Pellucid marginal degeneration coexistent with cornea plana in one member of a family exhibiting a novel KERA mutation
http://www.100md.com
《英国眼科学杂志》
1 Division of Pediatric Ophthalmology, King Khaled Eye Specialist Hospital, PO Box 7191, Riyadh 11462, Saudi Arabia
2 Aragene Project, King Faisal Specialist Hospital and Research Center, MBC 03-8, PO Box 3354, Riyadh 11211, Saudi Arabia
Keywords: KERA; cornea plana; keratocan; pellucid marginal degeneration
Characterised by flattening of the normally convex corneal surface, small corneas, high hyperopia, and arcus senilis, autosomal recessive cornea plana is secondary to KERA mutation.1–3KERA encodes keratocan, an evolutionary conserved small leucine rich proteoglycan. Keratocan, highly and uniquely expressed in the cornea, is composed of core proteins consisting mostly of leucine rich repeats (LRRs).1–3 All patients documented to be homozygous for one of the four previously reported KERA mutations have disruption of LRR architecture and demonstrate similar cornea plana phenotypes.1–3 In contrast, corneal pellucid marginal degeneration (PMD) is an idiopathic progressive ectatic corneal disorder that is clinically diagnosed by characteristic thinning, resultant "against the rule" astigmatism, and absence of opacity.4 We report a case of superior PMD coexistent with cornea plana in a family exhibiting a novel KERA mutation and document the ophthalmic findings of the family.
Case series
Twelve individuals from a Saudi nuclear family were studied after institutional review board approval and family informed consent had been obtained from the family. Clinical findings and diagnoses are summarised in figures 1 and 2, and table 1. Only one family member (patient 4) had a history of progressive visual difficulty over the last several years, and this was due to an increasing astigmatic refractive error. Axial lengths and keratometry readings were recorded using the Zeiss IOL-Master (2001 model), and corneal topography was performed using the Bausch & Lomb Orbiscan 2Z (2002 model).
Figure 1 The family pedigree.
Figure 2 (A) The small flat corneas of a typical patient (No 3) are shown. (B) The slit lamp appearance of patient 3 is shown. (C) In addition to small flat corneas and early arcus senilis, patient 4 also demonstrated superior corneal thinning (arrow, LE) with associated corneal ectasia characteristic of superior pellucid marginal corneal degeneration. (D) Topography, LE of patient 4 shows the characteristic high astigmatism of superior pellucid marginal corneal degeneration.
Table 1 Pertinent biometric and clinical characteristics of the family are summarised
All family members underwent KERA DNA sequencing using methods previously described.3 A novel mutation was detected in exon 2, , changing an arginine amino acid at position 279 to a stop codon . The resultant truncated protein lacks the terminal 73 amino acids of normal keratocan. This mutation was homozygous in the five siblings with clinically evident cornea plana (Nos 3, 5, 7, 11, 12) and the sister with clinical findings of PMD and cornea plana (No 4). All other family members (Nos 1, 2, 6, 8, 9, 10) were heterozygous for the mutation and clinically unaffected.
Comment
All four previously reported KERA mutations disrupt keratocan LRR architecture and are associated with similar corneal phenotypes in documented homozygotes.1–3 The current mutation similarly disrupts LLR function, as the prematurely truncated protein lacks two LRRs of normal keratocan and is associated with the expected cornea plana phenotype. Interestingly, one homozygous individual (No 4) demonstrates corneal findings compatible with both superior PMD (corneal thinning with astigmatism) and autosomal recessive cornea plana (small corneas, arcus senilis)—the presence of arcus senilis excludes classic PMD alone by definition.4,5 It is unlikely that the KERA mutation itself is responsible for the PMD findings in this individual. The sectorial thinning and progressive high astigmatism characteristic of superior PMD have not been reported in individuals documented to be homozygous for KERA mutation or in other pedigrees consistent with autosomal recessive cornea plana.1–3,6 The PMD findings of patient 4 are most likely the result of coincidence—that is, the occurrence of both cornea plana and PMD in the same individual. However, a defect in a poorly understood mechanism other than KERA itself that is responsible for normal keratocan function cannot be completely excluded as an explanation for these findings.7
References
Pellegata NS, Dieguez-Lucena JL, Joensuu T, et al. Mutations in KERA, encoding keratocan, cause cornea plana. Nat Genet 2000;25:91–5.
Lehmann OJ, El-Ashry MF, Ebenezer N, et al. A novel keratocan mutation causing autosomal recessive cornea plana. Invest Ophthalmol Vis Sci 2001;42:3118–22.
Khan AO, Al-Saif A, Kamburosis M. A novel KERA mutation associated with autosomal recessive cornea plana. Ophthal Genet 2004;25:147–52.
Sridhar MS, Mashesh S, Bansal AK, et al. Pellucid marginal corneal degeneration. Ophthalmology 2004;111:1102–7.
Sridhar MS, Mahesh S, Bansak AK, et al. Superior pellucid marginal corneal degeneration. Eye 2004;18:393–9.
Forsius H, Damsten M, Eriksson AW, et al. Autosmal recessive cornea plana. A clinical and genetic study of 78 cases in Finland. Acta Ophthalmol Scand 1998;76:196–203.
Dipple KM, McCabe ERB. Phenotypes of patients with "simple" Mendelian disorders are complex traits: thresholds, modifiers, and systems dynamics. Am J Hum Genet 2000;66:1729–35.(A O Khan1, M Aldahmesh2, )
2 Aragene Project, King Faisal Specialist Hospital and Research Center, MBC 03-8, PO Box 3354, Riyadh 11211, Saudi Arabia
Keywords: KERA; cornea plana; keratocan; pellucid marginal degeneration
Characterised by flattening of the normally convex corneal surface, small corneas, high hyperopia, and arcus senilis, autosomal recessive cornea plana is secondary to KERA mutation.1–3KERA encodes keratocan, an evolutionary conserved small leucine rich proteoglycan. Keratocan, highly and uniquely expressed in the cornea, is composed of core proteins consisting mostly of leucine rich repeats (LRRs).1–3 All patients documented to be homozygous for one of the four previously reported KERA mutations have disruption of LRR architecture and demonstrate similar cornea plana phenotypes.1–3 In contrast, corneal pellucid marginal degeneration (PMD) is an idiopathic progressive ectatic corneal disorder that is clinically diagnosed by characteristic thinning, resultant "against the rule" astigmatism, and absence of opacity.4 We report a case of superior PMD coexistent with cornea plana in a family exhibiting a novel KERA mutation and document the ophthalmic findings of the family.
Case series
Twelve individuals from a Saudi nuclear family were studied after institutional review board approval and family informed consent had been obtained from the family. Clinical findings and diagnoses are summarised in figures 1 and 2, and table 1. Only one family member (patient 4) had a history of progressive visual difficulty over the last several years, and this was due to an increasing astigmatic refractive error. Axial lengths and keratometry readings were recorded using the Zeiss IOL-Master (2001 model), and corneal topography was performed using the Bausch & Lomb Orbiscan 2Z (2002 model).
Figure 1 The family pedigree.
Figure 2 (A) The small flat corneas of a typical patient (No 3) are shown. (B) The slit lamp appearance of patient 3 is shown. (C) In addition to small flat corneas and early arcus senilis, patient 4 also demonstrated superior corneal thinning (arrow, LE) with associated corneal ectasia characteristic of superior pellucid marginal corneal degeneration. (D) Topography, LE of patient 4 shows the characteristic high astigmatism of superior pellucid marginal corneal degeneration.
Table 1 Pertinent biometric and clinical characteristics of the family are summarised
All family members underwent KERA DNA sequencing using methods previously described.3 A novel mutation was detected in exon 2, , changing an arginine amino acid at position 279 to a stop codon . The resultant truncated protein lacks the terminal 73 amino acids of normal keratocan. This mutation was homozygous in the five siblings with clinically evident cornea plana (Nos 3, 5, 7, 11, 12) and the sister with clinical findings of PMD and cornea plana (No 4). All other family members (Nos 1, 2, 6, 8, 9, 10) were heterozygous for the mutation and clinically unaffected.
Comment
All four previously reported KERA mutations disrupt keratocan LRR architecture and are associated with similar corneal phenotypes in documented homozygotes.1–3 The current mutation similarly disrupts LLR function, as the prematurely truncated protein lacks two LRRs of normal keratocan and is associated with the expected cornea plana phenotype. Interestingly, one homozygous individual (No 4) demonstrates corneal findings compatible with both superior PMD (corneal thinning with astigmatism) and autosomal recessive cornea plana (small corneas, arcus senilis)—the presence of arcus senilis excludes classic PMD alone by definition.4,5 It is unlikely that the KERA mutation itself is responsible for the PMD findings in this individual. The sectorial thinning and progressive high astigmatism characteristic of superior PMD have not been reported in individuals documented to be homozygous for KERA mutation or in other pedigrees consistent with autosomal recessive cornea plana.1–3,6 The PMD findings of patient 4 are most likely the result of coincidence—that is, the occurrence of both cornea plana and PMD in the same individual. However, a defect in a poorly understood mechanism other than KERA itself that is responsible for normal keratocan function cannot be completely excluded as an explanation for these findings.7
References
Pellegata NS, Dieguez-Lucena JL, Joensuu T, et al. Mutations in KERA, encoding keratocan, cause cornea plana. Nat Genet 2000;25:91–5.
Lehmann OJ, El-Ashry MF, Ebenezer N, et al. A novel keratocan mutation causing autosomal recessive cornea plana. Invest Ophthalmol Vis Sci 2001;42:3118–22.
Khan AO, Al-Saif A, Kamburosis M. A novel KERA mutation associated with autosomal recessive cornea plana. Ophthal Genet 2004;25:147–52.
Sridhar MS, Mashesh S, Bansal AK, et al. Pellucid marginal corneal degeneration. Ophthalmology 2004;111:1102–7.
Sridhar MS, Mahesh S, Bansak AK, et al. Superior pellucid marginal corneal degeneration. Eye 2004;18:393–9.
Forsius H, Damsten M, Eriksson AW, et al. Autosmal recessive cornea plana. A clinical and genetic study of 78 cases in Finland. Acta Ophthalmol Scand 1998;76:196–203.
Dipple KM, McCabe ERB. Phenotypes of patients with "simple" Mendelian disorders are complex traits: thresholds, modifiers, and systems dynamics. Am J Hum Genet 2000;66:1729–35.(A O Khan1, M Aldahmesh2, )