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Corneal dystrophies: for professionals

Overview

Prevalence
  • Variable depending on phenotype and poulation
Inheritance
  • Autosomal dominant (most common)
  • Autosomal recessive
  • X-linked
Genes involved (OMIM No.)
Symptoms
  • Variable severity and age of onset
  • Asymptomatic
  • Foreign body sensation
  • Painful recurrent corneal erosions
  • Visual loss
Ocular features
Systemic features
Key investigations
  • Refraction and contact lens assessment
  • Scheimpflug imaging (Pentacam)/anterior segment OCT (AS-OCT): Assess corneal thickness and shape
  • AS-OCT can also identify abnormalities in the anterior chamber angle and iris
  • Specular and confocal microscopy: Identify characteristic patterns of different types of endothelial dystrophies
  • Histology of excised tissue is rarely required
  • Audiometry should be considered for patients with suspected Harboyan syndrome
Molecular diagnosisNext generation sequencing
  • Targeted gene panels (anterior segment dysgenesis)
  • Whole exome sequencing
  • Whole genome sequencing
Management
  • Visual rehabilitation with glasses/rigid contact lenses (CLs)
  • Topical lubricants/extended wear CLs
  • Surgical management if pain from recurrent erosions or visual loss from corneal opacities/irregular astigmatism
Therapies under research
  • Cultured corneal endothelial cells
  • Gene silencing
  • Antisense RNA oligonucleotides
  • Gene editing (CRISPR/Cas9)
  • Neuroprotection

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Clinical phenotype and genetics

Corneal dystrophies encompass a group of genetically heterogeneous disorders of the cornea which are bilateral and symmetrical. As a result, the phenotypes are diverse, in terms of age of onset, clinical appearance, effect on corneal transparency and vision, disease progression and mode of inheritance. Extraocular features are uncommon and thus, systemic metabolic diseases associated with corneal opacities (even if the conditions are apparently restricted to the cornea) should not be considered as corneal dystrophies.

Corneal dystrophies are classified based on the anatomic layer that is primarily affected according to the revised International Committee for Classification of Corneal Dystrophies (IC3D) classification. The phenotypes discussed herein are not exhaustive. Readers are directed to other review articles for more comprehensive information of each phenotype.

Suggested reading materials

1) Epithelial and sub-epithelial dystrophies

2) Epithelial-stromal TGFBI-associated corneal dystrophies

3) Stromal corneal dystrophies

4) Endothelial corneal dystrophies

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Key investigations

Ocular

1) Refraction and contact lens assessment

Visual potential can be maximised by addressing any associated refractive errors. This is especially important in young children who are at risk of developing amblyopia.

2) Examination of other family members

Examining first degree relatives is important and identification of other affected family members can confirm the genetic nature of the condition.

3) Scheimpflug imaging (Pentacam) and/or anterior segment ocular coherence tomography (AS-OCT)

Both of these modalities can provide details about the corneal shape and thickness. AS-OCT can also help determine the corneal layer involved and identify any anterior chamber angle and iris abnormalities (e.g. peripheral anterior synechiae in posterior polymorphous corneal dystrophy).

4) Specular and confocal microscopy

Both offer visualisation of the endothelial cells in vivo, which is particularly useful to identify characteristic patterns of endothelial change. For example, in Fuchs endothelial corneal dystrophy, guttata appear as round hyporeflective areas with occasional central highlight in the endothelial level on confocal microscopy.

5) Histology of excised corneal tissues

This can provide supportive information but it is rarely required to achieve a diagnosis, particularly in the current age of genomic medicine.

Systemic

Corneal dystrophies by definition are not associated with any extraocular involvement. Routine systemic investigations are usually not required except for children with suspected congenital hereditary endothelial dystrophy (audiometry—due to association with Harboyan syndrome) or Schnyder corneal dystrophy (serum lipid profile +/- plasma electrophoresis).

Children with unexplained bilateral corneal opacities should be referred to a paediatrician for further systemic assessment and investigations.

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Diagnosis

Corneal dystrophies can usually be diagnosed clinically. Genetic testing can be undertaken to confirm the diagnosis (e.g early-onset posterior polymorphous corneal dystrophy can be difficult to distinguish clinically from congenital hereditary endothelial dystrophy), 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

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Management

This section covers the general management approaches for corneal dystrophies. Further details can be obtained from the associated webpages outlined in the “Clinical phenotype” section.

In the initial stages, patients are usually managed supportively with the following approaches:

  • Correcting any significant refractive errors with glasses or rigid contact lenses
  • Close visual monitoring in children and commencement of amblyopia treatment if detected
  • Topical lubricants and extended wear therapeutic contact lens for recurrent corneal erosions; topical antibiotics can be added during acute flare-ups to prevent secondary infections
  • Topical hypertonic (5%) sodium chloride eye drops for corneal oedema associated with endothelial dysfunction
  • Monitoring for secondary glaucoma in children with posterior polymorphous corneal dystrophy
  • Most cases can be monitored by optometrists and referred back to the clinical service when necessary (e.g. if surgical interventions are required) unless continuous medical input is needed

Surgical management should be considered if there is risk of amblyopia (in early-onset disease), subjective perception of visual limitation (in adults) or pain from recurrent corneal erosions. The type of procedure depends on the corneal layer involved. These are:  

  • Alcohol epitheliectomy with mechanical debridement— suitable for superficial lesions (up to Bowman’s layer) without causing corneal thinning [1]
  • Excimer laser superficial phototherapeutic keratectomy (PTK)—a relatively non-invasive procedure suitable for removal of sub-epithelial and anterior stromal lesions, delaying the need for corneal transplantation (may cause corneal thinning and hypermetropic shift)
  • Corneal transplants—lamellar keratoplasties (DALK) for deeper stromal dystrophies and endothelial keratoplasties (DSEK/DSAEK and DMEK) for endothelial dystrophies
  • Penetrating keratoplasty may not be as popular now but it is technically less challenging to perform compared to endothelial keratoplasty

Majority of epithelial and stromal dystrophies tend to recur in the graft with time, although surgeries can often be repeated. [2-4]

Family management and counselling

Corneal dystrophies can be inherited in the following Mendelian patterns:

Patients and families require genetic counselling and can seek advice for family planning including prenatal testing and preimplantation genetic diagnosis.

Emotional and social support

Eye Clinic Liaison Officers (ECLOs) act as an initial point of contact for newly diagnosed patients and their parents in clinic. They provide emotional and practical support to help patients and parents deal with their diagnosis and maintain independence. They work closely with the local council’s sensory support team and are able to advise on the broad range of services provided, such as visual rehabilitation, home assessment, work and access to qualified teachers for children with visual impairment (QTVI) among other services.

Related links

Referral to a specialist centre

In the UK, patients should be referred to their local genomic ophthalmology (if available) or clinical genetics services to receive a more comprehensive genetic management of their conditions (genetic testing and genetic counselling) and having the opportunity to participate in clinical research.

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Current research in corneal dystrophies

1) Gene/allele-based therapies

Modern genetic sequencing technologies have enabled detailed genotyping in various corneal dystrophies. This has subsequently led to the development of gene/allele-based therapies such as the following:

2) Cell-based therapy

The lack of donor corneal grafts with healthy endothelium has made tissue-engineered endothelial grafts an attractive solution. The grafts can be cultured from foetal/adult corneal stem cells or progenitors, or reprogrammed from terminally differentiated corneal cells to progenitor cells. However, the development of a reliable in vitro cell cultivation protocol for clinical application and the delivery techniques of the cultured endothelial cells remain challenges that need to be overcome before tissue engineering therapy can be implemented.[5,6]

Related links

3) Neuroprotection

Neuroprotective agents encompass a broad range of therapies that aim to promote cell survival and preserving function. Oxidative stress [7], endoplasmic reticulum stress (from accumulation of misfolded proteins) [8] and apoptosis[9] have been implicated as underlying disease mechanisms of FECD. A few candidate drugs have been identified:

Related links

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Further information and support

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References

  1.  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
  2.  Cheng J, Qi X, Zhao J, Zhai H, Xie L. Comparison of penetrating keratoplasty and deep lamellar keratoplasty for macular corneal dystrophy and risk factors of recurrence. Ophthalmology. Jan 2013;120(1):34-9. doi:10.1016/j.ophtha.2012.07.037
  3.  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
  4.  Hieda O, Kawasaki S, Yamamura K, Nakatsukasa M, Kinoshita S, Sotozono C. Clinical outcomes and time to recurrence of phototherapeutic keratectomy in Japan. Medicine (Baltimore). Jul 2019;98(27):e16216. doi:10.1097/MD.0000000000016216
  5.  Okumura N, Kinoshita S, Koizumi N. Cell-Based Approach for Treatment of Corneal Endothelial Dysfunction. Cornea. 2014;33:S37-S41. doi:10.1097/ico.0000000000000229
  6.  Chen S, Zhu Q, Sun H, et al. Advances in culture, expansion and mechanistic studies of corneal endothelial cells: a systematic review. Journal of Biomedical Science. 2019/01/04 2019;26(1):2. doi:10.1186/s12929-018-0492-7
  7.  Jurkunas UV, Bitar MS, Funaki T, Azizi B. Evidence of oxidative stress in the pathogenesis of fuchs endothelial corneal dystrophy. Am J Pathol. Nov 2010;177(5):2278-89. doi:10.2353/ajpath.2010.100279
  8.  Engler C, Kelliher C, Spitze AR, Speck CL, Eberhart CG, Jun AS. Unfolded protein response in fuchs endothelial corneal dystrophy: a unifying pathogenic pathway? Am J Ophthalmol. Feb 2010;149(2):194-202.e2. doi:10.1016/j.ajo.2009.09.009
  9.  Borderie VM, Baudrimont M, Vallée A, Ereau TL, Gray F, Laroche L. Corneal endothelial cell apoptosis in patients with Fuchs’ dystrophy. Invest Ophthalmol Vis Sci. Aug 2000;41(9):2501-5

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Updated on January 18, 2021
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