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Original Investigation | Ophthalmic Molecular Genetics

Further Genetic and Clinical Insights of Posterior Polymorphous Corneal Dystrophy 3

Petra Liskova, MD, PhD1,2; Michalis Palos, MD2; Alison J. Hardcastle, PhD3; Andrea L. Vincent, MBChB4
[+] Author Affiliations
1Laboratory of the Biology and Pathology of the Eye, Institute of Inherited Metabolic Disorders, First Faculty of Medicine, Charles University in Prague, and General University Hospital in Prague, Prague, Czech Republic
2Department of Ophthalmology, First Faculty of Medicine, Charles University in Prague, and General University Hospital in Prague, Prague, Czech Republic
3UCL Institute of Ophthalmology, University College London, London, England
4Department of Ophthalmology, New Zealand National Eye Centre, Faculty of Medical and Health Sciences, University of Auckland, and Eye Department, Greenlane Clinical Centre, Auckland District Health Board, Auckland, New Zealand
JAMA Ophthalmol. 2013;131(10):1296-1303. doi:10.1001/jamaophthalmol.2013.405.
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Importance  Posterior polymorphous corneal dystrophy (PPCD) is a very rare disorder characterized by primary changes of the posterior corneal layers. Sequence variants in 3 genes are associated with the development of PPCD, including ZEB1 that is responsible for PPCD3. Evidence suggests at least 1 more gene remains to be identified.

Objective  To determine the molecular genetic cause of PPCD3.

Design  We performed extensive ophthalmological examination, including rotating Scheimpflug imaging technology and specular microscopy, and direct sequencing of the ZEB1 coding region. Comprehensive review of published PPCD3-causing variants was undertaken.

Setting  Ophthalmology department of a university hospital.

Participants  Four Czech probands.

Main Outcomes and Measures  Results of ophthalmological examination and direct sequencing of the ZEB1 coding region.

Results  The following 2 novel frameshift mutations within ZEB1 were identified: c.2617dup in exon 8 in a 22-year-old woman, considered to be most likely de novo in origin, and c.698dup in exon 6 in a 20-year-old man. The first patient had mild changes consistent with PPCD and bilateral best-corrected visual acuity of 1.00. The corneal phenotype of the patient in the second case was more severe, with best-corrected visual acuity of 0.40 OD and 0.05 OS. Corneas of both probands were abnormally steep (keratometry readings, flat ≥ 47.4 diopters [D] and steep ≥ 49.2 D) with increased pachymetry values but no pattern indicative of keratoconus. Specular microscopy in both patients revealed reduced endothelial cell density (range, 1055/mm2 to 1655/mm2). Both probands had a history of surgery for inguinal hernia; the male patient also reported hydrocele.

Conclusions and Relevance  Nucleotide changes within the coding region of ZEB1 underlie the pathogenesis of PPCD in 4 of 23 Czech probands (17%). The cumulative de novo ZEB1 mutation rate is at least 14%. Possible involvement of ZEB1 sequence variants not readily identified by direct sequencing of coding regions needs to be further investigated. Our findings also have implications for patient counseling.

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Figures

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Figure 1.
Slitlamp Photographs of Corneas With Posterior Polymorphous Corneal Dystrophy 3

A, Right cornea of case 1. Arrowhead indicates a typical vesicular-like lesion with its surrounding halo. Irregular opacification and uneven posterior surface (arrows) with occasional presence of vesicular-like lesions (arrowhead) are visible in the remaining photographs. B and C, Narrow slit-beam view and wider slit-beam view, respectively, of the right cornea of proband 2. D and E, Wider slit-beam view and narrow slit-beam view, respectively, of the left cornea of proband 2.

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Figure 2.
Specular Microscopy of Corneas With Posterior Polymorphous Corneal Dystrophy 3

A, Pleomorphic cells with polymegathism and 1 dark lesion (arrow) most likely representing a protrusion of Descemet membrane. B-G, Altered endothelial cell phenotype (arrowheads) and irregularities of the posterior surface (asterisks). H, Cornea of an age-matched control subject.

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Figure 3.
Rotating Scheimpflug Imaging Data of the Corneas in Case 1

A and C, Front sagittal curvature maps of the right and left eyes, respectively. B and D, Pachymetric maps (Pachy) of the right and left eyes, respectively. E and F, Corneal thickness spatial profiles of the right and left eyes, respectively, represented by a red line with triangles and compared with dotted black lines indicating the mean and 2 SD values obtained in a healthy population. G and H, Single image of the right and left eyes on the vertical meridian, respectively. Arrows indicate areas of irregularity and opacification. Abs indicates absolute scale with 61 colors for each refractive step shown in diopter (D) or 10 µm in pachymetry maps.

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Figure 4.
Rotating Scheimpflug Imaging Data of the Right Cornea in Case 2

A, Front sagittal curvature map. B, Pachymetric map (Pachy). C, Corneal thickness spatial profile, represented by a red line with triangles and compared with dotted black lines indicating the mean and 2 SD values of a healthy population. D and E, Single images on the horizontal and vertical meridians, respectively. Arrows indicate areas of irregularity and opacification. Abs indicates absolute scale with 61 colors for each refractive step shown in diopter (D) or 10 µm in pachymetry maps.

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