Congenital corneal opacities: a review with a focus on genetics

Congenital corneal opacities present in approximately 3/100,000 newborns. Many different disorders may result in corneal opacifications of infancy, including Peters' anomaly (PA), congenital hereditary endothelial dystrophy (CHED), congenital hereditary stromal dystrophy (CHSD) and posterior polymorphous dystrophy (PPMD). Current studies have localized defects using genetic testing in PA, CHED, CHSD and PPMD. Identifying mutations for specific disorders may lead to better understanding of the underlying pathogeneses and may help with diagnosis and prognosis. This article will review the clinical presentations, treatments and genetics of Peters' anomaly, congenital hereditary endothelial dystrophy, congenital hereditary stromal dystrophy and posterior polymorphous dystrophy.     

Homozygosity mapping and linkage analysis demonstrate that autosomal recessive congenital hereditary endothelial dystrophy (CHED) and autosomal dominant CHED are genetically distinct

BACKGROUND: Congenital hereditary endothelial dystrophy (CHED) is a corneal dystrophy characterised by diffuse bilateral corneal clouding resulting in impaired vision. It is inherited in either an autosomal dominant (AD) or autosomal recessive (AR) manner. The AD form of CHED has been mapped to the pericentromeric region of chromosome 20. Another endothelial dystrophy, posterior polymorphous dystrophy (PPM), has been linked to a larger but overlapping region on chromosome 20. A large, Irish, consanguineous family with AR CHED was investigated to determine if there was linkage to this region. METHODS: The technique of linkage analysis with polymorphic microsatellite markers amplified by polymerase chain reaction (PCR) was used. In addition, a DNA pooling approach to homozygosity mapping was employed to demonstrate the efficiency of this method. RESULTS: Conventional genetic analysis in addition to a pooled DNA strategy excludes linkage of AR CHED to the AD CHED and larger PPMD loci. CONCLUSION: This demonstrates that AR CHED is genetically distinct from AD CHED and PPMD.     

An immunohistochemical analysis and comparison of posterior polymorphous dystrophy with congenital hereditary endothelial dystrophy

PURPOSE: To evaluate the immunohistochemical profiles of the abnormal endothelial cells of posterior polymorphous dystrophy (PPMD) and congenital hereditary endothelial dystrophy (CHED). METHODS: Formalin-fixed, paraffin-embedded sections of seven corneas with the diagnosis of PPMD (seven patients), six corneas with the diagnosis of CHED (four patients), and five control corneas were stained with hematoxylin-eosin. Adjacent histologic sections were stained with monoclonal antibodies that react with pancytokeratin, AE1/AE3, cytokeratin (CK) 7, CK 20, CAM 5.2, and epithelial membrane antigen. The immunoreactivity of the corneal endothelium was assessed by light microscopy. RESULTS: The endothelial cells stained positive for pancytokeratin and CK 7 in seven of seven corneas of patients with PPMD and five of six corneas of patients with CHED; variable positivity was seen to AE1, AE3, and CAM 5.2. The endothelium was uniformly negative to staining by CK 20. The epithelium stained positive with pancytokeratin, AE1, and AE3. All control corneas were negative for pancytokeratin, CK 7, and CK 20. CONCLUSION: The abnormal endothelium in both PPMD and CHED expresses similar CKs, including CK 7, which is not present in normal endothelium or surface epithelium. This may indicate a shared developmental abnormality in these conditions, as previously suggested by ultrastructural studies and genetic mapping.     

Exclusion of AR-CHED from the chromosome 20 region containing the PPMD and AD-CHED loci

Congenital hereditary endothelial dystrophy (CHED) is a disorder of the corneal endothelium and has been recognized to segregate in families with both autosomal dominant (AD) and autosomal recessive (AR) modes of transmission. AD-CHED has been previously linked to the pericentric region of chromosome 20. Posterior polymorphous dystrophy (PPMD), a corneal endothelial disorder showing phenotypic overlap with CHED, has also been previously genetically mapped to this region. The genetic interval containing AD-CHED is within the larger genetic interval containing the PPMD locus. This study sought to determine whether AR-CHED segregating in a consanguineous Saudi Arabian pedigree is linked to the previously mapped and overlapping loci for AD-CHED and PPMD on the pericentric region of chromosome 20. Forty members of a consanguineous Saudi Arabian pedigree segregating AR-CHED were ascertained. Short tandem-repeat polymorphic markers from the 20 cM interval on chromosome 20 containing both the PPMD and AD-CHED loci were used to genotype these individuals. LOD score analysis of the genotype data with the MENDEL software package utilizing a model of autosomal recessive inheritance with complete penetrance showed exclusion of CHED from the entire PPMD/AD-CHED interval by utilizing overlapping intervals of LOD scores of at least -2. The results obtained demonstrate that AR-CHED is not allelic to either AD-CHED or PPMD, although it has been proposed that AD-CHED may be allelic to PPMD. Thus, there are at least two genes responsible for CHED and PPMD.     

Clinicopathologic correlation and genetic analysis in a case of posterior polymorphous corneal dystrophy

PURPOSE: To evaluate the clinical history, histopathology, and genetics of posterior polymorphous corneal dystrophy (PPMD) in a woman with a prominent retrocorneal membrane. DESIGN: Observational case report and genetic analysis of her family, UM:139. METHODS: Records were reviewed from a case and associated family members. The diagnosis of PPMD was based on clinical examination, immunohistochemical staining, electron microscopy, and screening of genetic markers from regions previously reported to be associated with PPMD. RESULTS: Over 17 years, the proband with PPMD had 25 ocular procedures performed for glaucoma, cataract, cornea, retina, and postoperative problems. A prominent retrocorneal membrane grew onto the crystalline lens and intraocular lens (IOL). Histopathology revealed stratified epithelial-like cells on iris from an iridectomy and stratified corneal endothelium on a corneal button. Electron microscopy on the cornea revealed microvilli, tonofilaments, and desmosomes consistent with endothelial transformation, which was confirmed by positive anticytokeratin (CK) AE1/AE3 and CAM 5.2 immunoreactivity. Negative immunoreactivity in epithelium and positive in endothelium with anti-CK 7 supported the diagnosis of PPMD rather than epithelial downgrowth. Multiple relatives were affected with PPMD with apparent autosomal dominant inheritance, but surprisingly, the PPMD, congenital hereditary endothelial dystrophy 1 (CHED1) and CHED2 loci on chromosome 20 and the collagen, type VIII, alpha-2 (COL8A2) gene were excluded by linkage and haplotype analyses. CONCLUSIONS: We are unaware of previous PPMD reports describing the unusual feature of a retrocorneal membrane extending onto the crystalline lens and IOL. In addition, this family suggests another PPMD locus.     

Imaging posterior polymorphous corneal dystrophy by in vivo confocal microscopy

To identify features of posterior polymorphous dystrophy (PPMD) by in vivo confocal microscopy, the corneas of a female patient with PPMD were examined using slit‐lamp biomicroscopy and slit‐scanning in vivo confocal microscopy. Characteristic endothelial vesicular and band lesions were seen clinically and easily identified using in vivo confocal microscopy. However, endothelial pleomorphism, an increased density and reflectance of posterior stromal keratocytes, and prominence of corneal nerves were also delineated. In vivo confocal microscopy enhances clinicopathological diagnosis and follow up of corneal dystrophies with subtle clinical presentations, such as PPMD.     

角膜内皮营养不良分子遗传学研究进展

角膜内皮(后部)营养不良(endothelial corneal dystrophy,ECD)是由原发性角膜内皮功能紊乱引起的一种角膜营养不良,其遗传方式和临床表型都具有异质性的特点。随着分子遗传学的发展,一些ECD致病基因相继被发现,为遗传咨询、基因诊断、指导治疗奠定了基础。我们主要讨论Fuchs角膜内皮营养不良、多形性角膜后层营养不良、先天性遗传性角膜内皮营养不良的分子遗传学研究进展。     

Corneal dystrophies. II. Endothelial dystrophies

In general, endothelial dystrophies present three types of clinical manifestations: 1) production of collagenous tissue posterior to Descemet's membrane which appears as cornea guttata, polymorphic excrescences or gray sheets; 2) a disrupted endothelial mosaic in specular reflection; and 3) corneal edema as a reflection of decreased endothelial barrier and pump functions. In this review, the authors discuss three endothelial dystrophies — Fuchs', posterior polymorphous and congenital hereditary. They describe the clinical, histopathologic and biochemical features, and illustrate each dystrophy with a composite drawing. Dystrophies of the epithelium, Bowman's layer, and stroma were reviewed separately in the September–October 1978 issue of this journal.     

Fuchs Endothelial Corneal Dystrophy in a Heterozygous Carrier of Congenital Hereditary Endothelial Dystrophy Type 2 with a Novel Mutation in SLC4A11

Purpose: Congenital hereditary endothelial dystrophy (CHED) is a rare genetic disorder caused by mutations in corneal endothelial cells. CHED can be divided into 2 types by the modes of inheritance; CHED type 1 (CHED1) with autosomal dominant inheritance and CHED type 2 (CHED2) with autosomal recessive inheritance. Mutations in the sodium bicarbonate transporter-like solute carrier family 4 member 11 (SLC4A11) gene result CHED2.

Methods: A 37 years old female was clinically diagnosed as CHED2. Peripheral blood from the patient and her family members was obtained under informed consents. Genomic DNA was extracted in their WBCs, and whole exons and exon-intron boundaries of the SLC4A11 gene were amplified using polymerase chain reaction. The amplified materials were analyzed by direct sequencing method.

Results: The sequencing results of the SLC4A11 gene showed a novel homozygous mutation in exon 9 (c.1158C?>?A, p.C386*) in the proband with CHED2 phenotype. Her father and sister showing normal cornea were heterozygous carriers of the mutation. Her mother showing late onset Fuchs endothelial corneal dystrophy (FECD) also had the same mutation heterozygously.

Discussion: We report a novel nonsense mutation of the SLC4A11 gene in the patient with CHED2. In addition, one of heterozygous carriers in this family showed features of late onset FECD. Close clinical ocular examination for the heterozygous carriers should be performed to detect late onset FECD.     

A novel decorin gene mutation in congenital hereditary stromal dystrophy: a Korean family

A 43-year-old man developed decreased vision in the right eye that had persisted for seven years. Under slit lamp examination, corneal clouding was noted with normal endothelium and ocular structure. From the clinical evidence, we suspected that the patient had congenital hereditary stromal dystrophy (CHSD). He and his family underwent a genetic analysis. Penetrating keratoplasty was conducted, and the corneal button was investigated for histopathologic confirmation via both light and electron microscopy. The histopathologic results revealed mildly loosened stromal structures, which exhibited an almost normal arrangement and differed slightly from the previous findings of CHSD cases. With regard to the genetic aspects, the patient and his mother harbored a novel point mutation of the decorin gene. This genetic mutation is also distinct from previously described deletion mutations of the decorin gene. This case involved delayed penetration of mild clinical symptoms with the histological feature of a loosened fiber arrangement in the corneal stroma. We concluded that this condition was a mild form of CHSD. However, from another perspective, this case could be considered as "decorin gene-associated corneal dystrophy," which is distinct from CHSD. Further evaluation will be required for appropriate clinical, histopathologic and genetic approaches for such cases.     

Corneal dystrophies among patients undergoing keratoplasty in Saudi Arabia

Diseases leading to corneal opacities are inflammations, infections, metabolic causes, trauma, or genetically determined diseases. Corneal dystrophies may lead to corneal blindness. A clinical and pathological review of 2,108 corneal specimens received from December 1983 to January 1988 revealed 86 (4%) corneal specimens with corneal dystrophies. Fifty-three (62%) patients had macular dystrophy, 11 (13%) had congenital hereditary endothelial dystrophy (CHED), 12 (14%) had Fuchs' corneal dystrophy, 5 (6%) had lattice corneal dystrophy, and 3 (4%) had granular dystrophy. Macular dystrophy appears to be the most common cause of corneal dystrophy in Saudi Arabia. Twenty-two (42%) patients with macular dystrophy and 10 (91%) patients with CHED were the result of consanguineous marriages. Genetic counseling is advisable among families who carry the trait of CHED or macular corneal dystrophy.     

Challenges in pediatric endothelial keratoplasty

We performed endothelial keratoplasty (EK) in three eyes of two siblings (2.5 years, male and 3.5 years, female) with congenital hereditary endothelial dystrophy (CHED) and report the intraoperative and postoperative difficulties. Repeated iris prolapse, apprehension of crystalline lens touch due to positive vitreous pressure, and need for frequent air injections to attach the graft were intraoperative challenges in all three eyes. These were addressed by use of Sheet''s glide instead of Busin''s glide during graft insertion and suturing of main and side ports before air injection. One eye had graft dislocation on second postoperative day due to eye rubbing by the child. Graft was repositioned with air and a venting incision was created. Postoperative examination required repeated general anesthesia. Corneal edema resolved completely in all three eyes. Present case series highlights the possible intraoperative and postoperative challenges and their solutions in pediatric EK for CHED.     

Posterior Polymorphous Dystrophy of the Cornea

The family of a patient manifesting posterior polymorphous dystrophy, (PPMD), of the cornea was investigated to determine the genetic characteristics and clinical expression of the condition.     

Coexistent congenital hereditary endothelial dystrophy and congenital glaucoma

PURPOSE: To retrospectively evaluate the coexistence of congenital glaucoma with congenital hereditary endothelial dystrophy. METHODS: Ten infants presented to our hospital with diffuse corneal edema and bilaterally elevated intraocular pressure (IOP). These patients were diagnosed with congenital glaucoma. All patients underwent trabeculotomy with trabeculectomy for control of IOP. Although IOP was normalized in all patients, corneal edema persisted. These patients underwent penetrating keratoplasty, and the buttons were subjected to histopathologic examination. RESULTS: The corneal grafts remained clear in all patients. The histopathologic examination of the excised corneal buttons showed diffuse stromal edema, loss of the endothelial cell layer, and thickening of the posterior non-banded portion of the Descemet membrane, suggestive of congenital hereditary endothelial dystrophy. CONCLUSIONS: Congenital hereditary endothelial dystrophy may coexist with congenital glaucoma. This combination should be suspected where persistent and total corneal opacification fails to resolve after normalization of IOP.     

Corneal dystrophies. I. Dystrophies of the epithelium,Bowman's layer and stroma

Most corneal dystrophies are autosomal dominant, bilateral disorders that primarily affect one layer of an otherwise normal cornea, progress slowly after their appearance in the first or second decade, and are not associated with a systemic disease. Epithelial basement membrane dystrophy and Fuchs' endothelial dystrophy are seen commonly by the general ophthalmologist; fleck, posterior polymorphous, granular or lattice dystrophies are seen more rarely, and others may never be seen in general office practice. While the distinctive clinical appearance of most corneal dystrophies allows accurate diagnosis, the integration of slitlamp findings with histopathologic and biochemical findings aids in the understanding of the clinical observations and provides a more rational basis for therapy. Transmission electron microscopy is the most accurate method of histopathologic diagnosis. Epithelial dystrophies usually manifest intraepithelial cysts and abnormal basement membrane. In stromal dystrophies, an abnormal substance accumulates within the keratocytes or among the collagen fibrils; it may be an excess normal metabolite (like glycosaminoglycans in macular dystrophy), a material not usually present (like amyloid in lattice dystrophy), or a substance of unknown composition (like hyaline in granular dystrophy). Each dystrophy is illustrated with a composite drawing. Endothelial dystrophies will be reviewed separately in a second article.     

Corneoscleral transplantation in congenital corneal staphyloma and Peters' anomaly

An infant born with bilateral corneal clouding diagnosed clinically as congenital anterior staphyloma and Peters' anomaly was confirmed histopathologically. This case report demonstrates one clinical spectrum of Peters' anomaly. The clinical course and histopathologic findings are detailed as is a unique surgical approach of corneoscleral graft used to perserve the right globe.     

Descemet's stripping endothelial keratoplasty (DSEK) for children with congenital hereditary endothelial dystrophy: surgical challenges and 1-year outcomes

Purpose

To evaluate the outcomes of Descemet's stripping endothelial keratoplasty (DSEK) in patients with congenital hereditary endothelial dystrophy (CHED).

Methods

Retrospective, interventional case series of five eyes of five patients with congenital hereditary endothelial dystrophy (CHED) undergoing Descemet's stripping endothelial keratoplasty (DSEK) from June 2009 to June 2010 by a single surgeon. Patients were evaluated during the postoperative period for visual acuity, refraction, corneal clarity, lenticule status, and intraocular pressure. Anterior segment ocular coherence tomography (OCT) and confocal microscopy were performed when possible.

Results

Three male and two female children with an average age of 7.8?years (range 5–12?years) with CHED underwent DSEK. Surgery was uneventful in all patients and the lenticules stayed attached during the postoperative period. All the patients had 1-year follow-up. Corneal clarity improved in all the patients over the period of follow-up. Anterior segment OCT showed a gradual reduction in the thickness of the central corneal thickness and the graft over a period of time.

Conclusions

DSEK is a viable alternative to penetrating keratoplasty in patients with CHED with distinct advantages of reduced postoperative astigmatism and potential reduction of postoperative complications.     

Subepithelial amyloid deposits in congenital hereditary endothelial dystrophy: a histopathologic study of five cases

PURPOSE: To report the clinical, histologic, ultrastructural, and immunohistochemical features of congenital hereditary endothelial dystrophy (CHED) associated with subepithelial amyloid deposits. METHODS: The clinical features of seven patients and histologic characteristics of eight corneal buttons were evaluated. The corneal specimens included five cases with histologic features of CHED associated with subepithelial amyloid. The remaining three corneal buttons of CHED without amyloid were obtained from the fellow eye of an affected patient and from siblings of two affected patients. Light microscopic studies were performed on sections stained with hematoxylin and eosin, periodic acid Schiff stain, and Congo red stain with and without permanganate bleach. Immunohistochemistry with an antibody to the amyloid AA protein and lambda and kappa light chains was done on all specimens. Electron microscopy was performed on three corneal specimens. The cases were followed for 1-9 years. RESULTS: The notable clinical findings included decreased vision, history of parental consanguinity (4/7 cases), and affected siblings (5/7 cases). Examination revealed nystagmus (5/7 cases) and bilateral ground-glass corneas in all patients. In addition, central subepithelial whitish opacities were noted in patients with CHED and amyloid. Three patients had associated congenital glaucoma. The patients underwent penetrating keratoplasty at a mean age of 10 years. Histologically, five corneal buttons of CHED revealed varying degrees of subepithelial amyloid deposits associated with a subepithelial fibrous pannus. Immunohistochemically, the deposits were nonreactive to anti-amyloid A antibody but were immunoreactive with an antibody to lambda light chains in two cases. Electron microscopy confirmed the presence of subepithelial amyloid. Thickening of Descemet's membrane and attenuation of corneal endothelial cells, noted in all cases, was consistent with features of CHED. The corneal buttons from the fellow eye and the siblings showed histologic features of CHED, with a subepithelial fibrous pannus without amyloid deposits. Spheroidal degeneration was noted in two corneal specimens. To date, no recurrence of the amyloid deposits has been seen in the grafts. CONCLUSIONS: This study demonstrates that subepithelial amyloidosis may be rarely associated with a recessive form of congenital hereditary endothelial dystrophy. The clinical, histologic, and immunohistochemical features suggest a secondary form of amyloidosis.