Individual phenotypic variances in a family with Avellino corneal dystrophy
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Avellino corneal dystrophy (ACD) is an autosomal dominant disorder, characterized by the presence of deposits in the anterior stroma, and results from a specific mutation (R124H) in the transforming growth factor beta-induced gene (TGFBI). This report presents corneal dystrophy of the Bowman layer as a rare phenotypic appearance of ACD and a high intra-familial variability of phenotype in patients with ACD.
A 56 year-old Caucasian woman with recurrent corneal erosions was diagnosed with corneal dystrophy of the Bowman layer after a clinical examination. Optical coherence tomography of the anterior segment (AS-OCT) mainly demonstrated deposits in the Bowman layer and a few deposits in the superficial stroma. Her son, a 36 year-old man, has a typical clinical presentation of ACD with all the deposits arranged in stromal layers. In his case, the opacities resemble snowflakes between the granular deposits, and AS-OCT shows large, snowflake-like deposits in the superficial and deep stroma without accumulation in the Bowman layer. Genetic screening in both cases shows the heterozygous R124H mutation in the TGFBI gene.
The clinical finding of the granular-lattice corneal dystrophy in which deposits are located in the Bowman layer may be an atypical presentation of ACD. This paper demonstrates a high degree of variability in the quantity and form of deposits between ACD heterozygotes. This is the first description of Avellino corneal dystrophy in the Balkans and in Serbia.
KeywordsCornea Avellino corneal dystrophy R124H mutation AS-OCT
Online Mendelian inheritance in man®
Transforming growth factor, beta-induced
Anterior segment optical coherence tomography
Goldmann applanation tonometer
Polymerase chain reaction.
Granular corneal dystrophy type II (CGD2, OMIM 607541), also called Avellino corneal dystrophy (ACD) or combined granular-lattice corneal dystrophy, is a rare form of autosomal dominant corneal dystrophy. The corneal opacities are result of a specific mutation (R124H) in transforming growth factor beta-induced gene (TGFBI, OMIM 601692, formerly called BIGH3) . Mutations in the same gene also cause Thiel-Behnke (602082), Reis-Bücklers (608470), granular (Groenouw) type I (121900), lattice type I (122200) and epithelial basement membrane dystrophy (121820) .
The combined features of lattice and granular dystrophies in the same cornea resulting from mutations in the same gene raises the questions of validity of relying solely on clinical and histological evidence to classify disease. Modern genotyping now enables greater accuracy in the nosology and the International Committee for Classification of Corneal Dystrophies (IC3D) has already incorporated this information into their recent reclassification of these dystrophies . Initial clinical symptoms of the heterozygous form of ACD appear during the first or second decade of life. ACD is characterized clinically by the corneal opacities that are shaped like snowflakes, discs, stars, and rings. Corneal opcitities are a bilateral formation of discrete, asymmetric, focal, grey-white granular and lattice deposits in the anterior stroma of cornea with clear areas between these deposits. There is a considerable variation of the nature and quantity of the stromal deposits both within and among families, a common characteristic of autosomal dominant disorders. In this case report, profound differences exist in the severity of the phenotypic expression within the same family, as well an atypical localization of deposits, which is in the epithelium and the Bowman layer.
Written informed consent was obtained before initiation of the exam. The cases study was approved by the ethics committee Zvezdara University Medical Center according to the principles of good clinical practice and with the ethical principles of the Declaration of Helsinki.
A 56-year-old woman had a history of progressively decreasing visual acuity, recurrent corneal erosions and mild foreign body sensation in both eyes for about a year. Her medical history included rheumatoid arthritis and high blood pressure (hypertension). She was on therapy: methotrexate, folic acid, ibuprofen and ramipril. The patient complained of decreased vision, photosensitivity, and pain in both eyes.
Genomic DNA was extracted from EDTA-anticoagulated venous leucocytes using the PureLinkTM Genomic DNA Mini Kit (Invitrogen, Carlsbad, CA, USA). PCR products were purified by GeneJET PCR Purification Kit (Thermo Scientific) and then sequenced using the ABI Prism BigDye Terminator Kit (Applied Biosystems) on 3130 Genetic Analyzer (Applied Biosystems). The presence of genetic variations was analyzed using the Sequencing Analysis Software v5.2 Patch 2 (Applied Biosystems). Molecular genetic analysis of all exons of TGFBI gene showed a single heterozygous nucleotide substitution, G to A at the position 418 in the exon 4 and it did not identify other mutations (including R124C) in either of the cases. This mutation replaces amino acid arginine to histidine at codon 124 (R124H). The patient was not motivated for the surgical treatment of ACD, with pending consent for cataract surgery.
ACD is typically an anterior stromal dystrophy, which has large intra and/or interfamilial phenotypic variation. Atypical and rare clinical presentation of Case 1 is characterized by deposits placed in the sub-epithelial and Bowman's corneal layers. The recurrent corneal erosions are a rare clinical feature of ACD. Spectrum of clinical changes in corneal dystrophy associated with TGFBI gene may show an accumulation of deposits in the epithelium, Bowman’s layer and stroma regardless of the type of point mutations. SL Edelstein et al. describe the clinical presentation similar to ACD with genotype of lattice corneal dystrophy (R124C) . A clinical finding of lattice and/or granular deposits due to possible errors in clinical diagnosis requires genetic determination of mutation types. The degree of phenotypic expression is likely determined by the regulation and control mechanisms of TGFBI gene, which have not been fully clarified to this date. Due to the variable phenotypic expression of KE, Han et al. suggest slit lamp examinations at frequent intervals in heterozygotes for the R124H mutation . By reviewing the available literature, we have not found the occurrence of systemic diseases associated with ACD. In our case, we presented comorbidity with RA and DM1 in the patients with ACD. Several papers have described mutations of the TGFBI gene, which may be related to RA, DM, atherosclerosis and other systemic diseases [6, 7]. As a relatively novel and non-invasive imaging technique of the anterior segment, ultra high resolution AS-OCT helps us demonstrate different morphologic characteristics of ACD in vivo. To our knowledge, this is the first report describing ACD in Southeastern Europe, the Balkans and Serbia.
Written informed consent was obtained from the patient for publication of this Case report and any accompanying images. A copy of the written consent is available for review by the Series Editor of this journal.
Professor Jelena Milasin, Department of Genetics, School of Dental Medicine University of Belgrade, for providing technical assistance and valuable comments.
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