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Corneal dystrophy

Summary
Background
Epithelial dystrophies
Cogan (epithelial basement membrane) dystrophy
Meesmann (epithelial) corneal dystrophy
Bowman layer/anterior stromal dystrophies
Reis-Bücklers corneal dystrophy
Thiel-Behnke corneal dystrophy
Stromal dystrophies
Macular corneal dystrophy
Granular corneal dystrophy type 1 (classic)
Granular corneal dystrophy type II
Lattice corneal dystrophy, TGFB1 type
Meretoja syndrome
Schnyder (crystalline) corneal dystrophy
Other Bowman layer/anterior stromal dystrophies for interest
Descemet membrane and endothelial dystrophies
Fuch’s endothelial corneal dystrophy
Summary table
Radiology in Focus
Optical Coherence Tomography (OCT)
References
Author(s)

Summary

Corneal dystrophies are a group of progressive disorders involving abnormal, usually bilateral deposition of substances in the cornea, which can eventually opacify the cornea and obstruct vision. Underlying genetic abnormalities have been identified for most corneal dystrophies, and most are hereditary.

Background

Over 20 corneal dystrophies exist, which affect all parts of the cornea and are categorised by anatomical location.

The many corneal dystrophies share several traits:

They are usually hereditary
They can occur in otherwise healthy people
Disease is bilateral
Most progress gradually
They usually begin in one of the five layers of the cornea (epithelium, Bowman’s layer, stromal, Descemet’s membrane, endothelium), and may later spread to nearby layers

Some corneal dystrophies cause severe visual impairment, whilst others cause mild or no visual problems, and are diagnosed incidentally during an eye examination. Common features of disease that has progressed are recurrent corneal erosions, blurring of vision and reduced corneal sensation.

Epithelial dystrophies

Cogan (epithelial basement membrane) dystrophy

The commonest corneal epithelial dystrophy
Inheritance: usually sporadic, occurring without a family history. Rarely, it can be inherited (autosomal dominant, AD) and involve the TGFB1 gene

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Mutations in the TGFB1 gene, which encodes ‘transforming growth factor beta induced’, causes several forms of corneal dystrophies. Other than Reis-Buckler’s dystrophy, TGFB1 mutations are found in: epithelial basement membrane dystrophy; Thiel-Behnke dystrophy; granular corneal dystrophy; and lattice corneal dystrophy.

Histology: thickening of the basement membrane, deposition of fibrillary protein between the basement membrane and Bowman layer
Presentation: onset typically during teenage years; 〜1/10 patients develop corneal erosions in their 20s; the remainder remain asymptomatic
Lesions are best visualised by retroillumination on slit-lamp or scleral scatter. The following signs are characteristic: “fingerprint-like” subepithelial ridges; “map-like” subepithelial opacities; and “dot-like” intraepithelial cysts.

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Cogan dystrophy is also known as ‘map-dot-fingerprint dystrophy’ (MDF dystrophy) due to these characteristic signs.

Meesmann (epithelial) corneal dystrophy

Rare, non-progressive abnormality of corneal epithelial metabolism
Inheritance: AD, involving a KRT3 or KRT12 gene mutation
Histology: intraepithelial cysts of uniform size, irregular thickening of the epithelial basement membrane
Presentation: asymptomatic; or recurrent corneal erosions + blurring of vision (usually mild)
Treatment: lubrication

Meesmann corneal dystrophy. Multiple opaque spots in the corneal epithelium. Image courtesy of Klintworth.

Meesmann corneal dystrophy. This slit-lamp photograph demonstrates the microcytic appearance of the corneal epithelium. Image courtesy of Szaflik et al.

Other epithelial and subepithelial dystrophies for further reading (but less likely to be tested in the Duke-Elder exam) are:

Subepithelial mutinous corneal dystrophy
Lisch epithelial corneal dystrophy
Gelatinous drop-like corneal dystrophy

Bowman layer/anterior stromal dystrophies

Reis-Bücklers corneal dystrophy

An anterior variant of granular stromal dystrophy (GCD type 3), also known as ‘corneal basement dystrophy type 1 (CBD1)
Inheritance: AD, TGFB1 gene defect
Histology: replacement of the Bowman’s layer by connective tissue bands
Presentation: severe recurrent corneal erosions in childhood ± visual impairment
Signs: grey-white subepithelial opacities, most dense centrally, forming a reticular pattern with increasing age
Treatment: excimer laser phototherapeutic keratectomy (PTK), to treat the recurrent erosions, achieves satisfactory control in some

Reis-Bücklers corneal dystrophy. Note the reticular opacity in the superficial cornea. Image courtesy of Klintworth.

Thiel-Behnke corneal dystrophy

Also known as ‘honeycomb-shaped corneal dystrophy’ or ‘corneal basement dystrophy type II’ (CBD2)
Less severe than Reis-Bücklers
Inheritance: AD, TGFB1 defect
Histology: Bowman’s layer “curly fibres” on electron microscopy
Presentation: recurrent erosions in childhood
Signs: subepithelial opacities in a ‘honeycomb-like’ arrangement (these opacities are less defined than the lesions in Reis-Bücklers dystrophy)

Stromal dystrophies

Macular corneal dystrophy

Inheritance: autosomal recessive (AR), CHST6 gene
Histology: aggregations of glycosaminoglycans intra- and extracellularly that stain with Alcian blue and colloidal iron
Presentation: early visual deterioration (by the end of the first decade) + recurrent erosions are very common
Signs: dense, poorly delineated greyish-white spots centrally in the anterior stroma, and peripherally in the posterior stroma. Eventually, the full thickness of the stroma will be involved
Treatment: penetrating keratoplasty. Recurrence is common

Granular corneal dystrophy type 1 (classic)

Inheritance: AD, TGFB1 gene. Homozygous disease is more severe
Histology: amorphous hyaline deposits staining bright red with Masson trichrome
Presentation: glare, photophobia, blurring (as progression occurs). Recurrent erosions are rare
Signs: discrete white central anterior stromal deposits resembling ‘sugar granules’. Gradual confluence and diffuse haze result in visual impairment
Treatment: penetrating/deep lamellar keratoplasty is usually required by the 5th decade

Granular corneal dystrophy type I. Numerous irregular shaped discrete crumb-like corneal opacities. Image courtesy of Klintworth.

Granular corneal dystrophy type II

Also known as ‘Avellino’ or ‘combined granular-lattice dystrophy’
Inheritance: AD, TGFB1 gene
Histology: hyaline and amyloid
Presentation: mild recurrent erosions, later visual impairment
Signs: fine superficial opacities later become stellate/annular lesions. These are usually present by the end of the first decade in heterozygotes
Refractive surgery is contraindicated, as corneal trauma accelerates progression of the dystrophy

Images from members of a family with granular corneal dystrophy type II. Image A (from a 6-year-old female) shows dense and confluent opacities; Image B (from a 32-year-old male, father of the patient in image A) shows star- and disc-shaped opacities. Image courtesy of Cho et al.

Lattice corneal dystrophy, TGFB1 type

This is the classic form of lattice dystrophy
Inheritance: AD, TGFB1 gene
Histology: amyloid with Congo red staining, which exhibits ‘apple-green’ birefringence with a polarising filter
Presentation: recurrent erosions in childhood
Signs: anterior stromal dots, coalescing into a fine filamentous lattice that gradually spreads across the cornea, but spares the periphery
Treatment: penetrating or deep lamellar keratoplasty often required

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The above stromal corneal dystrophies and their associated histological findings and stains can be remembered with the following mnemonic:

“Marilyn Monroe Always Gets Her Men in L.A. County”

“Marilyn Monroe Always” = Macular dystrophy, Mucopolysaccharide, Alcian blue
“Gets Her Men” = Granular dystrophy, Hyaline materials, Masson trichome
“L.A. County” = Lattice dystrophy, Amyloid, Congo red

Meretoja syndrome

Also known as ‘lattice corneal dystrophy, gelsolin type’
Can look like lattice dystrophy but is a systemic condition with associated neuropathies (of peripheral and cranial nerves), autonomic features and ‘mask-like facies’
Inheritance: AD, GSN gene
Histology: amyloid deposits in the corneal stroma that stain with Congo red
Signs: stromal lattice lines starting in the periphery and spreading centrally

Schnyder (crystalline) corneal dystrophy

Disorder of corneal lipid metabolism sometimes associated with systemic dyslipidaemia
Inheritance: AD, UBIAD1 gene
Histology: phospholipid and cholesterol deposits
Presentation: visual impairment + glare
Signs: early central haze, progressing to full-thickness involvement over time. In 〜1/2, subepithelial crystalline opacities. Prominent corneal arcus
Treatment: excimer keratectomy or corneal transplantation

Other Bowman layer/anterior stromal dystrophies for interest

François central cloudy dystrophy
Congenital stromal corneal dystrophy
Fleck corneal dystrophy
Posterior amorphous corneal dystrophy
Pre-Descemet corneal dystrophy

Descemet membrane and endothelial dystrophies

Fuch’s endothelial corneal dystrophy

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Fuch’s endothelial dystrophy is perhaps the most important corneal dystrophy to learn about for the Duke-Elder exam

The most common corneal dystrophy
Inheritance: AD, COL8A2 gene (in the early-onset variant), TCF4 gene (in most other cases)
Pathophysiology: failure of sodium-potassium pump in corneal endothelium —> fluid accumulation + bilateral accelerated endothelial cell loss. Corneal oedema can be worsened after eye surgery (e.g. cataract surgery)

Epidemiology

More common in females (typically with a middle-age to late-age of onset)
Associated with an increased risk of open-angle glaucoma

Presentation:

Blurry vision (due to corneal oedema), worse in the morning, clearing towards the end of the day
Blurry vision is worse in the morning because the eyes are shut overnight, and so corneal fluid evaporation is limited. The eyes are open and blinking throughout the day, enabling better clearing of the accumulated fluid

Signs

Cornea guttata: irregular warts on Descemet membrane
On specular microscopy: dark spots (due to endothelial cell loss) which progress to a “beaten metal” appearance
Central stromal oedema, with epithelial oedema in more advanced cases with presence of microcysts and bullae (bullous keratopathy). Rupture of bullae exposes nerve fibres causing pain

Management

Conservative: topical sodium chloride 5% drops, reduction of IOP + use of a hairdryer to rehydrate the cornea
For ruptured bullae: bandage contact lenses, cycloplegics, antibiotic ointment + lubricants
Surgical: posterior lamellar keratoplasties e.g. Descement Membrane Endothelial Keratoplasty (DMEK) and Descemet’s Stripping Automated Endothelial Keratoplasty (DSAEK), and penetrating keratoplasty, can treat severe disease

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Cataract surgery can cause persistent corneal oedema due to endothelial cell loss, particularly if the preoperative central corneal thickness is more than 630-640µm. A ‘triple procedure’ (combined cataract surgery, lens implantation + keratoplasty) can be considered in eyes with corneal oedema.

Fuch’s corneal dystrophy. The cornea is markedly opaque due to extensive oedema caused by a loss of endothelial cells that normally maintain the hydrophilic corneal stroma in a deturgescent state (i.e. a state of relative dehydration, necessary to maintain the transparency of the cornea). Image courtesy of Klintworth.

Other Descemet membrane and endothelial dystrophies:

Posterior polymorphous corneal dystrophy
Congenital hereditary endothelial dystrophy

Summary table

Here we have included a summary table of the above corneal dystrophies with their associated inheritance patterns, involved genes and key signs to look out for in exam questions.

Name	Inheritance pattern	Gene	Key signs/histological findings
Epithelial dystrophies
Cogan’s (epithelial basement membrane) dystrophy	Usually not inherited	TGFB1 gene may be involved	Thickening of basement membrane. O/E: “fingerprint-like” subepithelial ridges, “map-like” subepithelial opacities; “dot-like” intraepithelial cysts
Meesmann corneal dystrophy	AD	KRT3, KRT12	Intraepithelial cysts, thickening of basement membrane
Bowman’s/anterior stromal dystrophies
Reis-Bückler’s corneal dystrophy	AD	TGFB1	Connective tissue bands replace Bowman’s layer. O/E: grey subepithelial opacities —> reticular pattern
Thiel-Behnke corneal dystrophy	AD	TGFB1	Bowman’s layer “curly fibres” (electron microscopy). O/E: “honeycomb-like” subepithelial opacities
Stromal dystrophies
Macular corneal dystrophy	AR	CHST6	Glycosaminoglycan aggregations (Alcian blue and colloidal iron stain).
Granular dystrophy	AD	TGFB1	Type 1: hyaline (bright red with Masson trichrome). Type 2: hyaline + amyloid
Lattice dystrophy	AD	TGFB1	Amyloid (Congo red stain)
Schnyder corneal dystrophy	AD	UBIAD1	Histology: phospholipid and cholesterol deposits. O/E: central haze —> full-thickness involvement. Subepithelial crystalline opacities in 〜50%. Corneal arcus.
Meretoja syndrome	AD	GSN	Amyloid (Congo red stain)
Descemet membrane and endothelial dystrophies
Fuch’s endothelial dystrophy	AD	COL8A2	Cornea guttata, “beaten metal” appearance, central stromal oedema. Can progress to bullous keratopathy

Radiology in Focus

Corneal dystrophies are a group of inherited disorders characterised by the accumulation of abnormal material in the cornea, leading to visual impairment. While clinical examination is essential for diagnosis, various imaging techniques can provide valuable insights into the extent of corneal involvement, the specific type of dystrophy, and any associated complications.

Optical Coherence Tomography (OCT)

OCT provides high-resolution cross-sectional images of the cornea, allowing for detailed assessment of the corneal layers. It can help visualise the depth and extent of opacities, assess corneal thickness, and identify any associated changes in the anterior segment.

This 30-year-old Chinese female presented for evaluation of granular corneal dystrophy. She had a strong family history of cornea problems suggesting an autosomal dominant inheritance which supported the diagnosis of BIGH3 (Transforming Growth Factor Beta 1 gene, TGFβ1) related disease. Vision was 20/20 in both eyes. Her OCT is shown below:

OCT of granular corneal dystrophy. Image source.

References

Salmon, John F., and Jack J. Kanski. Kanski’s Clinical Ophthalmology: A Systematic Approach. Ninth Edition, Elsevier, 2020.
Klintworth, Gordon K. ‘Corneal Dystrophies’. Orphanet Journal of Rare Diseases, vol. 4, Feb. 2009, p. 7. PubMed Central, https://doi.org/10.1186/1750-1172-4-7.
Szaflik, Jacek P., et al. ‘Genetics of Meesmann Corneal Dystrophy: A Novel Mutation in the Keratin 3 Gene in an Asymptomatic Family Suggests Genotype-Phenotype Correlation’. Molecular Vision, vol. 14, Sept. 2008, pp. 1713–18. PubMed Central, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2538492/.
Cho, Kyong Jin, et al. ‘TGFBI Gene Mutations in a Korean Population with Corneal Dystrophy’. Molecular Vision, vol. 18, July 2012, pp. 2012–21. PubMed Central, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3413419/.

Author(s)

Jessica Mendall

Jessica is a final year medical student studying in London. She previously studied preclinical medicine in Oxford, intercalating in Systems Neuroscience and Molecular Pathology. She is particularly interested in Ophthalmology, medical education and clinical research.

Dr Abhiyan Bhandari

Abhiyan is the Co-Founder and Radiology & Imaging Lead of Ophtnotes. He is a doctor who graduated from UCL Medical School in London. He scored in the top 10% of candidates who sat the Duke Elder examination and runs ophthalmology and Duke Elder revision sessions aimed at medical students. He also runs a YouTube channel aimed at medical students, covering topics ranging from study tips, productivity and vlogs of his journey through medical school.