Stickler Syndrome, Type I

A number sign (#) is used with this entry because Stickler syndrome type I (STL1), sometimes called the membranous vitreous type, is caused by heterozygous mutation in the COL2A1 gene (120140) on chromosome 12q13.

Description

Stickler syndrome is a clinically variable and genetically heterogeneous disorder characterized by ocular, auditory, skeletal, and orofacial abnormalities. Most forms of Stickler syndrome are characterized by the eye findings of high myopia, vitreoretinal degeneration, retinal detachment, and cataracts. Additional findings may include midline clefting (cleft palate or bifid uvula), Pierre Robin sequence, flat midface, sensorineural or conductive hearing loss, mild spondyloepiphyseal dysplasia, and early-onset osteoarthritis (summary by Baker et al., 2011).

Genetic Heterogeneity of Stickler Syndrome

See 609508 for a form of Stickler syndrome type I that is solely or predominantly ocular and is also caused by mutation in the COL2A1 gene. Stickler syndrome type II (STL2; 604841), sometimes called the beaded vitreous type, is caused by mutation in the COL11A1 gene (120280) on chromosome 1p21. These forms of Stickler syndrome are autosomal dominant.

Autosomal recessive forms of Stickler syndrome include Stickler syndrome type IV (STL4; 614134), caused by mutation in the COL9A1 gene (120210) on chromosome 6q13, and Stickler syndrome type V (STL5; 614284), caused by mutation in the COL9A2 gene (120260) on chromosome 1p34.

A disorder previously designated Stickler syndrome type III (STL3), or 'nonocular Stickler syndrome,' has been reclassified as a form of otospondylomegaepiphyseal dysplasia (OSMEDA; 184840).

Clinical Features

Stickler et al. (1965), from a long experience at the Mayo Clinic with multiple members of a kindred, described a new dominant entity consisting of progressive myopia beginning in the first decade of life and resulting in retinal detachment and blindness. Affected persons also exhibited premature degenerative changes in various joints with abnormal epiphyseal development and slight hypermobility in some. In a second paper, Stickler and Pugh (1967) pointed out that the family reported by David (1953) probably had the same condition. Changes in vertebrae and hearing deficit were also noted. Opitz et al. (1972) suggested that the patients reported by Smith (1969), Walker (1971), and others may have had this syndrome.

Opitz et al. (1972) noted that affected persons may present neonatally with the Pierre Robin syndrome (261800). Hall (1974) described a family in which 1 infant had died of Pierre Robin anomaly. The mother had spent the first 18 months of her life hospitalized for Pierre Robin syndrome. Later she developed progressive myopia, cataract, and bilateral retinal detachments leading to bilateral enucleation in her teens. Young affected members had midface hypoplasia. None had joint hyperextensibility or marfanoid habitus. Any deafness in the family was apparently explained by otitis media. Although neither examination nor history gave any reason to suspect a skeletal abnormality, skeletal x-rays showed mild flattening of epiphyses and mild irregularity of the margins of the vertebral bodies (all changes suggesting a mild spondyloepiphyseal dysplasia).

Kelly et al. (1982) reported an infant with Robin anomaly, myopia and dumbbell-shaped femora and humeri whose father had the Stickler syndrome. The father, aged 24 years, was blind from age 9 years from glaucoma, cataracts, and recurrent retinal detachments, and was 186 cm tall, with 'stiffness' of his legs. A brother of the proband, aged 4 years, had had prominence of the knees and ankles as an infant and showed severe myopia with retinal thinning. Kelly et al. (1982) suggested that Weissenbacher-Zweyuller syndrome (WZS; 184840) is a neonatal expression of the Stickler syndrome.

Among 57 patients with Stickler syndrome, Liberfarb and Goldblatt (1986) found that 50% of females and 43% of males had mitral valve prolapse. They suggested that Stickler syndrome should be considered in cases of dominantly inherited mitral valve prolapse with or without joint laxity and slender bones, just as it must be considered in all cases of Pierre Robin syndrome, dominantly inherited myopia with or without retinal detachment and deafness, and dominantly inherited cleft palate. Ahmad et al. (2003) studied the prevalence of mitral valve prolapse in 78 patients from 25 pedigrees in the UK in whom the clinical diagnosis of Stickler syndrome had been confirmed by molecular genetic analysis. None of the patients was found to have clinical evidence of cardiovascular disease, and none had significant mitral or other valvular prolapse on echocardiography. Ahmad et al. (2003) suggested that routine echocardiography and use of preoperative antibiotics are unnecessary in general and should be reserved for those individual cases where there is clear clinical indication.

Spallone (1987) studied 10 families with multiple cases and 2 isolated cases of Stickler syndrome. The validity of the diagnosis might be questioned in some of these cases inasmuch as ectopia lentis was present in 5. All 12 probands had retinal detachment. The diagnosis of Stickler syndrome was made on the basis of ocular lesions (mainly retinal detachment in high congenital myopia and vitreoretinal degeneration) and nonocular lesions.

Seery et al. (1990) found cataracts of various types or aphakia in 115 of 231 eyes of patients with Stickler syndrome. The most frequent and distinctive lesions, described as wedge and fleck cataracts, accounted for 40 of the 93 cataracts observed.

Clinical Variability

Temple (1989) reviewed the clinical variability in Stickler syndrome and discussed phenotypic overlap with Marshall syndrome (154780), Wagner syndrome (143200), and Weissenbacher-Zweymuller syndrome (184840).

Zlotogora et al. (1992) concluded from a study of 3 families and a review of the literature that variability in Stickler syndrome is mainly interfamilial; within families less variability is found. In one of their families, all the affected members had high-grade myopia and most developed retinal detachment at a young age. In the second family, the major symptoms were cleft palate and characteristic facial changes associated with mild ocular changes. In the third family, all patients had a marfanoid habitus, high myopia, and mental retardation. This variability may reflect the heterogeneity that is demonstrated by presence or absence of linkage to COL2A1. In family B of Zlotogora et al. (1992), Annunen et al. (1999) found a G988V missense mutation in the COL11A1 gene (120280.0003).

Snead and Yates (1999) provided a review of the clinical and molecular aspects of Stickler syndrome. They discussed the diagnostic features, molecular basis of the condition, and the nosologic difficulties in differentiation from Wagner syndrome, Marshall syndrome, and Weissenbacher-Zweymuller syndrome.

To define variations in the clinical manifestations of Stickler syndrome, Stickler et al. (2001) sent questionnaires to 612 members of the UK and US Stickler support groups. Of 316 usable replies, 95% of persons had eye problems (retinal detachment in 60%, myopia in 90%, and blindness in 4%). Facial abnormalities, including flat face, small mandible, or cleft palate, were present in 84% of individuals; 70% had hearing loss; and 90% had joint problems, primarily early joint pain from degenerative joint disease. Treatment included cryotherapy and laser therapy for retinal detachment, repair of cleft palate, use of hearing and mobility aids, and joint replacements. Stickler et al. (2001) concluded that there are wide variations of symptoms and signs among affected persons, even within the same family. There are delays in diagnosis, lack of understanding among family members, denial about the risk of serious eye problems, and joint disease.

Miyamoto et al. (2005) described a 22-year-old Japanese female whose major complaints were bilateral pain and stiffness of knees, hips, and elbows. The parents were nonconsanguineous, and there was no remarkable family history. Her height was 155 cm. She had suffered from bilateral sensorineural hearing loss since the age of 2 years. She had mild myopia but showed no sign of retinal detachment or vitreoretinal degeneration, and she had undergone surgery to correct cleft palate at the age of 2 years. Radiographic examination demonstrated early onset of osteoarthritis of the knees and hip joints, enlarged epiphyses, and platyspondyly.

Diagnosis

Using clinical data on 22 patients from 6 families with type I Stickler syndrome and known mutations in COL2A1, Rose et al. (2005) developed a diagnostic nosology based on molecular or family history data and characteristic ocular, orofacial, auditory, and musculoskeletal findings. In 90 patients from 38 families who presented for evaluation of possible Stickler syndrome, Rose et al. (2005) found that their criteria had 98% sensitivity when applied to clinically affected Stickler patients and 86% specificity when applied to patients unaffected based on clinical and/or molecular analysis.

Ang et al. (2007) emphasized the importance of vitreous examination and vitreoretinal phenotyping in the diagnosis of Stickler syndrome. The authors reported 2 unrelated patients who were each found to have 2 dominant gene defects. A female had Albright hereditary osteodystrophy (AHO; see 103580) inherited from her mother and Stickler syndrome type I resulting from a de novo COL2A1 mutation. An unrelated male had Treacher-Collins syndrome (TCOF; 154500) inherited from the father and Stickler syndrome type II resulting from a maternal COL11A1 mutation. The cases illustrated the difficulty in diagnosing Stickler syndrome based on facial and systemic examination alone, particularly when features of other disorders are present. In both patients, Stickler syndrome was diagnosed later than AHO and TCOF, respectively, but prophylactic cryotherapy was successful in the girl.

Olavarrieta et al. (2008) reported an unusual Spanish family in which the male proband had branchiootorenal syndrome (BOR1; 113650), associated with a heterozygous de novo mutation in the EYA1 gene (601653.0015), and Stickler syndrome type I, associated with a heterozygous mutation in the COL2A1 gene. The patient's mother and brother, both of whom had Stickler syndrome and the COL2A1 mutation, did not carry the EYA1 mutation. All 3 patients had myopia, vitreous anomaly, and flat face, characteristic of Stickler syndrome; the brothers had cleft palate. The proband also had branchial fistulae, preauricular pits, renal agenesis, and mixed hearing loss consistent with BOR1 syndrome. The brother with Stickler syndrome had conductive hearing loss due to infection and surgery. Olavarrieta et al. (2008) emphasized that both disorders show phenotypic variability as well as overlapping features, which can complicate a precise diagnosis. Thorough clinical evaluation is necessary to identify coexisting genetic syndromes in the same patient.

Prenatal Diagnosis

Lisi et al. (2002) noted that approximately two-thirds of Stickler syndrome cases are associated with COL2A1 gene mutations. They described a 3-generation family with Stickler syndrome in which linkage analysis suggested COL2A1 to be the causative gene. On the basis of these data, 2 prenatal diagnoses were performed which analyzed the 3-prime VNTR polymorphism of the COL2A1 gene on amniocyte DNA and thereby provided the family with genetic counseling and pediatric support at the time of delivery.

Mapping

Francomano et al. (1986) obtained preliminary evidence suggesting that the type II collagen gene may be the site of the mutation in Stickler syndrome; no recombination was found with polymorphisms of the COL2A1 locus. Francomano et al. (1987) found no recombinants and a total lod score of 3.59 at theta = 0.0 for linkage of the Stickler syndrome and COL2A1.

Priestley et al. (1990) presented evidence supporting linkage; by amplification of a variable region 3-prime to the COL2A1 gene, they found 5 distinguishable alleles, of which 3 were segregating in a 3-generation Stickler syndrome pedigree. The lod score in favor of linkage was 2.86 at zero recombination.

Heterogeneity

Weaver et al. (1989) found evidence of recombination between COL2A1 and the Stickler syndrome locus (which they symbolized AOM) in some families.

Knowlton et al. (1989) demonstrated no recombination between COL2A1 and Stickler syndrome in 2 families; the maximum lod score was 3.52 in the first and 1.20 in the second at a recombination distance of zero. However, in a third family, at least 1 crossover was observed.

Schwartz et al. (1989) used the Wagner eponym for vitreoretinal degeneration without extraocular manifestations and the Stickler eponym for the form with extraocular manifestations in the skeleton and craniofacial system. In a family that answered the description for the Wagner type, they found segregation discordant with COL2A1 RFLPs. In 4 families with a phenotype consistent with Stickler syndrome, 2 showed recombinants with COL2A1 RFLPs.

Vintiner et al. (1991) studied 6 multigeneration families. In 2 of them, they found crossovers between the disease locus and COL2A1. In 1 family, with typical findings, a translocation t(5;17)(q15;q23) was found to segregate with the disease in 4 affected relatives. They suggested that one or the other of the breakpoints could be the position of a second gene responsible for Stickler syndrome.

Bonaventure et al. (1992) described a 3-generation family with Stickler syndrome in which linkage to COL2A1 was excluded. Affected patients showed myopia with frequent retinal detachment or glaucoma. Most of them had characteristic facial dysmorphism, the Pierre Robin sequence being observed in 4. Neonatal radiologic signs of the Weissenbacher-Zweymuller syndrome were also noticed.

Wilkin et al. (1998) found evidence for at least 4 loci for Stickler syndrome. They analyzed the clinical findings of 8 families with Stickler syndrome and compared them with the results of linkage studies using a marker for the type II collagen gene (COL2A1). In 6 families there was linkage of the phenotype to COL2A1. The manifestations were similar to those of the original Stickler syndrome family (Stickler et al., 1965) and resembled the phenotype of the previously reported individuals of families with Stickler syndrome in whom a dominant mutation in the COL2A1 gene had been identified. Linkage to COL2A1 was excluded in the 2 remaining families. The most striking difference between these 2 types of families was the absence of severe myopia and retinal detachment in the 2 unlinked families. In the COL2A1 unlinked families, linkage of the phenotype to COL11A1 and COL11A2 was also excluded, thus suggesting the existence of at least a fourth locus for Stickler syndrome.

Molecular Genetics

In affected members of 2 unrelated families with Stickler syndrome, Ahmad et al. (1990, 1991) and Ahmad et al. (1993) identified different heterozygous nonsense mutations in the COL2A1 gene (120140.0005; 120140.0010).

In a family with Stickler syndrome, Brown et al. (1992) found that 4 affected members had deletion of a single basepair resulting in a translational frameshift in exon 40 of the COL2A1 gene (120140.0008).

Ritvaniemi et al. (1993) described a fourth mutation in the COL2A1 gene as the cause of Stickler syndrome (120140.0015). Like the 3 previously described mutations causing the disease, it also introduced a premature termination signal, the mutation being a single base deletion in exon 43 resulting in a frameshift and a stop codon in exon 44. Since only one mutation introducing a premature termination codon was found in the course of defining 120 or more mutations in types I and III procollagen, the results suggested that stop mutations may have a special relationship to Stickler syndrome.

Williams et al. (1996) confirmed that the first kindred described with Stickler syndrome (Stickler et al., 1965) had a mutation in the COL2A1 gene (120140.0024). The family was a large Minnesota kindred which had been examined at the Mayo Clinic as early as 1897 by Dr. C. H. Mayo.

Freddi et al. (2000) described a novel strategy for screening families with type I Stickler syndrome due to nonsense mutations in the COL2A1 gene, using a modified RNA-based protein truncation test. To overcome the problem of the unavailability of collagen II-producing cartilage cells, they performed RT-PCR on the illegitimate transcripts of accessible cells (lymphoblasts and fibroblasts), which were preincubated with cycloheximide to prevent nonsense mutation-induced mRNA decay. The 5 overlapping RT-PCR fragments covering the COL2A1 coding region were then transcribed and translated in vitro to identify smaller truncated protein products resulting from a premature stop codon. Using this method, Freddi et al. (2000) screened a 4-generation family with Stickler syndrome and identified a protein-truncating mutation that was present in all affected individuals. Targeted sequencing identified the mutation as a transition at the 5-prime splice donor site of intron 25 (120140.0032), resulting in a translational frameshift that introduced a premature stop codon. Mutant mRNA was undetectable without cycloheximide protection, demonstrating that the mutant mRNA was subjected to nonsense-mediated mRNA decay. As well as providing further evidence that type I Stickler syndrome results from premature stop codon mutations of the COL2A1 gene, this study suggested that mutant mRNA instability leading to haploinsufficiency may also be an important but previously unrecognized molecular basis of Stickler syndrome. The authors concluded that this rapid test for COL2A1 nonsense mutations is of particular clinical importance to families with Stickler syndrome, where the identification of individuals who are at risk for this potentially preventable form of blindness will allow them to undergo regular ophthalmologic surveillance and preventive or early ameliorative treatment.

Wilkin et al. (2000) analyzed 40 patients with Stickler syndrome using a method to screen the COL2A1 (120140) gene rapidly for common sites of mutations. COL2A1 has 10 in-frame CGA codons that can mutate to TGA stop codons by a methylation-deamination mechanism. The authors analyzed these 10 codons using restriction endonuclease analysis or allele-specific amplification. Mutations at 5 COL2A1 CGA codons were identified in 8 of the 40 patients, suggesting that these are common sites of mutation in Stickler syndrome. The authors proposed that these common sites should be analyzed as a first step in the search for mutations in Stickler syndrome.

In a patient with Stickler syndrome who had a clinical diagnosis of otospondylomegaepiphyseal dysplasia (OSMED; 215150), Miyamoto et al. (2005) identified a novel COL2A1 mutation (120140.0048).

Richards et al. (2006) presented results from 50 families that had presented with the STL1 membranous vitreous phenotype and on which COL2A1 screening by exon sequencing was performed. Mutations were detected in 47 (94%) of the families consisting of 166 affected and 78 unaffected individuals. They also found 3 mutations in the alternatively spliced exon 2 of the COL2A1 gene resulting in the predominantly ocular form of type I Stickler syndrome (609508). The predominantly ocular form of type I Stickler syndrome was not confined, however, to mutations in exon 2; using splicing reporter constructs Richards et al. (2006) demonstrated that a mutant GC donor splice site in intron 51 can be spliced normally, thus contributing to the predominantly ocular phenotype in the family in which it occurred (120140.0049).

Genotype/Phenotype Correlations

Annunen et al. (1999) identified 15 novel mutations in the COL11A1 gene and 8 in the COL2A1 gene in patients with Marshall syndrome, Stickler syndrome, or Stickler-like syndrome. Most of the mutations in the COL11A1 gene altered the splicing consensus sequences, but all of them affected the splicing-consensus sequences of 54-bp exons, as reported by Griffith et al. (1998). In addition, 1 patient had a genomic deletion resulting in the loss of a 54-bp exon. Nine out of 10 of these mutations affected the splicing of 54-bp exons in the region spanning exons 38 to 54 of the gene. Although more than one-third of the exons in this region are 90 or 108 bp long, no splicing mutations were found in them. Six of the COL2A1 gene mutations resulted in a premature translation-termination codon, and 2 of the mutations altered the splicing-consensus sequences. These 2 patients had features typical of Stickler syndrome, with no signs of more severe chondrodysplasias, such as spondyloepiphyseal dysplasia (183900) or Kniest dysplasia (156550). For this reason, it is likely that the mutations in the splicing-consensus sequences lead to cryptic splice sites and thus to premature translation-termination codons, as was reported in the original Stickler kindred (Stickler et al., 1965) (120140.0024). Some phenotypic differences between Stickler syndrome patients with COL2A1 mutations and those with COL11A1 mutations related to deafness. With only 1 exception, the COL11A1 mutations were associated by early-onset hearing loss, requiring hearing aids, whereas the patients with COL2A1 mutations had normal hearing or only slight hearing impairment. There were also differences in ocular findings. Although almost all of the patients with COL2A1 mutations had vitreoretinal degeneration and retinal detachment, those with COL11A1 mutations seldom showed such eye findings. The conclusion of Annunen et al. (1999) was that patients with a splicing mutation in a 54-bp exon or with a mutation causing a 54-bp deletion in the C-terminal half of the COL11A1 gene more frequently showed the findings of Marshall syndrome, and that the mutations in the COL2A1 gene leading to a premature translation-termination codon caused the more classic Stickler syndrome phenotype. This genotype-phenotype correlation supported the old suspicion of 2 separate entities. However, other mutations in the COL11A1 gene resulted in overlapping phenotypes of Marshall and Stickler syndromes, possibly explaining the conflicting reports on the nosology of these 2 entities.

Richards et al. (2000) stated that vitreous slit-lamp biomicroscopy can distinguish between Stickler syndrome patients with COL2A1 mutations (which are usually due to premature termination codons that result in haploinsufficiency of type II collagen) and those with dominant-negative mutations in COL11A1 (120280). The former produce a characteristic congenital 'membranous' anomaly of the vitreous; the COL11A1 mutations produce a different 'beaded' vitreous phenotype. They described 2 novel dominant-negative mutations in COL2A1 that result in Stickler syndrome. Both altered amino acids in the X position of the Gly-X-Y triple-helical region. A recurrent R365C mutation (120140.0033) occurred in 2 unrelated sporadic cases and resulted in the membranous vitreous anomaly associated with haploinsufficiency. In another large family showing linkage to COL2A1, with a lod score of 2.8, an L467F mutation (120140.0034) produced a novel 'afibrillar' vitreous gel devoid of all normal lamellar structure.

Liberfarb et al. (2003) performed genotype/phenotype correlations in 47 affected members from 10 families with 7 defined mutations in the COL2A1 gene based on review of medical records and clinical evaluation of 25 additional family members from 6 of the 10 families. The ages ranged from 2 to 73 years with a mean age of 34.7 years. The classic Stickler phenotype was expressed clinically in all 10 Stickler families with COL2A1 mutations and all had evidence of vitreous degeneration type 1. Myopia was present in 41 of 47 family members. There was considerable interfamilial and intrafamilial variability in clinical expression. The prevalence of certain clinical features was a function of age. Liberfarb et al. (2003) concluded that it is difficult to predict the severity of the phenotype based on the genotype of COL2A1 mutation.

In 188 probands with a clinical diagnosis of Stickler syndrome, Hoornaert et al. (2010) analyzed the COL2A1 gene using a mutation-scanning technique and bidirectional fluorescent sequencing, as well as MPLA for the detection of intragenic deletions. They identified 77 distinct COL2A1 mutations, most of which were loss-of-function alterations, in 100 of the probands. The presence of vitreous anomalies, retinal tears or detachments, cleft palate, and a positive family history were shown to be good indicators for a COL2A1 defect.

Pathogenesis

Richards et al. (2000) stated their working hypothesis for the different vitreous phenotypes seen with COL2A1 and COL11A1 mutations in Stickler syndrome. They suggested that at a specific stage of fetal eye development, a critical mass of collagen is required for proper formation of the secondary vitreous. Haploinsufficiency of type II collagen results in this threshold not being met, and only a vestigial gel forms in the retrolental space. This anomaly is congenital and appears to be clinically static, suggesting that subsequent accumulation of type II collagen cannot compensate for this stage-specific shortfall in the major constituent of the vitreous. Type XI collagen is a quantitatively minor component, and mutations in COL11A1 do not stop the bulk formation of the vitreous gel; however, because of the role of type XI collagen in the control of fibril diameter, COL11A1 mutations result in abnormal fibrillogenesis. This appears to be reflected in the variability of lamellar bundle organization seen on slit-lamp examination of the vitreous.

History

Herrmann et al. (1975) suggested that Stickler syndrome is 'the most common autosomal dominant connective tissue dysplasia in the North American Midwest.' Furthermore, they thought that 'the Stickler syndrome may have been the condition affecting Abraham Lincoln and his son, Tad.' Others had thought Lincoln had Marfan syndrome (154700). In descendants of Lincoln's grandparents a mutation causing SCA5 was found; see 600224.