Synthesis
Comparative & differential-diagnosis tables
For diagnostic support, this section brings together all the data scattered throughout the course in two complementary formats: first, differential-diagnosis tables organised by clinical presentation, then comparative synthesis tables organised by anatomical group and according to the international IC3D classification.
How to read these tables
The differential tables start from the observed sign (cysts, deposits, endothelial appearance) and contrast the entities that share it. The comparative tables start from the entity and line up gene/locus, inheritance, affected layer, deposit type, histological stain and risk of recurrence on graft. No data have been removed from the text: these grids condense what is developed in the preceding chapters.
A. Differential-diagnosis tables
A1. Epithelial opacities and cysts
Distinguishing intra-epithelial cysts and opacities
| Entity | Appearance of cysts / opacities | Optimal illumination | Relation to limbus | Discriminating feature |
|---|
| Meesmann | Multiple, clear, diffuse cysts | Direct illumination (diffuse opacities) and retro-illumination | Spares the limbus | Isolated clear cysts, otherwise clear cornea |
| Lisch | Clustered/confluent, feathery cysts | Retro-illumination | Extend to the limbus (limbal origin) | "Feathery" appearance, readily whiter than Meesmann |
| Cogan (dots) | Pearly-white intra-epithelial cysts, in a central cluster | Not seen on direct illumination | Central | Associated with map/fingerprint, basement-membrane reduplication |
| Cornea verticillata | Ultrafine cysts grouped in a whorl | Retro-illumination; direct examination: brown comet-like lines | Inferior point of the cornea | Whorl-like distribution (iatrogenic/Fabry) |
| Early acanthamoeba keratitis | Epithelial cysts, sometimes very numerous | Direct illumination | Variable | Pain +++ disproportionate, contact-lens context |
| Iatrogenic "ADC" cysts | Intra-epithelial cysts | Direct illumination | Variable | Context of chemotherapy with antibody-drug conjugates |
A2. Stromal deposits
Distinguishing the stromal deposits of the dystrophies (TGFBI and non-TGFBI)
| Dystrophy | Deposit type | Histological stain | Stroma between deposits | Recurrence on graft |
|---|
| Lattice | Amyloid (branching lines) | Congo red (apple-green birefringence) | Clear initially | Frequent — the most frequent, ≈ 9 years |
| Granular type 1 | Well-demarcated granular hyaline deposits | Masson trichrome (red) | Clear between the granules | Frequent — the earliest |
| Granular type 2 (Avellino) | Mixed hyaline + amyloid deposits | Masson and Congo red | Clear | Frequent |
| Macular (Groenouw II) | Glycosaminoglycans (keratan sulfate) | Alcian blue, colloidal iron, PAS | Not transparent (diffuse haze) | Slower (non-TGFBI) |
| Schnyder | Cholesterol and phospholipids (crystals) | Sudan black / oil red (fresh tissue) | Clear, then lipoid arc | Possible |
| Fleck | GAG + lipids within certain keratocytes | Alcian blue + Sudan black | Clear (asymptomatic) | Not applicable (graft not required) |
Pitfall
The distinction between macular and granular rests on five points: recessive inheritance, reduced corneal thickness, involvement extending to the limbus, involvement of the entire stroma, and stromal haze between the deposits from an early age. A TGFBI stromal dystrophy may moreover be complicated by recurrent corneal pain and mimic an anterior dystrophy: clinical semiological analysis remains decisive.
A3. Endothelial and Descemet involvement
Distinguishing the endothelial dystrophies
| Entity | Age / onset | Endothelial appearance | Corneal oedema | Discriminating feature |
|---|
| Fuchs (FECD) | Adult (late forms) | Cornea guttata, thickened Descemet | Progressive, late | Confluent central guttae, most often sporadic |
| PPCD (posterior polymorphous) | Early, often asymptomatic | Vesicular, band-like, geographic lesions | Rare, if decompensation | Endothelial cells with epithelial behaviour; variable penetrance |
| CHED | Congenital | Diffusely abnormal endothelium/Descemet | Oedema from birth | AR, SLC4A11 gene; incomplete central endothelial migration |
B. Comparative synthesis tables
B1. Anterior dystrophies (epithelial, basement membrane, Bowman)
Comparison of the anterior dystrophies
| Dystrophy | Gene / locus | Inheritance | Layer | Recurrence on graft |
|---|
| Meesmann | Cytokeratin CK3 / CK12 | AD | Epithelium only | — |
| Gelatinous drop-like (GDLD) | M1S1 / TACSTD2, 1p32 | AR (Japanese predominance) | Epithelial & subepithelial → stroma | Rapid |
| Cogan (map-dot-fingerprint) | Most often sporadic (collagen XVII) | Sporadic; AD rare | Epithelium & basement membrane | Not applicable (debridement) |
| Reis-Bücklers / Bowman (granular type 3) | TGFBI, R124L | AD | Bowman & anterior stroma | Frequent |
| Thiel-Behnke | TGFBI, R555Q | AD | Bowman & anterior stroma | Frequent |
B2. Stromal dystrophies
Comparison of the stromal dystrophies
| Dystrophy | Gene / locus | Inheritance | Deposited substance | Recurrence on graft |
|---|
| Lattice | TGFBI (including L518P) | AD | Amyloid | Frequent (≈ 9 years) |
| Granular type 1 | TGFBI, R555W | AD | Hyaline | Frequent (the earliest) |
| Macular (Groenouw II) | CHST6, 16q22.1 (non-TGFBI) | AR | Keratan sulfate (GAG) | Slower |
| Schnyder | UbiA (1p36) | AD | Cholesterol / phospholipids | Possible |
| Fleck | PIKFYVE, 2q35 | AD | GAG + lipids (keratocytes) | Treatment rarely required |
| Posterior amorphous | 12q21 deletion (keratocan, lumican, decorin, epiphycan) | AD | Posterior stroma (abnormal matrix) | Rarely operated |
B3. Endothelial dystrophies
Comparison of the endothelial dystrophies
| Dystrophy | Gene / locus | Inheritance | Target | Onset |
|---|
| Fuchs (FECD) | Multiple loci (FECD1–8; TCF4/CTG the most frequent) | Mostly sporadic; AD in certain forms | Endothelium & Descemet | Adult |
| PPCD (posterior polymorphous) | Heterogeneous (3 loci) | AD, variable penetrance | Descemet & endothelium | Early |
| CHED | SLC4A11, 20p13 | AR | Descemet & endothelium | Congenital |
B4. Master table — IC3D classification
The reference classification (IC3D, Weiss et al., Cornea 2015 2nd ed.; 2024 3rd ed.) divides the dystrophies into four groups according to the cellular origin of the deposits, and assigns each entity a level of evidence (category 1 = fully demonstrated on clinical, histopathological and genetic grounds; category 4 = suspected entity).
The four IC3D groups and their principal entities
| IC3D group | Layer(s) | Representative entities | Key gene(s) |
|---|
| 1. Epithelial & subepithelial | Epithelium, basement membrane | Meesmann, Lisch, Cogan (map-dot-fingerprint), gelatinous drop-like | KRT3/KRT12, TACSTD2 |
| 2. Epithelial-stromal TGFBI | Bowman & stroma (several layers) | Reis-Bücklers, Thiel-Behnke, lattice, granular types 1/2 | TGFBI |
| 3. Stromal | Stroma | Macular, Schnyder, Fleck, posterior amorphous | CHST6, UbiA, PIKFYVE |
| 4. Endothelial | Endothelium & Descemet | Fuchs (FECD), PPCD, CHED | TCF4, SLC4A11 |
IC3D 3rd ed. update (2024)
The 3rd edition, open access, incorporates the publications from 2014 to 2023 and updates 22 standardised templates, each accompanied by the gene and locus when known. The grouping sets apart the TGFBI dystrophies (group 2), which involve several layers rather than a single one. Of note: posterior amorphous corneal dystrophy has moved from category 3 to category 1.
References
References
- Références des données récentes ajoutées ci-dessus (classification IC3D, génétique et traitements).
- 1. Weiss JS, Møller HU, Aldave AJ, et al. IC3D classification of corneal dystrophies – edition 2. Cornea. 2015;34(2):117-159.
- 2. Weiss JS, Rapuano CJ, Seitz B, et al. IC3D classification of corneal dystrophies – edition 3. Cornea. 2024;43(4):466-527.
- 3. Munier FL, Korvatska E, Djemaï A, et al. Kerato-epithelin mutations in four 5q31-linked corneal dystrophies. Nat Genet. 1997.
- 4. Wieben ED, Aleff RA, Tosakulwong N, et al. A common trinucleotide repeat expansion within the transcription factor 4 (TCF4) gene predicts Fuchs corneal dystrophy. PLoS One. 2012.
- 5. Fautsch MP, Wieben ED, Baratz KH, et al. TCF4-mediated Fuchs endothelial corneal dystrophy: insights into a common trinucleotide repeat-associated disease. Prog Retin Eye Res. 2021.
- 6. Moloney G, Petsoglou C, Ball M, et al. Descemetorhexis without grafting for Fuchs endothelial dystrophy – supplementation with topical ripasudil. Cornea. 2017;36:642-648.
- 7. Dinh R, Rapuano CJ, Cohen EJ, Laibson PR. Recurrence of corneal dystrophy after excimer laser phototherapeutic keratectomy. Ophthalmology. 1999.
- 8. Management of stromal corneal dystrophies: review of the literature with a focus on phototherapeutic keratectomy and keratoplasty. Vision (Basel). 2023.