Stickler Syndrome, Type Ii

A number sign (#) is used with this entry because of evidence that Stickler syndrome type II (STL2) is caused by heterozygous mutation in the COL11A1 gene (120280) on chromosome 1p21.

Marshall syndrome (154780) is an allelic disorder with overlapping features.

For a general phenotypic description and a discussion of genetic heterogeneity of Stickler syndrome, see 108300.

Clinical Features

Richards et al. (1996) studied a 4-generation family with 9 normal individuals and 7 affected with Stickler syndrome. All affected individuals had the characteristic ocular, auditory, and orofacial features of Stickler syndrome. They noted that abnormal vitreous architecture is a hallmark of this syndrome and that this feature was a prerequisite for the diagnosis. In all affected individuals there was congenital nonprogressive myopia of a high degree. Linkage to the COL2A1 gene (120140) was excluded.

Martin et al. (1999) pointed out that patients with Stickler syndrome type I (108300) due to mutations in COL2A1, the most frequent form, exhibit a characteristic 'membranous' or type 1 vitreous phenotype. Those patients with Stickler syndrome type II due to mutations in COL11A1 show a 'beaded' or type 2 vitreous phenotype.

Poulson et al. (2004) examined 31 affected members from 6 pedigrees with confirmed mutations in the COL11A1 gene, all of whom exhibited the 'beaded' type 2 vitreous phenotype. Twenty-seven (87%) of these patients were myopic, 38% had paravascular lattice retinopathy, and 64% either had cataract or were aphakic or pseudophakic. Of the 15 patients with cataract, 5 exhibited the wedge-shaped cortical opacities typical of Stickler syndrome. Thirteen patients (42%) had suffered retinal detachment, at an average age of 34 years; 6 (19%) had bilateral detachments. Thirty-seven percent showed evidence of midline clefting, and 80% were found to have mild or moderate high-tone sensorineural hearing loss. None had evidence of mitral valve prolapse.

Mapping

Sirko-Osadsa et al. (1996) presented evidence that a form of Stickler syndrome is caused by a mutation in the COL11A1 gene on chromosome 1p21. They identified and used intragenic and highly linked markers of COL11A1 to show that this locus was linked to Stickler syndrome in families in which linkage to COL11A2 (120290) and COL2A1 (120140) had been excluded.

In a 4-generation family segregating Stickler syndrome, Richards et al. (1996) excluded linkage to the COL2A1 gene and demonstrated linkage to the COL11A1 gene region. The CA repeat polymorphic markers D1S223 and D1S206, located 2 cM from COL11A1, gave maximum lod scores of 2.7 and 1.2, respectively (theta = 0).

In 5 families with the type 2 vitreous phenotype, Martin et al. (1999) searched for linkage in 4 candidate genes: COL2A1, COL5A2 (120190), COL11A1, and COL11A2. Two families were linked to COL11A1, and sequencing identified mutations resulting in shortened collagen chains, one through exon skipping and the other through a multiexon deletion. One of the families showed weak linkage to COL5A2 but sequencing the open reading frame failed to identify a mutation. In the remaining 2 families, all 4 loci were excluded by linkage analysis. These data confirmed that mutations in COL11A1 cause Stickler syndrome with the type 2 vitreous phenotype and also revealed further locus heterogeneity.

Molecular Genetics

In a family with Stickler syndrome showing linkage to COL11A1, Richards et al. (1996) performed mutation analysis of COL11A1 on RT-PCR products using RNA extracted from cultured dermal fibroblasts. In total, 14 overlapping cDNA products, which covered the entire open reading frame, were analyzed. SSCP analysis of cDNA products indicated sequence variation in affected individuals. Sequence analysis revealed that affected individuals were heterozygous for a single-basepair change that led to a substitution of glycine 97 for valine (120280.0001) and disruption of the Gly-X-Y collagen sequence. SSCP analysis of 100 chromosomes from 50 unrelated controls revealed only the pattern of bands seen in normal family members. Richards et al. (1996) concluded that whereas mutations in genes encoding collagen XI can give rise to some manifestations of Stickler syndrome, only mutations in COL11A1 lead to the full syndrome with vitreoretinal features.

Majava et al. (2007) analyzed 44 patients with a phenotype suggestive of Stickler syndrome or Marshall syndrome who were negative for mutations in the COL2A1 gene, and they identified mutations in COL11A1 in 10 patients (see, e.g., 120280.0002 and 120280.0006). Four of the 10 mutation-positive patients were diagnosed with Marshall syndrome, but the remaining 6 showed an overlapping Marshall/Stickler phenotype. Majava et al. (2007) concluded that heterozygous COL11A1 mutations can result in either Marshall syndrome or Stickler syndrome, and also in phenotypes that are difficult to classify with respect to the 2 disorders. A type I vitreous anomaly was diagnosed in a patient with a mutation in COL11A1 (120280.0006), suggesting that the vitreous phenotype does not always allow prediction of the defective gene in Stickler and Marshall syndromes.

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; see 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. Annunen et al. (1999) concluded 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.

Diagnosis

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; 103580) resulting from a maternal GNAS1 (139320) mutation and Stickler syndrome type I (108300) 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.