Stromal corneal dystrophies

4. Classical Stromal Dystrophies

Stromal dystrophies involve progressive deposition of insoluble metabolic substances within the extracellular matrix of the corneal stroma. The majority are driven by mutations in the TGFBI gene (transforming growth factor beta-induced, encoding keratoepithelin) on chromosome 5q31, with the critical exception of Macular corneal dystrophy (CHST6).

1. Lattice Corneal Dystrophy Type 1 (Biber-Haab-Dimmer)

• Genetics: Autosomal dominant; TGFBI gene, classic mutation Arg124Cys.
• Biomicroscopy: Central anterior and mid-stromal delicate, refractile, branching filamentous lines that interlace like a network of twigs, pipestems, or lattice ribbons, accompanied by subepithelial white dots. The peripheral 1 to 2 mm of cornea remains completely clear.
• Histology: Extracellular accumulation of amyloid within the stroma, separating collagen fibrils.
  • Congo Red: Stains amyloid orange-red, displaying characteristic apple-green birefringence and dichroism under cross-polarised light.
  • Thioflavin T: Demonstrates intense yellow-green fluorescence.
  • Transmission electron microscopy reveals non-branching, straight, randomly oriented fibrils measuring 8 to 10 nm in diameter.
• Clinical Course: Recurrent erosions are common in the second and third decades. Progressive central haze reduces visual acuity, eventually requiring deep anterior lamellar keratoplasty (DALK) or penetrating keratoplasty (PK). Lattice lines commonly recur in the donor graft after 5 to 15 years.
• Lattice Type 2 (Meretoja Syndrome): Caused by mutations in the GSN (gelsolin) gene on chromosome 9q33. An autosomal dominant systemic amyloidosis presenting with masked facies, cranial neuropathies (progressive facial nerve palsy), pendulous ears, and sparse peripheral lattice lines in older adults.

2. Granular Corneal Dystrophy Type 1 (Groenouw Type 1)

• Genetics: Autosomal dominant; TGFBI gene, classic mutation Arg555Trp.
• Biomicroscopy: Discrete, sharply demarcated, chalky-white, crumb-like or snowflake-like opacities localized to the central anterior and mid-stroma. Crucially, the intervening stroma between deposits is crystal clear, and a clear zone at the limbus is preserved. Visual acuity remains intact until middle age when deposits coalesce and stromal haze develops.
• Histology: Insoluble hyaline deposits that stain bright red with Masson trichrome. Negative for Congo red and Alcian blue. TEM reveals rod-shaped, electron-dense trapezoidal structures.

3. Granular Corneal Dystrophy Type 2 (Avellino Dystrophy)

• Genetics: Autosomal dominant; TGFBI gene, classic mutation Arg124His.
• Biomicroscopy: Combined clinical phenotype displaying superficial discrete granular "star-like" or snowflake opacities in early stages, with subsequent emergence of deeper, delicate branching lattice lines and spicules.
• Histopathology: Demonstrates both hyaline deposits (Masson trichrome positive) and amyloid deposits (Congo red positive with apple-green birefringence).

4. Macular Corneal Dystrophy (Groenouw Type 2)

• Genetics: Autosomal Recessive (the only major stromal dystrophy inherited recessively). Caused by loss-of-function mutations in the carbohydrate sulfotransferase 6 (CHST6) gene on chromosome 16q22.
• Pathophysiology: Defective sulfotransferase enzyme activity halts sulfation of corneal keratan sulfate. Keratocytes and endothelial cells synthesize abnormally low-sulfated or non-sulfated glycosaminoglycans (GAGs), which accumulate intra- and extracellularly, disrupting corneal collagen spacing.
• Biomicroscopy: Diffuse, ill-defined, grey-white ground-glass clouding throughout the stroma, studded with denser, irregular grey-white macules. Landmark differentiating feature: the opacities extend fully to the limbus without any clear peripheral zone, involve the full thickness of the stroma (from epithelium to endothelium), cause diffuse corneal thinning, and induce secondary guttae-like endothelial excrescences.
• Histology: Glycosaminoglycans (mucopolysaccharides) stain intensely with Alcian blue (bright blue) and Colloidal iron (Prussian blue), and are positive with Periodic acid-Schiff (PAS). Negative for Congo red and Masson trichrome.
• Course: Severe, early visual loss starting in childhood or adolescence. Requires full-thickness penetrating keratoplasty (PK) or deep anterior lamellar keratoplasty (DALK), though recurrence in donor tissue can occur.

Other Notable Stromal Dystrophies

• Schnyder Corneal Dystrophy (SCD): Autosomal dominant mutation in UBIAD1 (1p36). Characterised by subepithelial and anterior stromal crystalline deposits composed of unesterified cholesterol and phospholipids, progressive central disc-like haze, and an early-onset dense arcus lipoides. Stains with Oil Red O and Sudan black on frozen sections. Strongly associated with systemic hypercholesterolemia.
• Gelatinous Drop-like Corneal Dystrophy (GDLD): Autosomal recessive mutation in TACSTD2 (1p32). Results in massive subepithelial amyloid deposits forming elevated, yellowish-white, "mulberry-like" nodular masses that cause severe photophobia and visual loss in early life.

Comparative Clinicopathological Matrix of Stromal Dystrophies