The distinct ophthalmic phenotype of Knobloch syndrome in children.
ABSTRACT Knobloch syndrome is defined as a triad of occipital defect, high myopia and vitreo-retinal degeneration (often with later retinal detachment); however, the ocular phenotype is not well defined. This report characterises eye findings of the syndrome in children with genetically confirmed disease.
Case series of Saudi children with previously documented homozygous mutations in COL18A1 or ADAMTS18.
All eight children (4-15 years old; five families) had smooth (cryptless) irides, high myopia (-10 to -20 dioptres) and distinctive vitreo-retinal degeneration consisting of diffuse very severe retinal pigment epithelium atrophic changes with prominent choroidal vessel show, macular atrophic lesions with or without a 'punched out' appearance and white fibrillar vitreous condensations. In two probands and a sibling, this distinctive retinal appearance was the basis for initial clinical diagnosis. Six children had temporal ectopia lentis and four had posterior perinuclear lens opacity. Additional features included developmental delay (two), epilepsy (one) and heterotopic grey matter in the lateral ventricles (one). Four children had no clinically discernible occipital defect.
Taken together, smooth iridies, ectopia lentis and characteristic vitreo-retinal degeneration seem pathognomonic. Although it is a defining feature of the syndrome, clinically discernible occipital defect is not a sine qua non for the diagnosis. Ophthalmologists are uniquely able to diagnose Knobloch syndrome.
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ABSTRACT: Autosomal dominant mutation of the FBN1 gene (fibrillin-1) results in a spectrum of disease (type 1 fibrillopathies) ranging from Marfan syndrome with lens subluxation and cardiovascular complications to milder connective tissues phenotypes. The likelihood of FBN1 mutation in children referred to ophthalmologists because of lens subluxation is unclear. We report the results of routine FBN1 sequencing for children from inbred families referred with nontraumatic lens subluxation without cataract or vitreoretinal degeneration. Medical records of such patients from 2009 to 2012 were retrospectively reviewed. Eight identified probands (3-11 years old; 4 boys) from consanguineous and/or endogamous Saudi Arabian families all harbored FBN1 mutation-7 autosomal dominant and 1 autosomal recessive (homozygous). Four mutations were novel. One child had a family history for lens subluxation. Seven had facial and/or skeletal features suggestive of type 1 fibrillinopathy. The parents of the autosomal recessive case were confirmed to be heterozygous carriers without lens subluxation or other clinical signs of type 1 fibrillinopathy. Autosomal dominant type 1 fibrillinopathy was the major cause for lens subluxation in this cohort despite the fact that families were inbred and thus at higher risk for recessive disease. This highlights the frequency of new mutations in the gene and has important implications for genetic counseling and systemic assessment. The autosomal recessive case represents the fourth such case reported to date. Her heterozygous parents were unaffected carriers, suggesting that some FBN1 mutations can act as hypomorphic alleles rather than exhibiting the dominant negative effect typically attributed to FBN1 mutations.Journal of AAPOS: the official publication of the American Association for Pediatric Ophthalmology and Strabismus / American Association for Pediatric Ophthalmology and Strabismus 04/2014; 18(2):134-9. · 1.07 Impact Factor
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ABSTRACT: We have recently described an apparently novel ocular syndrome characterized by microcornea, myopic chorioretinal atrophy and telecanthus (MMCAT) in a number of Saudi families. Consistent with the presumed pseudodominant inheritance in one of the original families, we show that MMCAT maps to a single autozygous locus on chr16q23.1 in which exome sequencing revealed a homozygous missense change in ADAMTS18. Direct sequencing of this gene in four additional probands with the same phenotype revealed three additional homozygous changes in ADAMTS18 including two nonsense mutations. Reassuringly, the autozygomes of all probands overlap on the same chr16q23.1 locus, further supporting the positional mapping of MMCAT to ADAMTS18. ADAMTS18 encodes a member of a family of metalloproteinases that are known for their role in extracellular matrix remodeling, and previous work has shown a strong expression of Adamts18 in the developing eye. Our data suggest that ADAMTS18 plays an essential role in early eye development and that mutations therein cause a distinct eye phenotype that is mainly characterized by microcornea and high myopia. This article is protected by copyright. All rights reserved.Human Mutation 07/2013; · 5.21 Impact Factor
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ABSTRACT: Centered on the Arabian Peninsula, the Middle East encompasses Northern Africa to Western Asia. Primarily Arab and historically tribal, populations from this region often practice customary intrafamilial marriage (consanguinity), intratribal marriage (endogamy), and a preference for many offspring. These social factors increase the frequency of homozygosity, including homozygosity for gene mutation and thus for recessive ocular disease. This review highlights recent studies of ocular genetic disease in the Middle East. Among modern molecular genomic/genetic strategies, homozygosity mapping as a method to guide candidate gene analysis has been a powerful technique for the Middle East. Studies from the region have enhanced our understanding of ocular genetic conditions that are more common worldwide (such as pediatric glaucoma, pediatric cataract, and retinal dystrophy/dysfunction), rare worldwide (such as cornea plana, brittle cornea syndrome, and posterior microphthalmos), and currently only reported on the Arabian Peninsula (such as microcornea with myopic chorioretinal degeneration and telecanthus, familial retinal arterial macroaneurysms, and spherophakia with short stature). For some patients diagnosed with non-syndromic cataract or retinal dystrophy, genomic/genetic analysis uncovered recessive mutation in a syndrome gene and phenotypic reassessment confirmed the presence of the undiagnosed syndrome in the tested patients. Recent studies from the Middle East, many of which employed homozygosity mapping, have improved phenotype-genotype correlations for common and rare ocular genetic disease. In some instances genetic diagnosis revealed an undiagnosed syndrome. Reports of ocular genetic conditions thus far unique to the region have suggested novel ocular developmental pathways.Current opinion in ophthalmology 07/2013; · 2.49 Impact Factor