Congenital Stromal Corneal Dystrophy

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Article initiated by:

Oscar Chen

All contributors:

Mohammed Abdul Sami, Colleen Halfpenny, M.D., Augustine Hong, MD, Oscar Chen, Ravi Patel, MD, MBA

Assigned editor:

Ravi Patel, MD, MBA

Review:

Assigned status Update Pending

 by Ravi Patel, MD, MBA on March 25, 2024.

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Disease Entity

Congenital Stroma Corneal Dystrophy [ICD 10: H18.5 - Hereditary corneal dystrophy]

Disease

Congenital Stromal Corneal Dystrophy (CSCD) is a rare, congenital, autosomal dominant corneal dystrophy characterized by non-progressive or slowly progressive clouding of the corneal stroma that is not attributable to prior inflammation or systemic disease. The etiology of CSCD has been correlated with a deletion of the decorin gene on chromosome 12q22. CSCD has been reported to be present in individuals within the first few months after birth, although case reports of novel CSCD mutations have reported significantly delayed presentation. CSCD has been reported as “Congenital hereditary stromal dystrophy of the cornea,” “Congenital stromal dystrophy of the cornea,” “Dystrophia corneae parenchymatosa congenita,” and “Decorin-associated congenital stromal corneal dystrophy” in the literature.

Etiology

The etiology of CSCD has been correlated with a deletion of the decorin gene on chromosome 12q22. This condition was first reported in the literature in 1939 and has only been reported in 5 families so far. These families include a large French family reported, two American families, an extensively affected Norwegian family, a Belgian family, and potentially in an eastern Asian family with a novel decorin gene mutation. Its genetic derivation is noted to be autosomal dominant inheritance with complete penetrance.

Risk Factors

The limited reports of CSCD make it unclear in the literature whether there are significant risk factors. Given its autosomal dominant nature with complete penetration, an associated family history remains the most significant risk factor.  

General Pathology

Prior studies have reported multiple histologic findings including tightly packed, highly aligned collagen fibrils with a smaller diameter. Descemet’s membrane and corneal lamellae themselves have been noted to be normal, but CSCD has pronounced thickening of corneal stroma with separation of these corneal lamellae. Other histologic findings support abnormal zones with separation of corneal stromal lamellae by abnormal lucent ground substances. This separation is thought to be due to aberrant corneal fibrillogenesis. Analysis of corneal buttons demonstrated normal corneal epithelium and basement membrane, an irregular posterior Bowman’s layer, separation of lamellar of typical collagen fibrils by irregular layers made of thin filaments, normal keratocytes without inclusions that were numerable in the irregular layers, but normal corneal endothelium with occasional infiltrating cells.

Pathophysiology

CSCD is reported to involve a decorin gene deletion on chromosome 12q22. The decorin protein product is comprised of dermatan sulfate proteoglycans, which are involved in corneal fibril spacing and general lamellar adhesion of collagens; this spacing and adhesion is a major contributor to corneal transparency. Decorin is involved in connective tissues, such as collagen I, IV, fibronectin, transforming growth-factor beta, and has been implicated as an inhibitor of lateral collagen fibril growth as well as various cell processes. The abnormal, truncated decorin gene product in CSCD causes decorin accumulation in the cornea; this leads to abnormal spacing, fibril formation, and adhesion, leading to increased corneal opacification.

A case report in 2012 reported a potential novel nucleotide substitution (Thymine replacing Guanine at c. 1036) rather than a deletion in the decorin gene. Corneal collagen cross-linking was intact with this substitution, and the patient did not report significant vision loss until middle age. The authors concluded that this substitution represented a mild case of CSCD.

Primary prevention

No effective primary prevention methods have been reported for CSCD in the literature.  

Diagnosis

History

CSCD is a congenital condition, and family members of affected individuals report that corneal abnormalities were notable within a few months of birth. One Norwegian family was observed to have bilateral corneal opacities within the same period. A particular case report from 2012 identified a novel gene substitution reported progressive vision loss in a patient’s 30s due to a likely mild form of CSCD.

Physical examination

Slit lamp examination may reflect multiple, small corneal opacities throughout all layers of the cornea, frequently described as flakes or spots, which create a hazy description. The corneal surface may be marginally irregular or normal. One Norwegian family with 11 affected individuals reflected normal corneal diameter but increased corneal thickness, with a mean thickness of 673 μm and a range between 658 to 704 μm. Other reports stated no significant staining or evidence of vascularization with fluorescein staining, normal intraocular pressures, and normal or slightly reduced corneal sensitivity. While the physical exam may not be singularly conclusive, it is vital to perform an thorough exam especially if there is a notable family history.  

Signs and Symptoms

Although CSCD is noted to be non-progressive or slightly progressive, patients have reported decreased visual acuity with age. Given the congenital nature of the condition, strabismus and amblyopia have been common reported concerns in affected individuals. Clinical observations typically do not report corneal erosions or vascularization. Increased corneal opacification causes difficulty in assessing the endothelium. Some reports endorse severe photophobia or searching nystagmus as common in consanguineous individuals but are not typically reported to be common presenting symptoms.

Clinical diagnosis

CSCD may be diagnosed in individuals with a pertinent positive family history and suggestive correlated findings on either slit lamp examination or transmission electron microscopy. Gene-targeted testing or genomic testing may be utilized if these methods are inconclusive, dependent on the presenting phenotype and clinical suspicion.

Diagnostic procedures

The most significant diagnostic procedures for CSCD include slit lamp examination or transmission electron microscopy (TEM). TEM typically reflects normal collagen fibrils with separation of lamellae in an electron lucent ground substance. Other characteristics may include normal keratocyte appearance, normal Descemet’s membrane thickness with an irregular anterior, and posterior border, no vacuoles, and occasional infiltrating cells.

Further gene-targeted testing or genomic testing may be used for clarifying diagnostic purposes.  

Confocal microscopy may reflect normal superficial corneal epithelial cells and reflectivity in the anterior stroma due to numerous opacities, which make it difficult to assess the endothelium.

Laboratory test

Due to the scarcity of reported CSCD cases, it is difficult to extrapolate characteristic histopathology. As noted above, prior histologic findings have reported tightly packed lamellar with highly aligned small-diameter collagen fibrils, thickened corneal stroma, separated corneal lamellae, and a normal Descemet’s membrane. Transmission electron micrography shows and “electron-lucent” ground substance that contains these normal collagen fibers with separation of corneal stromal lamellae. One examination of corneal buttons after keratoplasty reports disturbed corneal lamellae and its fibrillar structure, with some diffuse stromal edema noted as well.

One case report of likely CSCD reported healthy Descemet’s membrane and endothelium with both Masson-trichrome and PAS staining, although genetic testing was unable to confirm the diagnosis.

Differential diagnosis

Congenital hereditary endothelial dystrophy

CHED is an autosomal recessive corneal dystrophy. This condition is primarily linked to a mutation in chromosome 20p13, which affects the SLC4A11 gene. The subsequent protein product is a transmembrane protein which normally pumps stromal fluid against the gradient into aqueous humor.  As a congenital condition, it may similarly present at birth or at an early age and present with corneal dystrophy, which manifests as a decrease in visual acuity. Like CSCD, CHED may lead to amblyopia or nystagmus due to occlusive corneal opacities. However, CHED’s differentiating factors include presence of corneal edema, thickened cornea, and diffuse opacification rather than the numerous flaky opacities seen in CSCD.  

Posterior polymorphous corneal dystrophy

PPMD is an autosomal dominant corneal dystrophy of both Descemet's membrane and corneal endothelium. This condition is linked to multiple loci on chromosomes 1, 8, 10, 20, which encode for products of the COL8A2, GRHL2, ZEB1, and OVOL2 genes, respectively. The multiple potential protein abnormalities make this condition susceptible to a wide clinical presentation. Typical characteristics include bilateral corneal opacification, corneal edema, thickened Descemet’s membrane, abnormal basement membrane, abnormal keratinized epithelialized cells, band-like lesions. and peripheral synechiae. Presenting patients may have increased corneal thickness or increased intraocular pressure with corneal edema, which should raise suspicion for PPMD, especially with a pertinent family history.

Posterior amorphous corneal dystrophy

PACD is an autosomal dominant corneal dystrophy. Patients with PACD reflect partial or full opacification of the posterior corneal lamellae and Descemet’s membrane, decreased corneal thickness, hyperopia, and a bilateral sheet-like opacification in the posterior stroma. GWAS studies on PACD have not clarified a specific genetic basis, but it has been linked to KERA, LUM, DCN, and EPYC genes (keratocan, lumican, decorin, and epiphycan, respectively), potentially on chromosome 12q21.33.

Macular Corneal Dystrophy

MCD is an autosomal recessive corneal dystrophy. Patients with MCD typically have progressive opacification of the cornea. Additionally, these patients present with decreased corneal thickness, progressively decreased visual acuity, involvement of the endothelium and Descemet’s membrane. MCD has been linked to a mutated CHST6 gene on chromosome 16q22, which leads to accumulated glycosaminoglycans and variable levels of keratan sulfate. Multiple phenotypes have been reported, and they are typically based on levels of keratan sulfate in the cornea and stroma.  

Fleck Corneal Dystrophy

FCD is an autosomal dominant corneal dystrophy. FCD has been primarily linked to a mutated PIKFYVE (or phosphatidylinositol 3-phosphate 5-kinase type III) gene on chromosome 2q35; this abnormal gene product leads to increased levels of glycosaminoglycans and lipids in keratocytes. Patients with FCD typically present with opacification of the corneal stromal layer, either due to round or semi-circular opacities with defined borders or cloudy infiltrates without well-defined borders.  

Management

General treatment

General treatment of CSCD begins with a thorough history and clinical evaluation. These include measures of visual acuity, refractive error, presence of strabismus, slit lamp examination, corneal thickness, and intraocular pressure.

Medical therapy

In patients with CSCD, contact lenses or glasses may be used to correct visual acuity due to refractory issues. The congenital nature of this condition necessitates ophthalmic evaluation soon after birth if there is a pertinent family history or confirmed genetic testing. Consistent ophthalmic follow-ups in children should be emphasized, especially if they require patching due to strabismus. Follow-up for adults is variable and dependent on if they have undergone penetrating keratoplasty. In patients with a positive or suspected family history, it is pertinent to refer to a consultation with a genetic counselor.  

Surgery

Surgical evaluation for penetrating keratoplasty (PK) in eligible patients with CSCD is recommended. Early intervention at an early age, preferably less than 7 years old, is likely to reduce rates of amblyopia. Most post-keratoplasty grafts have been reported to remain clear without further opacification.  

One paper from 2005 combined common characteristics in 18 eyes of patients who had undergone CSCD (4 unilateral and 7 bilateral eyes), at a mean age of 20 years old (range: 6-44 years old); these patients were followed up for a mean age of 19.5 years. 10 of the 18 transplanted corneas (56%) remained clear on follow-up examination, 6 of the 18 (33%) presented with minimal opacification, and the remaining 2 (11%) reflected moderate to severe opacification. In a patient with one of the patients with severe opacification, changes were first noticeable 15 months after keratoplasty and progressively worsened to equal the patient’s original opacification. However, the PK in his fellow eye remained clear up to thirty years afterwards. The second individual with moderate to severe unilateral opacification had no complications for up to twenty years after keratoplasty, but progressed along with secondary glaucoma, mydriasis, and chronic iridocyclitis.

A 2016 case report successfully conducted deep anterior lamellar keratoplasty (DALK) in a 4-year-old patient with highly suspected CSCD, although genetic testing was unable to be obtained. Per the report, DALK is preferable to PK if the endothelium is healthy. Theoretically, DALK would decrease chances of endothelial rejection and additional complications associated with PK.

Surgical follow up

Surgical follow-up for patients with CSCD includes education on subsequent blurry vision or irritation, and frequent initial follow-up appointments that may be tapered depending on the patient’s progress. These follow-up appointments should make note of IOP, corneal thickness or irregularities, post-operative complications, or signs of rejection.  

Patients should avoid participating in activities that may cause ocular trauma or chemical irritation, including any rubbing of their eyes. Parents of younger children should be educated on compliance with frequent postoperative examinations, checking on the child’s corneas with a focused light source, educated on topical steroid or antibiotic eye drops and risks of infection, and be educated on the progression of visual acuity in the future.

Complications

Complications are related to both the general population of CSCD patients and general keratoplasty considerations.  

General complications are related to postoperative infection, ineffective prevention of patients rubbing their eyes, corneal ulceration, or iris-cornea adhesions due to a robust inflammatory response in children. This inflammatory response causes increased fibrin formation which may cause subsequent iris-cornea adhesions, or contraction of the host the donor tissue interface, which may interfere with sutures. These are eventual risk factors for further complications such as suture abscesses or graft rejection. There is an increased risk of children physically irritating their eyes from rubbing or displaying discomfort due to postoperative eyedrops, which may break sutures or create further difficulty in post-operative care.  

Prognosis

Limited prognostic data exists in the literature, given the rarity of CSCD. Varied literature reported that visual acuities typically do not progress better than 20/200, but another report reported a final visual acuity of 20/30 in patients with CSCD.

Additional Resources

https://medlineplus.gov/genetics/condition/congenital-stromal-corneal-dystrophy/#inheritance

https://www.orpha.net/consor/cgi-bin/Disease_Search.php?lng=EN&data_id=14779&Disease_Disease_Search_diseaseGroup=Congenital-Stromal-Corneal-Dystrophy-&Disease_Disease_Search_diseaseType=Pat&Disease(s)/group%20of%20diseases=Congenital-stromal-corneal-dystrophy&title=Congenital%20stromal%20corneal%20dystrophy&search=Disease_Search_Simple