Posterior polymorphous corneal dystrophy (PPCD) is an autosomal dominant corneal dystrophy affecting the corneal endothelium and Descemet’s membrane. It is also called Schlichting dystrophy. The clinical presentation is highly variable, characterized by vesicular changes, snail-track lesions, and diffuse opacities 3).
PPCD is bilateral but often asymmetric. It typically presents in infancy or adolescence, and most cases are asymptomatic with a stationary or slowly progressive course. Corneal edema occurs in 20–30% of cases.
In the IC3D classification (revised 2015), the former autosomal dominant congenital hereditary endothelial dystrophy (CHED-AD) is reclassified as a mild form of PPCD 3,5). Associated ocular conditions include secondary glaucoma and keratoconus. Extraocular associations with Alport syndrome and abdominal wall hernia have also been reported.
ICD-10 code: H18.52.
Most cases are stationary or slowly progressive and often do not affect vision 3). However, in some cases, corneal edema progresses and leads to visual impairment, especially with OVOL2 mutations (PPCD1), which tend to be more severe 1). Regular ophthalmologic follow-up is important.
Many patients are asymptomatic. When corneal edema progresses, they may notice blurred vision (foggy vision). In severe cases, corneal opacity appears from infancy and affects visual development.
On the posterior corneal surface in PPCD, the following three morphological types are observed3).
| Type | Findings |
|---|---|
| Vesicular changes | Small vesicles with a blue-gray halo |
| Band lesions | Parallel linear elevations |
| Diffuse opacity | Extensive posterior corneal opacity |
Other clinical findings include the following.
PPCD exhibits genetic heterogeneity, with four loci identified. All genes are involved in the regulation of epithelial-mesenchymal transition (EMT) and its reverse process, mesenchymal-epithelial transition (MET) 1).
PPCD1 (OVOL2)
Locus: 20p11.2–q11.2. Ectopic expression due to OVOL2 promoter mutation.
Features: A zinc finger transcription factor that directly suppresses ZEB1 expression. Higher risk of corneal transplantation and secondary glaucoma compared to other subtypes 1).
iOCT-assisted corneal endothelial transplantation: Reported effective in severe infantile cases 2).
PPCD3 (ZEB1)
Locus: 10p11.22. LoF (loss-of-function) mutations in ZEB1. Haploinsufficiency is the disease mechanism.
Features: Over 50 pathogenic LoF mutations reported 1). Penetrance estimated at about 95%, but true penetrance may be lower 1). May be associated with corneal steepening.
pLI score: 0.994, indicating extremely high intolerance to haploinsufficiency 1).
Other subtypes include PPCD2 (1p34.3–p32.3) caused by COL8A2 mutations and PPCD4 (8q22.3–q24.12) caused by GRHL2 mutations. GRHL2 also directly suppresses ZEB1 transcription and is involved in EMT. The genotype-phenotype relationship shows significant individual variation even within the same family 1).
Because it is an autosomal dominant disorder, children of an affected individual have a 50% chance of inheriting the mutation. Taking a family history is important.
Distinguishing subtypes based on clinical findings alone is difficult, and genetic testing is necessary for definitive classification 1). Genotype is important for prognosis: OVOL2 mutations (PPCD1) have a higher likelihood of requiring corneal transplantation, and ZEB1 mutations (PPCD3) may be associated with corneal steepening.
| Disease | Key differentiating features |
|---|---|
| ICE syndrome | Unilateral, sporadic. PPCD is bilateral, hereditary3) |
| Fuchs endothelial dystrophy | Onset after age 40. Corneal guttae progress from the center |
| Descemet membrane rupture | History of forceps delivery or congenital glaucoma |
| Peters anomaly | Central corneal opacity, severe |
| CHED | Bilateral corneal edema from birth. AR inheritance |
ICE syndrome is unilateral and sporadic (non-hereditary), mainly occurring in adults. PPCD is bilateral, autosomal dominant, and findings appear from childhood3). Both diseases can present with endothelial abnormalities, iridocorneal adhesions, and pupillary deviation, but the presence or absence of family history and the pattern of onset are the main differentiating points.
Most cases of PPCD are asymptomatic and do not require treatment. Because of the risk of secondary glaucoma, regular monitoring of intraocular pressure is important.
If elevated intraocular pressure is observed, drug therapy is performed. Beta-blockers, alpha-adrenergic agonists, and carbonic anhydrase inhibitors are used. If drug therapy is insufficient, goniotomy or trabeculotomy may be considered.
Corneal transplantation is indicated when corneal edema persists and causes visual impairment. It is estimated that 20-25% of cases with corneal edema require corneal transplantation 2).
In pediatric cases, prevention of amblyopia is paramount, and early surgical intervention may be justified. Successful bilateral iOCT-assisted corneal endothelial transplantation in a 17-week-old infant has been reported 2).
Surgery is considered when corneal edema persists and causes visual impairment. 20-25% of cases with corneal edema require corneal transplantation 2). Surgery may also be necessary for secondary glaucoma that cannot be managed with medication. Many cases do not require surgery throughout life.
The core pathology of PPCD is abnormal epithelial-like transformation of corneal endothelial cells. Normal corneal endothelial cells form a monolayer of hexagonal cells, but in PPCD, they transform into multilayered epithelial-like cells resembling stratified squamous epithelium 4).
The four genes involved in PPCD (OVOL2, COL8A2, ZEB1, GRHL2) are all part of the mutual inhibition pathway regulating EMT/MET 1). ZEB1 is a transcription factor that promotes EMT, while OVOL2 and GRHL2 directly suppress ZEB1 transcription. Mutations in these genes disrupt the EMT/MET balance, leading to epithelial-like transformation of endothelial cells.
ZEB1 (TCF8) is a zinc finger transcription factor that induces EMT by suppressing E-cadherin expression. In ZEB1 knockout mice, ectopic expression of epithelial genes is observed in corneal endothelial and stromal cells, reproducing features of PPCD (abnormal corneal cell proliferation, corneal thickening, iridocorneal adhesions, and corneal-lenticular adhesions) 4).
Loss-of-function (LoF) mutations in ZEB1 cause PPCD3. More than 50 pathogenic LoF mutations have been reported, distributed relatively evenly across the gene, with no association with specific functional domains 1). This supports that PPCD3 results from haploinsufficiency of ZEB1 1).
In the corneal endothelium of PPCD, epithelial-like cells show positive staining for cytokeratins (CK7, CK19) and have desmosome-like intercellular junctions and surface microvilli. These abnormal cells become keratinized, secrete a defective basement membrane, and cause thickening of Descemet’s membrane. Nodular collagen deposits are observed on the posterior surface of Descemet’s membrane.
Dudakova et al. searched for ZEB1 LoF mutations in 3,616 exomes and 88 genomes and identified a novel c.1279C>T mutation 1). Ophthalmic examination of the heterozygous father and son revealed no findings of PPCD3. In gnomAD (141,456 individuals), eight different heterozygous ZEB1 LoF mutations were identified, suggesting that the penetrance of PPCD may be lower than the approximately 95% estimated from previous family studies 1).
Muijzer et al. performed bilateral iOCT-assisted DSAEK in a 17-week-old infant with PPCD1 due to a de novo duplication of the OVOL2 gene 2). Intraoperative microscope-integrated iOCT allowed high-resolution evaluation of graft orientation, adhesion, and interface even under corneal opacity. The right eye achieved corneal clarity and good visual development postoperatively, while the left eye required regrafting after graft detachment, ultimately resulting in a functional graft 2).
