corneal erosions

Cystinosis

Clinical Characteristics
Ocular Features: 

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.

Systemic Features: 

In the more common infantile form of cystinosis, accumulation of cystine leads to dysfunction in many organs.  Nephropathy, hypothyroidism, and growth retardation in the infantile type are major complications.  The kidney disease leads to a Fanconi syndrome type pattern of kidney failure.  Pancreatic insufficiency, ovarian failure, myopathy, and central nervous system signs are often seen.  Patients require renal transplantation, often in the first decade of life.  Slow eating and dysphagia are common.  Heterozygotes may have elevated levels of free cystine in leukocytes.

The later onset juvenile form of cystinosis presents with kidney failure secondary to glomerular damage instead of tubular dysfunction.  The age of diagnosis varies widely, however, anywhere from 2-26 years of age, with end-stage kidney failure occurring generally in the third decade.  Aminoaciduria is usually not present and growth is normal.

The adult-onset or benign type is also uncommon.  Patients with this non-nephropathic type (219750), of course, do not develop kidney disease but have demonstrable cystine deposits in the cornea, buffy coat, and bone marrow.  No proteinuria or amino aciduria is detectable.

Genetics

Cystinosis is an autosomal recessive disease that is found in individuals homozygous for mutations in the CTNS gene (17p13) that encodes cystinosin.  The most common mutation among Caucasians of European descent is a 57-kb deletion which sometimes includes contiguous and regulatory genes.  Other sequence variants have also been found.  High cystine levels can be demonstrated in leucocytes of heterozygotes, at least in the infantile form.   A large number of mutations, both homozygous and compound heterozygous, have been found .  The accumulation of cystine seems to result from impaired cystine transport across the lysosomal membrane and it has been suggested that the severity of disease depends on the amount of functional cystinosin produced by various mutations in the CTNS gene.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Topical cysteamine eye drops can dramatically reduce the number of cornea crystals and improve symptoms such as photophobia and visual acuity.  Oral administration of the same drug can be beneficial for systemic disease as well, especially if initiated before the age of two years.  It can also reduce the frequency and severity of posterior segment disease with the most benefit occurring in those who begin the drug early in life.  Improved kidney function and quality of life may be dramatic.

The chronic nature and multisystem involvement require lifelong monitoring of ocular and systemic disease.

References
Article Title: 

Corneal Dystrophy, Reis-Bücklers

Clinical Characteristics
Ocular Features: 

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.

Systemic Features: 

No systemic disease is associated with Reis-Bucklers corneal dystrophy.

Genetics

This disorder seems to be closely related to the more common Thiel-Behnke dystrophy as the corneal disease is caused in both cases by missense mutations in the TGFBI gene on chromosome 5 (5q31). The mutation in Reis-Bucklers results in a p.Arg124Leu amino acid substitution whereas most cases of Thiel-Behnke dystrophy are the result of a p. Arg555Gln substitution.  Both disorders are inherited in an autosomal dominant pattern.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Ablation of the diseased cornea can improve vision and provide temporary relief from the erosions.

References
Article Title: 

Reevaluation of corneal dystrophies of Bowman's layer and the anterior stroma (Reis-Bücklers and Thiel-Behnke types): a light and electron microscopic study of eight corneas and a review of the literature

Kuchle M, Green WR, Volcker HE, Barraquer J. Reevaluation of corneal dystrophies of Bowman's layer and the anterior stroma (Reis-Bucklers and Thiel-Behnke types): a light and electron microscopic study of eight corneas and a review of the literature. Cornea. 1995 Jul;14(4):333-54. Review.

PubMed ID: 
7671605

Corneal Dystrophy, Stocker-Holt

Clinical Characteristics
Ocular Features: 

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.

Systemic Features: 

No systemic problems are associated with this corneal disease.

Genetics

Stocker-Holt dystrophy is caused by mutations in KRT12 (17q12).  Like Meesmann dystrophy (122100), it follows an autosomal dominant pattern.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Treatment is largely directed at symptoms from epithelial erosions using hypertonic solutions and sometimes epithelial debridement.  The cystic changes tend to recur following removal of the offending epithelium and even after corneal replacement.

References
Article Title: 

Corneal Dystrophy, Avellino Type

Clinical Characteristics
Ocular Features: 

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.

Systemic Features: 

No systemic disease is associated with this disorder.

Genetics

Mutations in the TGFBI (5q31) have been found in this so-called combined dystrophy.   Autosomal dominant transmission is evident from familial cases.  Mutations in the same gene also cause Thiel-Behnke (602082), Reis-Bucklers (608470), granular (Groenouw) type I (121900), lattice type I (122200) and epithelial basement membrane dystrophy (121820).  The combined features of lattice and granular dystrophies in the same corneas resulting from mutations in the same gene calls into question the value of relying solely on clinical and histological evidence to classify disease.  Modern genotyping now enables greater accuracy in the nosology and already the Cornea Society has incorporated this information in its recent reclassification of these dystrophies (Cornea Society IC3D Corneal Dystrophies(c)). 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Penetrating keratoplasty can improve vision at least temporarily but deposits tend to recur.  LASIK has been reported to exacerbate the number and density of the opacities.  Patients treated with PRK may do better and can retain corneal clarity for a decade or more.

References
Article Title: 

Avellino corneal dystrophy after LASIK

Jun RM, Tchah H, Kim TI, Stulting RD, Jung SE, Seo KY, Lee DH, Kim EK. Avellino corneal dystrophy after LASIK. Ophthalmology. 2004 Mar;111(3):463-8.

PubMed ID: 
15019320

Corneal Dystrophy, Lattice Type I

Clinical Characteristics
Ocular Features: 

Lattice corneal dystrophy type I is one of the more common corneal dystrophies and occurs throughout the world.  Randomly oriented linear opacities resembling cotton threads accumulate in the central portions of the stroma.  These usually become apparent in the first decade of life although they are sometimes seen in infancy.  The peripheral cornea is relatively spared and intervening stromal areas are clear.  This is a progressive disorder in which vision during childhood is often normal but by the fifth and sixth decades most patients have severe visual impairment due to increasing accumulations of amyloid.  Corneal erosions may occur in the absence of stromal infiltrates.

Systemic Features: 

No systemic disease is found in LCD1 (as opposed to LCD type II).

Genetics

Type I lattice dystrophy is an autosomal dominant disorder as the result of mutations in the TGFBI gene (5q31).  Other corneal dystrophies (granular I or Groenouw type I, combined granular/lattice or Avellino type, Thiel-Behnke, Reis-Bucklers, epithelial basement membrane disease) have mutations in the same region of the same gene casting doubt on the value of using solely clinical and histologic distinctions in current classifications of these corneal disorders.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Recurrent corneal erosions benefit from standard treatments while penetrating keratoplasty may be necessary by the fifth decade to improve acuity.

References
Article Title: 

Corneal Dystrophy, Granular

Clinical Characteristics
Ocular Features: 

The corneal opacities in this disorder are usually located in the anterior stroma of the central cornea, and consist of discrete grayish-white, irregular granules with sharp margins.  The peripheral cornea and areas between the opacities remain clear.  The opacities may be apparent in the first decade but vision remains good throughout childhood.  The epithelial surface is usually smooth in children but adults can develop irregularities.  As the opacities enlarge and grow in number the cornea becomes increasingly opaque and older patients experience considerable loss of vision.  There is some variation in the number of opacities among individuals and considerable clinical heterogeneity occurs both within and between families.  The histologic appearance of the corneal deposits are said to be characteristic with eosinophilic deposits in the anterior stroma secondary to accumulations of mutant transforming growth factor beta induced protein.

The number and morphology of the granular deposits change throughout life, influenced to some extent by episodes of recurrent corneal erosions and age of patients.  Deposits become more annular and lattice-like in morphology, especially in the third decade and become more discoid by the fifth decade. 

It has been reported that the morphology and function of the meibomian glands are altered in this disease as well.

Systemic Features: 

No associated systemic disease has been described.

Genetics

This is another autosomal dominant corneal dystrophy resulting from mutations in the TGFBI gene (5q31) (others being Reis-Bucklers, Thiel-Behnke, lattice types I and IIIA, epithelial basement membrane disease, and Avellino). These are therefore allelic disorders of the same mutant gene.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Penetrating keratoplasty can be temporarily helpful in restoring vision but recurrence is common.  Opacities may also occur following the application of various types of refractive surgery (even in initially clear corneas).

References
Article Title: 

Corneal Dystrophy, Macular

Clinical Characteristics
Ocular Features: 

Macular corneal dystrophy is a progressive, bilateral disorder with increasing corneal cloudiness throughout life. The onset of corneal haze is variable.  It can be seen in infancy but usually becomes apparent in the second or later decades of life.  Visual impairment can be severe, especially by mid-life.  The stroma, Descemet membrane, and endothelium are involved as keratocytes and endothelial cells accumulate intracytoplasmic vacuoles of glycosaminoglycans.  Corneal thickness is reduced, presumably due to abnormally dense packing of collagen fibrils in the stroma.  The epithelium does not seem to be involved.

Based on immunohistochemical profiles of inclusions, as well as phenotypic differences, attempts have been made to distinguish at least three types of macular dystrophy, I, IA, and II.  This may not be justified as the same gene is involved, and especially since several types have been described within the same inbred family.  Most likely these are variations in the phenotypic expression of the same gene, a  feature of many genetic disorders.

Systemic Features: 

No extraocular abnormalities have been associated with this disorder.  However, variations in serum levels of antigenic keratin sulfate have been found.

Genetics

Homozygous mutations in the CHST6 gene (16q22) are responsible for this autosomal recessive corneal dystrophy.  More than 100 mutations have been found.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Full thickness and deep anterior lamellar keratoplasty can improve vision and relieve symptoms but the disease can recur in the graft.  More than 40% of grafts have recurrent opacities after 10 years.  The recurrence risk is higher in patients with disease onset at age 18 years or younger and in those who had keratoplasty before the age of 30 years.

References
Article Title: 

Corneal Dystrophy, Subepithelial Mucinous

Clinical Characteristics
Ocular Features: 

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.

Systemic Features: 

No systemic disease association has been reported.

Genetics

In the single 3 generation family reported, the pattern of inheritance was consistent with autosomal dominant inheritance.  No locus or mutation has been reported.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

The usual treatment for acute corneal erosions might be beneficial but other treatments have not been reported.  Penetrating keratoplasty and superficial keratectomy have been used on several patients but followup is not available.

References
Article Title: 

Corneal Dystrophy, Gelatinous Drop-like

Clinical Characteristics
Ocular Features: 

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.

Systemic Features: 

No systemic abnormalities occur as part of this syndrome.

Genetics

Autosomal recessive corneal amyloidosis results from multiple mutations in the M1S1 (TACSTD2) gene located on chromosome 1 (1p32).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No satisfactory permanent treatment has been found.  Ablative treatments may give temporary relief from symptoms and improve vision but the deposits recur within a few years.

References
Article Title: 

Corneal Dystrophy, Thiel-Behnke

Clinical Characteristics
Ocular Features: 

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).

Systemic Features: 

No systemic disease is associated with this corneal disease.

Genetics

Thiel-Behnke dystrophy is an autosomal dominant disorder.  However, it is genetically heterogeneous as mutations in at least two genes seem to produce the same phenotype. The majority of cases result from mutations in the TGFBI gene (5q31) but other corneal dystrophies (granular I or Groenouw type I, combined granular/lattice or Avellino type, Reis-Bucklers, epithelial basement membrane disease, and lattice type I) have mutations in the same gene.  This is a classic example of the variable expressivity of a single gene mutation characteristic of autosomal dominant disease. 

A second locus has been identified in a large 4 generation pedigree in which a presumed causative mutation was found on chromosome 10 (10q24). Some individuals in this family had evidence of two distinct types of dystrophies in the same cornea.  The responsible gene has not been identified. Genotyping is necessary to distinguish between the two disorders.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Ablative treatments of the diseased cornea can be effective in reducing symptoms for extended periods but eventually the degenerative changes recur.  Acute erosions can be treated with hyperosmotic agents with some improvement.

References
Article Title: 

Reevaluation of corneal dystrophies of Bowman's layer and the anterior stroma (Reis-Bücklers and Thiel-Behnke types): a light and electron microscopic study of eight corneas and a review of the literature

Kuchle M, Green WR, Volcker HE, Barraquer J. Reevaluation of corneal dystrophies of Bowman's layer and the anterior stroma (Reis-Bucklers and Thiel-Behnke types): a light and electron microscopic study of eight corneas and a review of the literature. Cornea. 1995 Jul;14(4):333-54. Review.

PubMed ID: 
7671605

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