Congenital Stromal Corneal Dystrophy (CSCD)
1. What is Congenital Stromal Corneal Dystrophy (CSCD)?
Section titled “1. What is Congenital Stromal Corneal Dystrophy (CSCD)?”Congenital stromal corneal dystrophy (CSCD) is an autosomal dominant corneal dystrophy caused by mutations in the decorin gene (DCN, 12q22). It presents with non-progressive or slowly progressive corneal stromal opacities from birth.
In the IC3D classification (revised 2015), it is categorized as a stromal dystrophy. Stromal corneal dystrophies include lattice and granular dystrophies associated with TGFBI gene mutations, but CSCD is a distinct disease entity due to decorin gene abnormality.
Epidemiology
Section titled “Epidemiology”CSCD is extremely rare, with only 5 families (France, 2 in the USA, Norway, Belgium) and one East Asian family reported to date. No precise incidence or prevalence statistics exist. The inheritance pattern is autosomal dominant with complete penetrance.
Both diseases cause congenital corneal opacities, but the causative genes and affected sites differ. CSCD is caused by an autosomal dominant mutation in the decorin gene (12q22), affecting the corneal stroma and presenting with flaky opacities. CHED is caused by an autosomal recessive mutation in the SLC4A11 gene (20p13), affecting the corneal endothelium and presenting with diffuse corneal edema. CHED is characterized by corneal edema, whereas edema is not prominent in CSCD.
2. Main Symptoms and Clinical Findings
Section titled “2. Main Symptoms and Clinical Findings”Subjective Symptoms
Section titled “Subjective Symptoms”Corneal opacities become apparent within a few months after birth. In addition to reduced vision due to opacities, amblyopia and strabismus are common complications. In consanguineous families, severe photophobia and searching nystagmus have also been reported. A 2012 case with a novel mutation reported a mild form where the patient first presented with vision loss in their 30s.
Clinical Findings
Section titled “Clinical Findings”Slit-lamp examination reveals numerous small opacities throughout the entire corneal thickness. The appearance is characteristically described as “flake-like” or “spotty,” giving a hazy appearance.
Corneal thickness is increased, with an average of 673 μm (range 658–704 μm) in 11 individuals from a Norwegian family1). Corneal diameter is normal, fluorescein staining is negative, and no neovascularization is observed. Intraocular pressure is normal, and corneal sensation is normal or slightly reduced2).
3. Causes and Risk Factors
Section titled “3. Causes and Risk Factors”Decorin Gene Mutation
Section titled “Decorin Gene Mutation”The causative gene is the decorin (DCN) gene on chromosome 12 (12q21.33)1,2). In most cases, a frameshift mutation within the decorin gene produces a truncated decorin lacking the C-terminal 33 amino acids (e.g., c.967delT, p.S323fsX5)1). Mouse models have shown that extracellular transport and deposition of truncated decorin are necessary for the formation of the CSCD phenotype3). In contrast, a c.1036 T>G (p.Cys346Gly) substitution has been reported in a mild form, where collagen crosslinking is maintained and patients do not experience significant vision loss until middle age.
Risk Factors
Section titled “Risk Factors”Because it is an autosomal dominant disorder with complete penetrance, children of an affected individual have a 50% chance of developing the condition. A relevant family history is the most important risk factor.
4. Diagnosis and Examination Methods
Section titled “4. Diagnosis and Examination Methods”Slit-Lamp Examination
Section titled “Slit-Lamp Examination”Flake-like opacities throughout the entire corneal thickness are observed. The corneal surface may be slightly irregular or normal. If opacities are severe, evaluation of the endothelium becomes difficult.
Transmission Electron Microscopy (TEM)
Section titled “Transmission Electron Microscopy (TEM)”A characteristic finding is the separation of collagen fiber lamellae within an electron-lucent matrix. The collagen fibers themselves are normal, but they are thin, highly aligned, and densely packed. Descemet’s membrane and the corneal epithelium are normal.
Genetic Testing
Section titled “Genetic Testing”Targeted sequencing of the DCN gene can provide a definitive diagnosis. If there is a positive family history and the proband’s mutation is known, carrier testing can also be performed.
Differential Diagnosis
Section titled “Differential Diagnosis”| Differential Diagnosis | Key Differences |
|---|---|
| CHED | AR inheritance, corneal edema present |
| PPCD | Affects Descemet’s membrane and endothelium |
| Macular corneal dystrophy | AR inheritance, progressive |
A clinical diagnosis is possible with a typical family history, slit-lamp findings, and TEM findings, but genetic testing (DCN gene analysis) is useful for a definitive diagnosis. Genetic testing is recommended especially in sporadic cases with unclear family history or when differentiation is difficult.
5. Standard Treatment
Section titled “5. Standard Treatment”Medical Treatment
Section titled “Medical Treatment”Glasses or contact lenses are used for refractive correction. Since this is a congenital condition, early detection and treatment of amblyopia (such as patching) are important. Currently, there is no medication that improves corneal opacity itself.
Surgical Treatment
Section titled “Surgical Treatment”Corneal transplantation to improve vision is the main surgical treatment. Early intervention before age 7 may reduce the incidence of amblyopia.
Penetrating keratoplasty (PK): This is the traditional standard procedure. A long-term study of 18 eyes (mean follow-up 19.5 years, range 3–36 years) reported that 56% maintained completely clear grafts 2). However, in children, rejection and suture management are challenges.
Deep anterior lamellar keratoplasty (DALK): Since the corneal endothelium is normal in CSCD, DALK is theoretically suitable 2). DALK has the advantage of avoiding the risk of endothelial rejection, and in CSCD with healthy endothelium, DALK is recommended as a preferable treatment option over PK.
In CSCD, since the corneal endothelium is normal, deep anterior lamellar keratoplasty, which preserves the endothelium, is theoretically superior. Deep anterior lamellar keratoplasty has no risk of endothelial rejection and offers long-term graft survival. However, its application to CSCD is still at the case report level, while PK has more long-term data. The decision is made case by case, considering the surgeon’s experience and the patient’s condition.
6. Pathophysiology and Detailed Mechanism
Section titled “6. Pathophysiology and Detailed Mechanism”Function of Decorin
Section titled “Function of Decorin”Decorin is a dermatan sulfate proteoglycan that maintains collagen fiber spacing and interlamellar adhesion in the corneal stroma. Through interactions with type I and IV collagen, fibronectin, and TGF-β, it inhibits lateral growth of collagen fibers. This uniform spacing is essential for maintaining corneal transparency.
The pathophysiology of corneal stromal dystrophies is diverse, involving different molecular pathways in each disease, such as lattice and granular dystrophies caused by TGFBI gene mutations. In CSCD, deletion of the decorin gene leads to accumulation of abnormal truncated decorin products in the cornea.
Mechanism of CSCD Development
Section titled “Mechanism of CSCD Development”Accumulation of truncated decorin disrupts the normal spacing of collagen fibers and induces abnormal fibrillogenesis. Histologically, normal collagen lamellae are separated by electron-lucent material, and the corneal stroma is markedly thickened. Descemet’s membrane, corneal endothelium, and corneal epithelium remain normal.
In the mild form caused by the c.1036 G>T substitution, collagen cross-linking is maintained, suggesting a possible genotype-phenotype correlation between the type of decorin mutation and clinical severity.
7. Recent Research and Future Perspectives
Section titled “7. Recent Research and Future Perspectives”CSCD is an ultra-rare disease reported in only 7 families in GeneReviews, and no large-scale clinical studies or randomized controlled trials exist2). The missense mutation caused by the c.1036 T>G substitution indicates the existence of a mild form of CSCD and has contributed to expanding the phenotypic spectrum.
Future challenges include elucidating the correlation between DCN gene mutations and clinical severity, accumulating long-term outcomes of DALK, and exploring the potential of gene therapy. Mouse model studies suggest that inhibition of extracellular transport of truncated decorin could be a therapeutic target3).
8. References
Section titled “8. References”- Bredrup C, Knappskog PM, Majewski J, Rødahl E, Boman H. Congenital stromal dystrophy of the cornea caused by a mutation in the decorin gene. Invest Ophthalmol Vis Sci. 2005;46(2):420-426.
- Rødahl E, Knappskog PM, Bredrup C, Boman H. Congenital stromal corneal dystrophy. In: Adam MP, et al, eds. GeneReviews®. Seattle: University of Washington; updated 2018.
- Mellgren AEC, Bruland O, Vedeler A, et al. Development of congenital stromal corneal dystrophy is dependent on export and extracellular deposition of truncated decorin. Invest Ophthalmol Vis Sci. 2015;56(5):2909-2915.