Jon P. Gieser,
Norman P. Blair
Heredofamilial vitreoretinal dystrophies affect the vitreous body and the retina, comprising a heterogeneous group of diseases. This chapter discusses heredofamilial vitreoretinal dystrophies including Stickler's syndrome, Marshall's syndrome, Kniest's syndrome, spondyloepiphyseal dysplasia congenita, achondrogenesis, hypochondroplasia, Wagner's disease, erosive vitreoretinopathy, snowflake vitreoretinal degeneration, juvenile hereditary retinoschisis, Goldmann-Favre tapetoretinal dystrophy, enhanced S-cone syndrome, and autosomal dominant vitreoretinochoroidopathy. Some of these conditions are clinically distinct and recognizable, whereas others represent a continuum of clinical disease. There has been some confusion in the clinical classification of the vitreoretinal dystrophies. As molecular genetics improves, progress in understanding not only pathogenesis but also classification will occur. Several other conditions that involve the retina and vitreous and may be influenced by genetics are discussed elsewhere in this treatise. These include lattice retinal degeneration, pathologic myopia, retinitis pigmentosa, and familial exudative vitreoretinopathy.
CONNECTIVE TISSUE DISEASES
A broad class of diseases known as connective tissue diseases manifests diverse vitreous and variable skeletal abnormalities. Among these diseases are Stickler's syndrome, Marshall's syndrome, Kniest's syndrome, spondyloepiphyseal dysplasia congenita, achondrogenesis, hypochondroplasia, Wagner's disease, and erosive vitreoretinopathy, and snowflake vitreoretinal degeneration. These conditions display tremendous phenotypic variability and affect numerous different tissues, often making classification and diagnosis difficult for the clinician. One commonality shared by these disorders is abnormal collagen production or processing. Collagen is the most ubiquitous constituent molecule in connective tissue. At least 15 types of collagen are present in the body, each having its own tissue distribution, biochemical structure, and physical properties. Collagens II, IX, and XI have the highest concentrations in ocular tissues, and diseases affecting these proteins may be nosologically organized according to the aberrant collagen.
MOLECULAR GENETICS OF COLLAGENOPATHIES
In 1979, Maumenee proposed that diseases such as Stickler's syndrome could be explained in terms of metabolic errors in collagen production and processing. The diverse tissues affected in these conditions have as primary constituents a large proportion of type II collagen, and Maumenee suspected that alterations of collagen protein caused Stickler's syndrome and other diseases.
Since then, the molecular genetics and biosynthesis of collagen production have been elucidated. The family of collagens represents a series of highly vulnerable gene-protein systems. All collagens are produced by biochemical pathways that involve numerous posttranslational events before assembly of mature collagen. Alteration of any of the biosynthetic pathways results in abnormal collagen.
In general, for type II collagen, mutations that yield an abnormal but partially functioning procollagen subunit are associated with far more severe clinical disease than mutations that completely prevent expression of one of the two alleles of collagen genes. For example, relatively mild Stickler's syndrome phenotypes can result from production of shortened polypeptide chains without a terminal carboxy unit, making the mutation equivalent to a stop codon. If a normal second COL2A1 gene were present, normal procollagen production could still continue, although at a slower rate. In contrast, in-frame mutations yield shorter but otherwise normal subunits that interfere with production of mature collagen by preventing incorporation of subunits into triple helices, producing the more severe collagenopathies.Additionally, somatic mosaicism may contribute to the clinical variability of these conditions. The variety of phenotypic abnormalities reported in these connective tissue diseases illustrates the phenomenon of variable expressivity and pleiotropism, commonly observed in the whole range of human autosomal dominant disorders of connective tissue.
Genetic heterogeneity is often evident in heredofamilial vitreoretinal dystrophies, with different gene mutations giving rise to different clinical phenotypes. The phenotypic variability of these diseases, often with subtle or overlapping clinical fidings, has traditionally made diagnosis of these diseases difficult. Additionally, genetic heterogeneity, varying categories of mutations, and alternative splicing, which is a process of tissue-restricted expression of exons in the generation of fial protein structures, are complicating factors that further obscure the genotype-phenotype association. Knowledge of various mutations has prompted mechanistic explanations for different phenotypes, and prediction of phenotype from knowledge of genotype may be possible, especially as the catalog of mutations expands.
For example, type II collagen, which is the predominant collagen in vitreous and cartilage, consists of three identical polypeptide chains, which are coded by the COL2A1 gene located on chromosome 12. Two different forms of type II collagen are native in vivo, as determined by constituent protein chains. These two forms arise by alternative splicing of the COL2A1 gene exons. Mutations in the involved genes have been documented to cause collagenopathies such as Stickler's syndrome. Mutations within exon 2 are associated with a predominantly ocular phenotype, presumably due to tissue-restricted expression of this exon in the vitreous in adults. In addition to type II collagen, other collagens including types XI and IX are minority constituents of the vitreous and axial skeleton. Collagenopathies may also result from production of defective collagens of these types. Linkage to a structural gene for type XI collagen was reported to cause a Stickler's variant in a large Dutch kindred. This gene, COL11A2, is found between chromosome 6p22 and 6p21.3 and is distinct from COL2A1. Other collagenopathies affecting another type of collagen from gene COL11A2 on chromosome 6 do not demonstrate any ocular manifestations but rather give rise to arthropathies. Furthermore, mutations in type IV collagen may be related to snowflake vitreoretinal degeneration. Whether abnormalities of production of other collagens or other connective tissue constituents play a role in the development of heredofamilial vitreoretinopathies has yet to be demonstrated.
TYPE II COLLAGENOPATHIES
A series of diseases of disordered type II collagen metabolism can be arranged according to their severity (Table 189.1).
TABLE 189.1 -- Type II Collagenopathies: A Spectrum of Disease
Variable mild systemic effects
Kniest's dysplasia and spondyloepiphyseal dysplasia congenita
Severe systemic effects
HEREDITARY PROGRESSIVE ARTHROOPHTHALMOPATHY-STICKLER'S SYNDROME
Hereditary progressive arthroophthalmopathy is a variably severe, progressive, debilitating connective tissue disease with both ocular and systemic manifestations. First reported in 1965, it is inherited in an autosomal dominant fashion with variable penetrance and expressivity.[5,6] It has an incidence of approximately 1 in 10000, making it the most common connective tissue dysplasia in the American Midwest.
Major ocular fidings include progressive axial myopia with vitreous syneresis and retinal detachment. The initial study of Stickler's syndrome reported a range of ?8 to ?18D of myopia, but moderate myopia is often seen. Myopia is congenital and axial, and progression occurs secondary to axial elongation over the first two decades of life. Variable astigmatism is present. Cataracts may occur at a young age and are often variable in nature. The most frequent and distinctive lesions have been described as wedge and fleck cataracts. Lens changes tend to progress with age. A characteristic fiding in the posterior segment is the presence of an optically empty vitreous cavity with vitreous syneresis and liquefaction. The vitreous may be fibrillar and coarse, behind which no formed structures are visible. Disordered fibrils may be present in the anterior vitreous. Vitreous membranes occur frequently and are often freely mobile, relatively dense, and avascular (Fig. 189.1). Attachments to the retina may be best observed with contact lens examination or binocular indirect ophthalmoscopy. Perivascularpigmentation along both arteries and veins, probably a variety of lattice retinal degeneration, often occurs along with peripheral vascular sheathing or narrowing. The perivascular pigmentation may extend far posteriorly in a radial fashion (Figs 189.2 and 189.3). These changes are highly characteristic of Stickler's syndrome, and, when present, should strongly suggest the diagnosis of Stickler's syndrome. Atrophy of the choriocapillaris and retinal pigment epithelium has been reported. Retinal breaks, often multiple, posterior, or large,[13-15] have been reported in up to 75% of patients. These breaks often lead to retinal detachments that respond poorly to surgical intervention. Stickler's syndrome is a frequent cause of giant retinal tears and is the primary cause of nontraumatic giant retinal tears in children. White with pressure has been observed, and has been reported to be a precursor lesion of giant retinal tears. Strabismus, glaucoma, retinoschisis, peripheral cystoid retinal degeneration, and optic atrophy may occur infrequently.[13,16]
FIGURE 189.1 Stickler's syndrome. Vitreous veils in the midperipheral retina.
FIGURE 189.2 Stickler's syndrome. Perivascular pigmentation similar to lattice retinal degeneration along with peripheral vascular sheathing or narrowing.
FIGURE 189.3 Stickler's syndrome. Wide-angle fundus photograph shows myopic appearance with midperipheral pigmentary degeneration.
Systemic fidings are highly variable and include a wide variety of orofacial and skeletal abnormalities. Midfacial flattening due to maxillary hypoplasia, cleft palate,[8,17] bifid uvula, high-arched palate, and other palatal abnormalities are quite common, seen in up to 75% of patients (Fig. 189.4). The bony abnormalities of the palate may be obscured by the soft palate, detectable only by palpation. Abnormal teeth and malocclusion may occur. A cleft lip is not present. The Pierre Robin sequence consisting of micrognathia, cleft palate, and glossoptosis is a nonspecific manifestation of several clinical entities but isassociated with Stickler's syndrome in approximately 50% of cases. The Pierre Robin sequence may predispose affected infants to life-threatening feeding and respiratory problems, although when associated with Stickler's syndrome, it may be less severe than when seen with other syndromes. Facial features may assume a normal appearance with time. Most patients will manifest some evidence of articular disease, although arthropathy may be very mild or perhaps visible only on radiographic analysis. Osteoarthritis of the large joints including the knees, hips, ankles, and wrists is common by the fourth decade of life (Fig. 189.5). Radiographic evidence of Stickler's syndrome includes mild spondyloepiphyseal dysplasia with flattening of the epiphyses, narrowing of the diaphyses, and widening of the metaphyses. Such radiographic abnormalities are often present but may be mild. Muscular hypoplasia and hypotonia, enlarged joints, joint hyperextensibility, marfanoid habitus, and bony abnormalities including kyphosis and scoliosis may be observed. Hearing loss is one of the most common systemic fidings of Stickler's syndrome. Conductive hearing loss from recurrent otitis media owing to cleft palate may occur, and sensorineural hearing loss may also be present. Mitral valve prolapse has been reported in up to 45% of patients. Intelligence is usually normal.
FIGURE 189.4 Stickler's syndrome. Characteristic facies of a patient with midfacial flattening and maxillary hypoplasia.
FIGURE 189.5 Stickler's syndrome. Early-onset degenerative osteoarthritis of the hip (arrows).
Clinical subclassification of Stickler's syndrome has been proposed on the basis of the vitreous abnormalities. Type 1 Stickler's syndrome is characterized by a membranous vitreous appearance and has been associated with mutations in the COL2A1 gene;[21-23] type 2 Stickler's syndrome manifests a different beaded vitreous phenotype and is caused by COL11A1 mutations.[23-25] In addition, one other group of Stickler's syndrome has only systemic abnormalities. This non-ocular type 3 Stickler's syndrome, with a phenotype displaying characteristic systemic abnormalities such as facial abnormalities, cleft palate, hearing loss, and arthropathies, but without high myopia, vitreoretinal degeneration, or retinal detachments, is caused by mutations in COL11A2,[26-28] a gene which is not expressed in ocular tissue.
The electroretinogram is reduced, although early in the disease it is frequently normal. Visual fields can be constricted in the presence of chorioretinal atrophy but may be normal. Fluorescein angiography in the areas of perivascular pigmentary degeneration reveals a zone of window defect on each side of the vessel with blockage of the choroidal fluorescence at the sites of pigment deposits.
Myopia and vitreous degeneration tend to be progressive. Vitreous degeneration leads to vitreous membrane formation by the age of 20 years. Progressive cataractous changes may require lens extraction. The perivascular pigmentary changes are progressive. They are usually not prominent within the first two decades but become so thereafter. Retinal detachment may occur at any age. Systemic fidings including osteoarthritis and hearing loss are usually progressive.
Owing to the high incidence of retinal detachment, patients with Stickler's syndrome and their blood relatives require frequent and careful funduscopic examination with special emphasis placed on detection of retinal breaks or detachments. Examination of apparently normal family members should be performed routinely into the third decade of life to exclude the possibility of Stickler's syndrome. Treatment of retinal breaks with laser photocoagulation or cryoretinopexy is advocated by most clinicians in order to improve long-term outcomes. Retinal detachment necessitates implementation of scleral buckling or vitreous surgery techniques. Surgical intervention has been associated with generally poor results, although the advent of vitreous microsurgical techniques has improved surgical outcomes. Cataract extraction is often required at a relatively young age owing to progressive lens opacities.
Genetic counseling and examination of at-risk family members are essential in this disease. Additionally, other medical specialties need to participate in the management of these complex patients. A pediatrician may be required in the delivery room to manage airway obstructions in at-risk infants. Evaluation by an otolaryngologist is important for young patients with recurrent otitis media, cleft palate, or the complete Pierre Robin sequence, and is especially important if feeding or respiratory problems are suspected. Plastic surgery may be necessary to correct cleft palate and the Pierre Robin sequence. Audiologic evaluation may be necessary to exclude various degrees of auditory impairment.
Molecular Genetics of Stickler's Syndrome
Stickler's syndrome is a genetically heterogeneous disorder. Approximately 75% of families have been demonstrated to have mutations in the type II collagen gene, COL2A1. Type 1 Stickler's syndrome is the result of mutations to the COL2A1 gene. Multiple distinct mutations in COL2A1 have been described,[30-35] including substitutions, deletions, and frameshift mutations, usually but not always closely linked with COL2A1.[36-43] Linkage analysis in one large pedigree with Stickler's syndrome excluded COL2A1 as a causative gene. Additionally, other studies have demonstrated recombination events, suggesting at least one other genetic locus may be responsible for type 2 Stickler's syndrome. This locus is associated with COL11A1 mutations on chromosome 1.[22-24] Non-ocular Stickler's syndrome type 3 is caused by mutations in COL11A2 on chromosome 6.[25-27] However, some data contradict the hypothesis that all COL2A1 mutations are associated with a type 1 vitreous and that mutations to COL11A1 always cause type 2 Stickler's syndrome. Further investigation will likely clarify the precise molecular defects involved.
Marshall's syndrome is an autosomal dominant condition whose relationship to Stickler's syndrome is unclear. First reported in 1958, Marshall's syndrome is characterized by axial myopia, vitreoretinal degeneration, retinal breaks and detachments, deafness, hypoplastic nasal bones with a particular facial appearance, and short stature. Retinal capillary hemangioma has been reported with Marshall-Stickler syndrome. Owing to clinical similarities, Marshall's and Stickler's syndromes have been equated by a number of investigators.[48-50] Other authors suggest that distinctive clinical appearances argue for nosologic splitting of these two conditions. Ayme and Preus suggest that facial features permit differentiation between the two syndromes. Hypoplastic nasal bones give a short nose in Marshall's syndrome compared with the long nose and midface in Stickler's syndrome. Also, a round face in Marshall's syndrome may be contrasted to a normal or elongated face in Stickler's syndrome. Finally, the short and stocky body habitus found in Marshall's syndrome is distinct from the thin, elongated habitus of Stickler's syndrome. Molecular studies will likely answer the question of genetic heterogeneity conclusively.
Molecular Genetics of Marshall's Syndrome
Marshall's syndrome has been reported to be allelic with a subset of Stickler's syndrome caused by mutations of the COL11A1 gene on chromosome 1. Other researchers have suggested that the alleged allelism is the result of misdiag-nosis of Marshall's syndrome in patients who would be more correctly diagnosed as having Stickler's syndrome. Further advances in molecular genetics will likely more precisely defie the mutations responsible for Marshall's syndrome.
KNIEST'S SYNDROME AND SPONDYLOEPIPHYSEAL DYSPLASIA CONGENITA
Kniest's syndrome and spondyloepiphyseal dysplasia congenita are autosomal dominant, moderately severe chondrodysplasias. Although distinctions may be made between Kniest's syndrome and spondyloepiphyseal dysplasia congenita on the basis of their systemic manifestations, they resemble Stickler's syndrome from an ophthalmic standpoint.
Ocular fidings are similar to those of Stickler's syndrome, and ophthalmologists may not distinguish between these diseases and Stickler's syndrome. High myopia, retinal breaks, and detachments are common and may frequently lead to ocular morbidity.
Systemic fidings are similar to but more pronounced and severe than those found in Stickler's syndrome. They include dwarfism, short trunk and small pelvis, kyphoscoliosis, and short limbs with large joints that have restricted mobility. Epiphyseal and metaphyseal dysplasia are prominent. Orofacial abnormalities include cleft palate, hearing loss, and flattened midface. Spondyloepiphyseal dysplasia congenita tends to cause less severe defects than does Kniest's syndrome. In contrast to those affected with spondyloepiphyseal dysplasia congenita, persons afflicted with Kniest's syndrome are shorter, have more severe joint contractures, and have involvement of the hands. Additionally, radiographic analysis demonstrates more significant changes in Kniest's syndrome than in spondyloepiphyseal dysplasia congenita.
Management is similar to that for Stickler's syndrome.
Molecular Genetics of Kniest's Syndrome and Spondyloepiphyseal Dysplasia Congenita
Linkage analysis has demonstrated that mutations in the COL2A1 gene responsible for Stickler's syndrome also result in Kniest's syndrome, spondyloepiphyseal dysplasia congenita, and other severe collagenopathies.[30,57,58]
ACHONDROGENESIS AND HYPOCHONDROPLASIA
Achondrogenesis and hypochondroplasia are autosomal dominant, severe chondrodysplasias. Patients with achondrogenesis have a severely underossified axial skeleton with short bones, a short trunk, and a prominent abdomen. Affected infants die in utero or shortly after birth. In hypochondroplasia, the trunk and bones are not as severely affected as in achondrogenesis. Nonetheless, infants survive only hours or weeks after birth. No clinical ophthalmic studies of these diseases have been reported.
OTHER TYPE II COLLAGENOPATHIES
At least one other unique mutation involving COL2A1 has been associated with retinal detachment. One amino acid change in the C-propeptide region of the molecule, glycine to aspartate, was associated with dominantly inherited rhegmatogenous retinal detachment, premature arthropathy, and development of phalangeal epiphyseal dysplasia, resulting in brachydactyly. Other mutations will likely be uncovered in the future.
A disease resembling Stickler's syndrome has been described in Labrador retrievers. Axial myopia and vitreous abnormalities leading to retinal tears and rhegmatogenous retinal detachment with proliferative vitreoretinopathy are seen in association with significant skeletal abnormalities. This animal model may prove to be of value in research in vitreoretinal dystrophies.[60,61]
WAGNER'S HYALOIDEORETINAL DYSTROPHY-WAGNER'S DISEASE
Wagner's disease is a rare autosomal dominant entity with 100% penetrance that was first reported in 1938.[62,63] Owing to its similarities to Stickler's syndrome, Wagner's disease has often been equated with Stickler's syndrome. In fact, the literature is replete with references to the Wagner-Stickler syndrome. Before 1965 when Stickler's syndrome was defied, Stickler's syndrome was often called Wagner's disease by retina specialists, especially those in the United States. This precedent led to confusion once Stickler's syndrome was described. Although these two vitreoretinal dystrophies share some clinical features, they are now considered distinct entities both genetically and phenotypically.
Ocular fidings of Wagner's disease are similar but not identical to those of Stickler's syndrome. Avascular vitreous veils and vitreous syneresis with an optically empty vitreous are invariably present, often at the equator. The membranes are best observed with Goldmann contact lens examination or binocular indirect ophthalmoscopy. Posterior or anterior cortical cataracts are common in patients in the third through fifth decades of life, progressing with age. Dislocated lenses were reported in Wagner's initial report, and spherophakia with subluxation was observed in descendants. Myopia of mild or moderate severity is often present in contrast to the moderate or high myopia seen in Stickler's syndrome. Contrary to previous reports, more recent reanalysis of the original pedigree demonstrated that patients with Wagner's disease are at increased risk for detachment, and 14% of the patients examined had a rhegmatogenous retinal detachment. However, complicated retinal detachments such as often occur in Stickler's syndrome do not generally occur, and conventional scleral buckling techniques are usually successful. Other patients developed peripheral traction retinal detachments that were thought to be caused by contraction and organization of peripheral vitreoretinal adhesions. Chorioretinal atrophy may be prominent, and retinal vessels can be attenuated and sheathed. Bone spicule pigmentation or perivascularpigmentation along both arteries and veins can occur. Optic atrophy may be present, and temporal dragging of the macula was reported in the original and the subsequent series of patients.
Systemic fidings have not been identified in Wagner's disease, in contrast to Stickler's syndrome. No orofacial or skeletal abnormalities are present. Radiologic studies of epiphyses of the spine, knees, hips, wrists, and ankles are normal. Auditory abnormalities do not generally develop, although one case of hearing loss in a 17yearold patient may have occurred.[62,64]
As in Stickler's syndrome, constriction of visual fields may occur with the development of chorioretinal atrophy. Dark adaptation may be normal but often becomes mildly to markedly abnormal with age. The electroretinogram may be normal initially but eventually is reduced markedly. The b-wave is predominantly affected. Rod response is diminished first, followed by cone response.[64,66,67] The electrophysiologic abnormalities often parallel the chorioretinal fidings.
Nyctalopia may be the first sign of the condition. Mild myopic correction may be needed early in life, but vision is usually good. Later, as cataracts develop, visual acuity may worsen, necessitating cataract extraction. Poor vision or visual-field defects may ensue with the development of chorioretinal or optic atrophy.
Because retinal detachment has been observed in Wagner's disease, prophylactic treatment of retinal breaks or tears with laser retinopexy or cryoretinopexy should be performed. Additionally, consistent vigilance for the development of retinal detachment is essential. As is true for Stickler's syndrome, cataract extraction may be required at a relatively young age. Genetic counseling and examination of all family members are imperative, and examination of normal family members should be performed routinely into the third decade of life to exclude the possibility of Wagner's syndrome, although genetic testing may eventually obviate the need for such surveillance.
Molecular Genetics of Wagner's Disease
The precise molecular basis of Wagner's disease is unknown although new studies have suggested answers. Prior to the advent of molecular analysis, many investigators concluded that Wagner's disease was merely a different phenotype of Stickler's syndrome or that specific mutations in the COL2A1 gene would lead to the Wagner phenotype. However, in 1988, Francomano and co-workers discovered a genetic locus for Wagner's disease distinct from that found in Stickler's syndrome, suggesting the presence of genetic heterogeneity between Stickler's syndrome and Wagner's disease. Other investigators subsequently postulated that specific mutations in the COL2A1 gene would lead to the Wagner phenotype, although retrospective analysis suggests that the patients examined may have had Stickler's syndrome rather than Wagner's disease. In 1995, Brown and associates performed linkage analysis on affected members of the family Wagner originally described and found linkage with markers that map to chromosome 5q13-14. In addition, genes coding for collagen types II (COL2A1 gene) and IX as well as five autosomal loci associated with retinitis pigmentosa were also excluded.[70,71]Subsequently, Wagner disease has been mapped to the long arm of chromosome 5 in region 14.3 (5q14.3). Chromosome 5q13-14 may contain genes that encode proteins that stabilize cartilage constituents and form the core of chondroitin sulfate proteoglycan. Alteration of metabolism of glycosaminoglycans or collagen production via a different mechanism from COL2A1 mutation seems plausible. Although the question of genetic heterogeneity for Wagner's disease is not settled, the genetic basis of Wagner's disease is clearly different from that of Stickler's syndrome, confirming clinical suspicions that Wagner's disease and Stickler's syndrome are separate clinical entities.
Erosive vitreoretinopathy is an entity that bears similarities to other vitreoretinal dystrophies. First described in 1994, this condition is inherited in an autosomal dominant pattern. Although erosive vitreoretinopathy resembles Stickler's syndrome clinically, it is much closer genetically to Wagner's disease.
Universal fidings included marked vitreous syneresis with formation of vitreous membranes, veils, and bands. Unlike Wagner's disease, erosive vitreoretinopathy does not yield an optically empty vitreous cavity. Additionally, atrophy and 'erosion' of the retinal pigment epithelium in the midperiphery allow for clear visualization of the choroidal circulation. End-stage disease may affect the posterior pole and gives rise to severe, geographic atrophy resembling choroideremia or end-stage retinitis pigmentosa (Fig. 189.6). Bone spicule formation has been reported. Retinal detachment is common, affecting up to 75% of affected individuals. As in Stickler's syndrome, the retinal breaks tend to be posterior and difficult to treat. Surgical results have been poor. Mild to moderate myopia is common, although high myopia is possible. Premature nuclear cataracts are common. Macular ectopia with temporal dragging has been reported.
FIGURE 189.6 Erosive vitreoretinopathy. Atrophy of the retinal pigment epithelium associated with clumps of hyperpigmentation of the retinal pigment epithelium in the midperipheral retina.
No systemic orofacial, skeletal, or auditory abnormalities have been documented. Radiologic examination of joints is unremarkable.
Visual-field defects correspond to the peripheral retinal pigment epithelial atrophy and include arcuate scotomas and ring scotomas that may lead to central fixation loss. Electroretinography demonstrates diffuse photoreceptor dysfunction with preservation but severe reduction of both rod and cone responses.
The clinical course is quite variable. Some patients are asymptomatic until age 40 years when nuclear cataracts becomevisually significant. Others have early nyctalopia or constricted visual fields after the second decade of life. Retinal detachment is a common cause of vision loss, necessitating vitreoretinal surgical techniques.
Genetic counseling is important for all patients and families. Also, all family members at risk must be examined to rule out the presence of retinal breaks or detachments that would need treatment. Cataract surgery may be required.
Molecular Genetics of Erosive Vitreoretinopathy
Brown and associates in 1995 demonstrated genetic linkage between the disease phenotype and markers along chromosome 5q13-14 in family members with erosive vitreoretinopathy. These investigators concluded that erosive vitreoretinopathy and Wagner's disease are allelic and suggested that alterations in collagen production may cause these diseases. It is not known which mutations give rise to erosive vitreoretinopathy and which cause Wagner's disease.
SNOWFLAKE VITREORETINAL DEGENERATION
First described in 1973, this rare disorder was demonstrated to be transmitted in an autosomal dominant pattern.
Clinical fidings are numerous and include refractive errors, usually myopia that progresses slightly with age but also some hyperopia and astigmatism. Anterior segment abnormalities include corneal guttata, thought to differentiate snowflake vitreoretinal degeneration from Stickler's syndrome and Wagner's disease. Cataracts are common, may occur early in life, and often necessitate cataract extraction. Extensive fibrillar degeneration of the vitreous with or without vitreous bands and strands over the retinal periphery are nearly universal. Sheathing of the retinal vessels is common, and the vessels often become attenuated in the periphery. Peripheral retinal abnormalities include minute, shiny crystalline-like deposits resembling snowflakes. White with pressure is a common fiding in the peripheral retina. Peripheral radial perivascular degeneration may also be observed in a minority of patients. Typical circumferential lattice peripheral retinal degeneration has not been reported. Retinal detachment is common, observed in 21% of all family members. Waxy pallor and dysmorphic optic nerve heads have been seen, and situs inversus of the central retinal vessels has been described.
No systemic orofacial, skeletal, or auditory abnormalities have been documented.
Elevated dark adaptation and reduced scotopic b-wave amplitude with dim white light are seen in most snowflake subjects.
The clinical course is quite variable. Many patients become symptomatic in mid-life when nuclear cataracts become visually significant. Retinal detachment may cause vision loss, necessitating vitreoretinal surgical techniques. However, the rate of retinal detachment in snowflake vitreoretinal degeneration is lower than that in Stickler's syndrome.
Genetic counseling may be important for snowflake patients and families. Also, all family members at risk must be examined to rule out the presence of retinal breaks or detachments that would need treatment. Cataract surgery may be required.
Molecular Genetics of Snowflake Vitreoretinal Degeneration
The disease gene causing snowflake vitreoretinal degeneration has been localized to a site on chromosome 2q36. At this locus, two genes encode the ?3 and ?4 chains of type IV collagen, both of which are components of basement membranes. This implicates abnormal type IV collagen production in the pathogenesis of snowflake vitreoretinal degeneration. The genetic and clinical evidence thus suggests that snowflake vitreoretinal degeneration is a entity distinct from other heredofamilial vitreoretinal dystrophies.
OTHER HEREDOFAMILIAL VITREORETINOPATHIES
JUVENILE HEREDITARY RETINOSCHISIS
Juvenile hereditary retinoschisis is a relatively rare vitreoretinal dystrophy causing foveal retinoschisis and sometimes peripheral retinoschisis. First described in 1898, juvenile hereditary retinoschisis has been shown to be transmitted in an x-linked fashion with 100% penetrance[80,81] but variable expressivity. Despite its X-linked transmission pattern, juvenile hereditary retinoschisis has been observed in females with consanguineous parents.[82,83]
The primary clinical feature of juvenile hereditary retinoschisis is foveal retinoschisis. Although it may be subtle, this sign is thought to be present in 98-100% of cases. In its classic form, which is best observed at a young age, the foveal lesion is found in approximately 70% of patients and is characterized by a stellate appearance formed by intraretinal microcystoid spaces in radial orientation (Fig. 189.7). It is usually bilateral but may be asymmetric. Over time, the cystoid spaces may enlarge,coalesce, and rupture. The macular pigmentation may become mottled and, in later stages, may resemble atrophic age-related macular degeneration.
FIGURE 189.7 Juvenile hereditary retinoschisis. Foveal microcystoid changes in the fovea.
Other ocular fidings include unilateral or bilateral peripheral retinoschisis in the inferotemporal quadrants in approximately 50% of cases, making it a less sensitive indicator of the presence of this disease than macular retinoschisis (Fig. 189.8). Peripheral retinoschisis is variably elevated and usually does not extend posteriorly past the arcades. Spontaneous regression of retinoschisis cavities has been documented. Inner retinal holes are seen in approximately 50% of eyes. Avascular or vascular vitreous veils may occur, probably representing various combinations of retinoschisis and large inner layer holes. Other peripheral retinal changes include perivascular sheathing, grayish spots, degeneration of the inner retina, microvascular anomalies, and even neovascularization of the retina. A tapetal sheen may be present. Variable amounts of retinal pigment epithelial pigmentation may occur, giving rise to pigmented demarcation lines, pigment clumping or mottling, and rarely, bone spicule formation. Optic atrophy has been reported. The incidence of retinal detachment is variable, developing in 0% of cases to approximately 20% of eyes. If retinal vessels are unsupported by surrounding tissue as typically occurs with large inner retinal holes, vitreous hemorrhage can occur and cause significant visual loss and morbidity.
FIGURE 189.8 Juvenile hereditary retinoschisis. Peripheral retinoschisis with the edge of the schisis cavity (arrows).
No systemic associations have been reported.
Color vision testing often yields a mild red-green dyschromatopsia. Early in the course of the disease, electroretinography typically demonstrates a normal a-wave with a significantly diminished b-wave (Fig. 189.9). These electroretinographic fidings are characteristic and may conclusively establish the diagnosis, even in young children. Later in the disease after secondary photoreceptor dysfunction, both a-waves and b-waves may be subnormal.[94-96] These results are consistent with the hypothesis that Müller's cell dysfunction is intimately involved in the pathogenesis of this disease, since Müller's cells are thought to play a primary role in the initiation and propagation of the b-wave. The electrooculogram is fairly normal until disease is very advanced, when it becomes subnormal. Fluorescein angiography demonstrates typical fidings that may be very useful in establishing a diagnosis. No staining or leakage of fluorescein dye occurs, differentiating juvenile hereditary retinoschisis from causes of cystoid macular edema.[97,98] Also, peripheral retinal capillary nonperfusion and other peripheral vascular abnormalities may be present.
FIGURE 189.9 Juvenile hereditary retinoschisis. Electroretinographic findings. Note the disproportionate loss in the amplitude of the b-wave as compared with the a-wave in the tracing taken with a high luminance white light flash stimulus.
Histopathologic studies have demonstrated splitting of the retina in the superficial retina, the inner limiting membrane, and nerve fiber layer.[101-103] Recent optical coherence tomographic fidings suggest that the primary abnormality of the fovea in patients with juvenile retinoschisis is actually located in the outer retina, specifically in the outer plexiform layer.Müller's cell dysfunction is presumed to be the cause of juvenile hereditary retinoschisis. This cell type spans much of the retinal thickness, and loss of its integrity has been postulated to explain the characteristic structural defects and functional deficits.Another theory suggests that vitreous traction caused by contracting or abnormally adherent vitreous may be the causative factor in the pathophysiology of juvenile hereditary retinoschisis.
Patients are often diagnosed at age 5 or 6 years when they fail a school eye examination, although typical fidings of juvenile hereditary retinoschisis have been observed in infants as young as 3 months.Other patients may present earlier with nystagmus or strabismus. Vision may remain stable during young adulthood but usually worsens slowly with advancing age. Retinal detachment and vitreous hemorrhage represent two of the most serious complications of juvenile hereditary retinoschisis. Juvenile hereditary retinoschisis is high in the differential diagnosis of vitreous hemorrhage in male children. Retinal detachment may occur when holes develop in both the outer and the inner retinal layers. Distinguishing between retinal detachment and retinoschisis may be difficult. A diagnosis may be established by utilizing diagnostic photocoagulation through the elevated retina; the presence of an attached outer retinal layer will give rise to a white chorioretinal burn. In cases uncomplicated by vitreous hemorrhage or retinal detachment, visual acuity remains fairly good until macular atrophy ensues in later years.
Given the generally slow, progressive course of this disease, no prophylactic treatment of peripheral or foveal retinoschisis is recommended. Laser photocoagulation and other attempts to flatten retinoschisis cavities have failed to demonstrate any benefit and have led to retinal detachments. If a retinal detachment does occur, scleral buckling surgery may be utilized with variable success. Occasionally, posterior retinal breaks or vitreous hemorrhage necessitates the use of vitrectomy techniques to achieve internal tamponade and retinal reattachment. Inner wall retinectomy during vitrectomy has been advocated in select cases. All patients and family members should receive genetic counseling and may benefit from genetic testing.
Molecular Genetics of Juvenile Hereditary Retinoschisis
Linkage analysis results reveal that the gene for juvenile hereditary retinoschisis localizes to the short arm of the X chromosome in the region Xp22.2. All results to date confirm the lack of genetic heterogeneity of juvenile retinoschisis. Since carriers of juvenile hereditary retinoschisis are asymptomatic, carrier detection is of considerable value. Availability of highly polymorphic genetic markers now permits detection of the carrier state with a theoretical reliability of at least 94.5%.
First reported in 1958, Goldmann-Favre tapetoretinal dystrophy is a rare, bilateral disease that is inherited in an autosomal recessive pattern. Its clinical features may mimic those of juvenile hereditary retinoschisis or retinitis pigmentosa, leading to diagnostic difficulty.
The primary features of Goldmann-Favre dystrophy are variable but generally include early-onset night blindness, congenital retinoschisis, pigmentary retinopathy resembling retinitis pigmentosa, and vitreous syneresis. The retinoschisis is variably present and may be peripheral or central. If peripheral retinoschisis is not present, diagnosis of Goldmann-Favre dystrophy may be more difficult without other characteristic clinical fidings. Peripheral retinoschisis involves the nerve fiber layer. The peripheral retinoschisis may extend posteriorly, at times connecting to macular lesions. Macular retinoschisis has a cystoid appearance and may resemble that associated with juvenile hereditary retinoschisis. It is often the cause of poor vision. Over time, macular pigmentary changes may take on the appearance of beaten metal. Retinal detachment may occur.
Peripheral retinal degenerative changes include chorioretinal atrophy and pigment clumping, which are usually located under areas of retinoschisis. The pigmentation may also assume a bone-spicule pattern, being found along retinal vessels or located at the posterior pole (Figs 189.10 and 189.11). Peripheral retinal vessels may be opaque or attenuated. They may manifest a dendritic configuration in the retinal periphery. Vitreous changes include syneresis that may appear similar to the optically empty vitreous in Stickler's syndrome or Wagner's disease. However, characteristic vitreous veils seen in Stickler's syndrome are not present. A fibrillar appearance of the condensed vitreous posterior to the lens has been noted. Vitreous cells may be present. Cortical or posterior subcapsular cataracts have been noted. Atrophic waxy pallor of the optic nerve may occur.
FIGURE 189.10 Goldmann-Favre dystrophy. Wide-angle fundus photograph shows peripheral retinal degenerative changes including chorioretinal atrophy, pigment clumping, and retinoschisis (arrows).
FIGURE 189.11 Goldmann-Favre dystrophy. Peripheral retinal pigment clumping.
No systemic associations have been reported.
Electrophysiologic testing is of particular benefit in diagnosis of this condition owing to unique characteristics among vitreoretinal dystrophies. The electroretinogram demonstrates markedly reduced or completely absent a-wave and b-wave amplitudes. If present, photopic and scotopic responses are similar, indicating an apparent absence of detectable rod activity. Additionally, the electroretinogram is accompanied by prolonged implicit times of both the a-wave and the b-wave.The electrooculogram demonstrates subnormal light-peak trough ratios.
Fluorescein angiography demonstrates variable leakage of fluorescein dye with cystoid leakage throughout the posterior pole, especially from the perifoveal capillary network, thus differentiating Goldmann-Favre dystrophy from juvenile hereditary retinoschisis. Peripheral nonperfusion and extensive leakage can be present, often beginning at the posterior edge of peripheral retinoschisis. Color vision testing may be normal. Constriction of visual fields may be noted symptomatically or on formal testing.
Individuals are often identified in the first decade of life when they are noted to have poor central vision and nyctalopia. If peripheral retinoschisis or classic peripheral retinal pigmentation is not present, diagnosis may be delayed. Visual loss is progressive and may especially involve night vision. Retinal detachment may occur at any time.
No specific treatment is available for Goldmann-Favre dystrophy. Early diagnosis and genetic counseling are important. Vigilance for development of retinal detachment should be maintained. Surgical intervention has been associated with poor outcomes, although the use of vitreous microsurgical techniques has improved surgical outcomes.
Molecular Genetics of Goldmann-Favre Dystrophy
Goldmann-Favre dystrophy has been associated with the NR2E3, formerly called photoreceptor-specific nuclear receptor or PNR, which is thought to encode a ligand-dependent transcription factor.Analysis of the NR2E3 gene has revealed its chromosomal position as 15q24. Mutations of the same gene have also been associated with enhanced S-cone syndrome. The precise mechanism of action of the mutated gene is uncertain at present.
ENHANCED S-CONE SYNDROME
Described in 1990, this retinal dystrophy bears close clinical resemblance to Goldmann-Favre dystrophy.
Patients with enhanced S-cone syndrome all have nyctalopia, and cystoid changes in the fovea may be similar to those seen in Goldmann-Favre dystrophy.
No systemic associations have been reported.
In enhanced S-cone syndrome, unique electroretinographic fidings are present and are mediated mainly by S (blue) cones. The b-wave is greatly enhanced under conditions of blue light stimulation. Also, the electroretinogram obtained under conditions of bright white light stimulation is similar to that obtained with dark adaptation even though the 30-Hz flicker response is markedly diminished.[122-124]
See discussion under Goldmann-Favre dystrophy.
Molecular Genetics of Enhanced S-Cone Syndrome
Enhanced S-cone syndrome has been associated with the NR2E3 gene, the same gene that has been linked with Goldmann-Favre dystrophy. Analysis of the NR2E3 gene has revealed its chromosomal position as 15q24.
Whether a high degree of genotype-phenotype correlation for particular mutations in the NR2E3 gene account for the clinical differences between enhanced S-cone syndrome and Goldmann-Favre dystrophy is unclear at the present time. Molecular analysis of patients with these conditions will likely elucidate answers to these questions.
AUTOSOMAL DOMINANT VITREORETINOCHOROIDOPATHY
First described in 1982, this fundus dystrophy is characterized by peripheral pigmentary retinopathy that is inherited in an autosomal dominant pattern with a high degree of penetrance. The condition is rare, having been observed in only a few families since its first report. Despite clinical characteristics similar to those found in retinitis pigmentosa, autosomal dominant vitreoretinochoroidopathy (ADVIRC) is distinguished from retinitis pigmentosa by the absence of nyctalopia and less visualfield constriction.
The main features of ADVIRC include peripheral retinal hypopigmentation and hyperpigmentation for 360 degrees. This pigmentary disturbance extends from the ora serrata posteriorly and has a discrete posterior boundary near the equator (Fig. 189.12). Retinal arteriolar narrowing and occlusion may be present. Posterior pole retinal neovascularization has been seen in some patients. Other vascular abnormalities including marked breakdown of the blood-retinal barrier throughout the posterior pole may be present, resulting in cystoid macular edema. This may be the main cause of visual symptoms and disability in affected patients. Pigment epithelial changes may occur in the macula after long-term, severe macular edema. Vitreous degeneration with cells and fibrillar condensation has been observed. Additionally, choroidal atrophy was present. Cataract formation at an early age was reported. Retinal detachment occurred in one patient who was previously aphakic, and the same patient subsequently developed a spontaneous vitreous hemorrhage. High myopia is not a feature of this disease, but moderate myopia has been noted. Epiretinal membranes have been reported.
FIGURE 189.12 Autosomal dominant vitreoretinochoroidopathy. Dense peripheral pigment deposits with a rather discrete posterior border. Note occasional clumps of pigment further posterior.
No systemic associations, including skeletal, facial, or joint abnormalities, have been reported.
The electroretinogram shows normal to slightly reduced rod and cone function. Electrooculogram demonstrates a marked reduction of the Arden ratio. Formal visual-field testing may be normal or may show only mild generalized bilateral constriction. Fluorescein angiography may show widespread, severe leakage in the posterior pole, sometimes with cystoid macular edema. Leakage from neovascularization may be seen. Peripherally, there is blockage of choroidal fluorescence by deposited pigment on a background of window defect.
Patients do not generally complain of nyctalopia or visual-field constriction. They may retain excellent vision, suggesting that the disease progresses extremely slowly. Additionally, histopathologic analyses of both young and old patients were remarkably similar, providing further evidence that progression is very slow. The peripheral pigmentary changes have been observed in the first few years of life.
Genetic counseling is recommended. Cataract extraction may be beneficial, resulting in generally good visual outcomes. Close observation for the development of retinal breaks or detachments appears to be unnecessary, as patients with ADVIRC do not appear to have an increased risk of retinal detachment. Retinal neovascularization has responded to local laser treatment. Widespread vascular leakage precludes laser treatment of discrete leaks. Pharmacologic treatment of macular edema with inhibitors of carbonic anhydrase and cyclooxygenase has been disappointing.
Molecular Genetics of ADVIRC
The autosomal dominant transmission pattern of ADVIRC has been determined by pedigree analysis. ADVIRC has been linked to the gene VMD2, a locus on the pericentromeric region of chromosome 11 associated with vitelliform macular dystrophy or Best disease. This gene appears to govern retinal pigment epithelium function, which is essential to normal mammalian retinal development and maintenance.
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