endothelial dystrophy

The signs and symptoms of this disorder are similar to those of other adult endothelial dystrophies.  Guttae appear in the fourth or fifth decade of life and gradually increase in number.  Diffuse corneal edema eventually develops with a corresponding decrease in acuity.  In late stages the corneal edema involves all layers including the epithelium, leading to painful corneal erosions. 

(OMIM has combined this disorder with PPCD1 (122000) based on genetic and clinical evidence.)

Early onset limbus-to-limbus corneal clouding is the outstanding feature.  Some asymmetry is often present.  Vision is minimally impaired if at all in many children but slow progression occurs and adults often become visually impaired.  Nystagmus does not develop.  Photophobia and tearing are common.  The corneal appearance can lead to the erroneous diagnosis of congenital glaucoma.  However, some infants actually do have congenital glaucoma as well leading some to suggest this may be a disorder of anterior chamber dysgenesis.  The edematous cornea may be of 2-3 times normal thickness.  It may appear generally hazy and sometimes has a diffuse ground glass appearance.  

The posterior surface often appears mottled and has been described as having a peau d'orange appearance.  The endothelium is attenuated or even absent histologically and abnormal, disorganized collagen fibrils have been found in a thickened Descemet layer by electron microscopy.  The remaining endothelial cells are often vacuolated and heaped in double layers, with some containing melanin granules.  Some atrophy and edema of the epithelium with partial loss of Bowman's can be seen histologically.

This is a rare disorder with multiple anterior segment anomalies.  The corneal stroma is thinned in the range of 330 to 460 um with uniform steepening (no cone).  The epithelium may be irregular and edematous, the stroma is diffusely hazy, and the endothelium is irregular with many guttae.  Anterior polar cataracts are likely congenital and often require removal before the age of 20 years.  The pupils are often eccentric and difficult to dilate.  The iris stroma may appear atrophic.  Visual acuity, even in the aphakic condition, is in the range of 20/30 to 20/160.

Histological studies show attenuation of the endothelium with cellular overlapping and aggregates of fibrillar material that stains for cytokeratin.  Descemet membrane is thickened as is the epithelial basement membrane and both intracellular and extracellular lipid deposition is seen throughout the stroma and the Bowman membrane.

There are a number of endothelial corneal dystrophies to which Fuchs name has been attached, including two that are early in onset, or even congenital (CHED1; 121700), (CHED2; 217700) and at least three that have an adult onset, one (Fuchs endothelial dystrophy, early onset; 136800) which has a relatively early onset and two considered to have a late onset: the one described here and another known as Fuchs Endothelial Dystropy, Late Onset 2 (613267).  Evidence for multiple distinct types comes from genotyping which reveals considerable genetic heterogeneity in spite of similar phenotypes (see Genetics).  All are progressive and degenerative with various degrees of visual disability.  Most have histologic changes in both the endothelial cells and Descemet membrane.

The entity described here likely is the classical disease described in the older literature.  It is certainly the most common, occurring in 4% of the population over the age of 40 years and for unknown reasons is more often found in females.  Guttae are formed as excrescences of Descemet's membrane and develop initially in the central cornea, beginning about the 5^th decade, gradually increasing in number and size toward the periphery. They tend to be relatively large, sharply peaked and often positioned at the cell-cell junctions of endothelial cells.  These are often best visualized by corneal transillumination.  Histologically, the posterior portion of Descemet membrane contains bundles and sheets of abnormal collagen.  Progressive corneal edema follows as endothelial cells are lost and the remaining ones are unable to maintain normal stromal hydration.  Fingerprint lines may be present.  The corneal edema may involve both stroma and epithelium and in advanced stages may lead to painful epithelial erosions.  The disease is relentless and early blurring of vision progresses to significant visual handicaps often requiring corneal transplantation in the 7^th and 8^th decades.

Corneal guttae are common in older individuals but usually are located more peripherally.  The diagnosis of Fuchs can best be made where the guttae are concentrated centrally and associated with stromal and epithelial edema.

This is one of several adult onset corneal endothelial dystrophy (see Fuchs endothelial corneal dystrophy, late onset, (610158) for more forms of adult Fuchs endothelial dystrophy).  The onset of this type is considerably earlier than in the more common adult onset type (610158) .  Endothelial disease has been noted as early as three years of age but onset is likely later than in the congenital forms (CHED1; 121700), (CHED2; 217700).  In early onset Fuchs dystrophy, most individuals have evident disease by the third and fourth decades and many have advanced disease by the fourth and fifth decades.  The sex ratio among affected individuals is closer to 1:1 in this disorder compared with the more common adult onset type in which the disease is more common in females.

In this early onset disorder the guttae are small and more rounded than those in the later onset endothelial dystrophies, and are closer to the center of the endothelial cells.  The progression of corneal decompensation is temporally similar to that of the late onset dystrophies, resulting in clinically advanced disease within 3 to 4 decades.  The progression of disease has been documented through quantifying the number of guttae over time.   Among 26 patients, the number increased as much as 29.1% over a 30 month period, and an exponential increase was noted after age 50 years.  The inferotemporal quadrant of the cornea had the greatest proportion of guttae.  As in other forms of endothelial corneal dystrophy, Descement's  membrane is thickened and exhibits nodularity with secondary apoptosis of endothelial cells.

Corneal clouding is usually evident at birth and in virtually all cases in the first decade of life.   Corneal edema is usually progressive and often leads to stromal scarring, neovascularization, and deposition of plaques eventually.  The ground glass appearance of the cornea at least initially is most pronounced peripherally.  When the ground glass appearance is present in young children, it may lead to the misdiagnosis of congenital glaucoma and some children have had glaucoma surgery.  However, no anatomic abnormalities of the anterior chamber angle have been observed and glaucoma does not seem to occur in this disorder as it does in CHED1.  Photophobia and tearing are uncommon. 

The corneal epithelium may become atrophic with partial loss of Bowman's membrane replaced by subepithelial fibrosis.  Corneal sensitivity is normal.  The stroma may have spheroidal degeneration resembling posterior polymorphous dystrophy.  Generalized edema may lead to marked thickening of the entire cornea.  The endothelium undergoes degeneration and cell loss is common, while those that remain often contain melanin granules.  Descemet's membrane is greatly thickened.  This condition may be stable in some individuals while others clearly have evidence of progression, and a few have some regression in childhood.  Vision may be quite good and few patients develop nystagmus.