Corneal stromal dystrophies are a group of hereditary diseases that cause corneal opacification due to the deposition of abnormal proteins or other substances in the corneal stroma. The 2015 revised IC3D (International Committee for Classification of Corneal Dystrophies) classification systematically categorizes them based on the lesion site and genetic mutation.
Mutations in the TGFBI (transforming growth factor β-induced) gene are responsible for many subtypes. The TGFBI gene is located on chromosome 5q31, and it is characteristic that a single amino acid change can lead to different clinical presentations. TGFBI gene mutations are involved in lattice corneal dystrophy type I, Reis-Bücklers corneal dystrophy, Thiel-Behnke corneal dystrophy, granular corneal dystrophy type II (Avellino corneal dystrophy), granular corneal dystrophy type I, and other corneal stromal dystrophies 8). TGFBIp is an extracellular matrix (ECM) protein that mediates cell adhesion through interactions with collagen, integrins, and fibronectin 8)9). To date, more than 70 TGFBI mutations have been identified, of which 41 are associated with lattice corneal dystrophy 3).
In the 2015 IC3D revision, the term “epithelial-stromal TGFBI-related dystrophy” was introduced to comprehensively classify a group of diseases in which opacities extend from the subepithelial layer to the deep stroma.
Lattice Corneal Dystrophy (LCD)
Causative gene: TGFBI (e.g., R124C)
Deposits: Amyloid
Features: Branching lattice-like linear opacities appear in the corneal stroma. Congo red stain positive, showing yellow-green birefringence under polarized light microscopy.
Granular Corneal Dystrophy (GCD)
Causative gene: TGFBI (type 1: R555W, type 2: R124H)
Deposits: Hyaline (type 1), hyaline + amyloid (type 2)
Features: Granular white opacities appear near the pupillary area. They stain red with Masson’s trichrome stain.
Macular corneal dystrophy (MCD)
Causative gene: CHST6
Deposits: Glycosaminoglycans (GAGs)
Features: Diffuse corneal opacification involving the full thickness of the stroma. Alcian blue stain positive. It is the only autosomal recessive subtype.
Other stromal dystrophies include Schnyder corneal dystrophy (cholesterol and phospholipid deposits) due to UBIAD1 mutation, gelatinous drop-like corneal dystrophy (GDLD) due to TACSTD2 mutation, lattice corneal dystrophy type 2 (Meretoja syndrome) due to GSN mutation, and congenital stromal corneal dystrophy due to DCN mutation.
It is a group of inherited corneal diseases in which abnormal protein (TGFBIp) deposits in the corneal stroma due to mutations in the TGFBI gene. A single amino acid difference can lead to markedly different clinical presentations such as lattice, granular, or Reis-Bücklers dystrophy. It is autosomal dominant and usually progresses bilaterally.
Common subjective symptoms of corneal stromal dystrophies include the following.
In LCD patients, recurrent epithelial erosion is often the initial symptom. In GCD, decreased vision due to opacity itself is the main complaint. In GDLD, decreased vision, photophobia, foreign body sensation, and tearing are the main symptoms 10).
Lattice corneal dystrophy (LCD): In typical cases (LCD1), branching lattice-like linear opacities appear in the anterior corneal stroma from the center to the mid-periphery. Ground-glass corneal opacity and subepithelial scarring are also present. Variant LCD may show late-onset and asymmetric distribution. In a case with Ser591Phe mutation reported in a Finnish family, symptoms first appeared at age 71, with translucent subepithelial irregularities and thick branching lattice-like opacities from the center to the mid-periphery 2).
Granular corneal dystrophy type 1 (GCD1): In the early stage, small, round, well-demarcated granular white to gray-white opacities are observed in the subepithelial and superficial stroma near the pupillary area. It is caused by the R555W mutation in heterozygotes, and homozygotes have a more severe course.
Granular corneal dystrophy type 2 (GCD2; Avellino corneal dystrophy): Caused by the R124H mutation. It is a mixed type with deposition of both hyaline and amyloid. In GCD2 patients after SMILE, deposits appeared at the surgical interface 2 months postoperatively, and at 33 months, deposits beneath Bowman’s layer and at the interface were simultaneously confirmed by FD-OCT 1).
Macular corneal dystrophy (MCD): Diffuse corneal opacity involves the full thickness of the stroma. It is caused by CHST6 gene mutation and inherited in an autosomal recessive pattern. It is the only recessive type among corneal dystrophies.
Schnyder corneal dystrophy: Characterized by ring-shaped to disc-shaped opacity in the central cornea. It is due to deposition of cholesterol and phospholipids. It is frequently associated with systemic dyslipidemia.
Gelatinous drop-like corneal dystrophy (GDLD): Gray-white elevated amyloid deposits cluster in the central cornea and interpalpebral fissure of both eyes, giving a characteristic mulberry-like appearance 10). Delayed staining, where fluorescence is observed a few minutes after fluorescein staining despite the absence of corneal epithelial damage, is a useful diagnostic finding 10).
In LCD patients, the corneal epithelium is fragile, posing a risk of secondary infection. Cases of bilateral Mooren’s ulcer complicating LCD1 have been reported 7). Additionally, cases of microsporidial keratitis have been reported in LCD corneas, suggesting increased susceptibility to infection due to epithelial damage 6). The prevalence of corneal dystrophy in the general population is estimated at 897 per million, with LCD accounting for less than 1% of these 6).
Most corneal stromal dystrophies are caused by point mutations in the TGFBI gene. The mutations and corresponding diseases are shown below.
| Mutation | Disease Name | Inheritance Pattern |
|---|---|---|
| R555W | Granular corneal dystrophy type 1 | AD |
| R124H | Granular corneal dystrophy type 2 | AD |
| R124C | Lattice corneal dystrophy type 1 | AD |
| R124L | Reis-Bücklers corneal dystrophy | AD |
| R555Q | Thiel-Behnke corneal dystrophy | AD |
| L527R | Lattice corneal dystrophy type 4 | AD |
| Ser591Phe | Variant LCD (late-onset) | AD |
AD: Autosomal dominant
New TGFBI mutations continue to be reported. The c.1772C>T (p.Ser591Phe) mutation identified in a Finnish family is located in the FAS1-4 domain of exon 13 and causes late-onset, asymmetric variant LCD 2). This mutation is not registered in the gnomAD database and was predicted to be pathogenic by multiple prediction programs 2). The same mutation has been independently confirmed in a US family 3). A different amino acid substitution at the same Ser591 position (Ser591Tyr) has been reported to show a TBCD-like phenotype, demonstrating that different mutations at the same codon can produce different clinical presentations 3).
Other causative genes besides TGFBI include CHST6 (MCD), UBIAD1 (Schnyder CD), TACSTD2 (GDLD), GSN (LCD2 / Meretoja syndrome), and DCN (congenital stromal corneal dystrophy).
In patients with TGFBI-related corneal dystrophies, refractive surgeries such as LASIK, PRK, and SMILE are known to exacerbate corneal deposits. After unilateral SMILE in a GCD2 patient, new deposits appeared at the surgical interface 2 months postoperatively, and the size, density, and number of deposits increased after 33 months 1). TGF-β is an essential factor in wound healing, and corneal epithelial trauma activates the TGFBI gene, increasing TGFBIp production 1). In a case of GCD1 exacerbation after LASIK, Masson’s trichrome-positive hyaline deposits were confirmed at the flap interface 5).
For patients with TGFBI-related corneal dystrophy, refractive surgeries such as LASIK, PRK, and SMILE are contraindicated. Surgical invasion of the cornea induces TGF-β, which exacerbates abnormal protein deposition. If there is a family history or suspected corneal opacity before surgery, genetic testing must be performed.
Characteristic findings are observed for each subtype. LCD shows lattice-like linear opacities, GCD shows granular white opacities, and MCD shows diffuse corneal opacities. In GCD2, translucent deposits and vacuoles (breadcrumb-like appearance) can be seen under retroillumination 5).
The depth and extent of deposits can be quantitatively assessed. In post-LASIK cases of GCD2, hyperreflective deposits at the flap interface (depths of 149 μm and 115 μm) were visualized 5). In LCD, hyperreflective deposits within the stroma are visible 2).
The morphology of deposits can be evaluated at the cellular level. In a post-LASIK case of GCD1, thin hyperreflective deposits from the basal epithelial layer to Bowman’s membrane and trapezoidal dense white deposits in the anterior to mid stroma were observed 5).
| Staining Method | Target Deposits | Associated Disease |
|---|---|---|
| Congo Red Stain | Amyloid | LCD, GDLD |
| Masson’s trichrome | Hyaline | GCD1, GCD2 |
| Alcian blue stain | GAG | MCD |
Under polarized light, Congo red-positive deposits show apple green birefringence. In GCD2, both amyloid and hyaline are deposited, so it is positive for both Congo red and Masson’s trichrome6).
It is useful for definitive diagnosis. Especially in variant LCD and atypical cases, genetic analysis is key to diagnosis2)3). In the diagnostic criteria for GDLD, combining genetic testing with other findings improves diagnostic accuracy in atypical cases10).
First choice for superficial corneal opacities. The opaque area is removed using an excimer laser. Effective for early lesions, but recurrence is inevitable due to the hereditary nature.
For refractory recurrent epithelial erosion in LCD, a combined technique of topography-guided transepithelial PRK and PTK has been reported4). In a 78-year-old male with LCD, both eyes were treated; corneal erosion disappeared 3 months postoperatively, and corrected visual acuity improved from 20/100 to 20/25 in the right eye and from 20/400 to 20/50 in the left eye4). Surface smoothing with a masking agent (1% hydroxymethylcellulose) and mitomycin C application were used concurrently4).
Depending on the progression of opacity, lamellar keratoplasty (LKP), deep anterior lamellar keratoplasty (DALK), or penetrating keratoplasty (PKP) is selected. In TGFBI-related dystrophies, deposits are mainly epithelial-derived, so lamellar transplantation is the first choice, but the risk of recurrence remains.
For cases of GCD1 exacerbation after LASIK, femtosecond laser-assisted sutureless anterior lamellar keratoplasty (F-SALK) has been reported to be effective 5). Graft clarity was maintained at 4+ at 6 months postoperatively, and corrected visual acuity improved from 6/24 to 6/12 5).
In a case of LCD1 complicated by bilateral Mooren’s ulcer, penetrating keratoplasty was performed under systemic cyclosporine, and corrected visual acuity of 20/30 was achieved in both eyes postoperatively 7). No recurrence of ulcer was observed for over 10 years 7).
In GDLD, PTK or corneal transplantation (superficial, deep anterior lamellar, or penetrating) is performed depending on the extent of opacity 10). Because it is a hereditary disease, the recurrence rate is very high, and multiple corneal transplants are often required 10). It is known that wearing soft contact lenses can suppress recurrence of amyloid deposition and prolong the interval between surgeries 10). GDLD was designated as an intractable disease in 2019, and patients with severity class III or higher are eligible for medical expense subsidies 10).
All corneal refractive surgeries including LASIK, PRK, and SMILE are contraindicated in patients with TGFBI-related corneal dystrophy 1)5).
PTK (First Choice)
Indications: Superficial opacities, recurrent epithelial erosions
Advantages: Minimally invasive, expected visual improvement
Challenges: Recurrence is inevitable due to hereditary nature. Combined PRK for refractive correction and surface regularization has also been reported 4)
Corneal Transplantation
Indications: Advanced opacities, deep lesions not amenable to PTK
Surgical techniques: Superficial, deep anterior lamellar, or penetrating keratoplasty selected based on lesion depth
Challenge: Risk of recurrence remains. In GDLD, multiple transplants are often required 10)
PTK is effective for removing superficial opacities and can improve vision, but because it is a genetic disease, recurrence is possible after several years. In case of recurrence, repeat PTK or corneal transplantation may be considered. Lifelong regular follow-up is important.
TGFBIp (keratoepithelin) encoded by the TGFBI gene is an ECM protein with an N-terminal secretory signal sequence, mediating cell adhesion through interactions with collagen, fibronectin, and integrins 8)9). Abnormal TGFBIp produced by TGFBI mutations is not properly degraded or cleared, accumulating and aggregating in the corneal stroma.
The nature of deposits differs depending on the type of mutation. The R124C mutation forms amyloid fibrils, presenting the clinical picture of LCD; the R555W mutation causes hyaline deposits, leading to GCD1. The R124H mutation (GCD2) results in a mixed type with both amyloid and hyaline deposits.
Rosetta-based structural prediction for the Ser591Phe mutation calculated a thermodynamic destabilization of ΔG = 23.5 REU 3). This reflects energetic frustration and is consistent with the destabilization pattern commonly seen in LCD-inducing mutations 3). The fact that different mutations at the same codon (Ser591Phe vs Ser591Tyr) result in different phenotypes (LCD vs TBCD-like) suggests that the type of amino acid substitution determines protein folding and aggregation mechanisms 3).
Corneal trauma induces TGF-β expression 1). TGF-β activates the TGFBI gene, increasing production of TGFBIp. Overproduction of mutant TGFBIp accelerates deposition. Since corneal epithelial cells produce more TGF-β than keratocytes in the corneal stroma, surgeries with greater epithelial damage lead to more pronounced exacerbation 1).
In GCD2, it has also been reported that TGFBIp causes delayed autophagic clearance via lysosomal dysfunction 1), suggesting a molecular mechanism in which mitochondrial dysfunction and increased cellular oxidative stress promote TGFBIp deposition 1). SMILE causes less epithelial damage compared to LASIK or PRK, so exacerbation of GCD2 may be somewhat milder, but it remains contraindicated 1).
In GDLD, TACSTD2 mutations cause impaired tight junction formation, leading to increased epithelial permeability. This increased permeability is thought to allow tear proteins to infiltrate the corneal stroma and deposit as amyloid.
The spectrum of TGFBI mutations continues to expand. The discovery of the Ser591Phe mutation 2) and its independent confirmation 3) demonstrated the genetic diversity of late-onset variant LCD. The finding that different substitutions at the same amino acid position result in different phenotypes 3) paves the way for elucidating mutation-specific molecular mechanisms.
Rosetta-based protein structure prediction has enabled quantitative assessment of the impact of TGFBI mutations on protein stability 3). Computational biology methods are becoming increasingly important for evaluating the pathogenicity of novel mutations and exploring therapeutic targets.
Combined PRK+PTK surgery is expected as a new treatment option for refractory epithelial erosions in LCD 4). Topography-guided surgery can simultaneously correct irregular astigmatism and remove opacities. F-SALK for GCD exacerbation after LASIK 5) also represents a new approach for cases with limited treatment options.
The first report of microsporidial keratitis in LCD corneas 6) has highlighted that epithelial barrier dysfunction in corneal dystrophy patients increases infection risk. Recurrence after therapeutic keratoplasty has also been reported, underscoring the importance of infection management in LCD patients.
Yes, GDLD was designated as an intractable disease (gelatinous drop-like corneal dystrophy) in 2019. If diagnosed as definite according to diagnostic criteria, it qualifies as a designated intractable disease, and patients with severity class III or higher (based on best-corrected visual acuity in the better eye) can receive medical expense subsidies.
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Choo CH, Chung DD, Ledwitch KV, et al. Confirmation of association of TGFBI p.Ser591Phe mutation with variant lattice corneal dystrophy. Ophthalmic Genet. 2022;43(4):530-533.
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Kayukawa K, Kitazawa K, Wakimasu K, et al. A case of lattice corneal dystrophy type 1 with bilateral Mooren’s ulcer. Am J Ophthalmol Case Rep. 2023;29:101796.
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Matthaei M, Hribek A, Clahsen T, et al. Fuchs endothelial corneal dystrophy: clinical, genetic, pathophysiologic, and therapeutic aspects. Annu Rev Vis Sci. 2019;5:151-175.
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