The Brittle Cornea Syndrome: Study of a family with five affected siblings

Abstract

Purpose To define the natural history,genotype‐phenotype correlation and differential diagnosis of the Brittle Cornea Syndrome (BCS),or Ehlers Danlos Syndrome (EDS) type VIB,caused by mutations in ZNF469 and PRDM5 Methods We evaluated one family in which 5 out of 8 siblings suffered from BCS. We performed complete eye and systemic evaluations of the siblings and their parents. We sequenced the candidate gene,ZNF469 Results On ocular evaluation we found keratoglobus and thinned corneas that tended to perforate spontaneously,as well as refractive errors caused by high myopia and irregular astigmatism. Progressive thinning of the corneas with keratoglobus led to visual deterioration due to spontaneous perforations and scarring. K readings were above 60 D and corneal thickness below 300um in 4 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 EDS VIA,the ocular manifestations of which consist of flattened corneal curvatures,fluid vitreous,radial perivascular lattice. Patients with BCS are often diagnosed as having the Marfan syndrome,even though spontaneous perforation of the cornea is not a feature of the latter condition. A 14bp insertion was found in exon 2 of ZNF469 Conclusion EDS VIB is a connective tissue disease referred to as BCS; it is characterized by keratoglobus,thinned corneas and Marfanoid body habitus. Two causative genes for BCS have been identified to date,ZNF469 and PRDM5. A 14bp insertion was found in exon 2 of ZNF469. It is possible to provide genetic counseling in the extended family