Wagner Syndrome Research Articles

Significant ophthalmoarthropathy associated with ectodermal dysplasia in a child with Marshall-Stickler overlap: a case report

BackgroundThe Marshall-Stickler phenotype is an autosomal dominant trait comprising ocular abnormalities, sensorineural hearing loss, craniofacial anomalies, and anhidrotic ectodermal dysplasia.Case presentationA 5-year-old boy from non-consanguineous family in Austria was born with features of Pierre-Robin association (cleft palate, micrognathia, and glossoptosis). Radiological examination at birth revealed coronal clefts of the vertebrae, platyspondyly, and flaring of the metaphyses of the long bones (features suggestive of the Weissenbacher-Zweymuller syndrome). Significant features of ectodermal dysplasia such as sparse hair, defective dentition, dysplastic nails, and deficient sweating associated with bouts of unexplained hyperthermia were present. These features not shared by Stickler syndrome, Wagner syndrome, or Weissenbacher – Zweymuller syndrome, all of which are conditions often confused with Marshall syndrome.ConclusionThere is continuing debate over the clinical overlap and differential diagnosis of Marshall and Stickler syndromes. We compared similar disorders, such as Weissenbacher-Zweymuller, and Wagner syndromes, and conclude that our present patient manifests Marshall-Stickler overlap. Focussing on subtle facial and ectodermal features may detract from recognising the serious outcome of congenital vitreous/myopia anomaly. Retinal detachment with subsequent blindness is a major risk in our current patient.

Clinical features of the congenital vitreoretinopathies

The inherited vitreoretinal degenerations or vitreoretinopathies are characterized by congenital and acquired disorders of the eye including early onset cataract, anomalies of the vitreous manifesting as optically empty vitreous, course fibrils, and membranes, and retinal detachment. These diseases include Stickler syndrome types I (STL1) and II (STL2), usually caused by mutations in COL2A1 and COL11A1 respectively. Wagner syndrome (WGN1) is associated with mutations in versican (CSPG2) and snowflake vitreoretinal degeneration (SVD) with a mutation in a potassium channel (KCNJ13). The cataract is often cortical and may be wedge-shaped, but does not distinguish between the different syndromes. The congenital vitreous defect is usually characterized as fibrillar degeneration (STL2, WGN1, and SVD) or as a vestigial membrane just behind the lens (STL1). Peripheral chorioretinal atrophy with nyctalopia is prominent in WGN1. Intraretinal crystals may be visible in the periphery using a contact lens in SVD and corneal guttae, a flat appearance to the optic nerve head and mild atrophy of the peripheral retinal pigment epithelium are also common features. Other vitreoretinal degenerations including a number of chondrodysplasias in addition to STL1 and STL2, enhanced S-cone syndrome caused by mutations in NR2E3, and autosomal dominant vitreoretinochoroidopathy caused by mutations in VMD2 are discussed. Patients with unexplained early onset cataract or retinal detachment should be carefully evaluated for vitreoretinal degeneration. Theses diseases share overlapping clinical features with common complex traits affecting the eye (myopia, corneal endothelial dystrophy, lattice degeneration), and may provide insight into the mechanisms of common eye diseases.

Identification of the genetic defect in the original Wagner syndrome family.

The aim of the present study was to determine the genetic defect in Wagner syndrome, a rare disorder belonging to the group of hereditary vitreoretinal degenerations. This disease has been genetically mapped to chromosome 5q14.3. Molecular analysis was performed in the progeny of the original pedigree described by Wagner in 1938. We searched for pathogenic mutations and their effects in two candidate genes, CSPG2 and EDIL3, which locate to the critical chromosomal interval. Reverse transcriptase polymerase chain reaction (RT-PCR) analysis was used to investigate potential splice defects of CSPG2 transcripts. While no alterations were detected in the exons of EDIL3, several changes were identified in the CSPG2 gene. Only one of the novel changes, a heterozygous G to A substitution of the first nucleotide in intron 8, cosegregates with the disease phenotype. This change disrupts the highly conserved splice donor sequence. In blood cells of an index patient, we found CSPG2 transcripts with normally spliced exon 8/9 junction but also two additional CSPG2 transcripts, which were not detected in the control. One lacks the entire exon 8, while the other is missing only the last 21 bp of exon 8. CSPG2 encodes versican, a large proteoglycan, which is an extracellular matrix component of the human vitreous and participates in the formation of the vitreous gel. The splice site mutation described here may lead to a complete lack of exon 8 in CSPG2 transcripts, which shortens the predicted protein by 1754 amino acids and leads to severe reduction of glycosaminoglycan attachment sites.

Identification of a Novel Splice Site Mutation of theCSPG2Gene in a Japanese Family with Wagner Syndrome

To investigate the genetic basis and clinical variability of Wagner syndrome, a rare, dominantly inherited vitreoretinopathy. Clinical examination, linkage analysis, and mutational screening were performed in a large, three-generation, consanguineous Japanese family with Wagner syndrome. The effect of splice site mutation was assessed by reverse transcriptase-polymerase chain reaction (RT-PCR) analysis with lymphoblastoid cell total RNAs generated from affected individuals. Ocular phenotypes of affected members included an empty vitreous with fibrillary condensations, avascular membrane, perivascular sheathing, and progressive chorioretinal dystrophy and were similar to those of the original Wagner syndrome family. All affected eyes examined exhibited pseudoexotropia with ectopic fovea. No systemic manifestations were observed. Genetic linkage confirmed disease segregation with the previously identified WGN1 locus on 5q13-q14. A heterozygous A-->G transversion at the second base of the 3'-acceptor splice site of intron 7 (c.4004-2 A-->G) of the chondroitin sulfate proteoglycan 2 (CSPG2) gene that cosegregated with the disease was identified. Results of RT-PCR analysis indicated that the c.4004-2 A-->G mutation activates a cryptic splice site, located 39 bp downstream from the authentic 3' splice acceptor site. This linkage study confirmed the genetic homogeneity of the Wagner syndrome. CSPG2 encodes versican, a large chondroitin sulfate proteoglycan, which, in vitreous, binds to hyaluronan and link protein and forms large aggregates that are important for maintaining structural integrity. Although the CSPG2 gene has been excluded as a candidate for causing Wagner syndrome, these data emphasize the necessity of further mutational screening in new families and careful functional characterization.

Clinical description and exclusion of candidate genes in a novel autosomal recessively inherited vitreoretinal dystrophy.

To describe the clinical phenotype of a novel autosomal recessively inherited vitreoretinal dystrophy in one generation of a family originating from eastern Switzerland. A clinical study including electroretinographic investigations followed by laboratory-based genetic and molecular analysis. Four affected and 3 unaffected members of the family were examined. Ten candidate regions were tested by linkage analysis with highly polymorphic molecular markers or with intragenic restriction fragment length polymorphisms. Of 8 siblings,4 were affected, showing high myopia with pronounced vitreous liquefaction, retinitis pigmentosa-like retinal degeneration, diffuse retinal pigment epithelium atrophy, macular staphylomata, and premature cataract formation. Strikingly abnormal results on electroretinograms, affecting both the rod and the cone systems, revealed an extensive defect of retinal function, unlike those usually found in pathologic myopia. No extraocular manifestations were observed. Three types of nonsyndromic high myopia, Stickler syndrome I, II, and III, Wagner syndrome, Knobloch syndrome, Goldmann-Favre dystrophy, and multiple vitreoretinopathies were excluded by linkage analysis. The reported phenotype as well as the results of molecular linkage analysis in the siblings described here suggest an autosomal recessively inherited vitreoretinal dystrophy, which, to our knowledge, has not been described until now.

Clinical Variability of Stickler Syndrome: Role of Exon 2 of the Collagen COL2A1 Gene

Stickler syndrome (progressive arthro-ophthalmopathy) is a genetically heterogeneous disorder resulting from mutations in at least three collagen genes. The most common disease-causing gene is COL2A1, a 54-exon–containing gene coding for type II collagen. At least 17 different mutations causing Stickler syndrome have been reported in this gene. Phenotypically, it is also a variably expressed disorder in which most patients present with a wide range of eye and extraocular manifestations including auditory, skeletal, and orofacial manifestations. Some patients, however, present without clinically apparent systemic findings. This observation has led to difficulty distinguishing this Stickler phenotype from other hereditary vitreoretinal degenerations, such as Wagner syndrome and Snowflake vitreoretinal degeneration. In this regard, review of the literature indicates type II collagen exists in two forms resulting from alternative splicing of exon 2 of the COL2A1 gene. One form, designated as type IIB (short form), is preferentially expressed in adult cartilage tissue. The other form, designated as type IIA (long form), is preferentially expressed in the vitreous body of the eye. Because of this selective tissue expression, mutations in exon 2 of the COL2A1 gene have been hypothesized to produce this Stickler syndrome phenotype with minimal or absent extraocular findings. We review the evidence for families with exon 2 mutations of the collagen COL2A1 gene presenting in a distinct manner from families with mutations in the remaining 53 exons, as well as other hereditary vitreoretinal degenerations without significant systemic manifestations.

Molecular genetics of rhegmatogenous retinal detachment.

Rhegmatogenous retinal detachment (RRD) most commonly occurs as a spontaneous event resulting from posterior vitreous detachment, typically between the ages of 40-70 yrs. It is also a feature in some inherited disorders, most commonly Stickler syndrome. The relationship between these inherited disorders and the spontaneous cases is unclear. Here in particular we review Stickler syndrome, and discuss the differential diagnosis of Stickler, Wagner and Marshall syndromes. Other rare inherited disorders associated with RRD are also briefly reviewed.

Stickler syndrome and vitreoretinal degeneration: correlation between locus mutation and vitreous phenotype. Apropos of a case

Autosomal dominant vitreoretinopathies are characterized by genetic heterogeneity. Structural mutations in COL2A1 are the most frequent cause of Stickler syndrome with ocular involvement. The affected patients have a characteristic vitreous alteration, so-called membranous vitreous, or type 1 vitreous phenotype. Recently a novel mutation in the gene encoding the alpha 1 chain of type XI collagen (COL11A1) was reported in rare Stickler pedigrees, with a different, so-called beaded or type 2 vitreous phenotype. Five patients of an Italian family affected by high myopia, high frequency of retinal detachment, and other systemic stigmata evocative of Stickler syndrome (flat midface, depressed nasal bridge, short nose, spondyloepiphyseal dysplasia and osteoarthritis) were studied. Genetic investigations were also performed, considering three candidate loci for Stickler syndrome and Wagner syndrome (COL2A1, COL11A1, WGN1). Segregation analysis was performed utilizing polymorphic markers. COL2A1 and WGN1 segregations were excluded; COL11A1 showed concordance with the disease. The vitreous phenotype of the family was a typical type 1 or "membranous" vitreous, although all the previously reported COL11A1-related Stickler syndromes had always shown the type 2 or "beaded" vitreous phenotype. The clear presence of the type 1 or "membranous" vitreous phenotype in our family, despite the probable mutation in the COL11A1 gene, suggests greater phenotypical heterogeneity and a more extensive mutation spectrum, even of the COL11A1 gene, than previously thought, explaining the basis for the different vitreous phenotypes seen in Stickler syndrome.

COL2A1 exon 2 mutations: relevance to the Stickler and Wagner syndromes

AIMSTo compare the clinical and molecular genetic features of two phenotypically distinct subgroups of families with type 1 Stickler syndrome.BACKGROUNDStickler syndrome (hereditary arthro-ophthalmopathy, McKusick Nos 108300 and 184840) is a...

Refined Genetic and Physical Localization of the Wagner Disease (WGN1) Locus and the Genes CRTL1 and CSPG2 to a 2- to 2.5-cM Region of Chromosome 5q14.3

Wagner syndrome (WGN1; MIM 143200), an autosomal dominant vitreoretinopathy characterized by chorioretinal atrophy, cataract, and retinal detachment, is linked to 5q14.3. Other vitreoretinopathies without systemic stigmata, including erosive vitreoretinopathy, are also linked to this region and are likely to be allelic. Within the critical region lie genes encoding two extracellular macromolecules, link protein (CRTL1) and versican (CSPG2), which are important in binding hyaluronan, a significant component of the mammalian vitreous gel, and which therefore represent excellent candidates for Wagner syndrome. Genetic mapping presented here in two further families reduces the critical region to approximately 2 cM. Subsequent refinement of the physical map allows ordering of known polymorphic microsatellites and excludes CRTL1 as a likely candidate for the disorder. CSPG2 is shown to lie within the critical region; however, analysis of the complete coding region of the mature peptide reveals no clear evidence that it is the gene underlying WGN1.

Ocular abnormalities in transgenic mice harboring mutations in the type II collagen gene.

To characterize the morphological changes in the eyes of transgenic mice harboring different mutations in type II collagen gene to elucidate the function of this collagen in the eye, and to find out whether these animals could function as models for the human arthro-ophthalmopathies of the Kniest, Stickler and Wagner types. Three genetically engineered mouse lines representing two types of mutations in the triple-helical domain of type II collagen and their nontransgenic littermates used as controls were analyzed on day 18.5 embryonic development. After genotyping by polymerase chain reaction (PCR) and Southern hybridization the embryos were prepared for routine histology. Polarization microscopy was done on hyaluronidase-treated sections. Histological analysis revealed several genotype-dependent abnormalities in the eyes of the transgenic mice. Most striking changes were observed in the vitreous architecture; in one line of mice the vitreous was tightly packed in the posterior region of the vitreous space with thick fibrils, empty cavities and dense membrane-like material. The other mutation resulted in reduced filament density of the vitreous. In the most severely affected phenotype the internal limiting membrane was detached from the retinal layers and was markedly thickened, and the posterior lens capsule was thickened. The anterior chamber was shallow or absent in all transgenic lines but was well formed in the normal animals. Changes were also observed in the lens, corneal and scleral structures. The ocular changes observed in transgenic mice harboring mutations in type II collagen gene show similarities to the human ocular findings in Kniest dysplasia, and in Stickler and Wagner syndromes. We therefore propose that these animals could serve as models for systematic analysis of vitreoretinal degeneration and other abnormalities, as seen in these syndromes.

Wagner症候群の神経耳科学的検討

We evaluated neurotological findings in a pedigree of 4 cases of Wagner's syndrome. Sensorineural hearing loss was present in 3 of the 4 cases. Two of the 3 cases exhibited a sensorineural hearing loss which was always at 2000 Hz.Another exhibited a high-frequency sensorineural hearing loss which showed positive recruitment at 8000 Hz.

533 WAGNER-STICKLER SYNDRCME: A GENETIC STUDY

Based on our study of 32 affected individuals in 10 families, we suggest that the Wagner and the Stickler syndromes could be the same disorder. Both the Wagner and the Stickler syndromes are autosomal dominant disorders with a similar pattern of eye abnormalities, including myopia, presenile cataracts, strabismus, vitreo-retinal degeneration, retinal detachment and retino-schisis. Only the Stickler syndrome has been associated with non-ocular problems, such as cleft palate, micrognathia, mid facial hypoplasia, hearing loss and degenerative arthritis. All of the index cases in our study were ascertained because of their retinal symptoms as having the Wagner syndrome. Three families were included in a report on Wagner syndrome in Arch Ophthal. 89:176, 1973 by Hirose et al.

Wagner's syndrome.

Wagner's syndrome.

Influence of the parental Rhesus types on the segregation of genetic abnormalities.

Abstract. Following the observation that in families with elliptocytosis parental Rhesus types may influence the elliptocytosis segregation in the children, the hypothesis has been put forward that in families with other genetic abnormalities, abnormal segregations of the affections may be expected to depend to some extent on the parental Rhesus types. Influence of the Rhesus type of the normal mating partners on the carrier: non‐carrier segregation in the children has been demonstrated for abnormal serum cholinesterase and for the chromosomal translocation D/21. Children of normal E+ mating partners in families with abnormal cholinesterase were found to have an excess of non‐affected; when the normal mating‐partner is E‐ there is an excess of carriers. In families with D/21 translocation an excess of carriers was found when the normal parent is E+. In a pedigree with Wagner's syndrome no such influence could be demonstrated, the amount of genetic information available being, however, relatively small. In families with the nail‐patella syndrome the Rhesus types of both parents appeared to be important, together with the sex of the offspring. Mating types involving Ccee produce an excess of non‐affected children, those with CCee an excess of affected sons and a deficiency of affected daughters. Mating types with neither Ccee or CCee produce a relative excess of affected daughters.These and other phenomena appear to indicate that genetic abnormalities are to some extent balanced polymorphisms, the selective mechanism being most probably selective fertilization. Selections of this kind, caused by the genetic, rather than by the external environment, may be of importance in limiting the increase of the genetic load in man which is generally expected to occur in the near future.