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Irene H. Maumenee, Abdulmunim F. Alharbi, Fatoumata Yanoga, Nathalie F. Azar; Natural History, Genotype-Phenotype Correlation and Differential Diagnosis of the Brittle Cornea Syndrome. Invest. Ophthalmol. Vis. Sci. 2011;52(14):2397.
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© ARVO (1962-2015); The Authors (2016-present)
To define the natural history, genotype-phenotype correlation and differential diagnosis of the Brittle Cornea Syndrome, a subtype of Ehlers Danlos syndrome, type VI
We evaluated one large consanguineous family originating from Saudi Arabia in which five out of eight siblings suffered from the Brittle Cornea Syndrome (BCS). We performed eye and systemic evaluations of the siblings and their parents including keratometry, measurement of corneal thickness, assessment of the vitreous and retina, skin elasticity, scarring and joint mobility. We sequenced the candidate gene, ZNF469.
On ocular evaluation we found keratoglobus and thinned corneas that tended to perforate spontaneously, as well as high refractive errors caused by high myopia and irregular astigmatism. Progressive thinning of the corneas with keratoglobus lead to visual deterioration due to spontaneous perforations and scarring. K readings were above 60 D and corneal thickness below 300um in 4 out of 10 eyes that had not developed perforation. Systemic manifestations included joint hypermobility, increased elasticity of the skin but no cigarette paper scars, kyphoscoliosis, and progressive conductive hearing loss. Cardiovascular disease was not observed. The systemic findings overlap the kyphoscoliotic type of Ehlers-Danlos syndrome (EDS-VIA), the ocular manifestations of which consist of flattened corneal curvatures, fluid vitreous and radial perivascular lattice, comparable to the Stickler syndrome. Patients with BCS are commonly diagnosed as having the Marfan syndrome, even though spontaneous perforation of the cornea is not a feature of that condition. A 14bp insertion was found in exon 2 of ZNF469.
Ehlers-Danlos syndrome VIB (EDS-VIB) is a connective tissue disease referred to as brittle cornea syndrome (BCS); it is characterized by keratoglobus, thinned corneas and a Marfanoid body habitus. One causative gene for the Brittle Cornea Syndrome has been identified, ZNF469, which encodes a Zinc Finger Protein. Four distinct mutations have been found to date: 1 bp del 5943 (5943 delA), 1 bp del 9527 (9527 delG), one missense mutation c.10016G-A, and an insertion in the present family. The clinical findings are milder in this family with fout out of ten eyes at risk not having developed a perforation. It is possible to provide genetic counseling in the extended family based on molecular screening.
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