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Supplemental Digital Content is Available in the Text., Purpose: This study aims to clinically and genetically report a case of coexisting Meesmann corneal dystrophy (MECD) and pseudo-unilateral lattice corneal dystrophy (LCD). Methods: Clinical characterization was supported by a complete ophthalmological evaluation, including visual acuity measurement and slit-lamp examination. Molecular diagnosis was performed by whole-exome sequencing analyzing the gelsolin, keratin K3 (KRT3), keratin K12, and transforming growth factor-beta–induced genes. Results: A 57-year-old woman presented with recurrent corneal erosions over 17 years and visual impairment in both eyes. Ophthalmological evaluation revealed multiple central tiny cysts in the epithelium of both eyes and lattice linear lesions only in the right cornea. In both eyes, a corneal posterior crocodile shagreen degeneration could also be observed. These findings were compatible with a MECD and a unilateral LCD. Molecular analysis identified the novel heterozygous nucleotide substitution c.1492G>A (amino acid change p.Glu498Lys) in the KRT3 gene, in cosegregation with the MECD familial phenotype. However, no genetic evidence supported the unique LCD phenotype observed in the patient. Conclusions: To the best of our knowledge, this is the first report of a pseudo-unilateral LCD in a patient with coexistent MECD. Moreover, the genetic analysis showed a novel mutation in the previously MECD-associated gene KRT3.

Purpose To determine the prevalence of the transforming growth factor (TGF) β–induced gene corneal dystrophies in refractive surgery candidates in China. Setting Five hospitals in China. Design Prospective case series. Method Refractive surgical candidates from 5 preselected eye hospitals/centers in China were recruited after providing informed consent. All patients had slitlamp biomicroscopy and collection of a buccal swab as a source of DNA for screening of the TGF β–induced gene for the 5 most common mutations associated with Reis-Buckler corneal dystrophy, Thiel-Behnke corneal dystrophy, granular corneal dystrophy type 1, granular corneal dystrophy type 2, and lattice corneal dystrophy type 1. Results Of the 2068 refractive surgery candidates analyzed, 4 had corneal opacities in both eyes on slitlamp examination. Screening for the TGF β–induced gene found the heterozygous p.R124H mutation associated with granular corneal dystrophy type 2 in each of the 4 individuals with corneal opacities as well as in a fifth individual who did not have any corneal opacities, for a prevalence of 0.24%. Exacerbation of dystrophic corneal deposition developed after laser refractive surgery in 2 individuals who did not have preoperative TGF β–induced gene screening. Conclusions The prevalence of the TGF β–induced gene corneal dystrophies in Chinese refractive surgery candidates was estimated to be approximately 0.24%. Genetic testing is recommended to identify and exclude from candidacy all individuals with a TGF β–induced gene dystrophy before elective keratorefractive surgery to avoid causing accelerated postoperative dystrophic deposition.

To update the 2008 International Classification of Corneal Dystrophies (IC3D) incorporating new clinical, histopathologic, and genetic information.The IC3D reviewed worldwide peer-reviewed articles for new information on corneal dystrophies published between 2008 and 2014. Using this information, corneal dystrophy templates and anatomic classification were updated. New clinical, histopathologic, and confocal photographs were added.On the basis of revisiting the cellular origin of corneal dystrophy, a modified anatomic classification is proposed consisting of (1) epithelial and subepithelial dystrophies, (2) epithelial-stromal TGFBI dystrophies, (3) stromal dystrophies, and (4) endothelial dystrophies. Most of the dystrophy templates are updated. The entity "Epithelial recurrent erosion dystrophies" actually includes a number of potentially distinct epithelial dystrophies (Franceschetti corneal dystrophy, Dystrophia Smolandiensis, and Dystrophia Helsinglandica) but must be differentiated from dystrophies such as TGFBI-induced dystrophies, which are also often associated with recurrent epithelial erosions. The chromosome locus of Thiel-Behnke corneal dystrophy is only located on 5q31. The entity previously designated as a variant of Thiel-Behnke corneal dystrophy on chromosome 10q24 may represent a novel corneal dystrophy. Congenital hereditary endothelial dystrophy (CHED, formerly CHED2) is most likely only an autosomal recessive disorder. The so-called autosomal dominant inherited CHED (formerly CHED1) is insufficiently distinct to continue to be considered a unique corneal dystrophy. On review of almost all of the published cases, the description appeared most similar to a type of posterior polymorphous corneal dystrophy linked to the same chromosome 20 locus (PPCD1). Confocal microscopy also has emerged as a helpful tool to reveal in vivo features of several corneal dystrophies that previously required histopathologic examination to definitively diagnose.This revision of the IC3D classification includes an updated anatomic classification of corneal dystrophies more accurately classifying TGFBI dystrophies that affect multiple layers rather than are confined to one corneal layer. Typical histopathologic and confocal images have been added to the corneal dystrophy templates.

PURPOSE To evaluate the question whether lattice corneal dystrophy type 1 (LCD1) is of epithelial or stromal origin. METHODS The landmark of advanced LCD1 shows central superficial haze and paracentral stromal lattice lines. In 16 eyes of 8 affected individuals of 2 families, a penetrating keratoplasty was performed. The follow-up was 8 to 16 years after penetrating keratoplasty. Slit-lamp documentation of the patients was evaluated in direct and indirect illumination with dilated pupil to assess the horizontal and vertical pattern of new deposits on the corneal graft. Three affected patients of 2 families are demonstrated in detail. A DNA analysis was performed. RESULTS Gene identification revealed a transforming growth factor beta-induced (TGFBI) Leu509Pro mutation in the first family, and a TGFBI Arg124Cys mutation in the second family. The demonstrated 5 corneal grafts of the 3 LCD1-patients showed diffuse opacities of distinct severity, beginning 3 to 4 years postoperatively, that were often combined with corneal erosions and consecutive pain. In none of our patients, we were able to detect any signs of lattice formation in the form of gray lines that run obliquely from the surface to the midstroma in direct illumination. In retroillumination, no lattice opacity units in the form of translucent and refractile lines were visible on the graft. CONCLUSIONS The TGFBI gene, that is responsible for LCD1, is expressed above all by the corneal epithelial cells but also by the keratocytes. We interpret the superficial diffuse LCD1 recurrences on the graft as the product of the epithelial cells, whereas the nonoccurrence of lattice lines as long as 18 years after keratoplasty, an indirect sign that the lattice lines are the product of the keratocytes. Thus, LCD1 seems to represent an epithelial-stromal entity, because both epithelial cells and keratocytes are involved.

To assess the indications, outcomes and time to recurrence of phototherapeutic keratectomy (PTK) for anterior corneal pathology. This study involved 714 eyes of 477 consecutive patients (mean age: 66.0 ± 15.2 years; range: 6–101 years) who underwent PTK as the initial surgical intervention for an anterior corneal pathology. In case of each patient, the cornea treated by PTK, followed up by slit-lamp examination and corrected distance visual acuity (CDVA) testing. Main outcome measures included Slit-lamp findings (1), CDVA (2), patients’ complaints (3). The mean follow-up period was 44.0 ± 38.8 months (range: 1–156 months). We treated 376 granular corneal dystrophy (GCD) eyes, 238 band keratopathy (BK) eyes, 23 epithelium attachment disorder eyes, 16 gelatinous drop-like corneal dystrophy (GDLD) eyes, 13 lattice corneal dystrophy (LCD) eyes, and 48 eyes with other corneal diseases. The CDVA significantly improved from LogMAR 0.65 ± 0.61 pre PTK to LogMAR 0.26 ± 0.39 post PTK. A 2 or more lines increase of CDVA was observed in GCD eyes (67.8%), BK eyes (49.2%), epithelium attachment disorder eyes (57.1%), GDLD eyes (87.5%), LCD eyes (76.9%), and other corneal disease eyes (60.4%). The recurrence of BK was rare. GCD recurred slowly. Epithelium attachment disorder eyes remitted simultaneously, and recurred comparatively faster. PTK was proved to be a successful therapy for all 6 corneal disease categories. Disease recurrence after PTK differed among the diseases, and surgeons should recognize the different rates of disease recurrence after PTK surgery.

Purpose An atypical case of late-onset lattice corneal dystrophy is described in a 61-year-old man without a family history of eye disease. Mutational analysis of the TGFBI gene excluded any pathogenic sequence variants. However, 2 years later, renal impairment and nephrotic syndrome were diagnosed, resulting in a diagnosis of systemic heavy-chain amyloidosis. Methods Slit-lamp examination, corneal photography, and in vivo confocal microscopy were performed. General systemic evaluation included blood and urine assessment, bone marrow and renal biopsies, and cardiologic evaluation. A DNA sample underwent initial mutational analysis of TGFBI and, subsequently, gelsolin. The renal biopsy sample was subject to direct protein sequencing by mass spectrometry. Results A bilateral, atypical, fine, midperipheral lattice corneal dystrophy with minor central subepithelial scarring was clinically characterized. Subsequently, abnormal renal functions with proteinuria, IgG lambda paraproteinemia, extensive deposition of amyloid in renal glomeruli, and increased plasma cells in bone marrow were identified. No pathogenic sequence mutations were identified in TGFBI or the gelsolin genes. Direct protein sequencing by mass spectrometry showed amyloid to be heavy-chain deposition rather than the more usual light-chain deposition. Conclusions Atypical midperipheral lattice corneal dystrophy presenting with adult onset and negative family history should arouse suspicion for an association with paraproteinemias or amyloidosis. Exclusion of TGFBI mutations should alert the clinician to the possibility of potentially life-threatening conditions, with referral for careful systemic evaluation.

PURPOSE The aim of this study was to report the persistent staining of corneal lattice lines resulting from the intraoperative use of trypan blue. METHODS This is a case series. RESULTS Four patients with lattice corneal dystrophy (LCD) who underwent either deep anterior lamellar keratoplasty or cataract extraction with intraoperative trypan blue use demonstrated persistent, postoperative trypan staining of lattice lines on slit-lamp examination out to final follow-up (range, 176 to 541 days postoperatively). CONCLUSIONS This case series demonstrates the previously unreported finding that intraoperative trypan blue stains corneal lattice lines in LCD. Trypan blue staining, localized in previous laboratory studies to amyloid deposits, seems to persist for months or longer and may be permanent in human tissue. Although the staining was not visually significant, animal models suggest a stimulatory effect on progression of amyloidosis. Clinicians should be aware of the potential for permanent corneal staining and possible disease progression with the use of intraoperative trypan blue in patients with LCD.

We report a patient with lattice corneal dystrophy type II, also known as Meretoja syndrome or familial amyloidosis Finnish type, who developed a corneal melt 15 days after uneventful phacoemulsification. Despite conservative treatment, the corneal melt resulted in perforation. Uneventful penetrating keratoplasty was performed, but delayed graft epithelial healing was noticed postoperatively. Corneal button histopathological evaluation confirmed the initial clinical diagnosis. To our knowledge, this is the first reported case of corneal melt and perforation in a patient with lattice corneal dystrophy type II.

Purpose To report clinical and histopathological characteristics of postoperative amyloidosis recurrence in a patient with lattice corneal dystrophy (LCD) type I. Methods The clinical manifestation of recurrent amyloidosis in the residual stroma was delineated in a patient with LCD type I after deep lamellar keratoplasty (DLKP) for 6.5 years. Complete removal of the residual recipient stroma and regrafting of a new cryopreserved donor button were accomplished by a secondary DLKP. The primary DLKP donor graft and the underlying residual stroma of the recipient obtained by the secondary DLKP were examined for analysis of histopathologic and ultrastructural changes. Results A tongue-shaped retained stroma with linear opacity was observed underneath the primary DLKP donor graft. The retained stromal layer was thoroughly detached from Descemet membrane, removed, and followed by grafting a new cryopreserved button. The primary donor button exhibited a normal epithelium, fewer keratocytes, an intact Descemet membrane, and mild positive Congo red staining in the middle layer of the stroma. The total retained recipient stroma removed by the secondary DLKP measured approximately 20 mum in thickness, showing thick and massive amyloid accumulation. The surface of the removed residual stroma toward Descemet membrane showed collagen fibers in an interwoven fashion without bundle structure under a scanning electron microscope. Conclusion Incomplete removal of the recipient stroma by DLKP can lead to the recurrence of amyloidosis in the residual stroma in patients with LCD. Clinical and histologic findings in the primary graft and in the residual recipient stroma implicate stromal genesis of recurrence of LCD after DLKP.

Purpose: To report a case of stellate and branching linear corneal stromal amyloid deposits secondary to trichiasis and the use of molecular genetic analysis to exclude lattice corneal dystrophy. Methods: Case report and review of the literature. A 30-year-old man with a history of chronic ocular irritation was found to have distichiasis, epiblepharon, and unilateral corneal amyloidosis indistinguishable from lattice corneal dystrophy. Screening of the TGFBI gene was performed to rule out a previously reported mutation associated with lattice corneal dystrophy. Result: A corneal biopsy performed before presentation to the authors confirmed the presence of corneal amyloidosis. Screening of exons 4, 11, 12, and 14 in the TGFBI gene identified 2 previously reported polymorphisms, Leu472Leu and Phe540Phe, but no other coding region changes. Conclusion: Corneal stromal amyloidosis clinically resembling lattice corneal dystrophy may be associated with trichiasis. The exclusion of a TGFBI-associated corneal dystrophy in this case, leaving trichiasis as the most likely cause of the corneal amyloid deposition, demonstrates the utility of molecular genetic analysis in confirming or refuting a presumptive clinical diagnosis.

PURPOSE: To report the clinical features and histopathology of a transplanted cornea that was immediately replaced because of the possible diagnosis of lattice corneal dystrophy in the graft in which histopathologic examination revealed a Zygomycetes infection. METHODS: A 19-year-old patient with keratoconus underwent deep anterior lamellar keratoplasty (DALK) in the right eye. The operation was uneventful, transplanting a corneal graft without Descemet membrane, harvested from a donor with signs of orbital trauma. RESULTS: Three days after keratoplasty, multiple refractile lines involving the entire donor stroma were observed. With the potential diagnosis of lattice dystrophy of the donor cornea, the graft was replaced and sent for histopathologic analysis, which revealed a Zygomycetes graft infection. CONCLUSIONS: This case report introduces Zygomycetes as a cause of donor-to-host infection and also suggests that corneas harvested from donors with signs of orbital trauma may be a risk factor for donor-to-recipient transmission of such fungal infections.

PURPOSE To report a patient with lattice corneal dystrophy type I (LCDI) who developed a triple anterior chamber after full-thickness lamellar keratoplasty (LKP). METHODS A 46-year-old woman underwent a full-thickness LKP in her right eye for visual disturbances caused by LCDI. Her visual acuity was 20/200 OD before surgery. A complete ophthalmic examination, including slit lamp biomicroscopy and optical coherence tomography (OCT), was performed before and after surgery. Molecular genetic analysis was performed on DNA extracted from the peripheral leukocytes. RESULTS The surgery was performed uneventfully; however, extra spaces posterior to the graft, along with the severe graft edema, were observed to form a triple anterior chamber a few days after surgery. The extra spaces resolved in 3 weeks with no surgical treatment, and her visual acuity improved to 20/20 OD without correction 3 months after surgery. The triple anterior chamber was clearly demonstrated by OCT, but not by slit lamp biomicroscopy. A heterozygous single base-pair transition (CGC to TGC, arginin to cysteine) was detected in codon 124 of the TGFBIgene in the patient. CONCLUSION The separation of the graft and the host's deep corneal tissue and a Descemet's membrane detachment in the host's cornea caused the triple anterior chamber. The Descemet's membrane detachment demonstrated the weak adhesion of the stroma and the Descemet's membrane, probably resulting from a dysfunction of the TGFBI protein caused by the mutation of the TGFBIgene. OCT is useful for the objective documentation of the posterior corneal region even with severe corneal edema.

PURPOSE To report two Japanese patients who were clinically diagnosed with late-onset and sporadic lattice corneal dystrophy (LCD) in whom a Leu527Arg mutation in the TGFBI gene was found. METHODS Molecular genetic analysis was performed on DNA extracted from peripheral leukocytes from the patients. Exons 4, 11, and 12 of the TGFBI gene were amplified by polymerase chain reaction and directly sequenced. Histopathologic study was performed on the corneal tissue obtained during deep lamellar keratoplasty (DLK) from one of the patients. RESULTS Patient 1 was a 74-year-old man who noticed a visual disturbance at the age of 72 years. Deep stromal opacities with nodular deposits and thick lattice lines were observed only in the right cornea, and DLK was performed. Patient 2 was an 82-year-old man who had LCD (similar in appearance to that in patient 1) in both eyes without visual disturbance. Neither of the patients had a family history of corneal problems and had no episode of corneal erosion. A heterozygous single base-pair transition (CTG to CGG, leucine to arginin) was detected in codon 527 of the TGFBI gene in both patients. No mutation was found in codons 124, 501, 518, 546, or 555. Histopathologically, relatively large amyloid deposits in the deep corneal stroma and ribbons of amyloid deposits just beneath the Bowman's layer were observed in the corneal tissue of patient 1. CONCLUSIONS Clinical features and pathologic findings of the late-onset form of LCD with an L527R mutation in the TGFBI gene were made clear.

Purpose To investigate mutations of the human transforming growth factor beta-induced gene (TGFBI), transforming growth factor-beta-induced gene product (betaig-h3, keratoepithelin), in Japanese patients with Avellino corneal dystrophy (ACD), lattice corneal dystrophy (LCD), granular corneal dystrophy (GCD), and Reis-Bucklers corneal dystrophy (RBCD). Methods Genomic DNA was extracted from the peripheral blood of 75 patients and 7 unaffected relatives from 60 families with ACD, 34 patients and 8 unaffected relatives from 21 families with LCD, 4 patients and 4 unaffected relatives from 4 families with GCD, and 4 patients and an unaffected relative from 3 families with RBCD. Fifty normal volunteers served as controls. Exons 4, 11, and 12 of the TGFBI gene were amplified by polymerase chain reaction and were directly sequenced. Results Six different heterozygous missense mutations were detected in codons R124, L518, L527, and R555 of the TGFBI gene in the 117 patients from 88 families. A R124H mutation was detected in the patients with ACD. A R124C mutation was detected in the patients with LCD type 1 (LCD1), L518P was in atypical LCDI, and L527R in LCD with opacities deep in stroma. A R555W mutation was detected in the patients with GCD. A R555Q mutation was detected in the patients with RBCD. Conclusions We conclude that codons R124 and R555 of the TGFBI gene are also hot spots in Japanese patients with ACD, LCD, GCD, and RBCD. Many Japanese patients with CD had ACD with R124H mutation. GCD with R555W mutation was rare.

PURPOSE To report three cases of seemingly unilateral dystrophy indistinguishable from type I classic lattice corneal dystrophy. METHODS Case study of three patients. Three patients, a 31-year-old man, a 44-year-old woman, and a 41-year-old man had multiple lattice lesions in one eye and an apparently healthy fellow eye. Two of these patients underwent penetrating keratoplasty because of poor vision. RESULTS Histopathologic examination of the excised corneal button of patient 2 showed amyloid deposits consistent with lattice. In the third patient, lattice lesions were noted in the other eye nearly 13 years after he was first examined. CONCLUSIONS Lattice corneal dystrophy is rarely unilateral. Lattice, even in unilateral cases, may cause significant vision loss to warrant penetrating keratoplasty. Lattice lesions may develop in the fellow eye many years later. This possibility should be explained to all patients with apparently unilateral lattice corneal dystrophy.

PURPOSE To present a patient with a genotype usually associated with lattice corneal dystrophy but with clinical and histopathologic features of advanced Avellino corneal dystrophy. METHODS Penetrating keratoplasty was performed with subsequent histopathologic analysis. For genetic testing, a 5-mL blood sample was taken after informed consent. Genetic sequencing was performed by the John and Marcia Carver Laboratory of the University of Iowa. The mutation was identified by direct sequencing through the positions of the coding sequences of the TGFBI gene that have been previously reported to have genetic variations (exons 4 and 11-14). RESULTS Corneal examination revealed bilateral lattice and multiple confluent subepithelial and anterior stromal granular opacities. Histopathologic examination showed amyloid deposits by Congo red stain and hyaline deposits by Masson trichrome stain, consistent with a diagnosis of Avellino dystrophy. Automated DNA sequencing revealed a heterozygous Arg124Cys (R124C) mutation in the coding sequence of the TGFBI gene on chromosome 5q31. Recurrent granular deposits developed in the corneal graft 14 months after surgery. CONCLUSIONS Our case presented with clinical and histopathologic findings consistent with a diagnosis of Avellino dystrophy and exhibited a genotype with R124C mutation. Avellino dystrophy has not previously been reported to be associated with the R124C mutation, which is usually associated with lattice corneal dystrophy. This also raises the issue as to whether classification of the corneal stromal dystrophies should be based primarily on phenotype/histopathology or on genotyping.

The purpose of this study was to report the association of phenotypic features characteristic of lattice corneal dystrophy (LCD) with a monoclonal gammopathy of undetermined significance (MGUS) after exclusion of a coding region mutation in transforming growth factor beta-induced (TGFBI) gene.Case report.Slit-lamp examination and collection of DNA for TGFBI screening were performed. A systemic evaluation was also performed to evaluate for conditions associated with systemic amyloidosis.A 65-year-old man demonstrated bilateral linear branching corneal stromal opacities characteristic of classic LCD. No mutations were found in any of the 17 exons of TGFBI or in the intron-exon boundary regions. Four previously described single nucleotide polymorphisms were identified: c.698CG (p.Leu217Leu; rs1442), c.1028AG (p.Val327Val; rs1054124), c.1416CT (p.Leu472Leu; rs1133170), and c.1667TC (p.Phe540Phe; rs4669). Serum protein electrophoresis revealed the presence of a monoclonal spike, and based on the results of additional investigations, the patient was diagnosed with MGUS.Although the presence of bilateral thin branching lattice lines in the corneal stroma is characteristic of classic LCD, this distinctive phenotype may not be associated with a TGFBI coding region mutation but instead with a myeloproliferative disorder such as MGUS. Therefore, appropriate genetic and serologic testing should be performed in patients with a late-onset LCD phenotype in the absence of a positive family history.

To compare the time necessary for complete epithelial healing after penetrating keratoplasty carried out for various corneal dystrophies.In a retrospective single-center study, 679 eyes that underwent nonmechanical keratoplasty were evaluated concerning postoperative epithelial healing time. On the basis of corneal pathology, the eyes were divided into 5 groups: group 1, lattice dystrophy (n = 9); group 2, macular dystrophy (n = 16); group 3, Fuchs dystrophy (n = 207); group 4, granular dystrophy (n = 13); group 5, keratoconus (n = 434). After keratoplasty, the time necessary for complete healing of the epithelial defect was compared among the groups.In lattice dystrophy, 22% showed delayed healing, in contrast to 0% in granular dystrophy. Mean time necessary for healing in group 1 (8.8 +/- 9.4 days) was significantly longer than in group 2 (2.5 +/- 2.5 days, P = 0.003), group 3 (4.4 +/- 4.1 days, P = 0.09), group 4 (2.2 +/- 1.4 days, P = 0.003), and group 5 (3.1 +/- 2.7 days, P = 0.005).In patients with lattice dystrophy, delayed epithelial healing after penetrating keratoplasty may be anticipated. Patients should be counseled accordingly.

Two sisters, aged 33 and 35, underwent uncomplicated penetrating keratoplasty for lattice corneal dystrophy type 1. Both patients, as well as their younger brother, had experienced frequent recurrent epithelial erosions prior to undergoing corneal grafting. Each sister has subsequently experienced painful, corneal epithelial macroerosions in the corneal graft, in the absence of any signs of recurrence of the lattice corneal dystrophy in the grafted tissue. With treatment each episode of macroerosion has resolved without complication. To our knowledge, this is the first report of epithelial erosions in a corneal graft without clinical evidence of recurrent lattice corneal dystrophy.

Newer biochemical, immunohistochemical, and cell culture techniques have been used to investigate metabolic abnormalities in corneal stromal dystrophies. Organ cultures of macular corneal dystrophy (MCD) have shown a defect in the synthesis of keratan sulphate proteoglycan. Alterations in corneal stromal glycoconjugates have also been detected using biotinylated lectins. An absence of normal keratan sulphate proteoglycan has been shown in the blood of patients with MCD. Granular corneal dystrophy (GCD) is associated with increased phospholipid, as shown by biochemical analysis and staining with Luxol-fast blue. Immunohistochemical stains revealed reactivity with antibodies against microfibrillar protein at the edges of the deposits. Clinically, recently described early features of lattice corneal dystrophy (LCD) include discrete ovoid subepithelial opacities, a diffuse central anterior stromal haze, and anterior stromal dots and filamentary lines. Early clinical recognition of these corneal genetic disorders, with appropriate studies to define their nature and possible pathogenetic mechanisms, are important in expanding our knowledge of this disease spectrum.