thus “removed” in most cartilage, sparing the patient the lethal skeletal phenotype of fibrochondrogenesis and explaining disproportionately severe hearing loss [5, 7, 8]. One example is the combination of a de novo in-frame deletion, NM_001854.4:c.4109_4126del, p.(Ala1370_Gly1375del), with inherited variant c.1245+2T>C, affecting exon 9 splicing, in a child with type 2 Stickler syndrome and severe hearing loss [25, 43]. In a case in Nixon's review, a synonymous variant, c.2607A>G p.Ala869Ala, altered splicing and reduced functional transcripts to approximately half, in trans with a C-propeptide variant [8]. Biallelic loss-of-function variants without exon 9 involvement cause type 1 fibrochondrogenesis, a short-limb dysplasia usually lethal at birth [41, 44].

2.4. COL11A2: non-ocular form (type 3)

Heterozygous COL11A2 variants are rare, usually act through a dominant-negative effect (missense variants in the helix, in-frame deletions, splicing alterations) and cause non-ocular Stickler syndrome, designated in the 2023 nosology as otospondylomegaepiphyseal dysplasia (OSMED), dominant form [4, 24, 45]. The first family described had a donor-site variant with in-frame skipping, and a similar, more severe recessive disease was associated with a glycine-to-arginine substitution in the same gene [27]. A second family had a heterozygous 27-base-pair deletion [28]. The recessive form (classical OSMED) results from homozygosity, and some variants have clinical expression only in homozygosity, whereas others cause, in heterozygosity, dominant OSMED or isolated hearing loss without facial or skeletal changes (DFNA13) [46]; in this dominant hearing loss, a U-shaped audiogram (mid-frequency loss, cookie-bite configuration) points towards COL11A2 or TECTA [47]. Biallelic variants have also been described in type 2 fibrochondrogenesis [33, 44]; Smith's attributes the dominant forms of fibrochondrogenesis to COL11A2 and the recessive forms to COL11A1, and cites the work that characterised dominant and recessive forms at this second locus, so both inheritance patterns coexist for COL11A2 [48].

2.5. Recessive forms due to collagen IX genes

Recessive forms result from biallelic loss-of-function variants, frequently homozygous and in consanguineous families, with complete absence of the protein [4, 5]. The first was COL9A1 variant p.R295X (author's designation; NM_001851.6:c.883C>T p.(Arg295Ter)), homozygous in four children from a Moroccan family, whose heterozygous parents and siblings had no signs of the syndrome [25, 29]; this was followed by COL9A1 variant p.R507X (NM_001851.6:c.1519C>T p.(Arg507Ter)) in two Turkish sisters [25, 49], a homozygous loss-of-function deletion in COL9A2 in a family with high myopia, vitreoretinal degeneration, retinal detachment, hearing loss and short stature [30], and COL9A3 variant NM_001853.4:c.1176_1198del p.(Gln393CysfsTer25) in the first recessive family for this gene [25, 31]. The fact that biallelic loss of any of the three chains causes a milder skeletal phenotype than biallelic loss of COL2A1 (lethal) or COL11A1 (fibrochondrogenesis) may be due to formation of alternative heterotrimers using the two remaining chains [8]. Heterozygous COL9A3 variants have been described in two families with peripheral vitreoretinal degeneration and retinal detachment, possibly through a dominant-negative effect [8]. Heterozygous carriers of the recessive forms are asymptomatic [4]. Heterozygous in-frame splicing variants in the same genes cause another disease, autosomal dominant multiple epiphyseal dysplasia, so zygosity and variant class determine interpretation [4, 33].

2.6. Non-collagen genes

LOXL3 encodes a lysyl oxidase-like oxidase that cross-links collagen II; the homozygous variant p.(Cys676Tyr) was proposed as a candidate cause in a consanguineous Saudi family through autozygome and exome analysis [8, 33, 50], and variant NM_032603.5:c.1036C>T p.(Arg346Trp) was described in a boy and his father, with pseudodominance [25, 51]. In 2026, three sisters with Pierre Robin sequence, high myopia and conductive hearing loss were described, with biallelic variants (one likely pathogenic and one of uncertain significance) and previously undescribed microcephaly and shortening of metacarpals and metatarsals [11]. Biallelic LOXL3 variants are also associated with isolated early-onset high myopia (MYP28) [33, 52]. In LRP2, the gene for Donnai-Barrow syndrome, homozygous variant NM_004525.3:c.11483A>G p.(Asp3828Gly) was identified in two siblings from a consanguineous Iraqi family with a predominantly ocular phenotype suggestive of Stickler syndrome; microglobulinuria was investigated only after the molecular result [25, 53]. GZF1 variants have been described in families with a Larsen spectrum phenotype with high myopia and retinal detachment [8, 54]. Heterozygous variant BMP4 c.130G>T p.(Gly44Ter) segregated with a dominant Stickler-like phenotype and renal dysplasia in a family; association with congenital abnormalities of the kidney and urinary tract distinguishes this subgroup [24, 55].

2.7. Gene-by-gene overview

The transcripts shown are MANE Select transcripts obtained in VariantValidator; numbering of types 6 to 8 in the table follows the English national service and French PNDS classification, which does not fully coincide with OMIM [5, 7, 25].

2.8. Tissue pathophysiology

In the eye, the congenital vitreous abnormality is pathognomonic and usually associated with non-progressive congenital myopia; a significant proportion of type 1 retinal detachments results from giant tears at the ora-retinal junction, which may occur at posterior vitreous detachment [8, 12, 26, 56]. In the inner ear, collagens II, IX and XI are present in hair cells and the tectorial membrane; reduced distortion-product otoacoustic emissions in type 1 suggest outer hair-cell dysfunction, and mouse models of Col11a2 and collagen IX deficiency show tectorial membrane alterations [23]. Conductive hearing loss results from otitis associated with cleft palate and Eustachian tube dysfunction, and tympanic membrane hypermobility has been described [23, 57]. In cartilage, reduction or abnormality of collagen II and XI compromises the growth and articular cartilage network, explaining mild spondyloepiphyseal dysplasia, cleft palate and early osteoarthritis [2, 24]. Penetrance is complete, with marked inter- and intrafamilial variability, partly explained by locus and allelic heterogeneity; somatic mosaicism can result in mildly affected parents of several fully affected children [2, 4, 58].

3. Clinical Spectrum and Manifestations by System

Expression is highly variable between and within families; variability is predominantly interfamilial, and the ocular phenotype tends to be concordant among affected family members [4, 9, 22]. Not all patients have every manifestation, and many are labelled only as myopic or arthritic [5]. In the survey by Stickler and colleagues, with 316 usable responses from 612 questionnaires, 95% reported eye problems (retinal detachment 60%, myopia 90%, blindness 4%), 84% facial abnormalities (flat face, small jaw or cleft palate), 70% hearing loss and 90% joint problems, mainly early joint pain from degenerative disease; the authors emphasise diagnostic delays and denial of ocular risk within families [9, 59]. As this was a self-report sample, these proportions are not equivalent to population frequencies.

3.1. Frequency of manifestations by gene

The table combines estimates from clinical series (Hoornaert 2010, Boothe 2020, Wang 2020), not population cohorts, and absence of a value (“—”) means it was not reported [4]. In Nixon's review, the combined recessive forms had myopia in 98%, retinal detachment in 18%, palatal abnormalities in 10%, hearing loss in 78% and joint pain in 15%, compared with 80%, 42–62%, 28–45%, 50–75% and 41–90%, respectively, in dominant forms; mean age in recessive patients was 11 years, underestimating lifetime risk [8].

3.2. Ocular manifestations

Myopia is typically congenital, high and non-progressive; Oxford reports that 15–20% of patients are not myopic and that moderate to severe myopia (greater than −5 dioptres) is common [9, 26]. Smith describes myopia before 6 years, which may be progressive, present in 40% before 10 years and 75% at 20 years, sometimes only after 50 years [22]. In a Danish cross-sectional study (71 genetically confirmed type 1 and 13 type 2 patients), median spherical equivalent was −6.00 D in type 1 and −6.75 D in type 2, mean axial length 25.99 and 26.55 mm, with no difference between subtypes and no progression in childhood; myopic maculopathy was present in 43% and 42%, and the probability of a more severe category increased 2.15-fold per millimetre of axial elongation (95% CI 1.14–4.04), but not with age [60]. The English service describes congenital megalophthalmos in types 1 and 2 and recessive forms [7, 61].

The vitreous abnormality is pathognomonic and has two main phenotypes: type 1, “membranous”, much more frequent, with vestigial gel occupying the immediate retrolental space and bounded by a distinct folded membrane, typical of COL2A1; and type 2, “beaded”, with sparse, irregularly thickened bundles of fibres throughout the vitreous cavity, typical of COL11A1 [4, 6, 22]. Patients with a COL11A1 variant and membranous vitreous have been described [4, 39]. In recessive forms, the vitreous is usually hypoplastic, and Smith describes, in types 4 and 5, degenerative liquefaction with partitioning of the gel into coalescing particles [8, 22]. In the COL11A2 form the vitreous is normal [24]. Other findings include pigmented paravascular lattice degeneration, cataract (including lamellar cataract), glaucoma, strabismus, foveal hypoplasia and, rarely, lens dislocation [5, 8, 22, 26]. In Boysen's systematic review (37 articles, 2324 patients), myopia occurred in 83%, retinal detachment in 45%, cataract in 59% of type 2 versus 36% of type 1, glaucoma in 10%, blindness in 6% and loss of vision in one eye in 10%; first detachment generally occurred in the second decade in type 1 and later in type 2 [62]. In a paediatric series of 97 children, 14% had glaucoma (median diagnostic age 8.5 years), including infantile-onset glaucoma in nine eyes of five patients, all requiring a drainage device, and glaucoma after intraocular surgery in 11 eyes [63]. In a US cohort from Utah and the Mayo Clinic, lattice degeneration was more frequent in COL2A1 (50%) than COL11A1 (8%), possibly influenced by the older age of the first group [64].

Retinal detachment is the most severe complication and can occur at any age, frequently due to a giant tear [9]. In type 1, approximately half of patients with detachment in one eye experience detachment in the second eye within four years without prophylaxis [7, 9]; the French PNDS, citing the literature, reports lifetime risk above 50% and fellow-eye risk above 80% after a first detachment [5, 8]. In the Cambridge series, 73% of 111 type 1 patients without prophylaxis (mean age 49 years) had experienced detachment, bilateral in 48% [65]. Carpenter's individual-participant-data meta-analysis (673 patients from 430 families, without prophylaxis) found detachment in 47% of COL2A1 and 28% of COL11A1 patients, with a relative risk of 1.78 (95% CI 1.30–2.43), moderate certainty and no possibility of estimating absolute risk [66]. Alsharif's meta-analysis (49 studies, 3492 individuals) estimated pooled detachment prevalence of 41.9% per patient (95% CI 33.8–50.2%) and 26.1% per eye, with high heterogeneity [67]. In a series from two tertiary centres with 58 genotyped patients with detachment, boys with COL2A1 had first detachment earlier (10.1 ± 5.7 years) than girls (21.3 ± 14.5 years), a difference not observed in COL11A1, in which detachment occurred earlier [68]. Smith reports that detachment may occur in childhood but usually after 20 years [22]; these data from different series should be interpreted in light of their selection criteria.

3.3. Craniofacial and oral manifestations

The face is flat, with malar and maxillary hypoplasia, a depressed nasal bridge, a short nose with anteverted nares, epicanthus and micrognathia; these features are more evident in childhood and attenuate with age, and adults may have a normal profile, so childhood photographs help assess adults [4, 9, 22]. Approximately 25% have a palatal abnormality according to Oxford and Bone Dysplasias, with submucous cleft frequently undiagnosed; the cleft may be broad U-shaped, narrow V-shaped or limited to a bifid uvula [2, 4, 9]. Micrognathia may form part of Pierre Robin sequence (micrognathia, glossoptosis, cleft palate) and compromise the airway enough to require neonatal tracheostomy; in most, micrognathia attenuates with growth and the maxilla and mandible tend to become proportionate [4, 69]. Stickler syndrome is the most frequent genetic cause of Robin sequence [22, 70]. Dental abnormalities and obstructive sleep apnoea syndrome have been described [5, 22]. A French study using 2D and 3D photography and machine learning distinguished patients from controls with 92% accuracy, rising to 96% when considering only the 3D orbitonasal region [71].

3.4. Hearing

Hearing loss is predominantly sensorineural and symmetrical; conductive or mixed loss occurs mainly in young children from serous otitis associated with cleft palate and Eustachian tube dysfunction, and may persist into adulthood [9, 23]. In an NIH series (46 adults from 29 families), approximately 60% had thresholds above the 95th percentile for age in at least two frequencies, mainly between 4000 and 8000 Hz, without progression exceeding presbycusis, and 46% had type AD tympanograms (middle-ear hypermobility) [57]. In type 1, a systematic review found hearing loss in 52%, mild, high-frequency and resembling early presbycusis, which is not detected by neonatal screening [23]. In types 2 and 3 prevalence is 69–83%, mild to moderate at low and middle frequencies and moderate to severe at high frequencies, sometimes U-shaped, more symptomatic at young ages [23]. In recessive collagen IX forms, hearing loss is present in all described patients, with a downsloping curve to severe or profound loss at high frequencies, and in the recessive COL11A1 form it is usually severe to profound [8, 23]. In LRP2 and LOXL3 forms, hearing was normal in most described patients [8, 23].

3.5. Musculoskeletal manifestations

In childhood, joint hypermobility (with an abnormal Beighton score), prominence of large joints and joint pain that may mimic juvenile idiopathic arthritis are frequent; early osteoarthritis develops later, particularly in weight-bearing joints [2, 9, 22]. In the dominant group, 41% report joint complaints by 9 years, 70% by 19 and 90% by 40, versus 26% in the younger recessive cases [22]. Osteoarthritis may require arthroplasty as early as the third or fourth decade, although it is more frequently mild [4, 7]. In an NIH series of 51 patients, 63% overall and 79% of adults had chronic hip pain, 34% of adults hip osteoarthritis and 16% of adults a history of femoral head failure in youth [9, 72]. In a series of 53 patients, 34% had scoliosis, 74% vertebral endplate irregularities, 64% Schmorl's nodes, 43% platyspondyly and 43% Scheuermann-like kyphosis; 85% of adults reported chronic low back pain and only one adult had no vertebral changes [73]. In 19 patients with confirmed type 1 syndrome there was a prior Legg-Calvé-Perthes disease diagnosis, providing an opportunity to identify children before retinal detachment [74]. Stature is normal or slightly lower than in unaffected relatives, and some patients have a marfanoid habitus with slender extremities and long fingers [2, 4, 9]. Platyspondyly may be mistaken for an osteoporotic vertebral fracture [7].

Radiologically, infants have coronal clefts in vertebral bodies and widening of the ends of the femora and tibiae; children have mild to moderate vertebral flattening and undermodelling of long bones with broad epiphyses and metaphyses; adults have irregular articular surfaces and secondary osteoarthritis [2]. Smith adds multiple Harris lines (67% in type 1), platyspondyly (21% in type 2, 6% in type 1), osteochondral defects (5% in type 1) and loss of lumbar lordosis (15% in type 1, 7% in type 2) [22]. GeneReviews states that there is no adequate documentation of odontoid hypoplasia with clinically relevant atlantoaxial instability in Stickler syndrome, unlike more severe type II collagenopathies [4].

3.6. Other manifestations

Mitral valve prolapse appears in Smith's list, which recommends periodic assessment of affected patients [22]. This association was contradicted in an English study of 78 molecularly confirmed patients from 25 families, with no significant prolapse on echocardiography, whose authors consider systematic echocardiographic screening and preoperative antibiotic prophylaxis unnecessary [26, 75]. Intelligence is normal [22, 26]. In a Brazilian series of five children with Robin sequence associated with Stickler syndrome, intelligence was preserved, but visual attention difficulties, attention deficit hyperactivity disorder symptoms in four, and signs of obstructive sleep apnoea in one case were present [76]. Dual sensory impairment can cause educational difficulties despite normal intelligence [2, 5]. In a cross-sectional questionnaire study, 92% of 24 adults reported chronic pain, as well as fatigue and anxiety symptoms [77].

3.7. Particular forms

In the predominantly ocular form (COL2A1 exon 2), detachment risk is high and systemic manifestations minimal; diagnosis depends on the ophthalmologist [3, 9, 37]. In the COL11A2 form, there is congenital sensorineural deafness, midface hypoplasia, cleft palate, enlarged joints and short-limb short stature without ocular changes; final height is approximately 148 cm in women and may be normal in men, and joint pain worsens in adulthood, frequently leading to early arthroplasty [46]. In recessive collagen IX forms, moderate to severe sensorineural hearing loss, moderate to high myopia with vitreoretinopathy and epiphyseal dysplasia predominate, without cleft palate; exudative retinal detachments were also observed in Nikopoulos's series, a new finding in the syndrome [8, 23, 49].

4. Clinical Recognition and Warning Signs

Diagnosis is frequently delayed, particularly in adults and ocular forms, and visual loss in a young child may not be reported until the second eye is involved [7, 78]. In newborns, the most frequent presentation in dominant forms is Robin sequence or cleft palate; in recessive forms, failed neonatal hearing screening; in children without a cleft, visual concerns between the early years and school age [22]. Smith recommends evaluating every newborn with Robin sequence for Stickler syndrome, particularly with a family history of cleft palate, dominantly inherited myopia, non-traumatic retinal detachment or mild spondyloepiphyseal dysplasia [22].

The English national service proposes referral for specialist assessment in the following situations: infants with congenital myopia and deafness; infants with cleft palate or Pierre Robin sequence and myopia; infants with joint hypermobility or epiphyseal dysplasia and myopia; and individuals with rhegmatogenous retinal detachment and a family history of rhegmatogenous retinal detachment [7, 24]. Isolated cleft palate alone is not an indication for referral [7]. Other warning signs include Legg-Calvé-Perthes disease, particularly bilateral and symmetrical, which may correspond to COL2A1 femoral head dysplasia, early hip and knee osteoarthritis, asymptomatic high-frequency hearing loss detected by audiometry and tympanic hypermobility [9, 35, 57, 74]. Orthopaedics, general paediatrics and paediatric rheumatology are frequent entry points [74].

Two screening tools have been proposed. In Wang's series (19 type 1 patients with a prior Perthes disease diagnosis), a simple scoring system would have classified nine of ten patients diagnosed with Perthes before detachment as high risk [74, 78]. In 2026, a questionnaire administered to children aged 4 to 10 years (26 from the general paediatric population and 28 with type 1 syndrome) achieved 93% sensitivity and 96% specificity, discriminating mainly through myopia, palatal abnormalities, family history of cleft palate and hypermobility; this was a small, single-centre case-control study with recruitment through the patient association, without prospective validation in an at-risk population [78].

Robin sequence should itself trigger a careful search for an aetiology: in van den Elzen's retrospective series (74 patients), the sequence was isolated in two-thirds, and Stickler syndrome and 22q11 deletion were the most frequent diagnoses in the complex group; the same text reports, from Shprintzen's series, that fewer than 20% of cases were isolated, with Stickler syndrome the most frequent associated diagnosis (34%) and 22q11 deletion accounting for 11% [69]. In a British national prospective study (259 patients), 28% had a syndrome, Stickler being most frequent (27% of syndromic cases); the authors advocate mandatory ophthalmological and genetic screening for Stickler syndrome in all patients with Robin sequence [79]. In a retrospective series from a tertiary children's hospital with 234 patients, 13.2% had Stickler syndrome and only one had a 22q11 deletion [80]. Smith describes the sequence as isolated in 38% and syndromic in 62%, including 29% Mendelian disorders, half of which were Stickler syndrome [70]. The European guideline reports that, on reassessment of 191 Dutch patients, diagnosis changed in 25.1% and Stickler syndrome was the most frequent Mendelian disorder (14.1%), and that in another series Stickler syndrome accounted for approximately 22% of diagnoses on reassessment after the first year [20]. Differences between series reflect differing definitions and inclusion criteria.

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Clinical criteria

No consensus diagnostic criteria have been published, and GeneReviews establishes diagnosis in the presence of typical clinical features and/or a heterozygous pathogenic (or likely pathogenic) variant in COL2A1, COL11A1 or COL11A2, or biallelic variants in COL9A1, COL9A2 or COL9A3 [4]. A variant of uncertain significance neither establishes nor excludes diagnosis [4]. Two proposed sets of criteria exist.

The criteria proposed by Snead and Yates require a congenital vitreous abnormality and at least one of the following: myopia beginning before 6 years; rhegmatogenous retinal detachment or pigmented paravascular lattice degeneration; joint hypermobility with an abnormal Beighton score, with or without radiological evidence of joint degeneration or dysplasia; sensorineural hearing loss confirmed by audiometry; midline cleft; and a first-degree relative with the diagnosis [9, 26].

Rose and colleagues' criteria were derived from 90 patients from 38 NIH families and assign points to orofacial, ocular, auditory and osteoarticular manifestations and family history or molecular data; a score of 5 or more was diagnostic, with 100% sensitivity in patients with a known COL2A1 variant, 98% in clinically affected patients and 86% specificity [81]. The following table reproduces the version adopted by the French PNDS (appendix 9, read in the original image); in the French original, the audiometric threshold appears as “4-8Hz”, an evident typographical error for 4–8 kHz, and any category-specific scoring ceilings from the original article could not be confirmed because full-text access was unavailable [5, 81].

Hoornaert and colleagues showed that vitreous abnormalities, retinal tears or detachments, cleft palate and a positive family history were good indicators of a COL2A1 defect and developed a score using binary regression; 20 of 23 sporadic patients with a variant had cleft palate or retinal detachment with a vitreous abnormality [34].

5.2. Clinical assessment

The French PNDS defines the initial ophthalmological examination: visual acuity with cycloplegic refraction, biomicroscopy looking for corneal, lens and vitreous changes, fundoscopy under mydriasis with peripheral observation, intraocular pressure, orthoptic assessment, axial length and optical coherence tomography (OCT) [5]. In children, examination of the periphery to the ora serrata may require examination under anaesthesia [7]. Otorhinolaryngological and maxillofacial examination includes the palate, feeding, hearing and investigation for obstructive sleep apnoea syndrome; rheumatological or physical medicine assessment evaluates pain, disability and degenerative joint disease [5]. Audiometry is useful in detecting frequently asymptomatic high-frequency hearing loss [9]. Radiographs may show mild spondyloepiphyseal dysplasia, small or dysplastic epiphyses, Perthes-like changes and early osteoarthritis [4, 5]. History should cover three generations, with directed questions about congenital myopia, retinal detachment, deafness, hyperlaxity in youth, osteoarthritis in the third or fourth decade, hip and knee problems and cleft palate [9].

5.3. Vitreous phenotyping

Biomicroscopy distinguishes membranous vitreous (COL2A1), beaded vitreous (COL11A1), hypoplastic vitreous (recessive forms, some COL2A1, BMP4, LOXL3) and normal vitreous (COL11A2) [7, 24, 38]. This classification guides molecular investigation but is difficult in paediatrics [5]. In the Cambridge series, phenotyping combined with molecular analysis identified the causative variant in more than 95% of 1673 patients from 785 families [7]. Phenotyping also allowed a family with a 30-year diagnosis of ocular Stickler syndrome to be reclassified as Wagner syndrome (variant VCAN NM_004385.5:c.4004-1G>A), with thickened posterior hyaloid membranes and no type 1 membranous abnormality [56].

5.4. Molecular tests

Source: GeneReviews, table 1, with data derived from HGMD [4]. The proportion of variants detected by each method is not equivalent to the test's clinical sensitivity.

GeneReviews proposes a multigene panel including COL2A1, COL11A1, COL11A2, COL9A1, COL9A2, COL9A3 and differential diagnosis genes, or exome or genome sequencing [4]. The French PNDS recommends a next-generation sequencing (NGS) panel with all known genes, performed in the index case and parents, emphasises that a negative panel does not exclude diagnosis, and allows genome sequencing [5]. Sequencing detects missense, nonsense, splicing variants and small insertions or deletions but does not usually detect exon or whole-gene deletions, which require deletion/duplication analysis (quantitative PCR, MLPA or targeted microarray) [4]. For type II collagenopathies, GeneReviews recommends that the panel include deletion/duplication analysis [35].

Limitations have practical consequences. Deep intronic variants escape exome-based panels: in case 4 of the English cohort, the six-gene panel was negative and only whole-COL2A1 sequencing, directed by membranous vitreous, identified NM_001844.5:c.2194-101G>T, whose effect (inclusion of 136 nucleotides with a premature termination codon) was demonstrated by minigene [7, 25]. Parental mosaicism may not be detected in leucocyte DNA: in case 5, approximately 8% of COL2A1 alleles in the clinically normal father carried variant NM_001844.5:c.1597C>T p.(Arg533Ter) [4, 7, 25]. Interpretation of splicing variants and apparently benign synonymous variants in trans requires functional and family studies, particularly in COL11A1 [8, 43]. Zygosity is decisive in collagen IX genes, because a single heterozygous variant does not explain recessive Stickler syndrome and in-frame splicing variants cause dominant multiple epiphyseal dysplasia [33]. The report should state the gene, transcript with version (for example NM_001844.5 for COL2A1 and NM_001854.4 for COL11A1), HGVS nomenclature, zygosity, ACMG/AMP classification and method limitations [4, 25].

5.5. Prenatal diagnosis

If the familial variant is known, prenatal diagnosis and preimplantation genetic testing are possible; ultrasound at 19–20 weeks may detect cleft palate, but its absence does not exclude diagnosis [4, 5]. In a fetus with cleft palate without a family history, a three-generation pedigree should be obtained and relatives with suggestive signs assessed; fetal testing is not usually offered without a known parental variant [4]. The French PNDS allows prenatal exome sequencing [5]. Micrognathia, cleft palate and polyhydramnios have been detected on prenatal ultrasound in patients with type 1 syndrome [35]. In the European guideline, Robin sequence should be considered from 18 weeks with an inferior facial angle below 45.5° or mandibular length 2 standard deviations below the mean, and on magnetic resonance imaging with isolated cleft palate, tongue shape index above 80% and inferior facial angle below 48° [20]. The French PNDS for Robin sequence reports good prenatal/postnatal concordance in fetuses with a family history of Robin sequence or Stickler syndrome, but 22% erroneous diagnoses of isolated sequence in the 15-year experience of Hôpital Necker [82].

5.6. Diagnostic algorithm

6. Differential Diagnosis

The differential is organised into three groups: other type II and XI collagenopathies sharing genes and manifestations; hereditary vitreoretinopathies with retinal detachment; and syndromes with Robin sequence, hypermobility or flat facies [4, 5, 35].

6.1. Type II and XI collagenopathies (allelic entities)

COL2A1 disorders form a continuum from lethal achondrogenesis and hypochondrogenesis to mild spondyloepiphyseal dysplasia with early osteoarthritis; Stickler syndrome lies in the intermediate severity group, and severity tends to remain consistent within families [35, 83]. Bone Dysplasias distinguishes spondyloepiphyseal dysplasia congenita and Kniest dysplasia by more severe vertebral and epiphyseal involvement, delayed ossification and marked short stature [2].

The distinction between Marshall syndrome and type 2 Stickler syndrome is debated: Oxford considers that most “Marshall syndromes” described on the basis of facial phenotype probably correspond to type 2 Stickler syndrome, whereas Smith and Khalifa's Saudi series support a distinct entity with dominant and recessive forms [9, 32, 85]. In Majava's series, the four patients with the Marshall phenotype had an intron 50 splicing variant and severe early-onset hearing loss [39].

6.2. Vitreoretinopathies and other causes of high myopia with retinal detachment

6.3. Robin sequence, flat facies and joints

In Robin sequence, the differential includes 22q11.2 deletion (conotruncal heart disease, hypocalcaemia, immunodeficiency), SATB2 syndrome, mandibulofacial dysostoses (Treacher Collins, with lower-eyelid coloboma and microtia; dysostosis with microcephaly due to EFTUD2), Nager syndrome with radial defects, Potter sequence, the oculo-auriculo-vertebral spectrum, cerebro-costo-mandibular syndrome with rib defects, and causes of fetal akinesia [69, 87]. Binder syndrome (maxillonasal dysplasia) may not be a distinct entity but a developmental abnormality observed in several syndromes, including Stickler [4, 5]. The facies of chondrodysplasia punctata may resemble that of Stickler syndrome, but epiphyseal stippling is absent in the latter [4, 9]. Familial Perthes disease with incomplete penetrance, multiple epiphyseal dysplasia and autosomal dominant spondyloarthropathy have no facial, visual or auditory changes [2, 9]. Bilateral, symmetrical, synchronous femoral head involvement suggests type II collagenopathy, and juvenile idiopathic arthritis and rheumatoid arthritis are distinguished by absence of facial, ophthalmological and auditory changes and presence of inflammatory signs [35]. In joint hypermobility, cleft palate, myopia, retinal detachment and epiphyseal dysplasia are more reliable diagnostic markers than hypermobility itself [88].

7. Treatments and Risk Management Strategies

7.1. Principles and organisation

No therapy corrects the collagen defect; management is multidisciplinary, preferably in a comprehensive craniofacial clinic (otorhinolaryngology, plastic and maxillofacial surgery, paediatric dentistry, orthodontics and medical genetics), with specialist ophthalmological follow-up [4, 5]. GeneReviews states that no clinical practice guidelines have been published for Stickler syndrome, and its management tables are expert recommendations [4]. The French PNDS, developed by the OPHTARA reference centre using HAS methodology but not validated by HAS, is currently the only specific national protocol identified in the sources consulted [5]. The 2019 recommendations for type II collagenopathies, obtained through a Delphi process with 11 experts (consensus on 22 of 24 revised statements), mainly cover severe skeletal forms [19, 35].

7.2. Initial evaluation after diagnosis

7.3. Prevention of retinal detachment

The rationale for prophylaxis is the high risk of detachment, frequently bilateral and in childhood, and inferior results of repair surgery: in the general population, anatomical success after one intervention is 80–90%, whereas in Stickler syndrome series more than 20% had inoperable detachment at presentation, primary success was 50% in one series and 55% in another, final anatomical success in a paediatric series was 60% with 20% enucleation or phthisis, and only 30% achieved 20/200 or better [12]. GeneReviews recommends prophylactic retinopexy for these reasons, and Oxford reports that prophylaxis reduces risk approximately tenfold and is particularly important in preverbal children [4, 9].

The Cambridge protocol consists of contiguous 360° transconjunctival cryotherapy to the juxtaoral retina, including the ora serrata, aiming to prevent elevation and progression of the posterior flap of a giant tear should it occur during posterior vitreous detachment; it is offered to all attached eyes of type 1 patients, regardless of lattice degeneration [12, 65]. Other groups use grid laser or circumferential barrage laser, whose efficacy appears to depend mainly on the posterior extent of treatment [5, 12]. Modified laser encirclement (ora secunda cerclage) applies grid burns from the ora serrata to 4 mm posteriorly and, in a second stage, beyond the vortex vein ampullae [12, 89]. A 360° scleral buckle is another option, particularly in the fellow eye after detachment [5, 90].

Interpretation requires caution. All published studies are retrospective, with historical or non-randomised controls, variable selection criteria and, in several, no molecular confirmation; the NIHR review (2011) considered risk of bias high in the two main studies and relative efficacy of cryotherapy and laser uncertain [62, 92]. There is no direct comparison between laser and cryotherapy, and ranking techniques from different series is invalid [12]. Hazard ratios describe relative reductions and should be read alongside the residual absolute rate (approximately 5–9% detachment after prophylaxis) [65, 67]. Two older series without benefit (Monin 1994, “Wagner-Stickler”, and Alshahrani 2015, without genetic confirmation or a control group) were considered poorly interpretable by the Cambridge group [12]. In a single-centre series with 86 patients (2012–2024), pre-existing retinal breaks and ora serrata dialysis were independent risk factors for detachment after prophylactic laser, emphasising the importance of complete peripheral examination before treatment [93]. In a survey of paediatric vitreoretinal surgeons, 76% mainly used laser, 12% cryotherapy and 12% prophylactic scleral buckling [5].

Sources differ in recommendation strength. The Cambridge group considers comparative cohort evidence “extremely strong” and advocates genotyping type 1 and type 2 patients for risk stratification and full information for an informed decision, including on behalf of children [12, 14]. GeneReviews recommends prophylactic retinopexy, and the type II collagenopathy review states “consider” prophylactic retinopexy in COL2A1 Stickler syndrome [4, 35]. The French PNDS considers evidence insufficient (level 4) for consensus recommendations on modality and timing, and mainly proposes surgical fellow-eye prevention through 360° buckling or retinopexy after a first detachment [5]. A series from two tertiary centres published in 2026 (58 genotyped patients with detachment) identified prophylaxis (360° laser or buckling) as the only independent protective factor and suggests that, if selected, it be performed before puberty, earlier in boys with COL2A1 and both sexes with COL11A1 [68]. In the COL11A2 form there is no indication for ocular prophylaxis because the eye is unaffected [24, 33]. In Wagner syndrome, where detachment is tractional, Cambridge protocol cryotherapy would not prevent the pathological mechanism [56].

7.4. Registered trials and developments over the last 12 months

No pharmacological or gene therapy trials registered on ClinicalTrials.gov were found for Stickler syndrome; the search covered only this registry and the stated databases, which does not exclude unregistered preclinical research [18].

7.5. Regulatory status

7.6. Treatment of manifestations

No doses are provided in this article because none of the sources consulted defines Stickler syndrome-specific regimens; anti-inflammatory drugs and analgesics follow the selected product label. In the English series, a 46-year-old woman with bilateral prophylaxis at 12 years and stable vision for 38 years was referred for hip arthroplasty after injections with transient effect, and an adolescent with trochanteric pain responded to analgesia, exercises and insoles [7]. Chronic pain, fatigue, mood and sleep disturbances should be sought and treated [7, 77].

7.7. Robin sequence

The ERN CRANIO European guideline, which excludes Robin sequences with a confirmed syndrome from management but applies its genetics recommendations to all, recommends: early referral to clinical genetics at a specialist centre, with reassessment at 2–3 years if there is no diagnosis; minimum testing with copy-number variation analysis and an exome-based panel of Robin sequence-associated genes (preferably in a trio), or, if impossible, at least CNV analysis and a targeted Stickler syndrome panel; continuous oximetry, baseline polysomnography and flexible nasoendoscopy; non-surgical treatment (prone or lateral positioning with oximetry, nasopharyngeal tube, palatal plate, CPAP) for mild to moderate apnoea; mandibular distraction osteogenesis or tracheostomy when non-surgical treatment fails, preferring tracheostomy in syndromic, low-weight or neurologically impaired patients; and avoidance of pharyngoplasty [20]. The 2016 international clinical consensus defined Robin sequence by micrognathia, glossoptosis and upper-airway obstruction, noted that obstruction signs may be intermittent and more evident during sleep, and recommended sleep studies [96]. The French PNDS for Robin sequence proposes prone positioning, nutritional support, a nasopharyngeal tube or non-invasive ventilation, labioglossopexy in experienced teams and tracheostomy on failure, and does not recommend mandibular distraction in France except in major mandibulofacial dysostoses [82]. Smith lists, in increasing order of invasiveness, prone positioning, nasopharyngeal tube, naso-oesophageal intubation, tongue-lip adhesion, mandibular distraction and tracheostomy, and reports mortality described up to 30%, higher in syndromic forms; obstruction may worsen in the first two months and hypoxia may occur without obvious clinical signs [70]. The Brazilian book recommends mandatory nasofibroscopy, nasopharyngeal intubation for cyanosis, apnoea or saturation ≤90%, and palatoplasty from 12 months, before decannulation in tracheostomised patients [87]. In a British study, children with syndromic Robin sequence were more dependent on airway devices (OR 2.02; 95% CI 1.13–3.64) [79].

7.8. Preventive measures and circumstances to avoid

GeneReviews and the PNDS advise avoiding contact and ball sports that may cause traumatic detachment, and the PNDS recommends protective eyewear [4, 5]. Both state that some physicians advise avoiding high-impact joint activities to delay arthropathy, but no supporting data exist [4, 5]. The English group recommends individually weighing the social and health benefits of sport against risk [7]. In type II collagenopathies with cervical instability, cervical hyperextension and hyperflexion should be avoided and the spine imaged before general anaesthesia; in Stickler syndrome, clinically relevant atlantoaxial instability is not documented [4, 35]. The English study without mitral prolapse considered systematic preoperative antibiotic prophylaxis unnecessary [75].

8. Reproductive Options and Family Counselling

8.1. Autosomal dominant forms (COL2A1, COL11A1, COL11A2)

Most patients have an affected parent; the proportion of de novo cases is unknown [4]. In an apparently isolated case, both parents should be examined (including the vitreous) and, if the proband's variant is known, tested [4, 7]. If the variant is not found in either parent, with biological parenthood confirmed, a de novo variant or germline, or somatic and germline, mosaicism in a potentially mildly affected parent should be considered; leucocyte testing may not detect somatic mosaicism and does not detect exclusively germline mosaicism [4, 58, 97]. Therefore, sibling risk for a proband with a variant not detected in parents is slightly above that of the general population, and risk is 50% if a parent is affected [4]. Each child of an affected person has a 50% probability of inheriting the variant, with variable expressivity and complete penetrance [4, 9]. In type II collagenopathies, severe and mild forms do not usually coexist in relatives with the same variant [35]. Intrafamilial variability prevents prediction of a child's phenotype severity from the parent's phenotype [4, 9].

8.2. Autosomal recessive forms

In COL9A1, COL9A2 or COL9A3 forms, parents are presumed heterozygous and asymptomatic; each sibling has a 25% probability of being affected, 50% of being an asymptomatic carrier and 25% of not being a carrier [4]. If only one parent has the variant, a de novo variant, parental mosaicism, an undetected deletion mimicking homozygosity on sequencing, or uniparental isodisomy should be considered [4]. An affected person's children are obligate carriers [4]. Consanguinity should prompt consideration of a recessive form [5]. Pseudodominance was described in a LOXL3 family in which the affected father and son were homozygous [51]. In the recessive COL11A1 form, one variant may be de novo and the other inherited; the phenotype of a dominant de novo variant may be modified by a recessive variant on the other allele [7, 43]. Carrier screening requires prior identification of familial variants [4].

8.3. At-risk relatives and predictive testing

Given variable expression, all first-degree relatives should be examined and offered specialist ophthalmological assessment [9]. Assessment may involve history, physical examination and ophthalmological, audiological and radiological evaluation, or testing for the familial variant; relatives in whom diagnosis cannot safely be excluded should be followed [4]. Predictive testing enables more effective guidance of retinal prophylaxis [9]. Adults with a normal face may have asymptomatic detachments, such as the father of two affected infants in the English cohort, who had unrecognised bilateral detachments [7].

8.4. Reproductive options

Once the variant is identified, prenatal diagnosis and preimplantation genetic testing are possible; Oxford states that prenatal diagnosis is technically possible but rarely requested [4, 5, 9]. Ultrasound at 19–20 weeks may detect cleft palate but does not exclude diagnosis [4]. The ideal counselling time is before pregnancy, and it should be offered to affected or carrier young adults [4]. Differences in perspective between professionals and families regarding use of prenatal and preimplantation diagnosis should be respected [4]. In type II collagenopathies, children of couples in whom both have dominant skeletal dysplasias may have double heterozygosity, with a different and more severe phenotype [35]. DNA banking should be considered in probands without a molecular diagnosis [4].

8.5. Communicating the diagnosis

The French PNDS recommends a dedicated consultation to communicate diagnosis, with the clinician, ophthalmologist and geneticist, introduction to patient associations and information about natural history, treatments, adverse effects and the need for regular follow-up, emphasising sudden visual loss [5].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Frequency

Prevalence is estimated at between 1:7,500 and 1:10,000; Smith reports 1 in 7,500 to 1 in 9,000 newborns, and a type II collagenopathy review cites an incidence of approximately 1:10,000 for all forms, a value presented by the NIH spinal study as similar to Marfan syndrome [9, 22, 35, 73]. These estimates do not derive from population studies, and the 2023 GeneReviews considers prevalence unknown [4]. The French PNDS states that the syndrome is more frequent in the United States and Europe and is underdiagnosed [5]. European congenital anomaly registries, capturing only cases recognised at birth, report much lower values: Orphanet records birth prevalence of 1.0 per 100,000 in Europe (EUROCAT 2005–2012) and 0.65 per 100,000 in France, also retaining 12.2 per 100,000 derived from GeneReviews [10]. The difference illustrates that the values measure different things (registered neonatal diagnosis versus an overall clinical estimate), and none should be taken as validated population prevalence. The recessive form has approximately 15 validated cases in Orphanet (prevalence class below 1 per million) and approximately 40 published cases, only four due to LOXL3 before the 2026 series of three sisters; the isolated ocular form has 38 cases recorded in Orphanet [8, 10, 11]. The English national service assessed 1673 patients from 785 families over ten years and receives approximately 70 new probands annually; in 2026 it had over 2000 registered patients [7, 78]. Regarding gene distribution, the French PNDS reports 80–90% of cases due to COL2A1 and 10–20% due to COL11A1, a proportion also cited by MacLachlan and colleagues in the US Utah and Mayo Clinic cohort (32 COL2A1 and 13 COL11A1 patients) [5, 64].

Robin sequence has a birth prevalence of 1:5,600 in the Netherlands (17.7 per 100,000) and 1:14,000 in Denmark, with literature variation between 1:3,900 and 1:122,400 depending on definitions [70, 98]; the French PNDS reports 1:10,000 to 1:14,000 and the Brazilian book 1:8,500 (range 1:2,000–1:30,000) [82, 87]. For isolated sequence, Orphanet records values between 3.5 and 18.8 per 100,000 births in European countries and Australia [10]. Approximately one-third of the cleft palate population may be classified as Robin sequence in the Netherlands [98].

9.2. Population data and founder groups

Published series mainly originate from the United Kingdom, United States, continental Europe and East Asia [7, 34, 81, 99]. A 2020 systematic review compiled 274 COL2A1 variants in 999 patients from 466 families, more than half truncating; in the 107 East Asian patients, truncating variants were associated with milder systemic phenotypes and splicing variants with more severe phenotypes, and recurrent variants were identified [99]. In the Korean multicentre series of 37 genetically confirmed patients, 30 had a COL2A1 variant and 7 COL11A1, and splicing variants were associated with retinal detachment in 71% [100]. Recessive forms have mainly been described in consanguineous families, including from Morocco, Turkey, Saudi Arabia and Iraq [29, 33, 49, 50, 53]. No COL2A1 or COL11A1 founder variants with a defined population frequency were identified in the sources consulted.

In Brazil, a series from a hospital with a craniofacial dysmorphology service, comprising 78 individuals from 21 families, identified 13 COL2A1 variants (9 novel), almost all in the triple-helical domain, without consistent genotype–phenotype correlation; selection based on cleft palate associated with craniofacial and ocular signs proved efficient in identifying the syndrome [101]. A Brazilian family with type 2 syndrome had COL11A1 variant NM_001854.4:c.3168+1G>A, identified by genome sequencing, whose genomic coordinate coincides with that obtained in VariantValidator [25, 102]. The Brazilian series of five children with Robin sequence and Stickler syndrome described the cognitive and behavioural profile mentioned in section 3 [76]. No epidemiological data from Portugal were found in the sources consulted; the Brazilian book cites a Universidade de Lisboa thesis on Pierre Robin sequence, which was not consulted [87].

9.3. Special populations

In preverbal children, retinal detachment may go unnoticed, justifying examination under anaesthesia when necessary and Oxford's emphasis on prophylaxis in this group [7, 9]. Dual sensory impairment (visual and auditory) affects development and schooling, and children with congenital hearing loss and myopia should be assessed for recessive forms [5, 8, 61]. The French PNDS provides for individualised support plans, educational support and measures to compensate for visual impairment [5]. In a qualitative study of Norwegian adults, participants described difficulties with work, relationships and identity, and unmet needs in healthcare and social protection systems [103]. No pregnancy-specific recommendations for Stickler syndrome were found in the sources consulted; GeneReviews for type II collagenopathies recommends obstetric assessment by a skeletal dysplasia specialist and caesarean section in a small pelvis, a situation mainly applicable to severe forms [35].

9.4. Resources

The French PNDS identifies ERN-EYE as the European network for rare eye diseases, the OPHTARA reference centre and SENSGENE network in France, and the AMAM and MyopiA associations [5]. The Robin sequence guideline was developed within ERN CRANIO [20], and ERN BOND is the European network for rare bone diseases [21]. GeneReviews lists Stickler Involved People (United States) and Stickler Syndrome UK [4]; Oxford also mentions the Cleft Lip and Palate Association, American Cleft Palate–Craniofacial Association and Pierre Robin Network [69].

10. Illustrative Clinical Case

10.1. Retinal detachment at 8 years with a truncating COL2A1 variant

Al-Qahtani and colleagues described an 8-year-old Saudi girl, born to non-consanguineous parents, who presented to the ophthalmological emergency department with sudden visual loss in the right eye of two days' duration [104]. She had high myopia (−17.00 D in the right eye and −15.00 D in the left) and midface hypoplasia, without evident cleft palate, uvular abnormality or micrognathia; she reported no joint or hearing complaints, but formal audiometry, joint assessment, skeletal radiographs and echocardiography were not performed [104]. Her three sisters had high myopia and her father, of short stature with a flat face, had retinal detachment operated on in childhood (pedigree in Figure 1) [104]. Corrected visual acuity was 20/80 in the right eye and 20/20 in the left; there were pigment cells in the anterior vitreous (Shafer's sign), vitreous with a sheet-like membranous configuration, inferior retinal detachment from a round hole with partial macular involvement and no posterior vitreous detachment, and, in the left eye, a myopic fundus with peripheral holes (Figure 2: wide-field retinal photograph showing inferior detachment and OCT with the fovea spared) [104].

The following day, she underwent chandelier-assisted scleral buckling with cryotherapy, and the fellow eye received prophylactic laser photocoagulation [104]. At four months, inferior recurrence occurred due to under-indentation (anterior band displacement), without proliferative vitreoretinopathy, corrected by revision with repeat cryotherapy and a sponge explant; three years later, the retina remained attached and acuity was 20/30 [104]. Clinical exome sequencing identified the heterozygous COL2A1 variant c.3642delT, p.(Gly1215Alafs*12), in exon 51, confirmed by Sanger sequencing, present in the father and absent in the mother, and classified by the authors as pathogenic (PVS1, PM2, PP1) (Figure 3) [104]. In normalised nomenclature, the variant corresponds to NM_001844.5:c.3642del, NP_001835.3:p.(Gly1215AlafsTer12), NC_000012.12:g.47975561del (VariantValidator), recorded in ClinVar as pathogenic (VCV000635549) [25, 105].

The case illustrates several points: absence of cleft and obvious systemic signs does not exclude the syndrome; family history of detachment in childhood and high myopia are warning signs; vitreous phenotyping supports diagnosis; and the truncating variant is consistent with the type 1 haploinsufficiency mechanism [4, 104]. Selection of buckling without vitrectomy and prophylactic laser in the fellow eye were the authors' decisions in this anatomical context and are not routine recommendations; some general statements in that article's discussion, such as that most COL2A1 variants are glycine substitutions, do not correspond to GeneReviews' description for Stickler syndrome, in which loss-of-function variants predominate [4, 104]. Incomplete assessment (hearing, skeleton, untested sisters) limits systemic characterisation.

10.2. Cases from the English national cohort

In the English national service's case series, a boy born with cleft palate without a family history had bilateral high myopic astigmatism at 3 years (−11.00/−3.50 × 180), was told detachment risk was “low”, and six months later presented with inoperable detachment from a giant tear progressing to phthisis bulbi [7]. At 6 years, the panel of six known genes was negative; examination under anaesthesia revealed a type 1 membranous abnormality and a 90° giant tear in the other eye, treated with prophylactic 360° cryotherapy, and complete COL2A1 sequencing identified deep intronic variant c.2194-101G>T, whose splicing effect was demonstrated by minigene (Figure 4) [7]. The description is valid in MANE transcript NM_001844.5 (NC_000012.12:g.47982710C>A), although the article does not specify the transcript used [25]. In another case, two siblings with Pierre Robin sequence, congenital myopia and profound hearing loss had a frameshift variant in COL11A1 exon 13 and intronic variant c.991-24A>G, creating an alternative exon 9 acceptor site and pathogenic only in tissues expressing that exon [7]. The vitreous phenotypes guiding these diagnoses are illustrated in Figure 2 of the same article (diagram and biomicroscopy of membranous and beaded vitreous) [7].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

The sources consulted do not describe reduced life expectancy, and prognosis depends mainly on vision, hearing and joint function [2, 4]. Blindness risk is the main threat: in the 2001 survey, 4% reported blindness, and in Boysen's systematic review 6% were blind and 10% had lost vision in one eye [59, 62]. The English group estimates that up to 30% of patients experience preventable visual loss in at least one eye [78]. Detachment surgery has high final anatomical success, but with multiple interventions and limited visual outcomes, particularly in children and proliferative vitreoretinopathy [12, 94]. In the Cambridge series, no patient with bilateral prophylaxis had bilateral detachment, and one patient treated at 12 years maintained stable vision for 38 years [7, 65]. Type 1 hearing loss is usually mild and no more progressive than presbycusis, whereas that of types 2, 3 and recessive forms is more severe and, in recessive forms, possibly progressive [23, 57]. Arthropathy progresses with age and may require arthroplasty in the fourth or fifth decade [4, 7]. In a Brazilian series, Robin sequence associated with Stickler had a good cognitive prognosis, and the French PNDS for Robin sequence considers intellectual prognosis normal in isolated sequence or sequence associated with bone disease, provided hypoxia is avoided [76, 82]. In Robin sequence, reported mortality reaches 30% in some series and is higher in syndromic forms [70].

11.2. Surveillance

Surveillance should be maintained throughout life because detachment can occur at any age, including adulthood, and at-risk relatives without diagnostic exclusion should be followed [4, 7, 9]. Patients should know the symptoms of posterior vitreous detachment and retinal detachment (including sudden visual loss) and have rapid access to assessment [5, 8]. In transition to adulthood, the PNDS provides for transfer from paediatric orthopaedics to rheumatology and educational and vocational guidance adapted to visual abilities [5].

12. Summary and Final Considerations

Stickler syndrome is a II/XI/IX fibril collagenopathy manifesting in the vitreous, inner ear and cartilage. Approximately 80% of cases result from loss-of-function COL2A1 variants, with haploinsufficiency, membranous vitreous and the highest retinal detachment risk; approximately 20% from dominant-negative COL11A1 variants, with beaded vitreous and more marked hearing loss; and a minority from COL11A2 (non-ocular form, equivalent to dominant OSMED) or recessive forms due to COL9A1, COL9A2, COL9A3, COL11A1 (exon 9) and non-collagen genes [4, 8, 24]. Diagnosis rests on the combination of congenital myopia, vitreous abnormality, cleft palate or Robin sequence, hearing loss and mild spondyloepiphyseal dysplasia, confirmed by a multigene panel; a negative result does not exclude diagnosis, and deep intronic variants and mosaicism require complementary methods [4, 5, 7].

Robin sequence is the main neonatal entry point, and Stickler syndrome is its most frequent syndromic cause, so the European guideline recommends including at least a panel for this syndrome in these newborns' genetic investigation [20, 79]. Management is multidisciplinary with no authorised targeted therapy. Detachment prevention through 360° cryotherapy or laser is supported by retrospective series and meta-analyses with relative risk reductions of approximately three- to tenfold in published hazard ratios, including, since September 2026, a series of 197 type 2 patients; no randomised trial exists, the only registered randomised trial was withdrawn, and a prospective single-arm study is now underway in the USA [13–15, 18, 67]. Sources differ in recommendation strength: the Cambridge group and GeneReviews recommend prophylaxis, whereas the French PNDS considers evidence insufficient for a consensus recommendation and prioritises fellow-eye prevention [4, 5, 12]. Genetic counselling should consider parental mosaicism in apparently de novo dominant forms and consanguinity in recessive forms, and assessment of all first-degree relatives identifies adults and children with unrecognised ocular risk [4, 7, 9].

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