- Email: [email protected]
Lattice corneal dystrophy type I without typical lattice lines: role of mutational analysis
debris on the road. The fragment from the grinding or cutting wheel or diamond saw may have been deposited on the road from previous roadwork in the area. We demonstrate that seemingly safe activities such as walking or running have small but significant health risks. Runners may consider the potential benefit of polycarbonate protective eyewear. Surgeons must become aware of this potential hazard as a source of intraocular foreign bodies. REFERENCES
1. Parver LM, Dannenberg AL, Blacklow B, et al. Characteristics and causes of penetrating eye injuries reported to the National Eye Trauma System Registry 1985–1991. Public Health Rep 1993;108:625–632. 2. Behrens-Baumann W, Praetorius G. Intraocular foreign bodies. 297 consecutive cases. Ophthalmologica 1989;198:84 –88. 3. Pieramici DJ, MacCumber MW, Humayun MU, et al. Openglobe injury. Updates on types of injuries and visual results. Ophthalmology 1996;103:1798 –1803. 4. Sternberg P Jr, de Juan E Jr, Michels RG, et al. Multivariate analysis of prognostic factors in penetrating ocular injuries. Am J Ophthalmol 1998;98:467–472. 5. Williams DF, Mieler WF, Abrams GW, et al. Results and prognostic factors in penetrating ocular injuries with retained intraocular foreign bodies. Ophthalmology 1988;95:911–916.
FIGURE 1. Central foreign body. Three intraocular foreign bodies: left to right corresponding to cases 1, 2, and 3.
● CASE 2:
A 69-year-old woman noticed reduced vision in her left eye while walking along a roadway. Her visual acuity was 6/9 in the right eye, and hand motions in the left eye. She had a full-thickness corneal laceration and cataract, beyond which there was no view. B-scan ultrasound demonstrated an intravitreal foreign body. Phacoemulsification, intraocular lens implanation, and pars plana vitrectomy with removal of a 1.5-mm intraocular foreign body weighing 9 mg were performed. Chemical analysis identified a flake of iron, most likely a steel alloy.
Lattice Corneal Dystrophy Type I Without Typical Lattice Lines: Role of Mutational Analysis
● CASE 3:
A 21-year-old man noticed reduced vision in his right eye while running along a roadway. His visual acuity was counting fingers in the right eye and 6/6 in the left eye. He had a full-thickness corneal laceration, cataract, and vitreous hemorrhage. B-scan ultrasound demonstrated an intravitreal foreign body. Phacoemulsification, intraocular lens implantation, pars plana vitrectomy with removal of a 1.5-mm intraocular foreign body weighing 14 mg were performed. Chemical analysis identified a steel of mainly iron with silicon, manganese, chromium, and vanadium. The potential origins include ball bearings, punches, blades, and rollers. Intraocular foreign bodies usually result from injuries occurring in the home or workplace or during recreation.1,2 Despite advances in vitreous microsurgical techniques, visual potential remains limited.3–5 Each injury occurred in a suburban area with single-lane traffic; the speed limit was 30 mph. Each patient was on the shoulder of the road, approximately 2 m from moving traffic. No patient was wearing eyeglasses or reported the presence of road construction in the immediate area. We hypothesize that the intraocular foreign bodies (Figure 1) consisted of projectiles that flew directly into the eye from passing rotating vehicle tires or from the road surface when the tire came into contact with the foreign body on the road surface. Chemical analysis revealed a variety of compositions of the metals involved, suggesting that the projectiles originated from pieces of metallic 586
AMERICAN JOURNAL
Shigeo Yoshida, MD, PhD, Ayako Yoshida, MD, PhD, Shintaro Nakao, MD, Aki Emori, MD, Takao Nakamura, MD, Kimihiko Fujisawa, MD, PhD, Yuji Kumano, MD, PhD, and Tatsuro Ishibashi, MD, PhD To describe a Japanese patient with lattice corneal dystrophy type I (LCD I) who lacked the typical lattice lines. DESIGN: Interventional case report. METHODS: A complete ophthalmologic examination was performed on a 54-year-old woman, and the TGFBI gene was analyzed by direct genomic sequencing. RESULTS: The patient had diffuse opacification of the central corneal stroma but without lattice lines and corneal epithelial erosions bilaterally. Molecular genetic analysis identified a lattice corneal dystrophy I–associPURPOSE:
Accepted for publication Sept 2, 2003. From the Department of Ophthalmology, Kyushu University Graduate School of Medicine, Fukuoka, Japan (S.Y., A.Y., S.N., A.E., T.N., K.F., T.I.), and Ohshima Hospital of Ophthalmology, Fukuoka, Japan (Y.K.). Inquiries to Shigeo Yoshida, MD, PhD, Department of Ophthalmology, Kyushu University Graduate School of Medicine, Fukuoka 8128582, Japan; fax: (⫹81) 92-642-5663; e-mail: [email protected] OF
OPHTHALMOLOGY
MARCH 2004
FIGURE 1. Slit-lamp photograph of corneas of a 54-year-old woman showing an oval, diffuse opacity occupying the central cornea of both eyes. No lattice lines are seen. There is also neovascular infiltration from the limbus of the cornea, some of which are indicated by arrows.
ated heterozygous missense alteration (C417T) that changed arginine in codon 124 to cysteine (R124C) in the TGFBI gene. CONCLUSIONS: The cornea of the patient appeared to represent late-stage lattice corneal dystrophy I, which suggests the existence of interactions of modifier genes, environmental factors during corneal aging, or both. The molecular genetic analysis of TGFBI can offer rapid, accurate diagnosis of patients with atypical corneal appearance. (Am J Ophthalmol 2004;137:586 –588. © 2004 by Elsevier Inc. All rights reserved.)
L
ATTICE CORNEAL DYSTROPHY IS AN INHERITED, PRI-
mary corneal amyloidosis that has been classified into four distinct subtypes: types I, II, III, and IIIA. Lattice corneal dystrophy I and IIIA are caused by point mutations in the transforming growth factor -induced (TGFBI) gene,1 and we have previously detected an LCD I-associated missense mutation (417C⬎T) in our patients with CD.2 The mutation is believed to cause an abnormal folding and precipitation of the encoded protein, leading to the accumulation of amyloid deposits within the cornea.3 Typically, patients with lattice corneal dystrophy I exhibit a lattice pattern of linear opacities in the corneal stroma that usually appears in the first decade of life.4 We report the case of a patient who had diffuse central corneal stromal opacity without any lattice lines, whose diagnosis of lattice corneal dystrophy I was confirmed by molecular genetic analysis. A 54-year-old woman presented with a complaint of decreased vision in both eyes. She had no history of ocular trauma and had been diagnosed with herpetic keratitis by another ophthalmologist. Her visual acuity was 20/800 in the right eye and hand motions in the left eye. The corneal stroma was diffusely opacified without any lattice lesions bilaterally (Figure 1). There were neovascular infiltrations VOL. 137, NO. 3
from the limbus, but corneal epithelial erosions were not observed. Intraocular pressure, anterior segments, and fundus were normal bilaterally, and no systemic abnormalities were found. Her 32-year-old daughter also had corneal opacities of unknown diagnosis. Although we tentatively diagnosed the patient with lattice corneal dystrophy, we could not exclude other possibilities such as syphilitic interstitial keratitis because the cornea lacked the characteristic lattice lines seen in lattice corneal dystrophy. We performed molecular genetic analysis with the patient’s informed consent. Genomic DNA was isolated, and exons 4, 11, 12, and 14 of TGFBI, which are the hot spots, were amplified and sequenced directly. In exon 4, a lattice corneal dystrophy I–associated heterozygous missense alteration (417C⬎T) that changed arginine in codon 124 to cysteine (Arg124Cys) was detected (Figure 2). None of the sequence alterations was detected in any of the 54 healthy, unrelated individuals without eye disease used as control subjects. The blood serological tests for syphilis were negative. Klintworth reported that the lattice lines in lattice corneal dystrophy I become more opaque and less distinct with age, and the stroma becomes progressively more hazy.4 Because we could not find any lattice lines, it is likely that the cornea represented a late stage of lattice corneal dystrophy I. This would suggest that there are as yet unknown interactions of modifier genes or environmental factors during corneal aging, although a change in the activity of a single TGFBI can be correlated with a clinical phenotype. It is also possible that an earlier corneal erosion might have accelerated the corneal opacities. Our observations clearly demonstrated the value of molecular genetic analysis of patients with lattice corneal dystrophy I, which can lead to a rapid and accurate diagnosis. Based on the molecular diagnosis, we were able
BRIEF REPORTS
587
FIGURE 2. Sequence analysis of exon 4 of TGFBI in the region encompassing codon 124. The arrow indicates the heterozygous lattice corneal dystrophy I–associated Arg124Cys (top panel) mutation. No equivalent mutation was detected in control subjects (bottom panel).
2. Yoshida S, Kumano Y, Yoshida A, et al. An analysis of BIGH3 mutations in patients with corneal dystrophies in the Kyushu district of Japan. Jpn J Ophthalmol 2002;46:469 –471. 3. Korvatska E, Henry H, Mashima Y, et al. Amyloid and non-amyloid forms of 5q31-linked corneal dystrophy resulting from kerato-epithelin mutations at Arg-124 are associated with abnormal turnover of the protein. J Biol Chem 2000; 275:11465–11469. 4. Klintworth GK. Lattice corneal dystrophy. An inherited variety of amyloidosis restricted to the cornea. Am J Pathol 1967;50:371–399. 5. Inoue K, Amano S, Oshika T, Sawa M, Tsuru T. A 10-year review of penetrating keratoplasty. Jpn J Ophthalmol 2000; 44:139 –145.
to counsel the patient that the rate of graft survival is approximately 75% for corneal transplantation5 and that her daughter should also undergo genetic analysis. Because there are mutational hot spots in TGFBI,2 molecular diagnosis should become a routine clinical procedure in those cases with ambiguous corneal signs.
REFERENCES
1. Munier FL, Korvatska E, Djemai A, et al. Kerato-epithelin mutations in four 5q31-linked corneal dystrophies. Nat Genet 1997;15:247–251.
588
AMERICAN JOURNAL
OF
OPHTHALMOLOGY
MARCH 2004
1. Parver LM, Dannenberg AL, Blacklow B, et al. Characteristics and causes of penetrating eye injuries reported to the National Eye Trauma System Registry 1985–1991. Public Health Rep 1993;108:625–632. 2. Behrens-Baumann W, Praetorius G. Intraocular foreign bodies. 297 consecutive cases. Ophthalmologica 1989;198:84 –88. 3. Pieramici DJ, MacCumber MW, Humayun MU, et al. Openglobe injury. Updates on types of injuries and visual results. Ophthalmology 1996;103:1798 –1803. 4. Sternberg P Jr, de Juan E Jr, Michels RG, et al. Multivariate analysis of prognostic factors in penetrating ocular injuries. Am J Ophthalmol 1998;98:467–472. 5. Williams DF, Mieler WF, Abrams GW, et al. Results and prognostic factors in penetrating ocular injuries with retained intraocular foreign bodies. Ophthalmology 1988;95:911–916.
FIGURE 1. Central foreign body. Three intraocular foreign bodies: left to right corresponding to cases 1, 2, and 3.
● CASE 2:
A 69-year-old woman noticed reduced vision in her left eye while walking along a roadway. Her visual acuity was 6/9 in the right eye, and hand motions in the left eye. She had a full-thickness corneal laceration and cataract, beyond which there was no view. B-scan ultrasound demonstrated an intravitreal foreign body. Phacoemulsification, intraocular lens implanation, and pars plana vitrectomy with removal of a 1.5-mm intraocular foreign body weighing 9 mg were performed. Chemical analysis identified a flake of iron, most likely a steel alloy.
Lattice Corneal Dystrophy Type I Without Typical Lattice Lines: Role of Mutational Analysis
● CASE 3:
A 21-year-old man noticed reduced vision in his right eye while running along a roadway. His visual acuity was counting fingers in the right eye and 6/6 in the left eye. He had a full-thickness corneal laceration, cataract, and vitreous hemorrhage. B-scan ultrasound demonstrated an intravitreal foreign body. Phacoemulsification, intraocular lens implantation, pars plana vitrectomy with removal of a 1.5-mm intraocular foreign body weighing 14 mg were performed. Chemical analysis identified a steel of mainly iron with silicon, manganese, chromium, and vanadium. The potential origins include ball bearings, punches, blades, and rollers. Intraocular foreign bodies usually result from injuries occurring in the home or workplace or during recreation.1,2 Despite advances in vitreous microsurgical techniques, visual potential remains limited.3–5 Each injury occurred in a suburban area with single-lane traffic; the speed limit was 30 mph. Each patient was on the shoulder of the road, approximately 2 m from moving traffic. No patient was wearing eyeglasses or reported the presence of road construction in the immediate area. We hypothesize that the intraocular foreign bodies (Figure 1) consisted of projectiles that flew directly into the eye from passing rotating vehicle tires or from the road surface when the tire came into contact with the foreign body on the road surface. Chemical analysis revealed a variety of compositions of the metals involved, suggesting that the projectiles originated from pieces of metallic 586
AMERICAN JOURNAL
Shigeo Yoshida, MD, PhD, Ayako Yoshida, MD, PhD, Shintaro Nakao, MD, Aki Emori, MD, Takao Nakamura, MD, Kimihiko Fujisawa, MD, PhD, Yuji Kumano, MD, PhD, and Tatsuro Ishibashi, MD, PhD To describe a Japanese patient with lattice corneal dystrophy type I (LCD I) who lacked the typical lattice lines. DESIGN: Interventional case report. METHODS: A complete ophthalmologic examination was performed on a 54-year-old woman, and the TGFBI gene was analyzed by direct genomic sequencing. RESULTS: The patient had diffuse opacification of the central corneal stroma but without lattice lines and corneal epithelial erosions bilaterally. Molecular genetic analysis identified a lattice corneal dystrophy I–associPURPOSE:
Accepted for publication Sept 2, 2003. From the Department of Ophthalmology, Kyushu University Graduate School of Medicine, Fukuoka, Japan (S.Y., A.Y., S.N., A.E., T.N., K.F., T.I.), and Ohshima Hospital of Ophthalmology, Fukuoka, Japan (Y.K.). Inquiries to Shigeo Yoshida, MD, PhD, Department of Ophthalmology, Kyushu University Graduate School of Medicine, Fukuoka 8128582, Japan; fax: (⫹81) 92-642-5663; e-mail: [email protected] OF
OPHTHALMOLOGY
MARCH 2004
FIGURE 1. Slit-lamp photograph of corneas of a 54-year-old woman showing an oval, diffuse opacity occupying the central cornea of both eyes. No lattice lines are seen. There is also neovascular infiltration from the limbus of the cornea, some of which are indicated by arrows.
ated heterozygous missense alteration (C417T) that changed arginine in codon 124 to cysteine (R124C) in the TGFBI gene. CONCLUSIONS: The cornea of the patient appeared to represent late-stage lattice corneal dystrophy I, which suggests the existence of interactions of modifier genes, environmental factors during corneal aging, or both. The molecular genetic analysis of TGFBI can offer rapid, accurate diagnosis of patients with atypical corneal appearance. (Am J Ophthalmol 2004;137:586 –588. © 2004 by Elsevier Inc. All rights reserved.)
L
ATTICE CORNEAL DYSTROPHY IS AN INHERITED, PRI-
mary corneal amyloidosis that has been classified into four distinct subtypes: types I, II, III, and IIIA. Lattice corneal dystrophy I and IIIA are caused by point mutations in the transforming growth factor -induced (TGFBI) gene,1 and we have previously detected an LCD I-associated missense mutation (417C⬎T) in our patients with CD.2 The mutation is believed to cause an abnormal folding and precipitation of the encoded protein, leading to the accumulation of amyloid deposits within the cornea.3 Typically, patients with lattice corneal dystrophy I exhibit a lattice pattern of linear opacities in the corneal stroma that usually appears in the first decade of life.4 We report the case of a patient who had diffuse central corneal stromal opacity without any lattice lines, whose diagnosis of lattice corneal dystrophy I was confirmed by molecular genetic analysis. A 54-year-old woman presented with a complaint of decreased vision in both eyes. She had no history of ocular trauma and had been diagnosed with herpetic keratitis by another ophthalmologist. Her visual acuity was 20/800 in the right eye and hand motions in the left eye. The corneal stroma was diffusely opacified without any lattice lesions bilaterally (Figure 1). There were neovascular infiltrations VOL. 137, NO. 3
from the limbus, but corneal epithelial erosions were not observed. Intraocular pressure, anterior segments, and fundus were normal bilaterally, and no systemic abnormalities were found. Her 32-year-old daughter also had corneal opacities of unknown diagnosis. Although we tentatively diagnosed the patient with lattice corneal dystrophy, we could not exclude other possibilities such as syphilitic interstitial keratitis because the cornea lacked the characteristic lattice lines seen in lattice corneal dystrophy. We performed molecular genetic analysis with the patient’s informed consent. Genomic DNA was isolated, and exons 4, 11, 12, and 14 of TGFBI, which are the hot spots, were amplified and sequenced directly. In exon 4, a lattice corneal dystrophy I–associated heterozygous missense alteration (417C⬎T) that changed arginine in codon 124 to cysteine (Arg124Cys) was detected (Figure 2). None of the sequence alterations was detected in any of the 54 healthy, unrelated individuals without eye disease used as control subjects. The blood serological tests for syphilis were negative. Klintworth reported that the lattice lines in lattice corneal dystrophy I become more opaque and less distinct with age, and the stroma becomes progressively more hazy.4 Because we could not find any lattice lines, it is likely that the cornea represented a late stage of lattice corneal dystrophy I. This would suggest that there are as yet unknown interactions of modifier genes or environmental factors during corneal aging, although a change in the activity of a single TGFBI can be correlated with a clinical phenotype. It is also possible that an earlier corneal erosion might have accelerated the corneal opacities. Our observations clearly demonstrated the value of molecular genetic analysis of patients with lattice corneal dystrophy I, which can lead to a rapid and accurate diagnosis. Based on the molecular diagnosis, we were able
BRIEF REPORTS
587
FIGURE 2. Sequence analysis of exon 4 of TGFBI in the region encompassing codon 124. The arrow indicates the heterozygous lattice corneal dystrophy I–associated Arg124Cys (top panel) mutation. No equivalent mutation was detected in control subjects (bottom panel).
2. Yoshida S, Kumano Y, Yoshida A, et al. An analysis of BIGH3 mutations in patients with corneal dystrophies in the Kyushu district of Japan. Jpn J Ophthalmol 2002;46:469 –471. 3. Korvatska E, Henry H, Mashima Y, et al. Amyloid and non-amyloid forms of 5q31-linked corneal dystrophy resulting from kerato-epithelin mutations at Arg-124 are associated with abnormal turnover of the protein. J Biol Chem 2000; 275:11465–11469. 4. Klintworth GK. Lattice corneal dystrophy. An inherited variety of amyloidosis restricted to the cornea. Am J Pathol 1967;50:371–399. 5. Inoue K, Amano S, Oshika T, Sawa M, Tsuru T. A 10-year review of penetrating keratoplasty. Jpn J Ophthalmol 2000; 44:139 –145.
to counsel the patient that the rate of graft survival is approximately 75% for corneal transplantation5 and that her daughter should also undergo genetic analysis. Because there are mutational hot spots in TGFBI,2 molecular diagnosis should become a routine clinical procedure in those cases with ambiguous corneal signs.
REFERENCES
1. Munier FL, Korvatska E, Djemai A, et al. Kerato-epithelin mutations in four 5q31-linked corneal dystrophies. Nat Genet 1997;15:247–251.
588
AMERICAN JOURNAL
OF
OPHTHALMOLOGY
MARCH 2004