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Ordan J Lehmann, Mika Asai-Coakwell, Hardeep Singh, Erin Strachan; Additional complexities in Axenfeld-Rieger Syndrome - implications for pediatric glaucoma. Invest. Ophthalmol. Vis. Sci. 2014;55(13):3797.
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To report a novel finding present in multiple molecularly characterized Axenfeld-Rieger Syndrome families: profoundly different disease severity between affected individuals in successive generations.
One cause of Axenfeld-Rieger Syndrome (ARS) is mutation of the forkhead transcription factor FOXC1. This results in a dominantly inherited and fully penetrant pediatric glaucoma phenotype. Our cases were derived from an extensively studied ARS cohort. Molecular investigations included Sanger sequencing and copy number detection, with clinical examination performed by a single ophthalmologist. Phenotypic documentation encompassed corneal and anterior segment photography, as well as cerebral MR imaging. This enabled the degree of corneal angiogenesis, and the severity of the iris and cerebral phenotypes associated with FOXC1-attributable ARS, to be accurately evaluated.
Three pedigrees were identified that exhibited unusual phenotypic features. The first, with a 1216kb FOXC1-encompassing deletion, comprises two mildly affected sisters (subtle iris hypoplasia without glaucoma) and their 3 sons (severe ARS) who required goniotomies/trabeculectomies in the first year of life for congenital glaucoma. The second, with a FOXC1 and FOXF2-encompassing 494kb deletion, consists of a highly functioning physician and his son. The son has much severer ARS, and profound intellectual impairment, while both have a similar degree of cerebral small vessel disease (CSVD). The final pedigree, with a FOXC1 frameshift mutation (p.P274RfsX41) comprises a mildly affected mother (glaucoma diagnosed at 27 years) and son with: buphthalmos (congenital glaucoma diagnosed at 4 months), significant corneal angiogenesis and more severe CSVD.
Since ARS severity is generally invariant between affected generations, such findings in pedigrees with coding mutations and gene dosage changes, demonstrate that additional factors influence the severity of FOXC1-induced disease in both the eye (ARS, corneal angiogenesis) and CNS (CSVD). Potentially, these include variants in other genes (‘second hit’), epigenetic effects or other mechanisms. Identifying these will be important for the scope such knowledge may provide to ameliorate the severity of this type of frequently-blinding pediatric glaucoma.
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