DiagnosisClinical 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): FigureFigure 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 pressureTestingTransmission 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]. FigureFigure 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 windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test AvailabilityDCNSequence analysisSequence variants 2100% 3Clinical1. The ability of the test method used to detect a mutation that is present in the indicated gene2. 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.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 CorrelationsBecause of limited data, no genotype-phenotype correlations are evident.

Differential DiagnosisBilateral congenital opacifications of the cornea can be caused by several disorders including:Congenital glaucomaMalformations of the anterior segmentInflammationSystemic storage disease Various corneal dystrophies [Krachmer et al 2004], primarily congenital hereditary endothelial dystrophy (OMIM 121700, 217700) Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations 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 pressureGenetics consultationTreatment of ManifestationsThe following are appropriate:Spectacles or contact lenses for correction of refractive errorsManagement of strabismusPenetrating 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 ComplicationsPatching to prevent amblyopia in children with strabismus is appropriate. SurveillanceVisual 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 RiskIn 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 InvestigationSearch 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.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Congenital Stromal Corneal Dystrophy: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDDCN12q21​.33DecorinDCN homepage - Mendelian genesDCNData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Congenital Stromal Corneal Dystrophy (View All in OMIM) View in own window 125255DECORIN; DCN 610048CORNEAL DYSTROPHY, CONGENITAL STROMAL; CSCDMolecular Genetic PathogenesisCorneal 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. Table 2. Selected DCN Pathologic Allelic VariantsView in own windowDNA Nucleotide ChangeProtein Amino Acid Change Reference Sequencesc.967delTp.Ser323Leufs*5NM_001920​.3
NP_001911​.1c.941delCp.Pro314Hisfs*14c.947delGp.Gly316Aspfs*12See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).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.