Congenital Stromal Corneal Dystrophy
Summary
Clinical characteristics.
Congenital stromal corneal dystrophy is characterized by the presence of bilateral corneal opacities that can be seen at or shortly after birth. The surface of the cornea is normal or slightly irregular; small opacities are seen throughout the stroma of the entire cornea and give the cornea a cloudy appearance. Strabismus is common. Nystagmus is uncommon. Amblyopia can develop in children.
Diagnosis/testing.
The diagnosis of congenital stromal corneal dystrophy is established in an individual with bilateral corneal opacities and characteristic findings on transmission electron microscopy. Identification of a heterozygous pathogenic variant in DCN by molecular genetic testing can confirm the diagnosis.
Management.
Treatment of manifestations: Spectacles or contact lenses for correction of refractive errors; patching and/or surgical correction of strabismus; penetrating or deep anterior lamellar keratoplasty.
Surveillance: Routine ophthalmologic examination with visual acuity at least every year in children; regular surveillance in adults as needed in those treated with keratoplasty.
Genetic counseling.
Congenital stromal corneal dystrophy is inherited in an autosomal dominant manner. Most individuals diagnosed with congenital stromal corneal dystrophy have an affected parent. Each child of an affected individual has a 50% chance of inheriting the pathogenic variant. If the variant has been identified in an affected family member, prenatal testing for a pregnancy at risk is possible.
Diagnosis
Suggestive Findings
Congenital stromal corneal dystrophy (CSCD) should be suspected in individuals with bilateral corneal opacities that are seen at or shortly after birth (see Figure 1), particularly if:
Figure 1.
Slit lamp photograph of the cornea showing slightly irregular surface and small flakes and spots throughout the corneal stroma
- The surface of the cornea is normal or slightly irregular.
- Small opacities are seen throughout the stroma of the entire cornea and give the cornea a cloudy appearance.
- The thickness of the cornea (as measured by ultrasonic pachymetry) is increased. Note: This finding may help distinguish CSCD from other disorders that have normal corneal thickness.
- Intraocular pressure is normal.
Transmission electron microscopy of the stroma shows layers of apparently normal collagen fibrils separated by abnormal layers with small filaments embedded in an electron-lucent ground substance (Figure 2) [Bredrup et al 2005].
Figure 2.
Transmission electron micrograph showing lamellae of normal collagen fibrils separated by abnormal layers of thin filaments in an electron lucent ground substance
Establishing the Diagnosis
The diagnosis of congenital stromal corneal dystrophy (CSCD) is established in an individual with the above Suggestive Findings. Identification of a heterozygous pathogenic variant in DCN by molecular genetic testing can confirm the diagnosis if clinical features and findings on transmission electron microscopy are inconclusive (see Table 1).
Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (chromosomal microarray analysis, exome sequencing, exome array, genome sequencing) depending on the phenotype.
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. The phenotype of CSCD is relatively characteristic, and individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1). Those with a phenotype indistinguishable from many other inherited disorders with congenital corneal opacification are more likely to be diagnosed using genomic testing (see Option 2).
Option 1
When the phenotypic and laboratory findings suggest the diagnosis of CSCD, molecular genetic testing approaches can include single-gene testing or use of a multigene panel:
- Single-gene testing. Sequence analysis of DCN detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected.Note: Congenital stromal corneal dystrophy is caused by aggregation or deposition of a truncated form of decorin [Bredrup et al 2010]. It is not clear if this is a gain-of-abnormal-function mechanism (see Molecular Genetics). Large intragenic deletion or duplication has not been reported, and testing for intragenic deletions or duplication is therefore unlikely to identify a disease-causing variant.
- A multigene panel that includes DCN and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Option 2
When the phenotype is indistinguishable from many other inherited disorders characterized by congenital corneal opacification, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in Congenital Stromal Corneal Dystrophy
| Gene 1 | Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by Method |
|---|---|---|
| DCN | Sequence analysis 3 | 4 families 4 |
| Gene-targeted deletion/duplication analysis 5 | Unknown 6 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
Bredrup et al [2005], Rødahl et al [2006], Kim et al [2011], Jing et al [2014]. In addition, Lee et al [2012] have reported a family with late onset of features resembling congenital stromal corneal dystrophy.
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 6.
Congenital stromal corneal dystrophy is caused by aggregation or deposition of a truncated form of decorin. It is not clear if this is a gain-of-abnormal-function mechanism (see Molecular Genetics). Large intragenic deletion or duplication has not been reported, and testing for intragenic deletions or duplication is therefore unlikely to identify a disease-causing variant.
Clinical Characteristics
Clinical Description
Only seven families with the characteristic findings of congenital stromal corneal dystrophy (CSCD) have been reported in the literature [Turpin et al 1939, Odland 1968, Witschel et al 1978, Van Ginderdeuren et al 2002, Kim et al 2011, Jing et al 2014, Acar et al 2016]. Some interfamilial variation has been noted among the affected individuals. In addition, Lee et al [2012] have reported a family with late onset of features resembling CSCD.
In a Norwegian family with 11 affected individuals, bilateral corneal opacities were observed at or slightly after birth [Bredrup et al 2005]. Slit lamp examination revealed small flakes and spots distributed in all layers of the stroma from limbus to limbus. The surface of the cornea was slightly irregular. Most affected individuals had best corrected visual acuity within the range of 0.3-0.63. Four out of 11 had strabismus. None had nystagmus. The corneal diameter was normal. Pachymetry revealed increased thickness of the cornea (mean: 673 μm; range: 658-704 μm).
Affected individuals reported deterioration in visual acuity with increasing age; opacities tended to increase with age. Penetrating keratoplasty was performed in 18 out of 22 eyes at a mean age of 20 years. The grafts remained clear in 56% of the eyes, and in an additional 33% only minimal opacities were seen within an observation period of three to 36 (mean: 19.5) years.
Some affected individuals in other studies reported photophobia [Van Ginderdeuren et al 2002] and nystagmus [Witschel et al 1978, Jing et al 2014], the latter most likely because of reduced visual acuity. Normal corneal thickness has also been described [Witschel et al 1978, Pouliquen et al 1979, Jing et al 2014] though not confirmed by pachymetry.
No findings in other organ systems have been noted.
Genotype-Phenotype Correlations
Because of limited data, no genotype-phenotype correlations are evident. In one family reported by Lee et al [2012], DCN pathogenic variant c.1036T>G was associated with a relatively mild form of late-onset disease resembling CSCD.
Penetrance
Penetrance is complete in the described families.
Nomenclature
Other names by which congenital stromal corneal dystrophy has been known:
- Dystrophia corneae parenchymatosa congenita
- Congenital stromal dystrophy of the cornea
- Congenital hereditary stromal dystrophy of the cornea
- Decorin-associated congenital stromal corneal dystrophy
Prevalence
CSCD is probably very rare. Seven families with a similar phenotype have been described. In four of these, molecular analyses have revealed DCN pathogenic variants (Table 3) [Bredrup et al 2005, Rødahl et al 2006, Kim et al 2011, Jing et al 2014].
Differential Diagnosis
Bilateral congenital opacifications of the cornea can be caused by several disorders/conditions (see Table 2):
- Various corneal dystrophies [Weiss et al 2015], primarily congenital hereditary endothelial dystrophy (OMIM 217700)
- Congenital glaucoma
- Systemic storage disease
- Malformations of the anterior segment
- Inflammation
Table 2.
Disorders with Bilateral Congenital Opacifications of the Cornea to Consider in the Differential Diagnosis of Congenital Stromal Corneal Dystrophy (CSCD)
| Disorder/ Condition | Gene(s) / Chromosome Locus | MOI | Additional Clinical Features of This Disorder | |
|---|---|---|---|---|
| Overlapping w/CSCD | Distinguishing from CSCD | |||
| Congenital hereditary endothelial dystrophy | SLC4A11 | AR |
|
|
| Posterior polymorphous corneal dystrophy | OVOL2 COL8A2 ZEB1 GRHL2 | AD | Corneal clouding w/corneal opacities |
|
| Posterior amorphous corneal dystrophy | 12q21.33 | AD | Corneal opacities |
|
| Congenital glaucoma | CYP1B1 LTBP2 TEK | AR 1 |
|
|
| Mucopolysaccharidosis (I, IV, VI) | IDUA GALNS ARSB | AR | Corneal clouding | Systemic involvement |
| Anterior segment dysgenesis (Peters anomaly) | CYP1B1 FOXC1 PAX6 FOXE3 NDP SLC4A11 HCCS PITX2 PITX3 | AR AD | Corneal clouding |
|
| Inflammation | NA | NA | Corneal clouding | Rarely present at birth |
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance
- 1.
Autosomal recessive inheritance only accounts for a proportion of congenital glaucoma cases.
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with congenital stromal corneal dystrophy (CSCD), the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended:
- Ophthalmologic evaluation that includes the following:
- Assessment of visual acuity
- Assessment of refractive error
- Assessment of motility and strabismus (orthoptic evaluation)
- Slit lamp examination
- Measurement of corneal thickness using pachymetry
- Measurement of intraocular pressure
- Consultation with a clinical geneticist and/or genetic counselor
Treatment of Manifestations
The following are appropriate:
- Spectacles or contact lenses for correction of refractive errors
- Patching and/or surgical correction of strabismus
- Keratoplasty. To reduce the risk of amblyopia, penetrating keratoplasty should be considered in children younger than age seven years. Most grafts remain clear after penetrating keratoplasty even in this age group. There is a single report of a successful deep anterior lamellar keratoplasty in a child age four years [Acar et al 2016].
Surveillance
Visual acuity and routine ophthalmologic examination should be performed at least every year in children. Regular surveillance in adults is not necessary unless they have undergone keratoplasty. Affected individuals should be informed about penetrating keratoplasty and advised to contact their eye doctor in case of reduced visual acuity or increased glare.
Agents/Circumstances to Avoid
Individuals who have undergone keratoplasty should avoid activities that could cause direct trauma to the eye. No other agents or circumstances need to be avoided.
Evaluation of Relatives at Risk
In families with known CSCD, at-risk children should be seen by an ophthalmologist within a few months after birth to determine if they have the condition. Alternatively, if the DCN pathogenic variant in the family has been identified, molecular genetic testing of at-risk children can be pursued.
It is appropriate to clarify the status of at-risk relatives of an affected individual within a few months after birth in order to identify as early as possible those who would benefit from prompt ophthalmologic examination. Evaluations can include:
- Molecular genetic testing if the pathogenic variant in the family is known;
- Ophthalmologic evaluation if the pathogenic variant in the family is not known.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Therapies Under Investigation
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.