Cause
FECD is a degenerative disease of the corneal endothelium with accumulation of focal outgrowths called guttae (drops) and thickening of Descemets membrane, leading to corneal edema and loss of vision. The corneal endothelial cell layer and its basement membrane (Descemets membrane) act as a barrier to hydration of the corneal stroma by aqueous humor and are "pump" cells of the cornea that function to maintain hydration of the cornea at a specific level that maintains corneal stromal clarity through precise spatial arrangement of collagen fibers. In FED, Descemets membrane is grossly thickened with accumulation of abnormal wide-spaced collagen and numerous guttae. Corneal endothelial cells in end-stage FED are reduced in number and appear attenuated, causing progressive stromal edema (swelling). Progressive endothelial cell loss causes relative influx of aqueous humor into the cornea, leading to swelling (corneal stromal edema), which results in blurred vision. Eventually, the epithelium also becomes edematous, resulting in more severe visual impairment. Focal blisters of epithelial edema ("bullae") may be particularly painful when they burst.The inheritance of FECD is complex and polymorphic such that although inheritance is autosomal dominant there are genetic and environmental modifiers that determine the degree to which members of the same family express the disease. There is reasonable evidence of associations between transcription factor 4 (TCF4) genetic polymorphisms and risk of Fuchs endothelial dystrophy (FED). Endothelial cell loss may be aggravated or accelerated by intraocular trauma or surgery. A common scenario involves prolonged corneal swelling or edema following cataract surgery or other types of ocular surgery.
Differentiating between the two syndromes can be challenging. Genetics
The WT1 gene exists on chromosome 11 (at 11p13), and codes for a four zinc finger transcription factor. Its role as a transcription factor is related to proper kidney and gonadal development. The link between kidney and gonadal development and WT1 was highlighted in past studies looking at the related Denys-Drash syndrome. Results of various investigations identified the loss of function of WT1 to be a prerequisite of Wilms tumour development, and also a key trait of individuals with genital abnormalities.Mutations responsible for Frasier syndrome predominantly occur in intron 9 of the WT1 gene, specifically nucleotide substitutions that influence an intron splice site. Mutations in this region proved for the absence of three amino acids—K T S—between the third and fourth WT1 zinc fingers. Referring to the autosomal dominant expressive nature of this disease, it is only necessary for an individual to have one complement of the mutated intronic sequence to appear affected. Differing from the similar Denys-Drash syndrome, where a mutated form of the WT1 protein exists, Frasier syndrome expression works solely on the existence of a changed ratio of KTS isoforms: normal WT1 proteins including the KTS site (+KTS), and mutated, shortened proteins lacking the KTS site (–KTS). Through alternative splicing, a specific ratio of the two isoforms normally exists, though the mutation in the intron 9 splice site severely lowers levels of the +KTS isoform; this leads to Frasier syndrome.