1. Home
  2. Knowledge Base
  3. Conditions
  4. Epithelial-stromal TGFBI-associated corneal dystrophies: for professionals

Epithelial-stromal TGFBI-associated corneal dystrophies: for professionals


Clinical phenotype

Autosomal dominant variants in TGFBI are associated with a range of clinical phenotypes that affect the epithelium and stroma:

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
  • 8-11:10,000 in Korea for GCD2; unknown elsewhere
Corneal FeaturesReis-Bucklers corneal dystrophy and Thiel-Behnke corneal dystrophy
  • Irregularly shaped opacities in the anterior stroma
  • Opacities in RBCD have a geographic pattern while those in TBCD have a honeycomb pattern
  • Clinically very similar and not always possible to use these features to distinguish between the two
  • Both are associated with early-onset of recurrent erosions (1st decade of life)
Lattice corneal dystrophy
  • Intrastromal linear deposits (lattice lines) with variable amount of diffuse stromal haze centrally
Granular corneal dystrophy
  • Discrete stromal opacities with clear intervening stroma
  • Type 1: Small, circular superficial (breadcrumb) deposits that increase in number and deepen with age
  • Type 2: Snowflake-like, ring- or star-shaped lesions of fewer number than GCD1
  • GCD2 is a milder phenotype than GCD1
Symptoms
  • Disease onset: first two decades of life
  • Patients may be asymptomatic for many years despite early disease onset
  • Painful recurrent erosions with progressive visual deterioration
  • GCD least likely to cause painful erosions but deposits in GCD2 may be exacerbated by LASIK surgery[4]

Reis-Bucklers corneal dystrophy

Some yellow-brownish deposits on the cornea illuminated by light. A scan through the same cornea shows that the middle layer of the cornea has an irregular surface.
Slit lamp image demonstrating irregular opacity of the anterior corneal layer (A). The irregular stromal surface is well demonstrated on anterior segment OCT (B).

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

Lattice corneal dystrophy

Close up image of a cornea with haziness centrally. There are linear deposits throughout the periphery of this central area of haziness
Diffuse haze over the central cornea and linear lattice deposits in the mid corneal periphery (arrow)

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

Granular corneal dystrophy

Close up image of the cornea showing multiple irregular white deposits on the cornea
Slit beam image demonstrating deposits predominantly in the anterior stroma

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

Jump to top


Genetics

Gene (OMIM no.) and associated function
  • TGFBI (#601692)
  • Encodes transforming growth factor-beta-induced protein ig-h3 (Beta ig-h3)[5]
  • Comprised of four extracellular fasciclin (FAS1) domains that mediate cell adhesion
Genotype-phenotype relationship
  • Majority of cases are due to missense mutations at the hotspot residues Arg124 and Arg555
  • RBCD: p.Arg124Leu mutation
  • TBCD: p.Arg555Gln mutation
  • LCD: p.Arg124Cys mutations most frequent
  • GCD1: p.Arg555Trp mutations most frequent
  • GCD2: p.Arg124His mutation
Inheritance pattern

Jump to top


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

Jump to top


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

Jump to top


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]
A clear central corneal transplant
A patient with lattice corneal dystrophy after DALK transplant

Jump to top


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

Jump to top


Further information and support

Jump to top


References

  1.  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
  2.  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
  3.  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
  4.  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
  5.  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
  6.  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
  7.  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
  8.  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
  9.  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
  10.  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
  11.  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
  12.  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
  13.  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
  14.  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

Jump to top

Updated on November 30, 2020

Was this article helpful?