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Posterior polymorphous corneal dystrophy: for professionals


Clinical phenotype

Incidence
  • 1:80,000 in Czech Republic
  • Unknown elsewhere
Corneal Features
  • Descemet layer bands and endothelial cell vesicles
  • Slowly progressive/static phenotype with 1/3 developing secondary corneal oedema in adult age (from endothelial decompensation)
  • Iris abnormalities and peripheral anterior synechiae may be present causing secondary glaucoma
  • Very rarely present as congenital corneal oedema in the 1st decade of life due to severe endothelial dysfunction
Symptoms
  • Majority of patients are asymptomatic
  • Visual impairment mainly due to corneal oedema
  • Intra- and interfamilial phenotypic variability due to non-penetrance and variable expressivity
Close up image of a cornea showing diffuse haziness with white deposits on the innermost layer of the cornea, called the Descemet membrane.
Corneal oedema and the slit beam shows opacities at the level of Descemet membrane

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

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Genetics

Gene/Locus
(OMIM no.)
Phenotype (OMIM no.)Remarks
OVOL2 (#616441)Corneal dystrophy, posterior polymorphous, 1 (#122000)[1]
ZEB1 (#189909)Corneal dystrophy, posterior polymorphous, 3 (#609141)[4]
  • Mutations in ZEB1 account for about 45% of PPCD cases[4]
  • Null mutations cause the PPCD phenotype while missense mutations are associated with late-onset FECD[4-6]
  • Corneal steepening and astigmatism are common
GRHL2 (#608576)Corneal dystrophy, posterior polymorphous, 4 (#618031)[7]

Genetic changes associated with PPCD are inherited in an autosomal dominant manner. However, de novo sporadic heterozygous mutations in ZEB1 and GRHL2 have been reported and should be considered in probands without a positive family history.[6,7]

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Key investigations

  • Anterior segment OCT (AS-OCT) or Scheimpflug imaging (Pentacam)— To assess corneal shape and thickness
  • AS-OCT– Thickened Descemet membrane and amorphous hyperreflective materials and deposits at the posterior corneal surface protruding to the anterior chamber[8]
  • Specular microscopy—To assess overall endothelial cell density, variations in size (polymegathism) and shape (pleomorphism)
  • Confocal microscopy—Craters, streaks and cracks over the corneal endothelial surface[9,10]

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Diagnosis

Posterior polymorphous corneal dystrophy (PPCD) can be diagnosed clinically but early-onset disease may be difficult to distinguish from congenital hereditary endothelial 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
  • Topical hyperosmotic (5%) saline eye drops for early stages of corneal decompensation
  • Corneal transplantations are indicated if corneal opacities are causing significant visual impairment and not amenable to conservative treatment
  • Endothelial keratoplasty (EK) is the preferred surgical option due to faster visual recovery, less post-operative astigmatism, lower rejection rates and absence of sutures[11]
  • Descemet stripping endothelial keratoplasty (DSEK)[12]/Descemet stripping automated endothelial keratoplasty (DSAEK)[13] and Descemet membrane endothelial keratoplasty (DMEK)[14] are widely used EK techniques
  • Penetrating keratoplasty may be required in infants with congenital corneal opacity due to the technical challenges of performing EKs in this age group
  • Secondary glaucoma associated with PPCD typically requires management with tube implants due to high failure rate with conventional trabeculectomies

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Further information and support

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References

  1.  Davidson AE, Liskova P, Evans CJ, et al. Autosomal-Dominant Corneal Endothelial Dystrophies CHED1 and PPCD1 Are Allelic Disorders Caused by Non-coding Mutations in the Promoter of OVOL2. Am J Hum Genet. Jan 7 2016;98(1):75-89. doi:10.1016/j.ajhg.2015.11.018
  2.  Biswas S, Munier FL, Yardley J, et al. Missense mutations in COL8A2, the gene encoding the alpha2 chain of type VIII collagen, cause two forms of corneal endothelial dystrophy. Hum Mol Genet. Oct 1 2001;10(21):2415-23
  3.  Gottsch JD, Sundin OH, Liu SH, et al. Inheritance of a novel COL8A2 mutation defines a distinct early-onset subtype of fuchs corneal dystrophy. Invest Ophthalmol Vis Sci. Jun 2005;46(6):1934-9. doi:10.1167/iovs.04-0937
  4.  Krafchak CM, Pawar H, Moroi SE, et al. Mutations in TCF8 cause posterior polymorphous corneal dystrophy and ectopic expression of COL4A3 by corneal endothelial cells. Am J Hum Genet. Nov 2005;77(5):694-708. doi:10.1086/497348
  5.  Liskova P, Evans CJ, Davidson AE, et al. Heterozygous deletions at the ZEB1 locus verify haploinsufficiency as the mechanism of disease for posterior polymorphous corneal dystrophy type 3. Eur J Hum Genet. Jul 2016;24(7):985-91. doi:10.1038/ejhg.2015.232
  6.  Dudakova L, Evans CJ, Pontikos N, et al. The utility of massively parallel sequencing for posterior polymorphous corneal dystrophy type 3 molecular diagnosis. Exp Eye Res. May 2019;182:160-166. doi:10.1016/j.exer.2019.03.002
  7.  Liskova P, Dudakova L, Evans CJ, et al. Ectopic GRHL2 Expression Due to Non-coding Mutations Promotes Cell State Transition and Causes Posterior Polymorphous Corneal Dystrophy 4. Am J Hum Genet. Mar 1 2018;102(3):447-459. doi:10.1016/j.ajhg.2018.02.002
  8.  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
  9.  Patel DV, Grupcheva CN, McGhee CN. In vivo confocal microscopy of posterior polymorphous dystrophy. Cornea. Jul 2005;24(5):550-4. doi:10.1097/01.ico.0000153557.59407.20
  10.  Yeh SI, Liu TS, Ho CC, Cheng HC. In vivo confocal microscopy of combined pre-descemet membrane corneal dystrophy and fuchs endothelial dystrophy. Cornea. Feb 2011;30(2):222-4. doi:10.1097/ICO.0b013e3181e2cf3f
  11.  Baydoun L, Dapena I, Melles G. Evolution of Posterior Lamellar Keratoplasty: PK–DLEK–DSEK/DSAEK–DMEK–DMET. Current Treatment Options for Fuchs Endothelial Dystrophy. Springer; 2017:73-85
  12.  Price FW, Jr., Price MO. Descemet’s stripping with endothelial keratoplasty in 50 eyes: a refractive neutral corneal transplant. J Refract Surg. Jul-Aug 2005;21(4):339-45
  13.  Gorovoy MS. Descemet-stripping automated endothelial keratoplasty. Cornea. Sep 2006;25(8):886-9. doi:10.1097/01.ico.0000214224.90743.01
  14.  Melles GR, Ong TS, Ververs B, van der Wees J. Descemet membrane endothelial keratoplasty (DMEK). Cornea. Sep 2006;25(8):987-90. doi:10.1097/01.ico.0000248385.16896.34

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Updated on November 30, 2020
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