Key Features
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Range of developmental abnormalities affecting the retinal vasculature through the Wnt signaling pathway in Norrie’s disease and familial exudative vitreoretinopathy.
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Range of structural abnormalities in vitreous due to known mutations in Stickler’s syndrome and in retina due to known mutations in X-linked recessive juvenile retinoschisis.
Associated Features
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Autosomal dominant or X-linked recessive inheritance patterns.
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Loss of b-wave on electroretinography in X-linked recessive juvenile retinoschisis.
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Retinal pigment epithelial hyperplasia or atrophy in autosomal dominant vitreoretinochoroidopathy.
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Vitreoretinal traction and retinal detachment in Norrie’s disease, familial exudative vitreoretinopathy, X-linked juvenile retinoschisis, and Stickler’s syndrome.
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Epiphyseal dysplasia with premature degeneration of weight-bearing joints in Stickler’s syndrome.
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Osteopenia or osteoporosis in autosomal dominant familial exudative vitreoretinopathy.
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Deafness and mental retardation in many cases of Norrie’s disease.
Introduction
The hereditary vitreoretinopathies are a diverse group of disorders. Research into these rare diseases continues to illuminate the breadth of mechanisms that can lead to blindness.
Stickler’s syndrome is the result of abnormalities in a key structural building block of the connective tissue of the eye, collagen IIa, as well as collagen IXa and collagen XIa. X-linked, recessive, juvenile retinoschisis features abnormalities in the protein retinoschisin, which is believed to play an integral role in cell–cell adhesion within the retinal tissue. Autosomal dominant vitreoretinochoroidopathy (ADVIRC) is one of five diseases caused by mutations in the bestrophin gene. The phenotypic range of the bestrophinopathies includes Best disease and ADVIRC. Familial exudative vitreoretinopathy (FEVR) and Norrie’s disease are now increasingly understood to share ligand-receptor elements in the important Wnt signaling pathway that is central to vascular development within the eye.
The exact role of the vitreous body in these diseases is unknown and has received little attention. Sebag studied the anatomy of the vitreous body and its role in retinal diseases. Historically, vitreous was believed to play a passive role in the maintenance of the volume of the eye and surgically was avoided because of historically poor outcomes when disturbed. However, therapeutic vitrectomy with refinements in modern guillotine cutters became safe and accepted. As a result of considerable surgical experience, our management of vitreoretinal traction in hereditary retinal diseases is improving.
For each of the entities discussed in this chapter, a McKusick identification number is given. McKusick’s Mendelian Inheritance in Man is a textbook that is a catalog of genes and genetic disorders in man. The book and online version (Online Mendelian Inheritance in Man) are good references for discussing genetic diseases among researchers and clinicians. Recent advances in molecular biology continue to shed light not only on genes specific to the retina but increasingly reveal the complexity of larger developmental pathways and their exquisite regulation.
Stickler’s Syndrome
Introduction
Stickler’s syndrome is also known as hereditary arthro-ophthalmopathy. Its inheritance pattern is autosomal dominant with complete penetrance but widely variable expressivity. It is a progressive disorder with a high risk of both ocular and systemic morbidity. The clinical spectrum of affected patients who have Stickler’s syndrome includes high myopia, retinal detachments, and premature degenerative changes of cartilage.
Epidemiology and Pathogenesis
Stickler’s syndrome is the most common autosomal dominantly inherited connective tissue disorder in the American Midwest. The strongest case for the argument that vitreous body abnormalities cause retinal pathology arises primarily in Stickler’s syndrome. It is hypothesized that the vitreous degeneration is a direct effect of mutations in a structural protein, procollagen II. A significant advance in our understanding of Stickler’s syndrome (McKusick No. 120140) was the discovery of a type II collagen gene (COL2A1) mutation on the long arm of chromosome 12 in affected pedigrees. The gene product is a building block in various types of tissue. Structural alterations in the highly ordered vitreous body that arise from COL2A1 gene mutations cause vitreous degeneration and a high rate of complex retinal detachments. Translational frameshift mutations are a common pathway by which disease is produced in patients with Stickler’s syndrome. The original family of the Wagner’s syndrome (early onset cataracts, lattice degeneration of the retina, retinal detachment without involvement of nonocular tissues) is not linked to the COL2A1 gene and may be called Wagner’s syndrome type I.
Ocular Manifestations
High myopia (−8.00 to −18.00 diopters [D]) is the rule, as is an “optically empty” vitreous with abnormal membranes and strands. The optically empty vitreous refers to the presence of early onset, large lacunae of syneretic gel. It is best seen at the slit lamp through a widely dilated pupil. Dilated fundus examination typically reveals perivascular hyperpigmentary changes ( Fig. 6.17.1 ). Retinal breaks are common and may lead to complicated retinal detachments (50% of eyes in patients with Stickler’s syndrome). Giant retinal tears also may occur. Stickler’s syndrome–associated retinal detachments are notoriously difficult to repair, due in part to the abnormal adherence between the vitreous and the retina.
Other ocular manifestations include presenile cataracts (in those patients less than 45 years of age, with peripheral, comma-shaped, cortical opacities). Open-angle glaucoma and ocular hypertension are additional problems found in patients with Stickler’s syndrome.
Diagnosis and Ancillary Testing
Based on ocular findings alone, diagnostic precision can be difficult. Diagnostic criteria for Stickler’s syndrome were published by the National Institutes of Health (NIH) in 2005, based on orofacial, ocular, auditory, and skeletal abnormalities with family history or molecular data (COL2A1 mutations). Tests for the underlying gene defect are increasingly available to confirm a clinical diagnosis.
The electroretinography (ERG) changes are commensurate with axial myopia–reducing b-wave amplitudes. No intrinsic abnormality of the generators of the waveforms in the ERG appears to occur. Similarly, the perimetric abnormalities, if any, occur secondary to retinal detachments and do not result from abnormalities in the visual pathway directly. For the differential diagnosis of Stickler’s syndrome, see Box 6.17.1 .
Stickler’s Syndrome
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Wagner’s syndrome type I
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Erosive vitreoretinopathy
- •
High myopia (degenerative type)
- •
Goldmann–Favre disease
- •
Retinitis pigmentosa
X-Linked Juvenile Retinoschisis
- •
Cystoid macular edema
- •
Rhegmatogenous retinal detachment
- •
Stargardt disease (atrophic macula)
- •
Goldmann–Favre disease
- •
Senile retinoschisis
- •
Retinitis pigmentosa
Autosomal Dominant Vitreoretinochoroidopathy
- •
Autosomal dominant neovascular inflammatory vitreoretinopathy
- •
Retinitis pigmentosa
- •
Paving stone degeneration
Familial Exudative Vitreoretinopathy
- •
Retinopathy of prematurity
- •
Coats’ disease
- •
Incontinentia pigmenti
- •
Sickle cell disease
Norrie’s Disease
- •
Retinopathy of prematurity
- •
Persistent fetal vascular syndrome
- •
X-linked recessive familial exudative vitreoretinopathy
Differential diagnosis includes VCAN-related vitreoretinopathies of Wagner’s syndrome (OMIM # 143200 ) and erosive vitreoretinopathy (ERVR; OMIM *118661). Versican (VCAN) is the only gene mutation associated with these two autosomal dominantly inherited diseases, characterized by “optically empty vitreous,” myopia, variable night blindness and chorioretinal atrophy, but no systemic associations.
Systemic Associations
Of the diseases discussed in this chapter, both Stickler’s syndrome and some autosomal dominant familial exudative vitreoretinopathy patients have systemic complications involving the skeleton. Generalized epiphyseal dysplasia occurs, with premature degenerative changes in weight-bearing joints. Abnormalities of collagen that affect the head include submucous clefting of the palate and bifid uvula (75%; palpation with a gloved finger may be necessary to diagnose a submucous cleft). Midfacial flattening and the Pierre-Robin anomaly often are subtle, and radiographic studies may be required for diagnosis. Sensorineural hearing loss often may be overlooked, as well as mitral valve prolapse (50%), unless sought after in the systemic evaluation. The hearing loss is progressive and affects most individuals by middle age.
Treatment, Course, and Outcome
Early in life, corrective lenses based on a cycloplegic refraction are prescribed to prevent amblyopia. A multidisciplinary evaluation (otolaryngology, orthopedics) and genetic tests (COL2A1 gene) with genetic counseling are important components of a global approach to the family with Stickler’s syndrome. A good example of a growing phenomenon of self-organizing patient support groups is found in the United States at http://www.sticklers.org/sip/ and in the United Kingdom at http://www.stickler.org.uk/ . These groups serve multiple purposes, ranging from a source of scientific information to fundraising for research to find cures for the disease. Annual to semiannual retinal evaluation through dilated pupils with prophylactic treatment of new retinal tears is suggested for longitudinal follow-up. If retinal detachment does not occur, the visual morbidity is minimal. Low-vision evaluation may be beneficial for all patients who develop a serious loss of vision that affects activities of daily living.
Introduction
Stickler’s syndrome is also known as hereditary arthro-ophthalmopathy. Its inheritance pattern is autosomal dominant with complete penetrance but widely variable expressivity. It is a progressive disorder with a high risk of both ocular and systemic morbidity. The clinical spectrum of affected patients who have Stickler’s syndrome includes high myopia, retinal detachments, and premature degenerative changes of cartilage.
Epidemiology and Pathogenesis
Stickler’s syndrome is the most common autosomal dominantly inherited connective tissue disorder in the American Midwest. The strongest case for the argument that vitreous body abnormalities cause retinal pathology arises primarily in Stickler’s syndrome. It is hypothesized that the vitreous degeneration is a direct effect of mutations in a structural protein, procollagen II. A significant advance in our understanding of Stickler’s syndrome (McKusick No. 120140) was the discovery of a type II collagen gene (COL2A1) mutation on the long arm of chromosome 12 in affected pedigrees. The gene product is a building block in various types of tissue. Structural alterations in the highly ordered vitreous body that arise from COL2A1 gene mutations cause vitreous degeneration and a high rate of complex retinal detachments. Translational frameshift mutations are a common pathway by which disease is produced in patients with Stickler’s syndrome. The original family of the Wagner’s syndrome (early onset cataracts, lattice degeneration of the retina, retinal detachment without involvement of nonocular tissues) is not linked to the COL2A1 gene and may be called Wagner’s syndrome type I.
Ocular Manifestations
High myopia (−8.00 to −18.00 diopters [D]) is the rule, as is an “optically empty” vitreous with abnormal membranes and strands. The optically empty vitreous refers to the presence of early onset, large lacunae of syneretic gel. It is best seen at the slit lamp through a widely dilated pupil. Dilated fundus examination typically reveals perivascular hyperpigmentary changes ( Fig. 6.17.1 ). Retinal breaks are common and may lead to complicated retinal detachments (50% of eyes in patients with Stickler’s syndrome). Giant retinal tears also may occur. Stickler’s syndrome–associated retinal detachments are notoriously difficult to repair, due in part to the abnormal adherence between the vitreous and the retina.
Other ocular manifestations include presenile cataracts (in those patients less than 45 years of age, with peripheral, comma-shaped, cortical opacities). Open-angle glaucoma and ocular hypertension are additional problems found in patients with Stickler’s syndrome.
Diagnosis and Ancillary Testing
Based on ocular findings alone, diagnostic precision can be difficult. Diagnostic criteria for Stickler’s syndrome were published by the National Institutes of Health (NIH) in 2005, based on orofacial, ocular, auditory, and skeletal abnormalities with family history or molecular data (COL2A1 mutations). Tests for the underlying gene defect are increasingly available to confirm a clinical diagnosis.
The electroretinography (ERG) changes are commensurate with axial myopia–reducing b-wave amplitudes. No intrinsic abnormality of the generators of the waveforms in the ERG appears to occur. Similarly, the perimetric abnormalities, if any, occur secondary to retinal detachments and do not result from abnormalities in the visual pathway directly. For the differential diagnosis of Stickler’s syndrome, see Box 6.17.1 .
Stickler’s Syndrome
- •
Wagner’s syndrome type I
- •
Erosive vitreoretinopathy
- •
High myopia (degenerative type)
- •
Goldmann–Favre disease
- •
Retinitis pigmentosa
X-Linked Juvenile Retinoschisis
- •
Cystoid macular edema
- •
Rhegmatogenous retinal detachment
- •
Stargardt disease (atrophic macula)
- •
Goldmann–Favre disease
- •
Senile retinoschisis
- •
Retinitis pigmentosa
Autosomal Dominant Vitreoretinochoroidopathy
- •
Autosomal dominant neovascular inflammatory vitreoretinopathy
- •
Retinitis pigmentosa
- •
Paving stone degeneration
Familial Exudative Vitreoretinopathy
- •
Retinopathy of prematurity
- •
Coats’ disease
- •
Incontinentia pigmenti
- •
Sickle cell disease
Norrie’s Disease
- •
Retinopathy of prematurity
- •
Persistent fetal vascular syndrome
- •
X-linked recessive familial exudative vitreoretinopathy
Differential diagnosis includes VCAN-related vitreoretinopathies of Wagner’s syndrome (OMIM # 143200 ) and erosive vitreoretinopathy (ERVR; OMIM *118661). Versican (VCAN) is the only gene mutation associated with these two autosomal dominantly inherited diseases, characterized by “optically empty vitreous,” myopia, variable night blindness and chorioretinal atrophy, but no systemic associations.
Systemic Associations
Of the diseases discussed in this chapter, both Stickler’s syndrome and some autosomal dominant familial exudative vitreoretinopathy patients have systemic complications involving the skeleton. Generalized epiphyseal dysplasia occurs, with premature degenerative changes in weight-bearing joints. Abnormalities of collagen that affect the head include submucous clefting of the palate and bifid uvula (75%; palpation with a gloved finger may be necessary to diagnose a submucous cleft). Midfacial flattening and the Pierre-Robin anomaly often are subtle, and radiographic studies may be required for diagnosis. Sensorineural hearing loss often may be overlooked, as well as mitral valve prolapse (50%), unless sought after in the systemic evaluation. The hearing loss is progressive and affects most individuals by middle age.
Treatment, Course, and Outcome
Early in life, corrective lenses based on a cycloplegic refraction are prescribed to prevent amblyopia. A multidisciplinary evaluation (otolaryngology, orthopedics) and genetic tests (COL2A1 gene) with genetic counseling are important components of a global approach to the family with Stickler’s syndrome. A good example of a growing phenomenon of self-organizing patient support groups is found in the United States at http://www.sticklers.org/sip/ and in the United Kingdom at http://www.stickler.org.uk/ . These groups serve multiple purposes, ranging from a source of scientific information to fundraising for research to find cures for the disease. Annual to semiannual retinal evaluation through dilated pupils with prophylactic treatment of new retinal tears is suggested for longitudinal follow-up. If retinal detachment does not occur, the visual morbidity is minimal. Low-vision evaluation may be beneficial for all patients who develop a serious loss of vision that affects activities of daily living.
X-Linked Juvenile Retinoschisis
Introduction
X-linked juvenile retinoschisis (OMIM # 312700 ) is a vitreoretinal degeneration affecting males. The cystic, spoke-like foveal changes, visual acuity deterioration, peripheral retinoschisis, and loss of ERG b-wave are bilateral. Despite mutation heterogeneity, there are relatively uniform clinical characteristics, albeit with intrafamilial variation in onset and severity.
Epidemiology and Pathogenesis
Various deleterious mutations in RS1 encoding for retinoschisin are associated with X-linked juvenile retinoschisis (XLRS; McKusick No. 312700). In a knockout mouse model, the RS1h murine analog seems important in organization of retinal cell layers and structure of the retinal synapse throughout the entire retina, in contrast to macular dominance in humans.
Retinoschisin is a secreted, soluble homo-oligomeric complex that binds tightly to the surface of photoreceptors and bipolar cells to maintain the synapse. Wang et al. hypothesized that missense mutations lead to abnormal protein conformation and intracellular retention of these products.
Ocular Manifestations
Cystic-like, stellate maculopathy, or foveal schisis, is present almost universally in XLRS and may be the only abnormality detected by ophthalmoscopy in one-half of cases ( Fig. 6.17.2 ). Similar to the findings in Goldmann–Favre disease, no late leakage occurs on fluorescein angiography. In older patients, foveal schisis evolves into an atrophic maculopathy. The average visual acuity is 20/60 (6/18) at age 20 years and 20/200 (6/60) at age 60 years.
The classic histological studies of retinoschisis describe splitting in the anterior layers of the retina ( Fig. 6.17.3 ), typically in the inferotemporal quadrant, and bilaterally in 40% of patients. The inner layer balloons into the vitreous cavity, and unsupported retinal vessels may lead to recurrent vitreous hemorrhages from associated vitreous traction. Vitreous veils may overlie the retinoschisis. In XLRS, the vitreous exerts an effect on the bullous nature of the retinoschisis lesion. The elevation is seen to flatten after a posterior vitreous detachment has produced a separation between the vitreous face and the internal limiting membrane. It is as if the vitreous releases the inner layers of the retina, which allows them to settle back into an anatomical position.
The Mizuo–Nakamura phenomenon has been described in four unrelated men who suffered from X-linked recessive retinoschisis. Originally described in patients who had autosomal recessive Oguchi’s disease, a form of congenital stationary night blindness, this phenomenon also occurs in patients who have an X-linked cone dystrophy.
Diagnosis and Ancillary Testing
The diagnosis is largely based on clinical examination. In contrast to the histological studies showing anterior layer splitting, spectral domain optical coherence tomography (OCT) shows widespread cystic spaces in both inner and outer macular retina. OCT also reveals subtle structural changes throughout different layers of the retina that vary between the fovea and parafovea. OCT may ultimately improve our understanding of retinoschisis by nondestructively showing disease progression over time and the variation in the depth of retinal splitting by eccentricity from fovea to the periphery. Fluorescein angiography generally shows no leakage of dye or true cystoid macular edema in the posterior pole, whereas the periphery may show slow filling of opacified, dendritic retinal vessels.
The ERG shows selective loss of the b-wave amplitude for the scotopic, nonattenuated flash and loss of the oscillatory potentials ( Box 6.17.2 ). This ERG abnormality suggests a panretinal dysfunction in spite of the ophthalmoscopic appearance of only foveal retinal schisis. No consistent ERG findings are found in female carriers, although sporadic reports of abnormalities exist.
