Clinical Diagnosis

The clinical diagnosis of congenital stromal corneal dystrophy is based on the presence of bilateral corneal opacities that can be seen at or shortly after birth (see Figure 1):

Figure

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.
• Characteristically, small opacities seen throughout the stroma of the entire cornea give the cornea a cloudy appearance.
• The thickness of the cornea (as measured by ultrasonic pachymetry) is usually increased. Note: This finding may help distinguish congenital stromal corneal dystrophy from other disorders that have normal corneal thickness.
• Normal intraocular pressure

Testing

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

Figure 2. Transmission electron micrograph showing lamellae of normal collagen fibrils separated by abnormal layers of thin filaments in an electron lucent ground substance

Molecular Genetic Testing

Gene. DCN, encoding decorin, is the only gene in which mutations are known to cause congenital stromal corneal dystrophy [Bredrup et al 2005, Rødahl et al 2006, Kim et al 2011].

Table 1. Summary of Molecular Genetic Testing Used in Congenital Stromal Corneal Dystrophy

View in own window

Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1	Test Availability
DCN	Sequence analysis	Sequence variants 2	100% 3	Clinical

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

3. Sequence analysis has identified mutations in DCN in three families to date [Bredrup et al 2005, Rødahl et al 2006, Kim et al 2011]. All affected individuals examined in the three families have a DCN mutation.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).

Testing Strategy

To confirm/establish the diagnosis in a proband. The diagnosis of CSCD can be made clinically through ophthalmologic evaluation. Sequence analysis of DCN confirms the diagnosis.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

No other phenotypes are known to be associated with mutations in DCN.

Natural History

Only five families with congenital stromal corneal dystrophy 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]. Some interfamilial variation has been noted among the affected individuals.

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 0.63-0.3. 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 Gindedeuren et al 2002] and nystagmus [Witschel et al 1978], the latter most likely because of reduced visual acuity. Normal corneal thickness has also been described [Witschel et al 1978, Pouliquen et al 1979] (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.

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

Prevalence

Prevalence is probably very rare. Five families with a similar phenotype have been described. In three of these, molecular analyses have revealed DCN mutations (Table 2) [Bredrup et al 2005, Rødahl et al 2006, Kim et al 2011].

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with congenital stromal corneal dystrophy, ophthalmologic evaluation that includes the following is recommended:

• Assessment of visual acuity
• Assessment of refractive error
• Slit lamp examination
• Measurement of corneal thickness using pachymetry
• Measurement of intraocular pressure
• Genetics consultation

Treatment of Manifestations

The following are appropriate:

• Spectacles or contact lenses for correction of refractive errors
• Management of strabismus
• Penetrating keratoplasty. Most grafts remain clear after penetrating keratoplasty. Penetrating keratoplasty in children before the age of ten years has been performed successfully. However, only children with a risk for deep amblyopia should be considered for penetrating keratoplasty before age six or seven years.

Prevention of Secondary Complications

Patching to prevent amblyopia in children with strabismus is appropriate.

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 penetrating 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.

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 mutation in the family has been identified, molecular genetic testing of at-risk children can be pursued.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

Mode of Inheritance

Congenital stromal corneal dystrophy is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Most individuals diagnosed with congenital stromal corneal dystrophy have an affected parent.
• A proband with congenital stromal corneal dystrophy may have the disorder as the result of a new gene mutation. The proportion of cases caused by de novo mutations is unknown.
• Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include a complete eye examination with particular emphasis on visual acuity and slit lamp examination of the cornea and molecular genetic testing of the parents, if a DCN mutation has been identified in the proband.
• Evaluation of parents may determine that one is affected but has escaped previous diagnosis because a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.

Sibs of a proband

• The risk to the sibs of the proband depends on the genetic status of the proband’s parents.
• If a parent of the proband is affected, the risk to the sibs is 50%.
• When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
• Although not been reported, reduced penetrance in a parent of the proband or germline mosaicism are theoretically possible; thus, sibs of a proband with clinically unaffected parents may still be at increased risk for the disorder.

Offspring of a proband. Each child of an individual with congenital stromal corneal dystrophy has a 50% chance of inheriting the mutation.

Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent is affected, his or her family members may be at risk.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

No laboratories listed in the GeneTests™ Laboratory Directory offer molecular genetic testing for prenatal diagnosis of congenital stromal corneal dystrophy. However, prenatal testing may be available for families in which the disease-causing mutation has been identified. For laboratories offering custom prenatal testing, see .

Requests for prenatal testing for conditions which (like congenital stromal corneal dystrophy) do not affect intellect and have some treatment available are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Molecular Genetic Pathogenesis

Corneal transparency requires that collagen fibrils are properly organized with a uniform diameter and a regular interfibrillar space. CSCD is characterized by stromal opacities throughout the cornea. By transmission electron microscopy these opacities are seen as layers of amorphous material with thin filaments. The reported DCN mutations all lead to formation of a truncated decorin that has a tendency to aggregate in vitro. Decorin is found to accumulate in the amorphous areas. The authors hypothesize that truncated decorin accumulates in CSCD, thus causing the opacities [Bredrup et al 2010].

Normal allelic variants. DCN spans 3777 kb. The full-length gene consists of eight exons with the AUG start codon in exon 2.

An imperfect dinucleotide repeat variation is in intron 1. In a small cohort of individuals with type 1 diabetes, one of these variants was associated with slower progression of renal disease [De Cosmo et al 2002] (see Table A, HGMD).

Pathologic allelic variants. Three mutations associated with congenital stromal corneal dystrophy have been detected in DCN (Table 2) [Bredrup et al 2005, Rødahl et al 2006, Kim et al 2011]. All are frameshift mutations located in the last coding exon. The resulting proteins are predicted to have a few altered terminal amino acid residues and a deletion of the 33 C-terminal amino acids.

Normal gene product. Decorin is a member of the class I family of small leucine-rich repeat proteoglycans; other members of this class include biglycan and asporin. A 14-amino acid propeptide is cleaved from the N-terminal part to make the final “mature” core protein of 329 amino acids. The “mature” core protein is substituted with one chondroitin/dermatan sulphate glycosaminoglycan chain at Ser 4 residue and two or three N-linked oligosaccharides at Asn residues 181, 232, and 273. Decorin is distributed in a wide range of connective tissues and can bind to several biologically important molecules including collagen I, collagen VI, fibronectin, thrombospondin, epidermal growth factor receptor, insulin-like growth factor 1 receptor, and transforming growth factor beta. It has been implicated in a number of biologic processes, primarily in the regulation of collagen fibril morphology, but also in cell adhesion, angiogenesis, cell matrix formation, and regulation of cell proliferation [Schaefer & Iozzo 2008]. There is evidence suggesting that decorin is the main inhibitor of lateral growth of collagen fibrils [Zhang et al 2009]. In addition to its established role as a structural protein, decorin may play an important role as a regulatory protein.

Abnormal gene product. The three frameshift mutations so far detected in DCN are predicted to result in alteration of a few amino acids and premature protein truncation (i.e., of the 33 carboxy-terminal amino acids) [Bredrup et al 2005, Rødahl et al 2006, Kim et al 2011]. The predicted truncation is hypothesized to cause decorin to accumulate in the cornea thus causing corneal opacities. The mechanism of accumulation may be aggregation of decorin.

Note: Decorin has attracted particular attention in malignancies where the decorin protein has been shown to be a strong inhibitor of cell growth and to act as a pro-apoptotic agent. None of these studies concerns germline mutations in humans.

Literature Cited

1. 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;46:420–6. [PubMed: 15671264]
2. Bredrup C, Stang E, Bruland O, Palka BP, Young RD, Haavik J, Knappskog PM, Rødahl E. Decorin accumulation contributes to the stromal opacities found in congenital stromal corneal dystrophy. Invest Ophthalmol Vis Sci. 2010;51:5578–82. [PubMed: 20484579]
3. De Cosmo S, Tassi V, Thomas S, Piras GP, Trevisan R, Cavallo Perin P, Bacci S, Zucaro L, Cisternino C, Trischitta V, Viberti GC. The decorin gene 179 allelic variant is associated with a slower progression of renal disease in patients with type 1 diabetes. Nephron. 2002;92:72–6. [PubMed: 12187087]
4. Kim J-h, Ko JM, Lee I, Kim JY, Kim MJ, Tchah H. A novel mutation of the decorin gene identified in a Korean family with congenital hereditary stromal dystrophy. Cornea. 2011;30:1473–7. [PubMed: 21993463]
5. Krachmer JH, Mannis MJ, Holland EJ, eds. Cornea. Vol 1. 2 ed. Philadelphia, PA: Elsevier Mosby; 2004.
6. Odland M. Dystrophia corneae parenchymatosa congenita. A clinical, morphological and histochemical examination. Acta Ophthalmol (Copenh). 1968;46:477–85. [PubMed: 5304426]
7. Pouliquen Y, Lacombe E, Schreinzer C, Giraud JP, Savoldelli M. Familial congenital dystrophy of the corneal stroma: Turpin's syndrome (author's transl). J Fr Ophtalmol. 1979;2:115–25. [PubMed: 312637]
8. Rødahl E, Van Ginderdeuren R, Knappskog PM, Bredrup C, Boman H. A second decorin frame shift mutation in a family with congenital stromal corneal dystrophy. Am J Ophthalmol. 2006;142:520–1. [PubMed: 16935612]
9. Schaefer L, Iozzo RV. Biological functions of the small leucine-rich proteoglycans: from genetics to signal transduction. J Biol Chem. 2008;283:21305–9. [PMC free article: PMC2490788] [PubMed: 18463092]
10. Turpin R, Tisserand M, Sérane J. Opacités cornéennes héréditaires et congénitales réparties sur trios générations et atteignant deux jumelles monozygotes. Arch Ophthalmol (Paris). 1939;3:109–11.
11. Van Ginderdeuren R, De Vos R, Casteels I, Foets B. Report of a new family with dominant congenital heredity stromal dystrophy of the cornea. Cornea. 2002;21:118–20. [PubMed: 11805522]
12. Witschel H, Fine BS, Grützner P, McTigue JW. Congenital hereditary stromal dystrophy of the cornea. Arch Ophthalmol. 1978;96:1043–51. [PubMed: 350201]
13. Zhang G, Chen S, Goldoni S, Calder BW, Simpson HC, Owens RT, McQuillan DJ, Young MF, Iozzo RV, Birk DE. Genetic evidence for the coordinated regulation of collagen fibrillogenesis in the cornea by decorin and biglycan. J Biol Chem. 2009;284:8888–97. [PMC free article: PMC2659246] [PubMed: 19136671]

Suggested Reading

1. Ciralsky J, Colby K. Congenital corneal opacities: a review with a focus on genetics. Semin Ophthalmol. 2007;22:241–6. [PubMed: 18097987]
2. Weiss JS, Møller HU, Lisch W, Kinoshita S, Aldave AJ, Belin MW, Kivelä T, Busin M, Munier FL, Seitz B, Sutphin J, Bredrup C, Mannis MJ, Rapuano CJ, Van Rij G, Kim EK, Klintworth GK. The IC3D classification of corneal dystrophies. Cornea. 2008 Suppl 2:S1–83. [PMC free article: PMC2866169] [PubMed: 19337156]

Revision History

• 2 February 2012 (me) Comprehensive update posted live
• 25 November 2008 (me) Review posted live
• 10 September 2008 (er) Original submission