Dystrophies

Progressive, usually bilateral opacifying disorders

Inherited, non-inflammatory

Classified based on which part of the cornea is affected

Summary table

	Epithelial	Bowman’s layer	Stromal	Endothelial
Epithelial	Cogan’s microcystic dystrophy Meesman’s dystrophy Cogan’s map-dot-fingerprint dystrophy Labrador keratopathy	Reis-Buckler’s dystrophy Thiel-Behnke dystrophy	May extend into adjacent layers Lattice dystrophy Macular dystrophy Granular dystrophy Combined granular-lattice dystrophy (Avellino) Central cloudy dystrophy of Francois Central crystalline dystrophy of Schnyder	Characterised by corneal oedema Congenital hereditary endothelial dystrophy Iridocorneal endothelial syndrome Posterior polymorphous dystrophy Fuch’s endothelial dystrophy

Epithelial dystrophies

• Cogan’s (epithelial basement membrane or map-dot-fingerprint dystrophy)

  • Most common dystrophy (although Fuch’s most commonly diagnosed?)
  • Typically sporadic but rarely autosomal dominant
  • Thickened basement membrane with fibrillary protein and deficiency of the hemidesmosomes
  • 10% develop recurrent erosion syndrome
  • Dot like and microcystic lesions may be seen (sequestered epithelial cells)
  • Subepithelial map-like patterns (intraepithelial extensions of BM) with faint haze
  • Whorled fingerprint lines (fibrillar deposits)
  • Can cause irregular astigmatism

• Meesmann

  • Non-progressive, autosomal dominant inheritance
  • Thickening of the basement membrane, tiny intraepithelial cysts
  • Asymptomatic or recurrent erosions. Occasionally causes slightly decreased visual acuity
  • Associated with mutations in KRT3 or KRT12 (corneal keratin)

Bowman’s layer dystrophies

• Reis-Bucklers (aka corneal basement dystrophy type 1)

  • Autosomal dominant: TGFB1 gene (chromosome 5)

  • Bowman’s layer becomes replaced by connective tissue bands/sheets

    • Progressive

  • Subepithelial collagen deposits stain blue with Masson trichrome

  • Clinical features:

    • Severe recurrent corneal erosions in childhood
    • Grey-white geographic subepithelial opacities

  • Treatment of recurrent erosions, excimer keratectomy, penetrating keratoplasty (lesions commonly recur in the graft)

• Thiel-Behnke (aka honeycomb-shaped dystrophy and corneal basement dystrophy type 2)

  • Also AD inheritance and also affects TGFB1 gene

  • ‘Curly fibres’ in Bowman’s layer histologically: only electron microscopy can distinguish Reis-Buckler from Thiel-Behnke corneal dystrophy by identifying these fibres

  • Clinical features:

    • Recurrent erosions in childhood
    • Subepithelial opacities but less defined than in Reis-Bucklers

  • Treatment may not be needed

Stromal dystrophies

Lattice dystrophy (TGFB1 type aka BIGH3)

‘Classic’ lattice dystrophy

• Autosomal dominant, TGFB1 gene

• Essentially a primary localised corneal amyloidosis

• Amyloid on histology stains with Congo red with green birefringence

  • Also stains with crystal violet (showing metachromasia) and thioflavin T
  • Amyloid deposits in the anterior stroma

• Clinical features

  • Early onset recurrent erosions
  • Visual blurring
  • Anterior stromal dots developing into filamentous lattice shapes
    • Spare the peripheral cornea
    • Best seen on retroillumination
    • Clear intervening cornea
  • General stromal haze
  • Reduced corneal sensation

• Treatment: PK or DALK. Highest rate of recurrence in grafts

Lattice dystrophy (gelsolin type)

• In fact a systemic condition related to familial amyloidosis (Meretoja’s syndrome): accumulation of misfolded proteins forming beta-sheets instead of alpha helices.

• AD inheritance, GSN gene (completely different gene to the type 1 TGFB1 type).

• Amyloid seen in the stroma

• Clinical features

  • Irritation
  • Late visual blurring
  • Sparse stromal lattice centrally
  • Reduced corneal sensation
  • Associated cranial/peripheral neuropathy due to amyloid deposition, mask-like facies (due facial nerve paralysis), autonomic features, inelastic skin

• Treatment: keratoplasty

Gelatinous drop-like corneal dystrophy (GDLD)

• Autosomal recessive, tumour-associated calcium signal transducer 2 (TACSTD2)
• Characterised by severe corneal amyloidosis
• Presents in first decade: reduced vision, photophobia, FB sensation
• ‘Mulberry’-like gelatinous masses
• Recurs in corneal grafts

Granular dystrophy (type 1)

• ‘Classic’ granular dystrophy

• Autosomal dominant, TGFB1 gene

• Oldest patients

• Hyaline deposits stain red with Masson trichrome

• Features can be seen early in life but symptoms develop years later

• Clinical features

  • Glare and photophobia

  • Visual blurring

  • White central stromal deposits like sugar granules/bread crumbs

    • Increase in size and number, become confluent
    • The cornea between lesions is clear (cp. Macular dystrophy)

  • Reduced corneal sensation

• Treatment: PK or DALK

Granular dystrophy (type 2) aka Avellino or combined granular-lattice dystrophy

• Autosomal dominant, TGFB1 gene

• Hyaline and amyloid seen on histology (therefores stains with both congo red and masson trichrome)

• Clinical features

  • Late visual impairment
  • Fine progressive opacities forming stellate lesions, snowflake appearance
  • Deeper lattice lines

• Treatment may not be needed. Refractive surgery is contraindicated

Macular dystrophy

• Autosomal recessive, CHST6 gene (carbohydrate sulfotransferase on chromosome 16). Common in Iceland

• Most severe dystrophy in terms of visual loss

• Presents in youngest patients (cp other stromal dystrophies)

• Defect in the synthesis of keratan sulfate

  • ELISA can be done to detect sulfated keratan sulfate

• Aggregations of glycosaminoglycans/mucopolysaccharide which stain with Alcian blue or colloidal iron

• Clinical features

  • Early visual disturbance which may be severe

  • Recurrent erosions

  • Dense grey-white spots in the central stroma spreading to the periphery (limbus-to-limbus)

    • Cloudy cornea in between lesions
    • Eventually involves full thickness stroma

  • Reduced corneal sensation

• Treatment: PK

Schnyder (crystalline) dystrophy

• Disordered corneal lipid metabolism

• Present in 2nd and 3rd decade

• Associated with systemic dyslipidaemia

• Autosomal dominant, UBIAD1 gene

• Phospholipid and cholesterol deposits on histology

• Clinical features

  • Visual impairment and glare

    • Especially reduced photopic (light conditions) vision due to small pupil and light cannot pass around deposits (similar to PSCO cataracts). In scotopic conditions, the dilated pupil allows light in around the mid periphery of the cornea which tends to be clear

  • Progressive central haze

  • Subepithelial crystalline opacities: stain with Oil red O

  • Prominent corneal arcus lipoides

  • Reduced corneal sensation

• Treatment: excimer keratectomy or transplant (may recur in PKs)

Francois central cloudy dystrophy

• May be indistinguishable from crocodile shagreen: cloudy grey polygonal opacities
• Bilateral and symmetric
• Autosomal dominant
• Typically asymptomatic, not requiring treatment

Congenital hereditary stromal dystrophy

• Presents at birth
• Bilateral opacification of the central stroma with whitish flakes
• Non-progressive
• Thickened corneas
• Mutations in the decorin gene on chromosome 12

Fleck dystrophy

• Dandruff deposits in the stroma (sparing the other layers)
• Vision is preserved
• Autosomal dominant
• Typically non-progressive

Posterior amorphous dystrophy

• Bilateral slowly progressive
• Autosomal dominant
• Deep stromal opacification from limbus to limbus
• Central corneal thinning
• Associated: hypermetropia, iris processes, corectopia, iridocorneal adhesions (not glaucoma)

Descemet’s membrane and endothelial dystrophies

Fuchs endothelial dystrophy

• Bilateral accelerated endothelial cell loss (Na/K ATPase pump failure)

• F>M, develops in the 7th and 8th decades

• Associated with open angle glaucoma

• Typically sporadic, rarely AD with COL8A2 gene (also ZEB1, SLC4A11 or LOXHD1)

• Clinical features

  • Worsening visual blurring especially in the morning (due to oedema)

  • Corneal guttata: irregular excrescences on DM secreted by abnormal endothelial cells appear centrally (cp with normal Hassall-Henle bodies which are seen peripherally with age)

    • Histopathology shows multi-laminar Descemet’s membrane studded with excrescences
    • Specular microscopy shows: pleomorphism, polymethaism, reduced endothelial density

  • Tiny dark spots develop into beaten metal appearance

  • Central stromal oedema as cornea decompensates

  • Bowman’s membrane scarring

  • Epithelial oedema in advanced cases and bullous keratopathy which can cause acute pain if bullae rupture

  • Increased CCT on pachymetry: a thickness greater than 650 microns increases the risk of symptomatic and chronic corneal oedema after cataract surgery (same with cell counts <1000)

• Treatment:

  • Conservative: topical hypertonic saline, IOP-lowering therapy (beta-blockers preferred) , treatment of ruptured bullae
  • DSAEK/DMEK
  • Conjunctival flaps or amniotic membrane grafts if poor visual potential
  • Topical Rho-kinase inhibitors
  • Cataract surgery: may worsen disease so could be done with keratoplasty
  • NB: Fuch’s does not recur in PKs

Posterior polymorphous dystrophy

• Types 1 to 3

• Typically autosomal dominant

• Typically asymptomatic and not requiring treatment

• Vesicular lesions on the endothelium: may be subtle

  • Can mimic ICE syndrome but tends to affect older patients (and ICE is unilateral)

• The endothelium is abnormally multi-layered and has characteristics of the epithelium including desmosomes and microvilli

  • These cells may divide and migrate to the TM causing glaucoma

• Associated with Alport syndrome

Congenital hereditary endothelial dystrophy

• Focal or diffuse thickening of DM

• Types 1 (rare and less severe) and 2 (more common and associated with deafness aka Harboyan syndrome)

• Autosomal recessive

• Stationary: does not progress

• Clinical features

  • Photophobia and epiphora
  • Corneal clouding in neonatal/early life (epithelial oedema)
  • Blue tinted cornea due to thickening
  • Thickened stroma (cp. Congenital hereditary stromal dystrophy with cloudy stroma but normal thickness and normal epithelium)
  • Nystagmus: due to reduced visual sensory input
  • Normal IOP

• Treatment: lamellar or PK

TGFB1

• Locus 5q31

• Mutations in this gene cause all of the following

  • Granular
  • Reis-bucklers
  • Lattice type 1
  • Avellino

• Encodes keratoepithelin