Endothelial corneal dystrophies

5. Endothelial Corneal Dystrophies

Endothelial dystrophies are characterised by primary dysfunction, morphological transformation, or premature apoptosis of the post-mitotic corneal endothelium, compromising the endothelial sodium-potassium ATPase pump and barrier function, culminating in corneal stromal and epithelial oedema.

Fuchs Endothelial Corneal Dystrophy (FECD)

FECD is the most frequent primary endothelial dystrophy, exhibiting a marked female preponderance (female-to-male ratio approximately 3:1 to 4:1) with clinical onset typically in the 5th to 6th decades of life.

• Molecular genetics: An intronic CTG-repeat expansion in TCF4 on chromosome 18 is an important association in late-onset Fuchs endothelial corneal dystrophy, with prevalence varying by population and study. Toxic RNA and altered splicing are implicated. Rare early-onset disease can involve COL8A2; do not assign one repeat threshold or population percentage to all patients.
• Pathophysiology: Endothelial loss compromises pump and barrier function. Remaining cells enlarge (polymegathism) and lose regular hexagonal shape (pleomorphism). Guttae are excrescences of Descemet membrane. Cell counts help assess reserve, but no single count defines decompensation: clinical oedema, tomography and symptoms matter.
• Clinical Biomicroscopic Staging:
  • Stage 1 (Corneal Guttae): Central Descemet membrane excrescences displaying a classic "beaten metal" or "dewdrop" appearance on specular reflection. Asymptomatic.
  • Stage 2 (Stromal Oedema): Endothelial pump capacity fails. Fluid accumulates within the posterior and anterior stroma, manifesting as fine stromal haze and Descemet folds. Patients experience morning blur—vision is poor upon awakening due to lack of overnight tear film evaporation; vision gradually improves during the day as tear evaporation dehydrates the cornea.
  • Stage 3 (Bullous Keratopathy): Fluid enters the epithelium, forming microcysts that coalesce into large, fluid-filled subepithelial bullae. Rupture of bullae exposes corneal nerve endings, producing excruciating pain, tearing, and foreign body sensation.
  • Stage 4 (Avascular Subepithelial Fibrosis): Longstanding oedema stimulates subepithelial scarring and avascular pannus. Pain decreases as the fibrous tissue acts as a mechanical barrier against bullae rupture, but profound permanent visual loss ensues.
• Medical Therapy: Preservative-free hypertonic sodium chloride 5% drops (4 times daily) and ointment at bedtime; warm air blow-drying (using a hairdryer held at arm's length) upon waking to facilitate evaporation; intraocular pressure lowering to reduce aqueous hydrostatic filtration pressure.
• Surgical Therapy: Selective endothelial keratoplasty: Descemet Membrane Endothelial Keratoplasty (DMEK) or Descemet Stripping Automated Endothelial Keratoplasty (DSAEK). In early disease with purely central guttae, Descemetorhexis without Endothelial Keratoplasty (DWEK / DSO) combined with topical Rho-kinase (ROCK) inhibitors (e.g., ripasudil or netarsudil) allows peripheral endothelial cells to migrate centrally.

Posterior Polymorphous Corneal Dystrophy (PPCD / PPMD)

An autosomal dominant endothelial dystrophy associated with OVOL2 (chromosome 20), ZEB1 (chromosome 10), or GRHL2 (chromosome 8). The historical COL8A2 association remains uncertain.

• Pathogenesis: Endothelial cells undergo epithelial metaplasia—they develop desmosomes, tonofilaments, surface microvilli, express epithelial cytokeratins, and demonstrate an abnormal propensity to proliferate across tissue planes.
• Biomicroscopy: Manifests in three characteristic patterns on Descemet membrane:
  1. Vesicular Lesions: Discrete, circular, blister-like or crater-like lesions surrounded by a hazy grey-white halo.
  2. Curvilinear Bands: Parallel, elevated, scalloped ridges or "railroad tracks" crossing Descemet membrane.
  3. Geographic Sheets: Flat, diffuse, grey-white opacities.
• Glaucoma Association: The proliferating epithelial-like endothelial cells can migrate across the anterior chamber angle and trabecular meshwork, producing extensive peripheral anterior synechiae (PAS), corectopia, iris atrophy, and secondary angle-closure or open-angle glaucoma in approximately 15% to 25% of patients.

Congenital Hereditary Endothelial Dystrophy (CHED)

An autosomal recessive disorder (Category 1) caused by homozygous or compound heterozygous mutations in SLC4A11 on chromosome 20p13, which encodes an membrane transport protein.

• Clinical Features: Bilateral, diffuse, symmetrical, ground-glass corneal oedema present at birth or within the first months of life. Marked corneal thickening (pachymetry often $800$ to $> 1000\,\mu\text{m}$). Visual deprivation nystagmus develops early.
• Critical Board Differential: Must be distinguished from Primary Congenital Glaucoma (PCG). In CHED, the cornea is edematous and thickened, but intraocular pressure is normal, corneal diameter is normal (absence of buphthalmos), and Haab striae are absent.
• Harboyan Syndrome: The clinical triad of CHED combined with progressive, post-lingual sensorineural hearing loss (also caused by SLC4A11 mutations, reflecting inner ear fibrocytes).

Updated genetic classification

Epithelial recurrent erosion dystrophy (ERED) is now category 1 with COL17A1 on chromosome 10. Franceschetti, Smolandiensis and Helsinglandica phenotypes remain category 4 rather than being assigned the same confirmed genotype. See IC3D edition 3 for the current templates.

Case: deposits, erosions and an inheritance claim

A patient with recurrent erosions has fine superficial deposits; a relative has been told that a different stromal opacity is the same dystrophy. Establish the layer and morphology before assuming one family diagnosis. Slit-lamp illumination, photographs and selected imaging help distinguish epithelial or subepithelial disease from deeper amyloid, hyaline or endothelial change. Review onset, symptoms, symmetry and a pedigree, but remember that variable expression and incomplete histories can obscure inheritance. If molecular testing is considered, explain what a pathogenic result would establish and that an uncertain variant does not automatically rename the phenotype. Symptomatic erosions and visually significant deeper opacities also lead to different treatments. A superficial procedure that helps an anterior deposit does not replace diseased endothelium. Apply the IC3D category as a statement about supporting clinical, genetic and pathological evidence rather than as a severity score.