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Original Investigation | Clinical Sciences

Classification of Posterior Polymorphous Corneal Dystrophy as a Corneal Ectatic Disorder Following Confirmation of Associated Significant Corneal Steepening

Anthony J. Aldave, MD1; Lydia B. Ann1; Ricardo F. Frausto, BA1; Catherine K. Nguyen, BS1; Fei Yu, PhD1; Irving M. Raber, MD2
[+] Author Affiliations
1Jules Stein Eye Institute, David Geffen School of Medicine at University of California, Los Angeles
2Wills Eye Institute, Philadelphia, Pennsylvania
JAMA Ophthalmol. 2013;131(12):1583-1590. doi:10.1001/jamaophthalmol.2013.5036.
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Importance  The identification of steep corneal curvatures in a significant percentage of patients with posterior polymorphous corneal dystrophy (PPCD) confirms this previously reported association and suggests a role for the ZEB1 protein in keratocyte function.

Objective  To determine whether PPCD is characterized by significant corneal steepening.

Design, Setting, and Participants  Cross-sectional study at university-based and private ophthalmology practices of 38 individuals (27 affected and 11 unaffected) from 23 families with PPCD.

Exposure  Slitlamp examination and corneal topographic imaging were performed for individuals with PPCD and unaffected family members. Saliva or blood samples were obtained from each individual for DNA isolation and ZEB1 sequencing. Corneal ZEB1 expression was measured using immunohistochemistry.

Main Outcomes and Measures  Percentage of individuals affected with PPCD and controls with an average keratometric value greater than 48.0 diopters (D) in each eye; the mean keratometric value averaged for both eyes of individuals with PPCD and controls; and the correlation of ZEB1 mutation with keratometric value.

Results  ZEB1 coding region mutations were identified in 7 of the 27 affected individuals. Ten of the 38 individuals (26.3%) had average keratometric values greater than 48.0 D OU: 10 of 27 individuals with PPCD (37.0%; 6 of 7 individuals with ZEB1 mutations [85.7%] and 4 of 20 individuals without ZEB1 mutations [20.0%]) and 0 of 11 unaffected individuals (P = .04 for unaffected vs affected individuals; P = .004 for individuals with PPCD with vs without ZEB1 mutation). The mean keratometric value of each eye of affected individuals (48.2 D) was significantly greater than that of each eye of unaffected family members (44.1 D) (P = .03). Affected individuals with ZEB1 mutations demonstrated a mean keratometric value of 53.3 D, which was significantly greater than that of affected individuals without ZEB1 mutations (46.5 D; P = .004). Fluorescence immunohistochemistry demonstrated ZEB1 expression in keratocyte nuclei.

Conclusions and Relevance  Abnormally steep corneal curvatures are identified in 37% of all individuals with PPCD and 86% of affected individuals with PPCD secondary to ZEB1 mutations. ZEB1 is present in keratocyte nuclei, suggesting a role for ZEB1 in keratocyte function. Therefore, ZEB1 may play a role in both corneal stromal and endothelial development and function, and PPCD should be considered both an endothelial dystrophy and an ectatic disorder.

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Figure 1.
Slitlamp Photomicrographs of Individual With Posterior Polymorphous Corneal Dystrophy

Confluent areas of gray-white opacification are noted at the level of Descemet membrane (A), and scattered endothelial vesicles are seen with retroillumination against the red reflex (B). Screening of ZEB1 revealed the novel mutation: p.(Gln884Argfs*37).

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Figure 2.
Corneal Topographic Images of Individual With Posterior Polymorphous Corneal Dystrophy 3

The affected individual shown in Figure 1 demonstrates inferior temporal steepening in each cornea, with average keratometric values measuring 50.39 D in the right eye (R) and 48.61 D in the left eye (L). No clinical features of keratoconus were noted on slitlamp biomicroscopic imaging of either cornea.

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Figure 3.
Immunodetection of ZEB1 in Normal Donor Cornea

A, A cross-section of the cornea probed with anti-ZEB1 (red, 594 nm) and anti-CD34 (green, 488 nm) demonstrates ZEB1 expression in the epithelium, stroma, and endothelium. Nuclei are stained with 4′,6-diamidino-2-phenylindole (DAPI) (objective, original magnification ×10). B, Higher magnification views of the indicated sections of the cornea demonstrate that ZEB1 is present in the nuclei of epithelial cells, stromal keratocytes, and endothelial cells (oil objective, original magnification ×100).

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