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Purpose To investigate in vivo corneal changes of genetically confirmed Reis–Bücklers corneal dystrophy (RBCD) and Thiel–Behnke corneal dystrophy (TBCD) using anterior segment optical coherence tomography (AS-OCT). Design A single-center, prospective, comparative case series. Methods Seven patients from 3 pedigrees (3 males, 4 females) with RBCD [Arg124Leu (R124L) heterozygous missense mutation of human transforming growth factor beta-induced (TGFBI) gene] and 4 patients from 3 pedigrees (3 males, 1 female) with TBCD [Arg555Gln (R555Q) heterozygous missense mutation of TGFBI gene] were examined. Six patients with RBCD and three patients with TBCD exhibited recurrence after corneal surgery including penetrating keratoplasty, phototherapeutic keratectomy, and electrolysis. All patients were examined by slit-lamp biomicroscopy followed by AS-OCT. Selected AS-OCT images of the cornea were evaluated qualitatively for changes in shape and degree of light reflection of corneal deposits. Results Slit-lamp biomicroscopy showed characteristic irregular gray opacities in Bowman’s layer in each dystrophy: a geographic pattern in RBCD and a honeycomb pattern in TBCD. In each dystrophy, distinct characteristic deposits were observed by AS-OCT as a banding lesion in Bowman’s layer and its adjacent epithelium/stroma. In RBCD, the banding lesion was highly reflective and sharply margined at the stroma. In contrast, deposits in TBCD in the same layer showed a saw-tooth pattern toward the epithelium and poorly margined at the stroma. Conclusion AS-OCT is able to clearly identify characteristic in vivo corneal microstructural changes associated with RBCD and TBCD. As a result, in vivo differentiation of RBCD and TBCD can be achieved.

PURPOSE: To report long-term outcomes of sequential customized therapeutic keratectomy for Reis–Bücklers' corneal dystrophy. METHODS: This was a retrospective review of 14 eyes of 8 patients with Reis–Bücklers' corneal dystrophy that underwent surgical peeling with a spatula of the epithelium and subepithelial membrane present in Reis–Bücklers' corneal dystrophy, with subsequent sequential customized therapeutic keratectomy featuring a multi-step approach with sequential, repeated customized excimer laser photoablations alternating with repeat intraoperative topographies to monitor and progressively reduce corneal irregularities. RESULTS: At the last follow-up of 5.09 ± 4.67 years (range: 0.29 to 12.87 years), mean corrected distance visual acuity improved from 20/50 (range: 20/630 to 20/30) to 20/25 (range: 20/20 to 20/40) ( P < .01), whereas mean refraction changed from −0.29 ± 1.91 diopters (D) sphere and −0.75 ± 0.81 D cylinder preoperatively to 1.25 ± 2.10 D sphere and −1.08 ± 0.53 D cylinder postoperatively. Mean central keratometry values changed minimally from 42.67 ± 2.26 D preoperatively to 42.65 ± 2.30 D postoperatively. Coma significantly decreased from 0.60 ± 0.40 to 0.35 ± 0.28 μ m ( P < .05), whereas total higher order aberrations, spherical aberration, and trefoil remained stable. No patient underwent corneal transplantation. Disease recurrence required re-treatment using the same protocol in 14.28% of eyes (n = 2) for a mean of 5.86 ± 0.31 years (range: 5.64 to 6.08 years) after initial surgery. CONCLUSIONS: Five years after sequential customized therapeutic keratectomy, most eyes with Reis–Bücklers' corneal dystrophy showed improved visual acuity, stable refraction, and improved or stable higher order aberrations. [ J Refract Surg. 2018;34(10):682–688.]

Corneal dystrophies are a group of inherited disorders localized to various layers of the cornea that affect corneal transparency and visual acuity. The deposition of insoluble protein materials in the form of extracellular deposits or intracellular cysts is pathognomic. Mutations in TGFBI are responsible for superficial and stromal corneal dystrophies. The gene product, transforming growth factor β induced protein (TGFBIp) accumulates as insoluble deposits in various forms. The severity, clinicopathogenic variations, age of the onset, and location of the deposits depend on the type of amino acid alterations in the protein. Until 2006, 38 different pathogenic mutants were reported for the TGFBI-associated corneal dystrophies. This number has increased to 63 mutants, reported in more than 30 countries. There is no effective treatment to prevent, halt, or reverse the deposition of TGFBIp. This review presents a complete mutation update, classification of phenotypes, comprehensive reported incidents of various mutations, and current treatment options and their shortcomings. Future research directions and possible approaches to inhibiting disease progression are discussed.

PURPOSE The aim of this study was to describe a microkeratome-assisted 2-stage technique of superficial anterior lamellar keratoplasty (SALK) to manage Reis-Bucklers corneal dystrophy (RBCD). METHODS A microkeratome was used to create a 9-mm, 140-μm-thick corneal flap in the first stage. Four weeks later, in the second stage, a Hessberg-Baron suction trephine was used to perform a 7.0-mm central trephination up to a depth of 150 μm, within the corneal flap. Donor lamellar tissue was prepared using a microkeratome system, after which a vacuum punch was used to trephine a 7.0-mm lamellar button. This donor button was used to replace the central corneal flap in the recipient cornea without using any sutures. A bandage contact lens was applied for 2 weeks. RESULTS This modified technique of staged sutureless SALK was used in 4 eyes of 2 patients with RBCD. Postoperatively, all eyes experienced an improvement in both uncorrected and best spectacle-corrected visual acuities. The average best spectacle-corrected visual acuity was 20/30 at the last follow-up (19 months, range 16-22 months). The cornea remained clear in all eyes until the last follow-up without any evidence of recurrence of RBCD. CONCLUSIONS The staged technique of microkeratome-assisted SALK allows the replacement of superficial corneal stroma without the necessity for any sutures and seems to be a safe and effective method for the treatment of RBCD.

Background Reis-Bücklers corneal dystrophy (RBCD) was consistently reported as a corneal dystrophy only affected Bowman’s layer and superficial corneal stroma, and superficial keratectomy was a recommendation surgery for treatment in literatures. The study reported new histopathological and ultrastructural findings in RBCD caused by the Arg124Leu mutation of transforming growth factor induced (TGFBI) gene in a four-generation Chinese pedigree. Methods Subjects including eight patients and seven unaffected family members received slit-lamp biomicroscopy and photography. DNA was obtained from all subjects, and exons 4 and 11 to 14 of TGFBI gene were analyzed by polymerase chain reaction and the products were sequenced. Anterior segment optical coherence tomography (AS OCT) and in vivo confocal microscopy were conducted for ten eyes of five patients. Based on the results of AS OCT and in vivo confocal microscopy, deep anterior lamellar keratoplasty (DLKP) using cryopreserved donor cornea was applied for four eyes of four patients. Four lamellar dystrophic corneal buttons were studied by light and transmission electron microscopy, and TGFBI immunohistochemistry. Results Eight patients had typical clinical manifestations of RBCD presenting recurrent painful corneal erosion starting in their early first decades, along with age-dependent progressive geographic corneal opacities. TGFBI sequencing revealed a heterozygous mutation, Arg124Leu in all eight patients. Anterior segment optical coherence tomography and in vivo confocal microscopy showed the dystrophic deposits involved not only in subepithelial and superficial stroma, but also in mid- or posterior stroma in four examined advanced eyes. Light microscopy showed Bowman’s layer was absent, replaced by abnormal deposits stain bright red with Masson’s trichrome. In superficial cornea, the deposits stacked and produced three to five continuous bands parallel to the corneal collagen lamellae. In mid- to posterior stroma, numerous granular or dot- like aggregates were heavily scattered, and most of them presented around the nuclei of stromal keratocytes. Transmission electron microscopy revealed the multiple electron-dense rod-shaped deposits aggregated and formed a characteristic pattern of three to five continuous bands in superficial cornea, which were similar to those seen under light microscopy. In mid- to posterior stroma, clusters of rod-shaped bodies were scattered extracellular or intracellular of the stromal keratocytes between the stromal lamellae suggesting the close relationship between mutated proteins and keratocyte. Conclusions The study offer evidences indicating DLKP is a viable treatment option for advanced RBCD to avoid recurrence, and the mutated TGFBIp in dystrophic corneas are of keratocytes origin.

Citation information: Liang Q, Sun X & Jin X. TGFBI gene mutation in a Chinese pedigree with Reis-Bucklers corneal dystrophy. Ophthalmic Physiol Opt 2011. doi: 10.1111/j.1475-1313.2011.00867.x Abstract Purpose: To characterize the molecular defects in the TGFBI gene in a Chinese family with Reis-Bucklers corneal dystrophy (RBCD), and to study the relationship between the gene mutations and the clinical manifestations. Methods: Four generations of this family with RBCD were enrolled in the study. In addition to ophthalmic and histopathological examinations, polymerase chain reaction (PCR) amplification and analysis of nucleotide sequencing of exons 4, 12, 14 of TGFBI were performed. Results: The clinical manifestations of the disease were characterized by geographic opacities in the subepithelial layers and anterior stroma of the cornea. Confocal microscopy images of the cornea showed focal hyper-reflective materials deposited in the subepithelium and anterior stroma. It was confirmed by histopathology that Bowman’s membrane was mainly replaced by extracellular fibril material, which extended downwards into the superficial corneal stroma. Molecular genetic analysis revealed a single heterozygous G>T change at nucleotide 124 in exon 4 of TGFBI in all members (22) of the pedigree affected with RBCD, but not in the unaffected members. Conclusions: A p.Arg124Leu mutation of the TGFBI gene was detected in this Chinese pedigree with Reis-Bucklers corneal dystrophy. The phenotype of Reis-Bucklers corneal dystrophy in this family belongs to the geographic type. The molecular genetic studies combined with histopathology may be useful for the accurate diagnosis of this type of corneal dystrophy.

140 patients from 8 countries with granular corneal dystrophy Groenouw type I are described, and 21 slit-lamp photographs demonstrate inter-familial differences and intra-familial similarities. The clinical appearance varied from mild, with only a few granules on the cornea, to a monstrous course with an almost opaque cornea. The following diagnostic criteria are suggested for the disease, as these signs are described in extensively quoted key references and meet the descriptions in most papers on this subject: Dominant inheritance, as well as 1) typical slit-lamp appearance and/or 2) granules that stain with Masson trichrome histologically, and/or 3) rod-shaped bodies seen electron microscopically.

This paper maintains that Reis-Bücklers' corneal dystrophy and granular corneal dystrophy Groenouw type I are one and the same disease. Included are some of the technically best photographs of Reis-Bücklers' dystrophy found in the literature, and these are compared with photographs from patients with granular corneal dystrophy examined by the author. It is argued that most of the histological and ultrastructural findings on Reis Bücklers' dystrophy described in the literature are either congruent with what is found in granular corneal dystrophy or unspecific.

PURPOSE: Two patients were diagnosed with Reis-Bucklers corneal dystrophy (RBCD), although the pattern and severity of corneal opacification differed. To see whether there was a genetic basis for these phenotypic variations, we analyzed βig-h3, the gene that codes for kerato-epithelin and that contains a mutation (Arg555Gln) that causes RBCD. METHODS: A 30-year-old man with honeycomb-shaped subepithelial opacities in his central cornea and a 25-year-old man with progressive subepithelial geographic opacities were both considered to have RBCD. We isolated genomic DNA from leukocytes of the two patients and their family members and screened for an Arg555Gln kerato-epithelin mutation. Then we analyzed all exons of the gene using the single-strand conformation polymorphism (SSCP) technique to search for any other kerato-epithelin mutations. RESULTS: The patient with honeycomb-shaped opacities had an Arg555Gln kerato-epithelin mutation that caused his RBCD, whereas the patient with geographic opacities did not; instead, he had a new kerato-epithelin mutation (Arg124Leu), which cosegregated with his family members. CONCLUSIONS: The variant of RBCD characterized by honeycomb-shaped opacities is caused by an Arg555Gln kerato-epithelin mutation. On the other hand, a new kerato-epithelin mutation, Arg124Leu, was found to cause the RBCD variant characterized by recurrent epithelial erosions and progressive geographic subepithelial opacification. Codon 124 is a hot spot for kerato-epithelin mutations, where the mutations responsible for three autosomal dominant corneal dystrophies—lattice type I (Arg124Cys), Avellino (Arg124His), and the variant of RBCD with geographic rather than honeycomb opacities (Arg124Leu)—are located.

Purpose: To characterize the phenotype of Reis-Bücklers corneal dystrophy (RBCD) using in vivo and ex vivo imaging techniques. Methods: Five RBCD patients with penetrating keratoplasty (PK) were enrolled. Before surgery, all patients underwent a complete ophthalmological examination including slitlamp biomicroscopy, in vivo confocal microscopy (IVCM) and anterior segment (AS) optical coherence tomography (OCT). After PK, corneal buttons were examined by light and transmission electron microscopy (TEM). Correlations between in vivo and ex vivo images were analyzed. Results: In all cases, irregular geographic-like subepithelial gray-white opacities were observed in the central and mid-peripheral cornea. AS-OCT images of the cornea of all patients revealed hyperreflective homogeneous and continuous deposits concentrated at the level of Bowman's layer and anterior stroma. Using IVCM, a highly reflective irregular amorphous material was observed from intermediate epithelial cells to the anterior stroma. Sparse deposits of highly reflective material were also detected in the posterior stroma. TEM showed in all specimens basal epithelial cells containing small vesicles with rod-shaped dense material. Conclusions: IVCM and AS-OCT may be a useful adjunct to biomicroscopy for the diagnosis and management of RBCD. The correlations between the different in vivo and ex vivo imaging techniques emphasize the hypothesis of an epithelial origin for RBCD.

Purpose Recently several autosomal dominant corneal stromal dystrophies have been mapped to chromosome 5q. Therefore, we tested whether Reis-Bucklers' corneal dystrophy, an autosomal dominant trait, was also linked to the same region. Methods Five generations of a single family with Reis-Bucklers' corneal dystrophy were ascertained. Twenty-two family members were examined, and 11 were found to be affected. Blood was obtained for genetic linkage analysis. Results Several genetic markers on chromosome 5q were strongly suggestive of linkage or confirmed linkage (LOD score > 3.0). Multipoint analysis generated a maximum LOD score of 4.25 between D5S414 and IL-9. Conclusions Reis-Bucklers', lattice type 1, Avillino, and granular corneal dystrophies all map to the same genetic locus. This suggests that one of the following might be true: (1) that a corneal gene family exists in this region; (2) that these corneal dystrophies represent allelic heterogeneity (that is, different mutations within the same gene manifest as different phenotypes); or (3) that these are all the same disease.

OBJECTIVE: Mutations of the transforming growth factor β-induced ( TGFBI) gene were studied in a Chinese family with Reis—Bücklers corneal dystrophy (RBCD). METHODS: Six family members with RBCD and six unaffected family members were investigated. The pedigree showed a typical dominant inheritance pattern. Genomic DNA was extracted from peripheral leucocytes from all study participants. Exons 4, 12 and 14 of the TGFBI gene were analysed using polymerase chain reaction, and standard automated sequencing was performed. Corneal tissue sampled from the proband during phototherapeutic keratectomy was examined using transmission electron microscopy (TEM). RESULTS: A typical geographical pattern of fine opacities in Bowman's layer of the cornea was seen in all six patients on slit-lamp examination. An Arg555Gln (R555Q) mutation of the TGFBI gene was identified in all six patients but was absent in all unaffected family members. TEM revealed rod-shaped bodies in Bowman's layer of the cornea. CONCLUSIONS: In this Chinese family an R555Q mutation of the TGFBI gene was associated with RBCD. As the RBCD phenotype is usually associated with an R124L mutation, this novel genotype—phenotype correlation may prompt further investigation of Bowman's layer corneal dystrophy.

Purpose To report the efficacy of electrolysis as a treatment of corneal opacities in a young patient with the superficial variant of granular corneal dystrophy. Design Interventional case report. Methods An 11-year-old boy presented with subepithelial opacities in both eyes. His visual acuity was 0.2 in the left eye; he received corneal electrolysis under topical anesthesia. Results The electrolysis, which required only 5 minutes, resulted in the disappearance of the subepithelial opacities. His visual acuity improved to 0.4 on the next day and was 1.0 eight months later. The corneal curvature and thickness were not altered by the electrolysis. Conclusions Corneal electrolysis proved to be an effective treatment for subepithelial opacities, and we recommend electrolysis as an effective and simple treatment for young patients with SGCD.

Background : Mutations in the kerato-epithelin gene on chromosome 5 q 31 are known to cause four distinct autosomal dominant diseases of the human cornea: Reis-Bucklers, granular, lattice, and Avellino corneal dystrophy. Mutation of arginin to glutamine in codon 555 (R 555 Q) in kerato-epithelin was recently reported in four blood-related patients with Reis-Bucklers corneal dystrophy. Case : A 42-year-old female has had photophobia with decreasing vison since the age of 20 years. Her corrected visual acuity was 0.5 in both eyes. She showed subepithelial opacities in both corneas characteristic of Reis-Bucklers corneal dystrophy. Method : The DNA was extracted from leukocytes according to standard protocols. The keratoepithelin gene was examined for a mutation by the polymerase chain reaction and direct sequencing. Findings : We identified kerato-epithelin mutation R 555 Q. The patient's two children and 50 controls did not show missense mutation. Conclusion : Kerato-epithelin mutation R 555 Q was present in a Japanese patient with Reis-Bucklers corneal dystrophy.

Superficial keratectomy, penetrating and lamellar keratoplasty have all been advocated when intervention in Reis Bucklers' corneal dystrophy is necessary because of diminished visual acuity. In this study, 11 eyes were treated by phototherapeutic keratectomy with an excimer laser. Two eyes had previously been treated by penetrating keratoplasty. The visual acuity improved in all eyes, from an average of 6/60 to 6/9 with complete cessation of recurrent erosions. The technique was modified, with experience, to minimise the hyperopic shift that occurs with this procedure. Phototherapeutic keratectomy has significant advantages over other procedures and is now the procedure of choice once surgery is required in Reis Bucklers' dystrophy.

In the literature two types of anterior corneal dystrophy are referred to as Reis-Bucklers' dystrophy. These are the one originally described by Bucklers in 1949 and known by us as the geographical form, and a honeycomb form. On the basis of electron-microscopic findings the geographical form is considered by some authors today to be a superficial variant of the granular dystrophy (Groenouw I), while the honeycomb form is looked upon as the "true" Reis-Bucklers' dystrophy. However, there is no clinical resemblance between the honeycomb type and the dystrophy described by Bucklers. Clinically it is easy to distinguish the geographical and the honeycomb type, and this is important for the prognosis of a corneal graft. The present authors do not agree that the term granular dystrophy should include the dystrophy described by Bucklers. There is a lack of clarity concerning this type of dystrophy, and clinically it bears no resemblance to granular dystrophy. In the authors' opinion it would be preferable to speak of the geographical and the honeycomb form of Reis-Bucklers' dystrophy.

In Reis-BUcklers’ dystrophy an unknown pathomechanism in Bowman’s layer and the basal cells of the corneal epithelium results in recurrent epithelial erosions. The final stage is characterized by visual impairment due to irregular astigmatism and opacities in the superficial stroma. The treatment is superficial keratectomy, lamellar or perforating keratoplasty. This study presents the electron-microscopic findings in the epithelium and Bowman’s layer from samples obtained from 3 generations of the same family. All were diagnosed and treated in the University Eye Clinic of Hamburg.

A 46-year-old white woman had Reis-Bücklers corneal dystrophy; the disease had recurred in a corneal transplant within ten years of transplantation.

We treated five eyes of three patients with Reis-Bucklers' corneal dystrophy by blunt dissection of the subepithelial fibrous tissue layer. The postoperative follow-up ranged from four months to three years. Four of the five eyes had improved vision, and all four symptomatic eyes had cessation of the recurrent erosions. This simple effective technique eliminated the need for corneal transplantation.

We studied the cornea of a 51-year-old woman with recurrent Reis-Bucklers' dystrophy with the transmission electron microscope. The patient had had a superficial keratectomy nine years earlier. The epithelium removed in a second keratectomy contained distended endoplasmic reticulum and swollen mitochondria. The basal layer showed some cells in mitosis and a slight increase in the number of dark cells. The anterior portion of the removed stroma contained dense collagen fibrils, with the appearance of curly fibrils, which is characteristic of this disease. There were also severe degenerative changes in the stroma. These changes in the collagen fibers and alterations in keratocytes of the deeper layers were less severe than those of the superficial layer. A biopsy of the bulbar conjunctiva showed reduplication of the basement membrane.

Heretofore, only von Winkelman and Delleman 1 have reported recurrences of classical Reis-Bucklers' corneal dystrophy in previously grafted eyes; all recurrences were in the same pedigree and appeared in the early postoperative period. We have found delayed recurrence 15 years after graft and in a different family. This recurrence supports the opinion that the origin of the "curly filaments" or abnormal substance in Reis-Bucklers' is the basal epithelium. 2,3

Tight linkage was excluded for 8 markers in 37 blood relatives from 3 families, 29 of whom had granular corneal dystrophy (Groenouw I). Inconclusive results were obtained for linkage with four marker loci. The highest positive LOD score was 0.57 for linkage between glutamic pyruvic transaminase and granular corneal dystrophy. Tight linkage was excluded for glyoxalase-1 in eight individuals from one family with Schnyder's crystalline corneal dystrophy. Results were inconclusive for another six markers. Positive LOD scores were obtained for linkage with adenylate-kinase 1 and the ABO blood group, with values of 1.16 and 0.67, respectively. Among six blood relatives with Reis-Bucklers' corneal dystrophy, the highest positive LOD score was 1.17 for linkage with mitochondrial malic enzyme. For another six markers informative for linkage analysis, the results were inconsistent.

The anterior stroma, epithelium, and Bowman's layer have been proposed as the site of primary pathology in Reis-Bucklers' corneal dystrophy (RBCD). Immunofluorescent localization of laminin and bullous pemphigoid antigen (BPA) was compared with the ultrastructure of RBCD. As previously reported, patchy deposition of characteristic "peculiar curly" filaments was found in the supra-Bowman's, subepithelial fibrous tissue. We also recognized areas of early involvement with deposition of this "peculiar curly" material between a distorted epithelial basal lamina and a normal undisturbed Bowman's layer. In normal cornea, laminin and BPA localized to the epithelial basal lamina. In RBCD, laminin and BPA were in a piebald mosaic distribution throughout the aberrant subepithelial fibrous tissue between the basal lamina and the buried Bowman's layer. This indicates that RBCD is an epithelial disease, with the "peculiar curly" material paralleling the distribution of the attachment proteins.