Quick links
- Clinical phenotype
- Genetics
- Key investigations
- Diagnosis
- Management
- Current research
- Further information and support
- References
Clinical phenotype
Autosomal dominant variants in TGFBI are associated with a range of clinical phenotypes that affect the epithelium and stroma:
- Reis-Bucklers corneal dystrophy, RBCD (OMIM #608470)
- Thiel-Behnke corneal dystrophy, TBCD (OMIM #602082)
- Lattice corneal dystrophy (LCD), type 1 (OMIM #122200)
- Granular corneal dystrophy (GCD), type 1 (OMIM #121900) and type 2 (OMIM #607541)
Majority of cases involve the substitution of the amino acid arginine (missense mutations) at positions 124 and 555 (mutation hotspots) with genotype-phenotype correlation.[1-3]
Incidence |
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Corneal Features | Reis-Bucklers corneal dystrophy and Thiel-Behnke corneal dystrophy
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Symptoms |
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Reis-Bucklers corneal dystrophy

Credit: Mr Stephen Tuft, consultant ophthalmologist, Moorfields Eye Hospital, London
Lattice corneal dystrophy

Credit: Mr Stephen Tuft, consultant ophthalmologist, Moorfields Eye Hospital, London
Granular corneal dystrophy

Credit: Mr Stephen Tuft, consultant ophthalmologist, Moorfields Eye Hospital, London
Genetics
Gene (OMIM no.) and associated function | |
Genotype-phenotype relationship |
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Inheritance pattern |
Key investigations
- Anterior segment OCT: Irregular, hyper-reflective deposits at the anterior stroma, which disseminate up to the epithelium in RBCD and TBCD[6]
Related links
Diagnosis
TFGBI-associated corneal dystrophies can be diagnosed based on history and slit lamp examination. However, clinicians should be aware that systemic familial amyloidosis (Meratoja syndrome) has a similar ocular phenotype (corneal amyloidosis) to lattice corneal dystrophy. Meratoja syndrome is caused by a recurrent missense mutation (p.Asp187Tyr) in the GLN gene (OMIM #137350)[7] and is characterised by the following:
- Cranial (including the 6th and 7th cranial nerves) and peripheral neuropathy
- Amyloid cardiomyopathy
- Renal failure
- Characteristic skin laxity (cutis laxa)
- Mask-like facies which present in later life
Genetic testing can be undertaken to confirm the diagnosis of TGFBI-associated corneal dystrophies, facilitate genetic counselling, provide accurate advice on prognosis and future family planning, and aid in clinical trial participation.
This can be achieved through a variety of next generation sequencing (NGS) methods:
- Targeted gene panels (anterior segment dysgenesis)
- Whole exome sequencing
- Whole genome sequencing
Related links
Management
- Topical lubricants and/or extended wear therapeutic contact lenses are primary therapeutic options for recurrent corneal erosions; topical antibiotics can be added during acute flare-ups to prevent secondary infections
- Various surgical interventions are indicated depending on the depth of the lesions
- Alcohol epitheliectomy with mechanical debridement or excimer laser superficial phototherapeutic keratectomy (PTK) can be used to remove superficial lesions
- Corneal thickness must be measured prior to PTK as it may thin the cornea; Repeated attempts are limited as a result
- Alcohol-assisted mechanical debridement of the corneal epithelium provides good visual outcome for relatively superficial deposits (up to Bowman’s layer) without causing corneal thinning but it is unable to remove anterior stromal lesions like PTK[8]
- Corneal transplantations are indicated for lesions situated further towards the posterior stroma
- Deep anterior lamellar keratoplasty (DALK) are associated with better visual outcome compared to penetrating keratoplasty but disease recurrence limits graft survival (median duration of survival: 15.8 years)[9]
- LCD tends to recur sooner than GCD post-graft[10,11]

Current research
Our understanding of the underlying mechanisms of TGFBI-associated corneal dystrophies are limited by the lack of animal models, which in turn hampers our search for novel therapies. However, the recurrent nature of the mutations at the hotspot residues Arg124 and Arg555 might lend itself to gene editing (with CRISPR/Cas9) and gene silencing approaches (with short-interfering RNA [siRNA] molecules).[12]
Gene silencing or RNA interference is a naturally occurring process used by cells to regulate gene expression. siRNA is one of the three types of small RNA molecules that mediate this process.[13] This therapeutic approach is suitable for mutations that act in a dominant negative manner as it suppresses the transcription of the mutant allele while allowing expression of the normal allele. A lead siRNA candidate has been identified for LCD associated with the p.Arg124Cys variant.[14]
Related links
- Research Opportunities at Moorfields Eye Hospital UK
- Searching for current clinical research or trials
Further information and support
References
- Lisch W, Weiss JS. Clinical and genetic update of corneal dystrophies. Exp Eye Res. Sep 2019;186:107715. doi:10.1016/j.exer.2019.107715
- Evans CJ, Davidson AE, Carnt N, et al. Genotype-Phenotype Correlation for TGFBI Corneal Dystrophies Identifies p.(G623D) as a Novel Cause of Epithelial Basement Membrane Dystrophy. Investigative Ophthalmology & Visual Science. 2016;57(13):5407-5414. doi:10.1167/iovs.16-19818
- Chao-Shern C, DeDionisio LA, Jang JH, et al. Evaluation of TGFBI corneal dystrophy and molecular diagnostic testing. Eye (Lond). Jun 2019;33(6):874-881. doi:10.1038/s41433-019-0346-x
- Jun RM, Tchah H, Kim TI, et al. Avellino corneal dystrophy after LASIK. Ophthalmology. Mar 2004;111(3):463-8. doi:10.1016/j.ophtha.2003.06.026
- Munier FL, Korvatska E, Djemaï A, et al. Kerato-epithelin mutations in four 5q31-linked corneal dystrophies. Nat Genet. Mar 1997;15(3):247-51. doi:10.1038/ng0397-247
- Siebelmann S, Scholz P, Sonnenschein S, et al. Anterior segment optical coherence tomography for the diagnosis of corneal dystrophies according to the IC3D classification. Surv Ophthalmol. May-Jun 2018;63(3):365-380. doi:10.1016/j.survophthal.2017.08.001
- Maury CP, Kere J, Tolvanen R, de la Chapelle A. Finnish hereditary amyloidosis is caused by a single nucleotide substitution in the gelsolin gene. FEBS Lett. Dec 10 1990;276(1-2):75-7. doi:10.1016/0014-5793(90)80510-p
- Ashar JN, Latha M, Vaddavalli PK. Phototherapeutic keratectomy versus alcohol epitheliectomy with mechanical debridement for superficial variant of granular dystrophy: a paired eye comparison. Cont Lens Anterior Eye. Oct 2012;35(5):236-9. doi:10.1016/j.clae.2012.05.005
- Mohamed A, Chaurasia S, Ramappa M, Murthy SI, Garg P. Outcomes of keratoplasty in lattice corneal dystrophy in a large cohort of Indian eyes. Indian J Ophthalmol. May 2018;66(5):666-672. doi:10.4103/ijo.IJO_1150_17
- Unal M, Arslan OS, Atalay E, Mangan MS, Bilgin AB. Deep anterior lamellar keratoplasty for the treatment of stromal corneal dystrophies. Cornea. Mar 2013;32(3):301-5. doi:10.1097/ICO.0b013e31825718ca
- Marcon AS, Cohen EJ, Rapuano CJ, Laibson PR. Recurrence of corneal stromal dystrophies after penetrating keratoplasty. Cornea. Jan 2003;22(1):19-21. doi:10.1097/00003226-200301000-00005
- Christie KA, Robertson LJ, Conway C, et al. Mutation-Independent Allele-Specific Editing by CRISPR-Cas9, a Novel Approach to Treat Autosomal Dominant Disease. Mol Ther. Aug 5 2020;28(8):1846-1857. doi:10.1016/j.ymthe.2020.05.002
- Chery J. RNA therapeutics: RNAi and antisense mechanisms and clinical applications. Postdoc J. Jul 2016;4(7):35-50. doi:10.14304/surya.jpr.v4n7.5
- Courtney DG, Atkinson SD, Moore JE, et al. Development of allele-specific gene-silencing siRNAs for TGFBI Arg124Cys in lattice corneal dystrophy type I. Invest Ophthalmol Vis Sci. Feb 18 2014;55(2):977-85. doi:10.1167/iovs.13-13279