corneal erosions

Cystinosis is a clinically heterogeneous disorder that has been divided into three allelic forms based on the age of onset and the amount of kidney disease.  Since the three types are caused by mutations in the same CTNS gene they are discussed here as a single entity with emphasis on the similarities and differences.  All three cause significant corneal disease secondary to crystalline cystine deposits.

The early onset and most common form of cystinosis (219800) causes severe photophobia and even corneal erosions from accumulation of refractile cystine crystals which can be seen in the first years of life.  Accumulation of cystine in the retina leads to peripheral pigmentary changes that progress centrally and is present to some degree in all patients by age 7 years.  Mottling of the retinal pigment epithelium is the most common finding but there are often alternating areas of hyperpigmentation and depigmentation as well.  Visual fields may be markedly constricted.  Photoreceptor damage eventually leads to decreased rod and cone responses as recorded by ERG.  Visual acuity ranges from near normal to NLP.

The late-onset juvenile nephropathic (219900) form has a similar corneal profile but the pigmentary retinopathy occurs later than in the infantile disease.

The adult nonnephropathic form (219750) likewise has visible cystine crystals in the cornea.  This disorder should be considered in all healthy adults with a crystalline dystrophy of the cornea.  The pigmentary retinopathy does not occur.

This is an anterior corneal dystrophy involving the epithelium and Bowman membrane.  Opacities consisting of spots and lines form in the central portion of the anterior cornea creating haziness with relative sparring of the periphery.  These can be seen as early as 4-5 years of age but few symptoms occur until the epithelium breaks down causing painful corneal erosions.  Visual acuity eventually drops as the corneal haze increases along with increasing irregularity of the epithelial surface.

Ultrastructural studies reveal degenerative changes in all epithelial cells and almost complete Bowman membrane replacement with disoriented collagen fibrils.

A comparative histological study of Reis-Bucklers and Thiel-Behnke dystrophies concluded that these are distinct CDB (corneal dystrophy Bowman) disorders and suggested the former be called CDB type I, and the latter CDB type II.  Type II is considered unique on the basis of the ‘curly’ fibers seen in the Bowman and subepithelial layers, while type I has bandshaped granular Masson-positive subepithelial deposits and ‘rod-shaped bodies’ resembling granular dystrophy.  Type I described here generally leads to greater vision loss than type II.

Stocker-Holt dystrophy is clinically somewhat similar to Meesmann corneal dystrophy but is caused by a different mutation and is therefore discussed separately here.  Stocker and Holt in 1954 described this disorder among 20 descendents from Moravia who settled in North Carolina (Meesmann and Wilke's report in 1939 was based on patients in Germany).  Fine, grayish punctate epithelial opacities were found in the epithelium anterior to Bowman's throughout the entire cornea even in patients as young as 7 months old.  These stain with fluorescein and are accompanied by fine linear opacities that appear in a whorled pattern.  Outside of light sensitivity and glare reported by some patients, few are symptomatic.  Spontaneous, recurrent epithelial erosions can occur.  Corneal sensitivity is reduced. Contact lenses are poorly tolerated.  Visual acuity is generally around 20/50 but can be significantly worse.  Few require keratoplasty.

Meesmann dystrophy (122100) is superficially similar but the opacities are more numerous in the interpalpebral area and the surrounding epithelium is generally clear.

This disorder, reported so far in a single family, is an anterior corneal dystrophy with onset in the first decade of life.  The frequency of epithelial erosions tended to subside during adolescence but visual acuity continued to decline secondary to subepithelial nodular opacities and a generalized haze most dense centrally. No geographic lines are present and cystic changes in the epithelium were absent.  Bowman layer and deeper stuctures of the cornea are unaffected. Patients may have 20/30 vision into the fifth decade but after that it may decrease into the 20/400 range.  EM revealed accumulations of subepithelial fibrillar material.  Light microscopy and immunohistochemistry showed the material to be chondroitin-4-sulfate and dermatan sulfate.

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.

This type of anterior corneal dystrophy is genetically heterogeneous (caused by mutations in more than one locus). Recurrent corneal erosions are the main clinical feature and can begin in the first and second decades.  The epithelium is irregularly thickened while the Bowman layer and basal lamina of the basement membrane have degenerative changes which lead to the clinically evident honeycomb pattern of opacities.  Advanced changes in these tissues eventually leads to some vision loss.

The honeycomb pattern of degenerative changes in the corneal epithelium and Bowman membrane helps to distinguish this disorder from other anterior corneal dystrophies.  These are more prominent centrally with relative sparing of the juxtalimbal areas.  The epithelial basement membrane may be missing in some areas.  Histology is required for a definitive diagnosis with electron microscopy revealing characteristic 'curly' collagen fibrils in the subepithelial and anterior stromal tissues.  These degenerative changes tend to recur even after ablative procedures.

There is a great deal of clinical heterogeneity and the diagnosis is often unclear especially in younger individuals.  No doubt much of this is due to the fact that mutations in the major gene (TGFBI) responsible are also responsible for at least 5 other heritable corneal dystrophies and the argument can be made that all are variants of the same condition (vida infra).