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Congenital hereditary endothelial dystrophy: for professionals

Clinical phenotype

Incidence
  • 1:80,000 in Czech Republic
  • Unknown elsewhere
Corneal Features
  • Presents at or soon after birth
  • Bilateral diffuse corneal opacifications (ranging from hazy to milky appearance)
  • May be associated with nystagmus and amblyopia
  • Increased corneal thickness (usually 2-3 times of unaffected individuals)
Systemic association
  • Harboyan syndrome—CHED with sensorineural hearing loss[1]
  • Development of progressive hearing loss in apparently isolated CHED cases have been reported
  • No genotype-phenotype correlation
Close up image of a cornea that shows diffuse haziness and the centre is thickened.
A diffusely thickened cornea (central thickness >1,000µ) with secondary corneal oedema

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

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Genetics

Gene (OMIM no.) and associated function
  • SLC4A11 (#610206)[2]
  • Encodes a transmembrane protein found on the basolateral membrane of the corneal endothelium
  • Promotes transmembrane water flux regulated by the osmolarity of the extracellular environment[3]
Inheritance pattern

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Key investigations

  • Anterior segment OCT or Scheimpflug imaging (Pentacam)— To assess corneal shape and thickness
  • Specular and confocal microscopies—To identify endothelial abnormalities  
  • Audiometry to exclude Harboyan syndrome

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Diagnosis

Congenital hereditary endothelial dystrophy (CHED) can be diagnosed clinically but may be difficult to differentiate from early-onset posterior polymorphous corneal dystrophy. Genetic testing can be undertaken to confirm the diagnosis, 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

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Management

  • Visual rehabilitation with glasses or rigid contact lenses if refractive error is present
  • Corneal transplantation—penetrating or endothelial keratoplasties

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Current research

As tissues expressing SLC4A11 are relatively inaccessible for biopsy, it is difficult to study the effects of newly identified novel variants within its native genomic and cellular context. The use of induced pluripotent stem cell (IPSC)-derived corneal endothelial-like cells provides an attractive option to evaluate the functional impact of various SLC4A11 variants.[4] This could be expanded to investigate genetic mutations associated with other corneal endothelial disorders.

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Further information and support

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References

  1.  Desir J, Abramowicz M. Congenital hereditary endothelial dystrophy with progressive sensorineural deafness (Harboyan syndrome). Orphanet J Rare Dis. Oct 15 2008;3:28. doi:10.1186/1750-1172-3-28
  2.  Vithana EN, Morgan P, Sundaresan P, et al. Mutations in sodium-borate cotransporter SLC4A11 cause recessive congenital hereditary endothelial dystrophy (CHED2). Nat Genet. Jul 2006;38(7):755-7. doi:10.1038/ng1824
  3.  Vilas GL, Loganathan SK, Liu J, et al. Transmembrane water-flux through SLC4A11: a route defective in genetic corneal diseases. Hum Mol Genet. Nov 15 2013;22(22):4579-90. doi:10.1093/hmg/ddt307
  4.  Brejchova K, Dudakova L, Skalicka P, et al. IPSC-Derived Corneal Endothelial-like Cells Act as an Appropriate Model System to Assess the Impact of SLC4A11 Variants on Pre-mRNA Splicing. Investigative Ophthalmology & Visual Science. 2019;60(8):3084-3090. doi:10.1167/iovs.19-26930

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Updated on December 1, 2020
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