Chromosome abnormalities and the genetics of congenital corneal opacfication

Clinical and Academic Department of Ophthalmology, Great Ormond Street Hospital, London, UK.
Molecular vision (Impact Factor: 1.99). 06/2011; 17(180-82):1624-40.
Source: PubMed


Congenital corneal opacification (CCO) encompasses a broad spectrum of disorders that have different etiologies, including genetic and environmental. Terminology used in clinical phenotyping is commonly not specific enough to describe separate entities, for example both the terms Peters anomaly and sclerocornea have been ascribed to a clinical picture of total CCO, without investigating the presence or absence of iridocorneal adhesions. This is not only confusing but also unhelpful in determining valid genotype-phenotype correlations, and thereby revealing clues for pathogenesis. We undertook a systematic review of the literature focusing on CCO as part of anterior segment developmental anomalies (ASDA), and analyzed its association specifically with chromosomal abnormalities. Genes previously identified as being associated with CCO are also summarized. All reports were critically appraised to classify phenotypes according to described features, rather than the given diagnosis. Some interesting associations were found, and are discussed.

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    • "syndrome may have a hemizygous loss of function mutations on their remaining SCARF2 allele resulting in sclerocornea. In support of this hypothesis, we did not find mutations in the genes known to be responsible for CCO [Mataftsi et al., 2011]in our patient. At the present time, however, we cannot rule out the possibility that sclerocornea in our patient is caused by recessive or dominant mutations in another gene either not detected in our exome sequencing or not yet know to cause sclerocornea. "
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    ABSTRACT: Van den Ende-Gupta Syndrome (VDEGS) is an autosomal recessive disorder characterized by blepharophimosis, distinctive nose, hypoplastic maxilla, and skeletal abnormalities. Using homozygosity mapping in four VDEGS patients from three consanguineous families, Anastacio et al. [Anastacio et al. (2010); Am J Hum Genet 87:553-559] identified homozygous mutations in SCARF2, located at 22q11.2. Bedeschi et al. [2010] described a VDEGS patient with sclerocornea and cataracts with compound heterozygosity for the common 22q11.2 microdeletion and a hemizygous SCARF2 mutation. Because sclerocornea had been described in DiGeorge-velo-cardio-facial syndrome but not in VDEGS, they suggested that the ocular abnormalities were caused by the 22q11.2 microdeletion. We report on a 23-year-old male who presented with bilateral sclerocornea and the VDGEGS phenotype who was subsequently found to be homozygous for a 17 bp deletion in exon 4 of SCARF2. The occurrence of bilateral sclerocornea in our patient together with that of Bedeschi et al., suggests that the full VDEGS phenotype may include sclerocornea resulting from homozygosity or compound heterozygosity for loss of function variants in SCARF2. © 2014 Wiley Periodicals, Inc.
    Full-text · Article · May 2014 · American Journal of Medical Genetics Part A
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    • "Sclerocornea is a rare form of CCO. Genes implicated in CCO include paired box 6 (PAX6), pituitary homeobox 2 (PITX2), forkhead box C1 (FOXC1), forkhead box E3 (FOXE3), β1,3-galactosyltransferase-like (B3GALTL), and keratocan (KERA), indicating heterogeneity in a genetic aberration of CCO [21]. For surgical outcomes in infants with CCO, Comer et al. reported overall first graft survival at 12 months was 61%, with ten of 16 eyes retaining a clear corneal graft [10]. "
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    ABSTRACT: To understand whether the epithelial phenotype in total sclerocornea is corneal or conjunctival in origin. Four cases of total sclerocornea (male:female = 1:3; mean age = 5.4±4.3; 1-11 years old) who received penetrating keratoplasty (PKP) at our hospital between 2008 and 2011 were included. Corneal buttons obtained during PKP were used for transmission electron microscopy (TEM) as well as immunoconfocal microscopy for cytokeratins 3, 12, and 13, goblet cell mucin MUC5AC, connexin 43, stem cell markers p63 and ABCG2, laminin-5, and fibronectin. After a mean follow-up period of 38.8±14.0 (12-54) months, the grafts remained clear in half of the patients. TEM examination revealed a markedly attenuated Bowman's layer in the scleralized corneas, with irregular and variably thinned collagen lamellar layers, and disorganization and random distribution of collagen fibrils, which were much larger in diameter compared with a normal cornea. Immunoconfocal microscopy showed that keratin 3 was expressed in all four patients, while p63, ABCG2, and MUC5AC were all absent. Cornea-specific keratin 12 was universally expressed in Patients 1 to 3, while mucosa (including conjunctiva)-specific keratin 13 was negative in these patients. Interestingly, keratin 12 and 13 were expressed in Patient 4 in a mutually exclusive manner. Linear expression of laminin-5 in the basement membrane zone and similar expression of fibronectin were observed. The epithelia in total sclerocornea are essentially corneal in phenotype, but in the event of massive corneal angiogenesis, invasion by the conjunctival epithelium is possible.
    Full-text · Article · Apr 2014 · Molecular vision
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    • "The majority of cases occur sporadically, but recessive and dominant familial inheritance is also well documented [7,8]. Sclerocornea can occur alone, in association with other ocular defects, or with systemic features as part of a known syndromic entity [9,10]. "
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    ABSTRACT: To investigate the molecular epidemiological basis for the unusually high incidence of sclerocornea, aphakia, and microphthalmia in a village in the Tlaxcala province of central Mexico. A population census was performed in a village to identify all sclerocornea, aphakia, and microphthalmia cases. Molecular analysis of the previously identified Forkhead box protein E3 (FOXE3) mutation, c.292T>C (p.Y98H), was performed with PCR amplification and direct DNA sequencing. In addition, DNA from 405 randomly selected unaffected villagers was analyzed to establish the carrier frequency of the causal mutation. To identify the number of generations since the mutation arose in the village, 17 polymorphic markers distributed in a region of 6 Mb around the mutated locus were genotyped in the affected individuals, followed by DMLE software analysis to calculate mutation age. A total of 22 patients with sclerocornea, aphakia, and microphthalmia were identified in the village, rendering a disease prevalence of 2.52 cases per 1,000 habitants (1 in 397). The FOXE3 homozygous mutation was identified in all 17 affected subjects who consented to molecular analysis. Haplotype analysis indicated that the mutation arose 5.0-6.5 generations ago (approximately 106-138 years). Among the 405 unaffected villagers who were genotyped, ten heterozygote carriers were identified, yielding a population carrier frequency of approximately 1 in 40 and a predicted incidence of affected of 1 in 6,400 based on random marriages between two carriers in the village. This study demonstrates that a cluster of patients with sclerocornea, aphakia, and microphthalmia in a small Mexican village is due to a FOXE3 p.Y98H founder mutation that arose in the village just over a century ago at a time when a population migrated from a nearby village because of land disputes. The actual disease incidence is higher than the calculated predicted value and suggests non-random marriages (i.e., consanguinity) within the population. We can now offer the community more informed genetic counseling based on an accurate genetic test, thus increasing the likelihood of a better outcome for the families.
    Full-text · Article · Aug 2013 · Molecular vision
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