corneal dystrophy

Keratitis is the outstanding ocular manifestation but not all patients have corneal involvement.  Symptoms include photophobia, pain, tearing, and redness which may occur as early as one year of age.  Corneal neovascularization, ulceration and scarring may lead to decreased visual acuity.  Linear and star-like corneal opacities in the epithelium resembling dendrites (pseudodendritic keratitis) have been described together with thickening of the conjunctiva.  The corneal lesions do not stain.  The conjunctival epithelium, fibrocytes, and blood vessel endothelial cells contain an accumulation of large inclusion bodies and tyrosine crystal-like structures. 

The retina contains refractile glistening intraretinal crystals at all levels and choroidal vessels are said to be sclerosed.  The RPE atrophies and often forms pigment clumps.  The yellow-white crystals may be seen in the peripheral cornea and in the limbus.  Symptoms of night blindness and early vision loss begin about the third decade.  Night blindness is progressive as is the narrowing of the visual fields but this is highly variable between patients.  The visual field may show paracentral scotomas at some stage.  Central acuity can be normal until late in the disease when it becomes markedly impaired. Legal blindness can occur by the 5^th decade of life. 

The ERG may show lack of rod and cone responses late in the disease and color vision may be lost.  However, the ffERG and mfERGs show decreases in amplitude of scotopic and photopic responses in all patients, even younger ones.  The EOG becomes abnormal in late stages.  The degree of involvement may be asymmetrical.  Complex lipid inclusions can be seen histologically in choroidal, conjunctival and skin fibroblasts, as well as in keratocytes and lymphocytes.

Crystalline deposits have been detected mostly in the proximal portions of RPE cells adjacent to degenerated retinal  areas.  Most common are circular hyperrefractive structures in the outer nuclear layer adjacent to areas of degeneration.  Some patients have cystoid macular edema. Others in late stages have fundus changes that resemble choroideremia.

A corneal dystrophy is part of this syndrome.  Patients develop confluent, drop-like subepithelial whitish-brown infiltrates of the central cornea with some anterior stromal involvement together with stellate anterior cortical cataracts.  The intervening stroma appears hazy.  The epithelial surface remains intact but may be irregular over the superficial stromal infiltrates. The corneal opacities follow the skin and hand deformities and may be accompanied by a vascularized pannus.  Diagnosis can usually be made in the first decade of life.  Visual acuity in young adults may be reduced to the 20/80 - 20/100 range.

There is little to support the designation of a corneal dystrophy as 'Avellino type' but it is included in this database because it is entrenched in the literature.  It has features of both lattice dystrophy, type I, and granular dystrophy type I, which might be expected since all of these result from mutations in the same gene, TGFBI on chromosome 5.  Not surprisingly, reported cases have clinical and histological features of both lattice and granular dystrophy and hence are labeled as having combined granular-lattice corneal dystrophy.  There is considerable variation of the nature and quantity of the stromal deposits both within and among families, a common characteristic of autosomal dominant disorders.  Even though clinical evidence may suggest primarily lattice or granular dystrophy, histological studies can reveal changes characteristic of both.

Early cases could be traced to the Avellino region of Italy from which the title was derived but more recent reports have described families from around the world.

(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 rare congenital form of stromal dystrophy is sometimes considered a disorder of collagen fibrils with abnormally small diameters.  These may appear disorganized in areas.  Corneal opacities are often evident at birth or during the neonatal period.  Numerous small spots of fluffy, flaky deposits are found throughout the stroma creating a diffuse cloudy appearance and these may become more numerous with age indicating some progression.  The epithelium, Descemet membrane and the endothelium are not affected and the stroma is of normal or slightly increased thickness.  In some areas abnormal fibrillar layers are seen.  Although corneal erosions and photophobia are usually not clinically significant, acuity may be as low as hand motions and penetrating keratoplasty may be indicated.  In one series this was necessary at an average age of 20 years.  In the same series of 11 patients, 4 had strabismus, 3 eyes developed open angle glaucoma and band keratopathy was present in one patient.  Nystagmus has not been reported.

Deposition of abnormal decorin contributes to the stromal opacities. 

This stromal dystrophy may be congenital as it can be seen in the first years of life.  It is nonprogressive and generally has little clinical significance as it does not impair vision or require treatment in most cases.  It is usually diagnosed on routine examination from the presence of multiple, minute, whitish or grayish discrete opacities throughout the stroma.  The largest numbers are located centrally and posteriorly.  These may be flat, round or oval, and sometimes resemble snowflakes.  Keratocyte cell bodies contain cytoplasmic inclusions or vacuoles likely as the result of defective intracellular organelle trafficking.  Other layers such as the epithelium, Bowman layer, Descemet and endothelium are normal.  Expressivity is highly variable with considerable asymmetry of opacities in the two eyes and even unilateral involvement.

White, gelatinous deposits of amyloid are seen in the subepithelial region giving the surface of the cornea a multilobulated appearance resembling a mulberry.  These usually appear in the first decade of life and cause photophobia as well as tearing from irritation caused by a severe foreign body sensation.  The corneal changes are variable and some patients have only a mild amount of anterior stromal opacification while others have subepithelial vascularization.  Vision loss can be severe when the deposits coalesce to opacify the cornea.  These deposits are found in the subepithelial region but in some families it may also be found in the Bowman layer.   The appearance of fusiform deposits in the stroma in some patients has led some to categorize gelatinous drop-like corneal dystrophy as a lattice dystrophy and have designated it as type III.  GDLD seems to occur more commonly in Japan but often has a much later onset and the lattice appearance is more striking suggesting that it may be a unique form of corneal amyloidosis.  True GDLD, however, occurs in diverse ethnic groups throughout the US, Europe, Latin America, and the Asian subcontinent.  Cataracts have been reported in several young individuals with corneal amyloidosis.

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.