Ординатура / Офтальмология / Английские материалы / The Retina and its Disorders_Besharse, Bok_2011

Vitreoretinopathies Hereditary 254

255 Vitreoretinopathies Hereditary

Figure 1 Membranous vitreous phenotype in type 1 Stickler syndrome. Dotted line indicates detached posterior hyaloid membrane; solid line indicates the type 1 membranous anomaly.

Figure 2 Beaded vitreous phenotype in type 2 Stickler.

Many features are shared such as midfacial hypoplasia, spondyloepiphyseal abnormalities, cleft palate, and sensorineural hearing loss, but patients with Marshall syndrome are reported to also have ectodermal dysplasia with hypertrichosis and hypohyidrosis, calvarial thickening, and ocular hypertelorism. The term Marshall–Stickler syndrome has been used but is potentially confusing and best avoided until Marshall syndrome is better characterized on clinical and molecular genetic grounds.

Knobloch syndrome (OMIM #267750)

Knobloch syndrome has been molecularly characterized and results from a mutation in the gene coding for type XVIII collagen. It has a more extensive systemic phenotype than Stickler or Marshall syndrome with developmental abnormalities described in several major systems of the body, including lung hypoplasia, cardiac dextroversion, and renal abnormalities as well as the ocular features of a degenerative vitreous appearance, high myopia, and retinal degeneration with retinal detachment. The distinguishing clinical feature of Knobloch syndrome is the presence of an occipital encephalocele.

Marfan syndrome (OMIM #154700)

Marfan syndrome is an autosomal dominant connective tissue disorder associated with an abnormal vitreous appearance, myopic astigmatism, and characteristic skeletal features of increased height with disproportionately long limbs and digits, scoliosis and lumbar lordosis, joint laxity, narrow, high-arched palate, and anterior chest deformity (Figure 9). Ectopia lentis (with the lens typically dislocated superior and temporally; Figure 10) is the ocular major Ghent criterion for the diagnosis of Marfan syndrome. Retinal detachment, myopia, increased globe length, cornea plana, hypoplastic iris, glaucoma, and early nuclear sclerotic cataract are all minor criteria. Marfan syndrome has cardiovascular manifestations of mitral valve prolapse,

mitral regurgitation, dilation of the aortic root, and aortic regurgitation, with aneurysm of the aorta and aortic dissection being major life-threatening complications.

Vitreoretinopathies Associated with Progressive Retinal Dysfunction

The remaining hereditary vitreoretinopathies described in this article are purely ocular disorders. Those that are associated with retinal dysfunction – Wagner syndrome, erosive vitreoretinopathy, Goldmann–Favre syndrome, and enhanced S-cone syndrome (ESCS) – all have measurable electrophysiological changes of the retina demonstrated by recording a subnormal electroretinogram (ERG).

Figure 4 Congenital, quadrantic, lamellar cataract seen in both type 1 and type 2 Stickler syndrome.

Wagner syndrome (OMIM #143200)

The most striking finding in Wagner syndrome is the thickening and incomplete separation of the posterior hyaloid membrane, which tends to occur in a circular band and is variously described as a veil, sheets, or ropes. A large range of chorioretinal abnormalities have been described with the typical finding being chorioretinal atrophy with pigment migration into the retina (Figure 11). Electroretinographic responses are progressively subnormal (Figure 12) and visual-field testing demonstrates ring scotomas with eventual loss of central visual acuity. The chorioretinal pathology results in gradual progressive visual loss in the absence of retinal detachment, and has a progressive course. There is an association with early-onset cataract and mild myopia. Wagner syndrome is also associated with large angle kappas indicative of an ectopic fovea (Figure 13).

Prognosis in Wagner syndrome is poor with progressive visual loss. The risk of rhegmatogenous retinal detachment with Wagner syndrome is higher than that of the normal population, but the incidence does not appear to be as high as that seen in the Stickler syndromes.

The term Jansen syndrome has been used to describe a hereditary vitreoretinopathy but the clinical features reported are consistent with Wagner syndrome and linkage has been demonstrated in the original family to the same area as the causative gene in Wagner syndrome. The syndrome referred to as erosive vitreoretinopathy is reported to be associated with vitreous changes, hemeralopia with accompanying grossly reduced rod and cone responses, progressive chorioretinal atrophic changes, and combined traction-rhegmatogenous retinal detachments. Affected family members also had large angle kappas.

Figure 6 Kniest dysplasia demonstrating shortening of trunk and limbs.

Figure 7 Interphalangeal dysplasia in Kniest dysplasia.

Mutations in the same gene that cause Wagner syndrome have been implicated in erosive vitreoretinopathy. It is likely both Jansen syndrome and erosive vitreoretinopathy are phenotypic variants of Wagner syndrome.

Goldmann–Favre syndrome/enhanced S-cone dystrophy (OMIM #268100)

Patients with Goldmann–Favre syndrome have liquefaction and fibrillar changes of the vitreous, night blindness, equatorial chorioretinal atrophy and pigment clumping, peripheral and macular schisis, cortical lens opacities, rod–cone dysfunction, and diffuse vascular leakage on fluorescein angiography. Goldmann–Favre syndrome is inherited as an autosomal recessive disorder and is now known to be caused by a mutation in the same gene that causes ESCS (the NR2E3 gene). ESCS is the only inherited retinal disease

Figure 8 Spondyloepiphyseal dysplasia congenital demonstrating short stature and flattening of the midface.

Figure 9 Pectus excavatum in Marfan syndrome.

which exhibits a gain in photoreceptor function, with patients showing enhanced sensitivity to blue (short wavelength) light, with night blindness and loss of sensitivity to long and medium wavelengths. The ERG findings in this group of disorders demonstrate undetectable rod-isolated responses and reduced combined rod–cone responses.

Vitreoretinopathies Associated with Abnormal Retinal Vasculature

The clinical feature on ocular examination of the hereditary vitreoretinopathies in this category is an abnormal

vascular pattern on the retina. This is demonstrated in more subtle cases using fluorescein angiographic studies.

Familial exudative vitreoretinopathy (OMIM #133780, #601813, and #305390)

The primary pathological process in familial exudative vitreoretinopathy (FEVR) is believed to be a premature arrest of retinal angiogenesis and vascular differentiation resulting in incomplete vasculariszation of the peripheral retina. The failure to vascularize the retina is the unifying feature seen in all affected individuals but, by itself, is usually asymptomatic. Secondary changes include neovascularization, retinal exudates, peripheral snowflake vitreous changes, and retinal traction. Epiretinal traction from vitreous and retinal surface membrane is the usual cause of

Figure 10 Ectopia lentis with dislocation of the lens superiorly in Marfan syndrome.

retinal detachment and severe retinal distortion is a common finding resulting in retinal folds and tractional or combined tractional and rhegmatogenous retinal detachment (Figure 14). The prognosis is highly variable with some individuals blind by age 10 and others (sometimes within the same family) asymptomatic throughout adult life. The eye with the milder phenotype may have only a small avascular area, visible only on fluorescein angiography.

Autosomal dominant vitreochoroidopathy (OMIM #193220)

Autosomal dominant vitreochoroidopathy (ADVIRC) is characterized by vitreous liquefaction with or without peripheral vitreal condensations. Peripheral pigmentary changes typically occur at the equatorial region with a discrete posterior boundary associated with diffuse retinal vascular leakage, cystoid macular edema, and early-onset cataract. The peripheral pigmented band extends from the ora serrata to the equator for 360 of the retina. Other ocular associations are vitreous cells and condensation, puntate opacities in the retina, choroidal atrophy, and early nuclear sclerosis. The ERG responses are normal although the electroculogram (EOG) has been shown to be abnormal in ADVIRC.

Vitreoretinopathy Associated with Corneal Changes

The remaining category contains only one hereditary vitreoretinopathy called snowflake vitreoretinal degeneration named after the retinal appearance.

Snowflake vitreoretinal degeneration (OMIM #193230)

The pathognomic feature of snowflake vitreoretinal degeneration is the association with corneal guttata. Disk pallor is also a key feature of snowflake vitreoretinal degeneration not described in any of the other hereditary vitreoretinopathies. The vitreous has a fibrillar appearance. The snowflake-like opacities in the retina are small and may not be immediately obvious. Minor vascular abnormalities of small retinal vessels have been described in snowflake vitreoretinal degeneration.

Molecular Genetics of the Hereditary

Vitreoretinopathies

The classification in Table 1 correlates with genotype. Table 3 lists the causative genes that have been identified to date in the hereditary vitreoretinopathies with the protein affected (Table 3).

Mutations in genes coding for the structural components of vitreous result in a hereditary vitreoretinopathy. In common with connective tissues in other parts of the

body, vitreous is composed of an extracellular matrix with relatively few cells and the arrangement of the collagenous proteins, along with the high water content, maintains transparency. Vitreous collagen fibrils are heterotypic and have a core of type II and V/XI collagen, with type IX collagen on the surface. Mutations in genes coding for chains which comprise these three types of collagen result in the most common hereditary vitreoretinopathy, Stickler syndrome.

The majority of patients with Stickler syndrome have type 1 Stickler syndrome which is part of the spectrum of type II collagen disorders along with Kniest dysplasia and SEDC. Most have premature termination mutations of the COL2A1 gene and are characterized by a membranous vitreous appearance on biomicroscopy. Other pedigrees exhibit a different beaded vitreous phenotype and are associated with mutations in one of the genes coding for type V/XI collagen (COL11A1). Type 1 Stickler syndrome, in the majority of cases, results from haploinsufficiency from nonsense-mediated decay through point mutations or frameshifts, whereas type 2 Stickler syndrome results from dominant negative mutations.

Collagen types II and IX are expressed in both vitreous and cartilage, so Stickler syndrome is characterized by an

Figure 13 Pseudoexotropia in Wagner syndrome.

Figure 14 Retinal folds seen in familial exudative vitreoretinopathy.

ocular and skeletal phenotype. Cartilage also contains type XI collagen, which is similar to the type V/XI collagen of vitreous and they share the a1(XI) chain that is encoded by COL11A1; so mutations in this gene have an ocular and skeletal phenotype. A subgroup of Stickler syndrome, designated predominantly ocular, or ocular-only, has been shown to result from mutations of COL2A1 which are preferentially expressed in ocular tissues. Exon 2 of COL2A1 is spliced out of cartilage type II collagen and therefore mutations in exon 2 have a normal skeletal phenotype while displaying the characteristic ocular features of Stickler syndrome. Prior to detailed understanding of the molecular genetics of Stickler syndrome, the existence of patients demonstrating

ocular features without systemic findings was a source of confusion between Stickler syndrome and other vitreoretinal degenerative conditions without systemic involvement.

Fibrillins are one of the main constituents of extracellular microfibrils and these provide structural support in many tissues. Mutations in FBN1, encoding for fibrillin 1, are the major cause of Marfan syndrome. Mutations in a second gene, transforming growth factor beta receptor II (TGFBR2), have been found in patients fulfilling the clinical criteria for Marfan syndrome, but the mechanism for this remains to be clarified.

Wagner syndrome is a further example of a hereditary vitreoretinopathy which results from a mutation in a gene coding for a structural protein in the vitreous. CSPG2 encodes the core protein of a chondroitin sulfate proteoglycan called versican. Versican binds hyaluronan and therefore may contribute to the structure of the vitreous. Versican undergoes alternative splicing and several splice variants have been identified in the eye. All causative mutations to date affect the splicing of exon 7 of the CSPG2 gene which represents one of two glycosaminoglycan attachment sites. In Wagner syndrome there is an altered appearance to the vitreous, and progressive retinal dysfunction and hemeralopia even in the absence of retinal detachment, suggesting that versican has additional roles to being a structural component of the vitreous.

FEVR is also genetically heterogenous. All the causative genes to date in FEVR code for proteins involved in the Wnt signaling pathway. Frizzled homolog 4 (Drosophila) (FZD4) is a presumptive Wnt receptor, lipoprotein-receptor-related protein 5 (LRP5) can transduce Wnt signaling in vitro, and Norrie disease (Pseudoglioma) (NDP) encodes for norrin. Norrin is present in extracellular matrices and is thought to act as a ligandreceptor pair with FZD4. Although unrelated to Wnts, norrin may act on the Wnt signaling pathway through the frizzled receptor. Wnt receptors are implicated in retinal neovascularization. NDP mutations can also cause Norrie disease (characterized by incomplete retinal vascularization along with more extensive retinal degenerative changes, microphthalmia, and progressive mental disorder).

In general, the molecular genetics of the hereditary vitreoretinopathies demonstrate how mutations of key genes involved in ocular development and structure can result in different phenotypes. Goldmann–Favre syndrome is allelic with enhanced S-cone dystrophy (ESCD). The responsible gene encodes a retinal nuclear receptor involved in signaling pathways. ADVIRC is allelic with Best’s macular dystrophy and results from mutations in the VMD2 gene encoding a transmembrane chloride channel. Snowflake vitreoretinal dystrophy is caused by a mutation in a gene encoding a different transmembrane channel.

Of the hereditary vitreoretinopathies associated with skeletal abnormalities, the majority are inherited as an autosomal dominant trait. The exceptions are Stickler

syndrome specifically associated with COL9A1 mutations, and Knobloch syndrome, both of which have an autosomal recessive pattern of inheritance. Wagner syndrome/erosive vitreoretinopathy is inherited in an autosomal dominant pattern. Favre–Goldmann syndrome/ ESCD is autosomal recessive. Vitreoretinopathies associated with abnormal retinal vascularization are again inherited as autosomal dominant traits for the majority with the one exception being an X-linked form of FEVR. Snowflake vitreoretinal dystrophy is autosomal dominant.

See also: Rhegmatogenous Retinal Detachment; Secondary Photoreceptor Degenerations.

Further Reading

Ahmad, N. N., Ala-kokko, L. A., Knowlton, R. G., et al. (1991). Stop codon in the procollagen II (COL2A1) in a family with Stickler syndrome (arthro-ophthalmopathy). Proceedings of the National Academy of Sciences of the United States of America 88: 6624–6627.

Boileau, C., Jondeau, G., Babron, M-C., et al. (1993). Autosomal dominant Marfan-like connective-tissue disorder with aortic dilation and skeletal anomalies not linked to the fibrillin gene. American Journal of Human Genetics 53: 46–54.

Dietz, H. C., Cutting, G. R., Pyeritz, R. E., et al. (1991). Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature 352: 337–339.

Fullwood, P., Jones, J., Bundey, S., et al. (1993). X-linked exudative vitreoretinopathy: Clinical features and genetic linkage analysis.

British Journal of Ophthalmology 77: 168–170.

Hejtmancik, J. F., Jiao, X., Li, A., et al. (2008). Mutations in KCNJ13 cause autosomal-dominant snowflake vitreoretinal degeneration.

American Journal of Human Genetics 82(1): 174–180.

Miyamoto, T., Inoue, H., Sakamoto, Y., et al. (2005). Identification of a novel splice site mutation of the CSPG2 gene in a Japanese family with Wagner syndrome. Investigative Ophthalmology and Visual Science 46: 2726–2735.

Richards, A. J., Yates, J. R. W., Williams, R., et al. (1996). A family with stickler syndrome type 2 has a mutation in the COL11A1 gene

resulting in the substitution of glycine 97 by valine in alpha1(XI) collagen. Human Molecular Genetics 5(9): 1339–1343.

Robitaille, J., MacDonald, M. L., Kaykas, A., et al. (2002). Mutant frizzled-4 disrupts retinal angiogenesis in familial exudative vitreoretinopathy. Nature Genetics 32(2): 326–330.

Ryan, S. J., Hinton, D. R., Schachat, A. P., and Wilkensen, P. (eds.) (2006). Retina, 4th edn. Philadelphia, PA: Elsevier.

Sertie, A. L., Sossi, V., Camargo, A. A., et al. (2000). Collagen XVIII, containing an endogenous inhibitor of angiogenesis and tumor growth factor, plays a critical role in the maintenance of retinal structure and in neural tube closure (Knobloch syndrome). Human Molecular Genetics 9: 2051–2058.

Sharon, D., Sandberg, M. A., Caruso, R. C., Berson, E. L., and Dryja, T. P. (2003). Shared mutations in NR2E3 in enhanced S-cone syndrome, Goldmann–Favre syndrome, and many cases of clumped

pigmentary retinal degeneration. Archives of Ophthalmology 121(9): 1316–1323.

Taylor, D. and Hoyt, C. S. (eds.) (2005). Pediatric Ophthalmology and Strabismus, 3rd edn. Philadelphia, PA: Elsevier.

Tiller, G. E., Weis, M. A., Polumbo, P. A., et al. (1995). An RNA-splicing mutation (Gþ5IVS20) in the type II collagen gene (COL2A1) in a family with spondyloepiphyseal dysplasia congenital. American Journal of Human Genetics 56(2): 388–395.

Toomes, C., Bottomley, H. M., Jackson, R. M., et al. (2004). Mutations in LRP5 or FZD4 underlie the common familial exudative vitreretinopathy locus on chromosome 11q. American Journal of Human Genetics 74(4): 721–730.

Van Camp, G., Snoeckx, R. L., Hilgert, N., et al. (2006). A new autosomal recessive form of stickler syndrome is caused by a mutation in the COL9A1 gene. American Journal of Human Genetics

79(3): 449–457.

Winterpacht, A., Hilbert, M., Schwarze, U., et al. (1993). Kniest and Stickler dysplasia phenotypes caused by collagen type II gene (COL2A1) defect. Nature Genetics 3(4): 323–326.

Yardley, J., Leroy, B. P., Hart-Holden, N., et al. (2004). Mutations of VMD2 splicing regulators cause nanophthalmos and autosomal dominant vitreoretinochoroidopathy (ADVIRC). Investigative Ophthalmology and Visual Science 45(10): 3683–3689.

Relevant Website

http://www.ncbi.nlm.nih.gov – National Center for Biotechnology Information, Online Mendelian Inheritance in Man.

Glossary

Cell extrinsic signaling – It refers to the activation of a biological pathway within a particular cell by an extracellular factor such as a hormone and morphogen.

Cell intrinsic signaling – It refers to the activation of a biological pathway within a particular cell by a factor that is produced by that cell and is not secreted, such as a transcription factor. Differentiation – The process whereby a lessspecialized cell, such as a progenitor, becomes a specialized cell type. In general, a cell undergoing a differentiation program will exit the cell cycle and become restricted in the number of lineages it

can adopt.

Lineage commitment/fate specification – The process whereby cell intrinsic and extrinsic cues will direct a progenitor cell toward differentiating into a specific cell lineage or cell type.

Multipotency – The ability of a particular progenitor cell to give rise to a limited number of different cell lineages.

Retinal progenitor cell (RPC) – An undifferentiated, proliferating, multipotent cell located in the neuroblast layer of the developing retina. RPCs are competent to give rise to the six neural and one glial cell types found in the mature retina; however, as retinal development proceeds, the competence of an RPC becomes restricted. The undifferentiated state, proliferative capacity, and multipotency of RPCs is controlled by both cell extrinsic and intrinsic signaling factors.

Introduction

The six different types of neurons and the one glial cell type in the adult vertebrate retina are generated in a conserved temporal sequence from a pool of multipotential retinal progenitors cells (RPCs). Retinal ganglion cells (GCs), cone photoreceptors, horizontal cells, and half of the amacrine neurons are born during the embryonic period, while the remaining amacrine neurons, bipolar neurons, and Mu¨ller glia are born in the postnatal period. Rod photoreceptors are generated throughout histogenesis.

To explain the temporal sequence of neuron generation from multipotential progenitors, a competence model has been proposed in which RPCs progress irreversibly through a series of stages where they are competent to generate a limited number of cell types. Because, depending upon the species, retinal histogenesis occurs over several days to weeks, factors that influence proliferation, timing of differentiation, as well as cell fate will impact this program. The role of transcription factors in lineage specification of RPCs is well established and a growing body of evidence also implicates a role for intercellular signaling in this process. Here, we review the impact of major developmental signaling pathways such as Hedgehog, Wnt, Notch, transforming growth factor-b (TGF-b), and retinoic acid (RA) on the histogenic program in the vertebrate retina.

Notch

The notch pathway is an evolutionarily conserved intercellular signaling mechanism that regulates numerous cellular programs. Activation of notch signaling is initiated through interaction of the notch extracellular domain on the surface of one cell with the DSL ligands (Delta, Serrate, and Lag2) on the surface of a neighboring cell (Figure 1). Upon binding to the DSL ligand, notch is cleaved by the g-secretase complex releasing the notch intracellular domain (NICD). NICD translocates to the nucleus where it interacts with C-promoter binding factor 1/suppressor of hairless/longevity assurance gene 1 (CSL) complex and converts it from a transcriptional repressor to an activator. In the absence of notch signaling, CSL recruits corepressor proteins to form a transcriptional repressor complex, which inhibits target gene expression. The association of NICD with CSL displaces corepressors and recruits coactivators which results in transcriptional activation of basic helix–loop–helix (bHLH) transcription factors such as hairy and enhancer of split 1 and 5(Hes1 and Hes5).

Findings from early studies on the role of notch signaling in the retina suggest that one of its major functions is in controlling the timing of cell cycle exit and maintenance of the retinal progenitor pool. For example, in the frog, fish, rat, chick, and mouse retina the level of notch signaling is inversely proportional to the rate of cell cycle exit and neuronal differentiation. Similar to its actions in other regions of the central nervous system (CNS), the antidifferentiation effects of notch activity in the retina are associated with inhibition of proneural bHLH gene