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Other entities represented in this entry:
SNOMEDCT: 711162004; ORPHA: 263347, 3086; DO: 0111569;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 11q12.3 | Vitreoretinochoroidopathy | 193220 | Autosomal dominant | 3 | BEST1 | 607854 |
| 11q12.3 | ?Microcornea, rod-cone dystrophy, cataract, and posterior staphyloma 2 | 193220 | Autosomal dominant | 3 | BEST1 | 607854 |
A number sign (#) is used with this entry because of evidence that autosomal dominant vitreoretinochoroidopathy (VRCP) is caused by heterozygous mutation in the bestrophin-1 gene (BEST1; 607854) on chromosome 11q12.
Microcornea, rod-cone dystrophy, cataract, and posterior staphyloma-2 (MRCS2), a disorder with features that overlap those of VRCP, is also caused by heterozygous mutation in the BEST1 gene. One such family has been reported. For a discussion of genetic heterogeneity of MRCS, see 619082.
Under the designation autosomal dominant vitreoretinochoroidopathy (ADVIRC), Kaufman et al. (1982) described a seemingly 'new' fundus dystrophy characterized by chorioretinal hypopigmentation and hyperpigmentation, usually lying between the vortex veins and the ora serrata for 360 degrees. In this zone, a discrete posterior boundary, preretinal punctate white opacities, retinal arteriolar narrowing and occlusion, and, in some cases, choroidal atrophy are found. Most affected persons in the 1 kindred observed by Kaufman et al. (1982) had diffuse retinal vascular incompetence, cystoid macular edema, and presenile cataracts. Fibrillar condensation and a moderate pleocytosis characterized the vitreous. Progression was very slow. Electroretinogram was normal in younger affected persons and only moderately abnormal in older ones. Preretinal neovascularization was progressive in the proband. No systemic or skeletal abnormalities, high myopia, optically empty vitreous lattice degeneration, areas of white-without-pressure, retinal breaks or retinal detachment were found in any to point to a previously delineated entity.
Blair et al. (1984) described a second family with this disorder. Affected persons in 3 generations and male-to-male transmission confirmed autosomal dominant inheritance (although the authors pointed out that the changes were minimal in the father and paternal grandmother and 'possibly could be nonspecific').
Traboulsi and Payne (1993) described a third family with ADVIRC in which 13 members of 5 generations were affected. Visual acuity was 20/25 or better in all but 1 patient. All affected individuals had vitreous liquefaction with or without peripheral vitreal condensations. Peripheral pigmentary changes and choroidal atrophy were characteristic. Cataracts developed in 6 patients in their early forties and required extraction. One patient had glaucoma, 1 developed a retinal detachment, and 1 had a spontaneous vitreous hemorrhage. One instance of male-to-male transmission was observed. In a 70-year-old affected member of the pedigree described by Traboulsi and Payne (1993), Oh and Vallar (2006) found evidence of central cone dysfunction. The patient had normal full-field electroretinography (ERG) but focally reduced macular multifocal ERG. Ocular coherence tomography showed thinning of the fovea and perifoveal region of both eyes.
Hermann (1958) reported a French family with microphthalmia in 13 members of 4 generations. Six of the affected individuals also had pigmentary retinopathy, 5 had cataract (peripheral opacities as well as sutural and posterior polar), and 4 had glaucoma. The author noted that several individuals had dyschromatopsia, and nystagmus and strabismus were also observed in this family. No extraocular abnormalities were mentioned. Francois et al. (1993) examined 28 members of the family originally described by Hermann (1958), in which the 4 major features of microcornea, vitreoretinochoroidopathy, glaucoma, and cataract segregated in an autosomal dominant fashion. Francois et al. (1993) provided a detailed description of an affected woman, her 2 daughters, and the 2 affected children of 1 of the daughters: all 5 patients had bilateral microcornea and circumferential peripheral retinopathy involving pigmentary clumping and whitish dots, with atrophy around the optic disc extending to the macula; the 3 youngest patients had a whitish equatorial demarcation line bordering the retinopathy. The 2 oldest patients also had bilateral cataract and glaucoma, and the 65-year-old mother had bilateral microphthalmia and posterior staphyloma.
Lafaut et al. (2001) examined 12 affected and 4 unaffected members of a 3-generation Belgian family segregating autosomal dominant vitreoretinochoroidopathy. Characteristic annular peripheral pigmentary changes were present in all affected members, as well as chorioretinal atrophy varying from a tigroid appearance to marked atrophy. Seven patients had a fibrillary vitreous, although vitreal cells were seen in only 3 patients. Six patients developed premature cataracts. Four patients had microcornea and shallow anterior chamber without microphthalmia (although the reported axial length of the right eye of 1 of those 4 patients was 21.0 mm, and the axial lengths of 3 eyes in 2 other affected family members measured 21.2 mm, 21.9 mm, and 21.5 mm). Two patients developed acute angle-closure glaucoma at ages 64 and 45 years, and another developed subacute angle-closure glaucoma at age 35 years. Visual fields tended to constrict concentrically with age. Electrooculography was abnormal in the 10 affected family members tested and normal in 4 unaffected family members. ERG findings were variable: low-normal to normal rod and cone responses were found in 6 younger patients, whereas 3 older patients had mild to moderate reduction of cone and rod responses with near-normal latencies. Two patients, aged 37 and 61 years, had severely reduced rod and cone responses with moderately increased latencies; they were also the only patients who had extensive midperipheral and macular chorioretinal atrophy. Lafaut et al. (2001) concluded that the presentation of VRCP is variable and may be associated with microcornea, shallow anterior chamber, and angle-closure glaucoma.
In an affected sister and brother from a family with genetically confirmed ADVIRC, Burgess et al. (2009) described the proband with the typical phenotype involving a developmental anomaly of the anterior segment predisposing to angle closure glaucoma, early adult-onset cataract, and the typical fundus appearance of a broad post-oral circumferential band of atrophy and pigmentation. Her brother had a milder phenotype but also had the typical peripheral retinal abnormality.
Microcornea, Rod-Cone Dystrophy, Cataract, and Posterior Staphyloma-2
Reddy et al. (2003) described 6 patients from a 3-generation English family with a complex developmental disorder of the eye, typically involving night blindness during the second decade of life and poor vision due to cataracts before age 30 years, with cataract surgery required in the second or third decade. Older individuals had poor vision (ranging from no light perception to 20/400) while younger individuals retained good visual acuities (20/30). All individuals had small corneas, and 2 older individuals had chronic angle closure glaucoma. Younger individuals had pulverulent-like cataracts and moderate myopia; the older patients were aphakic due to previous cataract surgery. All affected members had retinal abnormalities consisting of peripheral retinal pigment epithelium atrophy and retinal pigmentation. In addition, there was evidence of a posterior staphyloma in 9 of 12 eyes; in younger individuals, there was a clear-cut demarcation line possibly related to the boundary of the staphyloma, anterior to which there was retinal pigmentation. Although clinical examination showed some features consistent with a diagnosis of nanophthalmos, patients did not have consistently reduced axial lengths: ultrasonography revealed eye sizes within the normal range except in the 3 eyes without staphyloma, which had axial lengths of 18.73 mm, 16.63 mm, and 16.44 mm. The ERG was extinguished in 2 older family members, and subnormal photopic and scotopic responses were demonstrated in a mother and her 2 children, 1 of whom had reduced scotopic responses compared to the photopic responses. No systemic disease or abnormality was identified as segregating with the retinal disease. Reddy et al. (2003) designated the phenotype in this family 'MRCS,' for microcornea, rod-cone dystrophy, cataract, and posterior staphyloma.
In a 3-generation English family with microcornea, rod-cone dystrophy, cataract, and posterior staphyloma, Reddy et al. (2003) performed PCR-based microsatellite marker genotyping using a positional candidate gene approach; they excluded linkage to other candidate microphthalmia loci and found suggestive linkage, with a maximum lod score of 2.01, to a region on 11q13 within the nanophthalmos-1 (NNO1; 600165) genetic interval.
In the then 4-generation Belgian family with a combined vitreous and retinal phenotype, originally reported by Lafaut et al. (2001), Yardley et al. (2004) found linkage to chromosome 11, with a maximum lod score of 3.26 at markers D11S4152 and D11S4200. Haplotype analysis using microsatellite markers narrowed the critical region to a 38-cM to 73-cM interval between D11S4152 and D11S4139, overlapping the putative loci for NNO1 and the MRCS phenotype.
Yardley et al. (2004) noted that both the Belgian family reported by Lafaut et al. (2001) and the English family reported by Reddy et al. (2003) had pathologically low electrooculograms, a clinical finding also seen in vitelliform macular dystrophy (VMD; 153700) caused by mutation in the BEST1 gene (607854), which lies within the critical region of linkage for both families. Yardley et al. (2004) therefore sequenced the BEST1 gene in those 2 families and 3 others that also had autosomal dominant developmental eye abnormalities associated with retinal dystrophy, including a 6-generation French family with vitreoretinochoroidopathy, microcornea, glaucoma, and cataract originally reported by Hermann (1958), and identified 3 different heterozygous mutations, respectively (607854.0019-607854.0021).
In an affected sister and brother from a family with ADVIRC, Burgess et al. (2009) identified heterozygosity for a missense mutation in the BEST1 gene (607854.0026).
Blair, N. P., Goldberg, M. F., Fishman, G. A., Salzano, T. Autosomal dominant vitreoretinochoroidopathy (ADVIRC). Brit. J. Ophthal. 68: 2-9, 1984. [PubMed: 6689931] [Full Text: https://doi.org/10.1136/bjo.68.1.2]
Burgess, R., MacLaren, R. E., Davidson, A. E., Urquhart, J. E., Holder, G. E., Robson, A. G., Moore, A. T., O'Keefe, R., Black, G. C. M., Manson, F. D. C. ADVIRC is caused by distinct mutations in BEST1 that alter pre-mRNA splicing. (Letter) J. Med. Genet. 46: 620-625, 2009. [PubMed: 18611979] [Full Text: https://doi.org/10.1136/jmg.2008.059881]
Francois, P., Puech, B., Hache, J. C., Laffineur, O. Heredo-dystrophie chorioretinovitreenne, microcornee, glaucome et cataracte. J. Franc. Ophtal. 16: 29-40, 1993. [PubMed: 8482797]
Hermann, P. Le syndrome: microphtalmie-retinite pigmentaire-glaucome. Arch. Ophtal. Rev. Gen. Ophtal. 18: 17-24, 1958. [PubMed: 13534955]
Kaufman, S. J., Goldberg, M. F., Orth, D. H., Fishman, G. A., Tessler, H., Mizuno, K. Autosomal dominant vitreoretinochoroidopathy. Arch. Ophthal. 100: 272-278, 1982. [PubMed: 7065944] [Full Text: https://doi.org/10.1001/archopht.1982.01030030274008]
Lafaut, B. A., Loeys, B., Leroy, B. P., Spileers, W., De Laey, J. J., Kestelyn, P. Clinical and electrophysiological findings in autosomal dominant vitreoretinochoroidopathy: report of a new pedigree. Graefes Arch. Clin. Exp. Ophthal. 239: 575-582, 2001. [PubMed: 11585313] [Full Text: https://doi.org/10.1007/s004170100318]
Oh, K. T., Vallar, C. Central cone dysfunction in autosomal dominant vitreoretinochoroidopathy (ADVIRC). Am. J. Ophthal. 141: 940-943, 2006. [PubMed: 16678511] [Full Text: https://doi.org/10.1016/j.ajo.2005.11.041]
Reddy, M. A., Francis, P. J., Berry, V., Bradshaw, K., Patel, R. J., Maher, E. R., Kumar, R., Bhattacharya, S. S., Moore, A. T. A clinical and molecular genetic study of a rare dominantly inherited syndrome (MRCS) comprising of microcornea, rod-cone dystrophy, cataract, and posterior staphyloma. Brit. J. Ophthal. 87: 197-202, 2003. [PubMed: 12543751] [Full Text: https://doi.org/10.1136/bjo.87.2.197]
Traboulsi, E. I., Payne, J. W. Autosomal dominant vitreoretinochoroidopathy: report of the third family. Arch. Ophthal. 111: 194-196, 1993. [PubMed: 8431155] [Full Text: https://doi.org/10.1001/archopht.1993.01090020048021]
Yardley, J., Leroy, B. P., Hart-Holden, N., Lafaut, B. A., Loeys, B., Messiaen, L. M., Perveen, R., Reddy, M. A., Bhattacharya, S. S., Traboulsi, E., Baralle, D., De Laey, J.-J., Puech, B., Kestelyn, P., Moore, A. T., Manson, F. D. C., Black, G. C. M. Mutations of VMD2 splicing regulators cause nanophthalmos and autosomal dominant vitreoretinochoroidopathy (ADVIRC). Invest. Ophthal. Vis. Sci. 45: 3683-3689, 2004. [PubMed: 15452077] [Full Text: https://doi.org/10.1167/iovs.04-0550]