How is stickler syndrome inherited

We reviewed medical records of 47 affected subjects from the 10 families for whom the clinical diagnosis of the Stickler syndrome was associated with mutations in the COL2A1 gene, to document the clinical features of the Stickler syndrome. Table 1 summarizes the genotypes and phenotypes in the 47 affected members of the 10 families with seven defined mutations in the COL2A1 gene based on review of medical records as well as clinical evaluations at NIH of 25 affected individuals from 6 of the 10 families Families 2, 3, 4, 5, 6, and 9.

In the group of 25 evaluated at NIH, there are 9 males and 16 females ranging in age from 2 to 73 years with a mean age of Three members of these families were less than 5 years old and had incomplete evaluations. Three additional members of the mutation-bearing families were also evaluated at NIH and found not to have the COL2A1 mutation causing Stickler syndrome in their families.

All individuals with the molecular diagnosis of Stickler syndrome who could be examined at NIH had vitreous degeneration type 1. Some individuals could not be examined young age or disability or previous surgical procedures. Vitreous changes in affected members of families not seen at NIH could not be documented fully. Myopia was reported in 41 of the 47 affected subjects with the molecular diagnosis of Stickler syndrome, with no refraction information for the remaining 6 affected subjects.

Considerable interfamilial and intrafamilial variability in clinical expression is apparent when one compares clinical features such as cleft palate and myopia in unrelated families with the same molecular diagnosis. For example, Families 5, 6, and 7 had a single base substitution in Arg causing a premature stop codon in exon 23 RX.

In Family 5, the proband had a repaired cleft palate. In Family 6, none of the three examined had palate abnormalities, and in Family 7, one of five had a cleft palate and one of five had a bifid uvula. Families 9 and 10 in our study have the same mutation, RX in exon In Family 9, all three affected relatives had abnormal palates: one had a repaired cleft palate, one had a submucous cleft palate, and the third had a bifid uvula and a submucous cleft palate; in Family 10, two of four had repaired cleft palate.

In Family 9, all three affected relatives were myopic, two mildly and one with high myopia. In Family 10, three of four affected relatives had an unspecified degree of myopia. There is no information about myopia in the fourth relative. Figure 2 illustrates the prevalence of certain clinical features as a function of age in those 25 subjects with defined mutations in COL2A1 evaluated at NIH. The following clinical features become more prevalent with advancing age: retinal detachments, cataracts, sensorineural hearing loss, early-onset degenerative joint disease, and skeletal abnormalities involving the spine and hips.

The degree of myopia mild, moderate, severe is not a function of age. However, when the prevalence of retinal detachments was examined as a function of degree of myopia, the prevalence of retinal detachments appeared to increase with increasing severity of myopia.

Bar graphs of the prevalence of certain clinical features as a function of the age of Stickler syndrome—affected patients with specific mutations in COL2A1. This scoring system assigns 1 or 2 points for various clinical findings. A score of 5 is necessary to qualify for a diagnosis of Stickler syndrome. All 25 subjects with molecular confirmation of COL2A1 mutations satisfied these diagnostic criteria mean diagnostic score 7. Three of the four affected individuals with diagnostic scores of 5 were 4 years old or younger.

Three molecularly excluded relatives evaluated at NIH did not meet the criteria for diagnosis. It should be noted that these diagnostic criteria are based on clinical findings, not on identification of a mutation. We studied 25 individuals from six families and reviewed the medical records of an additional 22 individuals for these and four additional families whose clinical diagnosis of the Stickler syndrome has been confirmed by finding mutations in COL2A1 , the human gene coding for type II procollagen.

These mutations are believed to act by haploinsufficiency 55 creating premature translation stop signals in COL2A1 , either via direct nonsense mutation or by frameshift mutation creating a downstream premature stop codon.

In a recent study based on data from usable questionnaires returned from individuals who reportedly have Stickler syndrome and belong to support groups in the United Kingdom, the United States, the Netherlands, Canada, and Australia, Stickler et al.

The presence or absence of hypermobile tympanic membranes was not reported. Stickler et al. Reasons for differences in prevalence of clinical features between our 25 patients with defined mutations in COL2A1 studied at NIH and those whose questionnaires were studied by Stickler et al.

In the 25 subjects evaluated at NIH, the mean age of the evaluated subjects was In the population reported on by Stickler et al. We demonstrated that the age of the subjects is an important variable to consider when comparing the prevalence of clinical features in Stickler populations. One would expect to find lower prevalence of retinal detachments and cataracts and higher prevalence of joint hypermobility in the more youthful population reported by Stickler et al.

In fact, the prevalence of retinal detachments was slightly lower in the population reported by Stickler et al. However, the prevalence of cataracts was higher in the Stickler et al. As is true for autosomal dominant genetic disorders in general, there is extreme variability in the clinical expression of the Stickler syndrome. This variability is interfamilial as well as intrafamilial. We have shown that interfamilial variation is present even when one compares clinical features such as cleft palate and myopia in unrelated families with the same molecular diagnosis.

As a result, molecular biology can assist in the prenatal as well as postnatal diagnosis of the disorder, but it is of little help in predicting the severity of the disease. Hereditary progressive arthroophthalmopathy. Mayo Clin Proc ; 40 : — CAS Google Scholar. Hereditary progressive arthroophthalmopathy, II: Additional observations, a hearing defect, and a report of a similar case.

Mayo Clin Proc ; 42 : — Google Scholar. The Stickler syndrome. N Engl J Med ; : — The Stickler syndrome hereditary arthroophthalmopathy. Birth Defects Orig Artic Ser ; 11 : 76— The Wagner-Stickler syndrome. J Pediatr ; 99 : — Share on: Facebook Twitter. Show references Kliegman RM, et al. Disorders involving cartilage matrix problems. In: Nelson Textbook of Pediatrics. Elsevier; Accessed July 11, Petty RE, et al. Primary disorders of connective tissue.

In: Textbook of Pediatric Rheumatology. Herring JA. Orthopaedic-related syndromes. In: Tachdjian's Pediatric Orthopaedics. Joint pain. Clouding of the lens of the eye. Cloudy lens. Depressed bridge of nose. Flat bridge of nose. Flat nasal bridge. Flat, nasal bridge. Flattened nasal bridge. Low nasal bridge. Low nasal root. Eye folds. Prominent eye folds. Decreased size of maxilla.

Decreased size of upper jaw. Maxillary deficiency. Maxillary retrusion. Small maxilla. Small upper jaw. Small upper jaw bones. Upper jaw deficiency. Upper jaw retrusion. Zygomatic flattening. Decreased size of midface. Midface deficiency. Underdevelopment of midface. Close sighted. Near sighted. Near sightedness. Detached retina. Decreased length of nose. Shortened nose. Corners of eye widely separated. Nasal tip, upturned. Upturned nasal tip.

Upturned nose. Upturned nostrils. Long slender fingers. Spider fingers. Abnormal heart rate. Heart rhythm disorders. Irregular heart beat. Irregular heartbeat.

Abnormal curving of the cornea or lens of the eye. Chronic infections of the middle ear. Cleft roof of mouth. Flat nose. Recessed nasal ridge. Acid reflux. Acid reflux disease. Knock knees. Retraction of the tongue. Joints move beyond expected range of motion. Hunched back. Round back. Abnormally large tongue. Increased size of tongue. Large tongue. Little lower jaw. Small jaw. Small lower jaw. Low or weak muscle tone.

Degenerative joint disease. Pigeon chest. Flattened vertebrae. Bulging eye. Eyeballs bulging out. In affected members of 2 unrelated families with Stickler syndrome, Ahmad et al. In a family with Stickler syndrome, Brown et al. Ritvaniemi et al. 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 Since only one mutation introducing a premature termination codon was found in the course of defining 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. The family was a large Minnesota kindred which had been examined at the Mayo Clinic as early as by Dr. Freddi et al. 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.

Targeted sequencing identified the mutation as a transition at the 5-prime splice donor site of intron 25 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.

The authors analyzed these 10 codons using restriction endonuclease analysis or allele-specific amplification. 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; , Miyamoto et al.

Richards et al. 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 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.

Annunen et al. Most of the mutations in the COL11A1 gene altered the splicing consensus sequences, but all of them affected the splicing-consensus sequences of bp exons, as reported by Griffith et al. In addition, 1 patient had a genomic deletion resulting in the loss of a bp exon. Nine out of 10 of these mutations affected the splicing of 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 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 or Kniest dysplasia 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.

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. 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.

The former produce a characteristic congenital 'membranous' anomaly of the vitreous; the COL11A1 mutations produce a different 'beaded' vitreous phenotype. Both altered amino acids in the X position of the Gly-X-Y triple-helical region.

A recurrent RC mutation In another large family showing linkage to COL2A1, with a lod score of 2. Liberfarb et al. The ages ranged from 2 to 73 years with a mean age of 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. In probands with a clinical diagnosis of Stickler syndrome, Hoornaert et al.

They identified 77 distinct COL2A1 mutations, most of which were loss-of-function alterations, in 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. 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. Herrmann et al. In descendants of Lincoln's grandparents a mutation causing SCA5 was found; see Ahmad, N. Abstract Am. A second mutation in the type II procollagen gene COL2A1 causing Stickler syndrome arthro-ophthalmopathy is also a premature termination codon. Prevalence of mitral valve prolapse in Stickler syndrome.

Ang, A. Vitreous phenotype: a key diagnostic sign in Stickler syndrome types 1 and 2 complicated by double heterozygosity. Annunen, S.

Baker, S. Beals, R. Hereditary arthro-ophthalmopathy the Stickler syndrome : report of a kindred with protrusio acetabuli. Blair, N. Hereditary progressive arthro-ophthalmopathy of Stickler. Bonaventure, J. Brown, D. Procollagen II gene mutation in Stickler syndrome. Daniel, R. Hyalo-retinopathy in the clefting syndrome.