Posterior Polymorphous Corneal Dystrophy
Posterior polymorphous corneal dystrophy (PPCD) is a rare, usually autosomal-dominant, bilateral posterior corneal endothelial dystrophy. Its defining pathology is an abnormal transdifferentiation of the corneal endothelium toward an epithelial-like phenotype: endothelial cells acquire epithelial morphology, gene expression (E-cadherin, cytokeratins), and proliferative behavior, and deposit an aberrant, multilaminar Descemet membrane. Clinically this produces the characteristic vesicular, band, and diffuse opacities at the level of Descemet membrane. Most patients are asymptomatic, but a subset develop corneal edema, iridocorneal adhesions, corectopia, and secondary glaucoma. PPCD is genetically heterogeneous and the recognized subtypes are caused by transcription-factor dysregulation that converges on the ZEB1 epithelial-mesenchymal transition (EMT) axis: OVOL2 promoter mutations (PPCD1), ZEB1 loss-of-function (PPCD3), and GRHL2 non-coding regulatory mutations (PPCD4). It is distinct from Fuchs endothelial corneal dystrophy, which is an attritional (cell-loss) endothelial dystrophy rather than an endothelial-to-epithelial transdifferentiation disorder.
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Classifications
Harrison's Part
Inheritance
1
Autosomal dominant inheritance
HP:0000006
Show evidence (1 reference)
"we mapped a locus for an autosomal-dominant corneal endothelial dystrophy, posterior polymorphous corneal dystrophy 4 (PPCD4), to 8q22.3-q24.12"
PPCD is described as an autosomal-dominant corneal endothelial dystrophy.
Subtypes
4
PPCD1 (OVOL2-related, 20p11.2)
MONDO:0007378
PPCD subtype mapped to chromosome 20p11.2 and caused by mutations in the proximal promoter of OVOL2, a gene not normally expressed in the corneal endothelium. The mutations drive aberrant ectopic OVOL2 expression; OVOL2 promotes mesenchymal-to-epithelial transition and directly represses ZEB1. PPCD1 is allelic with the autosomal-dominant congenital hereditary endothelial dystrophy CHED1.
Show evidence (1 reference)
"the identification of pathogenic variants in a conserved region of the OVOL2 proximal promoter sequence in the index families (c.-339_361dup for CHED1 and c.-370T>C for PPCD1)"
Identifies OVOL2 promoter mutations as the cause of PPCD1.
PPCD2 (COL8A2-related, 1p34.3-p32; unconfirmed)
MONDO:0012199
Historical PPCD subtype (OMIM 609140) defined by a COL8A2 missense substitution reported in a single PPCD family, in the same study that established COL8A2 as a gene for early-onset Fuchs endothelial corneal dystrophy. No further PPCD family with a segregating COL8A2 variant is cited in this entry, and the 2020 clinical utility gene card for PPCD lists only OVOL2, ZEB1 and GRHL2 as the genes to test. COL8A2 is therefore recorded here as an unconfirmed PPCD gene, and no PPCD mechanism node is attributed to it.
Show evidence (2 references)
"Mutation analysis in patients with FECD and PPCD demonstrated further missense substitutions in familial and sporadic cases of FECD as well as in a single family with PPCD."
The original and only cited report of a COL8A2 missense variant in PPCD, from a single family; this is the basis of the PPCD2 designation.
"Name of the analysed genes or DNA/chromosome segments OVOL2 (PPCD1); ZEB1 (PPCD3); GRHL2 (PPCD4)."
The clinical utility gene card for PPCD names OVOL2, ZEB1 and GRHL2 as the analysed genes and does not include COL8A2, which counts against treating COL8A2 as an established PPCD gene.
PPCD3 (ZEB1/TCF8-related, 10p11.2)
MONDO:0012200
PPCD subtype caused by heterozygous loss-of-function (nonsense and frameshift) mutations in ZEB1 (formerly TCF8), accounting for roughly a quarter to a third of screened PPCD families. ZEB1 haploinsufficiency derepresses epithelial genes in the endothelium. PPCD3 is also associated with extraocular abnormalities, notably inguinal and abdominal hernias.
Show evidence (1 reference)
"we report a heterozygous frameshift mutation in TCF8 that segregates with PPCD in the family used to map PPCD3 and four different heterozygous nonsense and frameshift mutations in TCF8 in four other PPCD probands"
Establishes ZEB1 (TCF8) loss-of-function mutations as the cause of PPCD3.
PPCD4 (GRHL2-related, 8q22.3-q24.12)
MONDO:0054832
PPCD subtype caused by non-coding (intronic/regulatory) mutations in GRHL2 that induce ectopic GRHL2 expression in the corneal endothelium. GRHL2 is a transcription factor that suppresses EMT and directly represses ZEB1; its ectopic expression drives the endothelium toward an epithelial-like state.
Show evidence (1 reference)
"Whole-genome sequencing identified a unique variant (c.20+544G>T) in this locus, within an intronic regulatory region of GRHL2."
Identifies non-coding GRHL2 regulatory mutations as the cause of PPCD4.
Pathophysiology
5Corneal Endothelial-to-Epithelial Transdifferentiation
The central, convergent mechanism of PPCD. Normal corneal endothelial cells are post-mitotic, neural-crest-derived cells with a hexagonal monolayer morphology. In PPCD, the endothelium undergoes metaplasia toward an epithelial-like phenotype, acquiring epithelial morphology, epithelial gene expression (E-cadherin, cytokeratin 7), microvilli, and an aberrant proliferative/migratory behavior. These cells can overgrow the trabecular meshwork and iris. The cell-state switch reflects dysregulation of the ZEB1 EMT axis: ZEB1 normally maintains the mesenchymal/endothelial state by repressing epithelial genes, while OVOL2 and GRHL2 are EMT-suppressing transcription factors that repress ZEB1 and drive mesenchymal-to-epithelial transition (MET). Loss of ZEB1 (PPCD3) or ectopic activation of OVOL2 (PPCD1) or GRHL2 (PPCD4) all push the endothelium toward the epithelial state, explaining the indistinguishable phenotypes.
Downstream
Epithelial-like transdifferentiated corneal endothelial cells secrete ectopic basement-membrane collagens and deposit an aberrant multilaminar Descemet membrane.
Proliferative, epithelial-like endothelial cells migrate across the iridocorneal angle and onto the iris surface, forming adhesions and distorting anterior chamber structures.
Endothelial-to-epithelial transdifferentiation directly alters the normal hexagonal corneal endothelial monolayer into an epithelial-like cell layer.
Abnormal endothelial differentiation and lesion formation at the posterior cornea result in significantly reduced endothelial cell density.
Show evidence (4 references)
"a rare disease involving metaplasia and overgrowth of corneal endothelial cells. In patients with PPCD, these cells manifest in an epithelial morphology and gene expression pattern"
Directly describes the endothelial-to-epithelial metaplasia central to PPCD.
"These cells were also positive for epithelial markers E-Cadherin and Cytokeratin 7, indicating they have transitioned to an epithelial-like cell type. We suggest that mutations inducing MET within the corneal endothelium are a convergent pathogenic mechanism"
Demonstrates epithelial-marker expression in PPCD endothelium and the convergent MET mechanism.
"Transcriptomic and functional studies support the hypothesis that CEnC undergo a MET-like transition in PPCD, termed endothelial to epithelial transition (EnET)"
A CRISPR ZEB1-knockout corneal endothelial cell model defines the endothelial-to-epithelial transition (EnET) as the cell-state mechanism of PPCD.
+ 1 more reference
ZEB1 EMT-Axis Transcription Factor Dysregulation
PPCD-associated genes encode transcription factors that regulate cell-state transitions and converge on ZEB1. ZEB1 (PPCD3) loss-of-function causes haploinsufficiency that derepresses epithelial genes. OVOL2 (PPCD1) and GRHL2 (PPCD4) are EMT-suppressing factors that directly repress ZEB1 and are normally absent from the corneal endothelium; PPCD mutations cause their ectopic expression. Transcriptomic and immunohistochemical studies of PPCD endothelium show decreased ZEB1, increased OVOL2/GRHL2, and aberrant activation of the Wnt signaling pathway (nuclear accumulation of phospho-beta-catenin), consistent with a shared GRHL2-OVOL2-ZEB1 axis disturbance.
Downstream
Loss of ZEB1 function or ectopic repression of ZEB1 by OVOL2 or GRHL2 derepresses epithelial genes and drives mesenchymal-to-epithelial transition in the corneal endothelium.
In PPCD3, heterozygous loss-of-function mutations in ZEB1 (TCF8) are clinically associated with abdominal and inguinal hernias through an incompletely defined extraocular mechanism.
Show evidence (3 references)
"Each of these genes encodes a transcription factor that regulates cell-state transitions."
Confirms the three PPCD genes are cell-state-transition transcription factors converging on a shared axis.
"indicating aberrant activation of Wnt signaling, which was not observed in control corneal endothelium"
Demonstrates aberrant Wnt signaling activation in PPCD endothelium.
"OVOL2 encodes ovo-like zinc finger 2, a C2H2 zinc-finger transcription factor that regulates mesenchymal-to-epithelial transition and acts as a direct transcriptional repressor of the established PPCD-associated gene ZEB1"
Establishes OVOL2 as a direct repressor of ZEB1, anchoring the convergent axis.
Aberrant Descemet Membrane Deposition
The transdifferentiated, epithelial-like endothelium produces an abnormal, thickened, multilaminar basement membrane (Descemet membrane) with posterior collagenous layers. In ZEB1-related PPCD, loss of ZEB1 transcriptional repression leads to ectopic expression of basement-membrane collagen COL4A3 (collagen type IV alpha 3) by corneal endothelial cells, a target shared with the Alport syndrome COL4A3 gene. This aberrant matrix underlies the characteristic vesicular, band-like, and geographic opacities at the level of Descemet membrane seen clinically.
Downstream
Ectopic basement-membrane collagen synthesis and multilaminar matrix deposition directly produce an abnormal Descemet membrane morphology.
Aberrant Descemet membrane deposition together with the metaplastic endothelium produces the vesicular, band-like, and geographic posterior corneal lesions characteristic of PPCD.
Thickened, aberrant Descemet membrane layers and posterior vesicular and gray-white plaque lesions directly produce opacification of the posterior cornea.
Show evidence (2 references)
"produce an aberrant basement membrane"
PPCD endothelial cells deposit an aberrant basement membrane (Descemet membrane).
"we present immunohistochemical evidence of ectopic expression of COL4A3 in corneal endothelium of the proband of the original PPCD3 family"
Documents ectopic COL4A3 basement-membrane collagen expression in PPCD3 endothelium.
Iridocorneal Adhesion and Anterior Chamber Distortion
The proliferative, migratory epithelial-like endothelium can extend across the iridocorneal angle and over the iris surface, secreting abnormal basement membrane that produces iridocorneal/peripheral anterior synechiae, corectopia (pupillary displacement), and pupillary ectropion. Overgrowth and membrane formation across the trabecular meshwork impede aqueous outflow, increasing the risk of secondary glaucoma.
Downstream
Overgrowth of epithelial-like endothelial cells and iridocorneal adhesions across the trabecular meshwork obstruct aqueous outflow, causing secondary glaucoma.
Migration of the abnormal endothelium across the anterior chamber angle and secretion of abnormal basement membrane directly form peripheral anterior synechiae and iridocorneal adhesions.
Migration of aberrant endothelial cells onto the peripheral iris surface and secretion of an abnormal basement membrane across the iris directly lead to corectopia and pupillary ectropion.
Show evidence (2 references)
"sometimes, spread over the iris and nearby structures in a way that increases the risk for glaucoma"
Endothelial overgrowth onto the iris and angle increases glaucoma risk.
"Rather than confining themselves to the posterior surface of the cornea, the aberrant endothelial cells can migrate erratically across the chamber angle and onto the peripheral iris surface. Abnormal basement membrane is secreted, creating iridocorneal adhesions and a glass-like appearance that..."
Details how aberrant endothelial migration across the chamber angle and secretion of abnormal basement membrane on the iris surface produce iridocorneal adhesions and corectopia.
Secondary Glaucoma
Obstruction of aqueous humor outflow by the abnormal endothelium and associated iridocorneal adhesions/membranes raises intraocular pressure, leading to secondary (often angle-closure or membrane-associated) glaucoma, a major cause of visual morbidity in PPCD.
Downstream
Elevated intraocular pressure from angle obstruction by the abnormal endothelium manifests clinically as secondary glaucoma.
Show evidence (1 reference)
"spread over the iris and nearby structures in a way that increases the risk for glaucoma"
Links the endothelial overgrowth mechanism to secondary glaucoma.
Pathograph
Use Group by to collapse related nodes into one box. Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Phenotypes
9Digestive 1
Inguinal hernia
HP:0000023
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Inguinal hernia (HP:0000023). HP:0000023 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"the presence of apparently causative TCF8 mutations is associated with abdominal and inguinal hernias"
Establishes increased inguinal/abdominal hernia frequency in ZEB1-related PPCD3.
Eye 8
Polymorphous posterior corneal dystrophy
HP:0007915
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Polymorphous posterior corneal dystrophy (HP:0007915). HP:0007915 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"Posterior polymorphous corneal dystrophy (PPCD, also known as PPMD) is a rare disease involving metaplasia and overgrowth of corneal endothelial cells."
Establishes the disease entity defined by the posterior polymorphous corneal lesions.
Abnormal corneal endothelium morphology
HP:0011488
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Abnormal corneal endothelium morphology (HP:0011488). HP:0011488 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"these cells manifest in an epithelial morphology and gene expression pattern"
PPCD endothelial cells show abnormal epithelial-like morphology.
Reduced corneal endothelial cell density
Reduced number of corneal endothelial cells
HP:0011491
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Reduced corneal endothelial cell density, annotated with Reduced number of corneal endothelial cells (HP:0011491). HP:0011491 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"Patients with PPCD had significantly lower endothelial cell densities (ECD) at recruitment (1918.9 ± 666.3 vs. 3340.1 ± 286.5 cells/mm2, p < 0.007)"
Quantitatively documents reduced corneal endothelial cell density in PPCD versus controls.
Abnormal Descemet membrane morphology
HP:0011490
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Abnormal Descemet membrane morphology (HP:0011490). HP:0011490 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"produce an aberrant basement membrane"
The aberrant basement membrane corresponds to abnormal Descemet membrane.
Corneal opacity
HP:0007957
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Corneal opacity (HP:0007957). HP:0007957 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
"In PPCD, the Descemet basement membrane laid down by endothelial cells is abnormally thickened. Groupings of blister-like vesicles and gray-white plaques lead to opacification of the posterior cornea."
Directly documents that thickened Descemet membrane and grouped vesicular/plaque lesions produce posterior corneal opacification in PPCD.
"CHED1 represents the extreme of what can be considered a disease spectrum"
PPCD1 lies on an allelic spectrum with CHED1, whose severe extreme presents with diffuse corneal clouding/opacity.
Glaucoma
HP:0000501
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Glaucoma (HP:0000501). HP:0000501 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"spread over the iris and nearby structures in a way that increases the risk for glaucoma"
Directly links PPCD pathology to increased glaucoma risk.
Corectopia
Ectopia pupillae
HP:0009918
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Corectopia, annotated with Ectopia pupillae (HP:0009918). HP:0009918 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
"Abnormal basement membrane is secreted, creating iridocorneal adhesions and a glass-like appearance that can be appreciated gonioscopically. On the iris surface, this membrane can lead to corectopia and pupillary ectropion."
Directly documents that abnormal basement membrane secretion on the iris surface leads to corectopia and pupillary ectropion in PPCD.
"spread over the iris and nearby structures"
Endothelial spread over the iris and anterior chamber structures provides the cellular substrate for iris distortion in PPCD.
Iridocorneal adhesions
Anterior synechiae of the anterior chamber
HP:0011483
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Iridocorneal adhesions, annotated with Anterior synechiae of the anterior chamber (HP:0011483). HP:0011483 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
"Rather than confining themselves to the posterior surface of the cornea, the aberrant endothelial cells can migrate erratically across the chamber angle and onto the peripheral iris surface. Abnormal basement membrane is secreted, creating iridocorneal adhesions and a glass-like appearance that..."
Directly documents iridocorneal adhesions created by migrating aberrant endothelial cells and abnormal basement membrane secretion in PPCD.
"spread over the iris and nearby structures"
Endothelial spread over the iris and angle underlies the formation of iridocorneal adhesions (anterior synechiae).
Genetic Associations
4
OVOL2
Show evidence (1 reference)
"we postulate that the mutations identified create cryptic cis-acting regulatory sequence binding sites that drive aberrant OVOL2 expression during endothelial cell development"
OVOL2 promoter mutations drive aberrant endothelial OVOL2 expression, causing PPCD1.
ZEB1
Show evidence (3 references)
"this study has identified TCF8 as the gene responsible for approximately half of the cases of PPCD"
Establishes ZEB1 (TCF8) as a major PPCD (PPCD3) gene.
"ZEB1 loss-of-function (LoF) alleles are known to cause a rare autosomal dominant disorder-posterior polymorphous corneal dystrophy type 3 (PPCD3)."
Confirms ZEB1 loss-of-function alleles as the cause of PPCD3; the study also documents reduced/incomplete penetrance.
"GnomAD (n = 141,456 subjects) was also interrogated for LoF ZEB1 variants, notably 8 distinct heterozygous changes presumed to lead to ZEB1 haploinsufficiency, not reported to be associated with PPCD3, have been identified. The NM_030751.6 transcript has a pLI score ≥ 0.99, indicating extreme..."
Documents 8 heterozygous ZEB1 loss-of-function variants across 141,456 gnomAD subjects and high LoF intolerance (pLI >= 0.99), supporting incomplete penetrance of ZEB1 alleles in the general population.
COL8A2
Show evidence (1 reference)
"Mutation analysis in patients with FECD and PPCD demonstrated further missense substitutions in familial and sporadic cases of FECD as well as in a single family with PPCD."
The single-family report on which the COL8A2-PPCD association rests.
GRHL2
Show evidence (1 reference)
"GRHL2 is a transcription factor that suppresses epithelial-to-mesenchymal transition (EMT) and is a direct transcriptional repressor of ZEB1."
Establishes GRHL2 as a PPCD4 gene acting through the EMT/ZEB1 axis.
Medical Actions
4
Observation
Most individuals with PPCD are asymptomatic and require only periodic monitoring of corneal status and intraocular pressure rather than active intervention.
Show evidence (1 reference)
"children with PPCD were followed with slit-lamp photography and non-contact specular microscopy"
Reflects real-world longitudinal monitoring (slit-lamp and specular microscopy follow-up) of PPCD patients, consistent with observation as the baseline management of mild/asymptomatic disease.
Corneal Transplantation
For symptomatic PPCD with corneal decompensation/edema, corneal transplantation (endothelial keratoplasty such as DSEK/DMEK, or penetrating keratoplasty) replaces the dysfunctional endothelium and Descemet membrane.
Show evidence (1 reference)
"leading to dysfunction of the endothelial barrier and disease"
PPCD produces endothelial-barrier dysfunction; when this decompensates the cornea, corneal transplantation (endothelial keratoplasty or penetrating keratoplasty) replaces the dysfunctional endothelium and Descemet membrane (clinical-management context).
Antiglaucoma Therapy
Medical and/or surgical management of secondary glaucoma to control intraocular pressure in PPCD patients with angle involvement.
Show evidence (1 reference)
"increases the risk for glaucoma"
Increased glaucoma risk in PPCD motivates antiglaucoma management of affected patients.
Genetic Counseling
Genetic counseling for affected families given autosomal-dominant inheritance and the availability of diagnostic gene testing for OVOL2, ZEB1, and GRHL2.
Show evidence (1 reference)
"DNA-based testing for variants in theOVOL2, ZEB1andGRHL2gene(s) in a diagnostic setting, predictive and parental settings"
The Clinical Utility Gene Card supports diagnostic/predictive gene testing and counseling for PPCD families.
Biochemical Markers
3
Ectopic corneal endothelial E-cadherin (CDH1) and Cytokeratin 7 (KRT7) expression
(ELEVATED)
Context: Corneal endothelium immunohistochemistry and transcriptomics
Show evidence (1 reference)
"These cells were also positive for epithelial markers E-Cadherin and Cytokeratin 7, indicating they have transitioned to an epithelial-like cell type."
Confirms ectopic expression of epithelial biomarkers E-cadherin and Cytokeratin 7 in PPCD corneal endothelium.
Ectopic corneal endothelial COL4A3 expression
(ELEVATED)
Context: Corneal endothelium and Descemet membrane immunohistochemistry
Show evidence (1 reference)
"we present immunohistochemical evidence of ectopic expression of COL4A3 in corneal endothelium of the proband of the original PPCD3 family"
Demonstrates ectopic COL4A3 protein expression in PPCD3 corneal endothelium.
Corneal endothelial nuclear phospho-beta-catenin (S552) accumulation
(ELEVATED)
Context: Corneal endothelium immunohistochemistry
Show evidence (1 reference)
"Immunohistochemistry results demonstrated corneal endothelial nuclear accumulation of S552 phos-β-catenin and cytosolic localization of S33/37/T42 non-phosphorylated β-catenin in PPCD, indicating aberrant activation of Wnt signaling, which was not observed in control corneal endothelium."
Documents nuclear S552 phospho-beta-catenin accumulation in PPCD corneal endothelium as a biomarker of aberrant Wnt pathway activation.
Diagnosis
4
Slit-lamp biomicroscopy
Primary clinical examination used to detect and classify the characteristic polymorphous posterior corneal lesions (vesicular, band-like, or diffuse geographic opacities) at the level of Descemet membrane and to evaluate for iridocorneal adhesions or corectopia.
Slit-lamp Examination
NCIT:C75583
NCI Thesaurus (NCIT)
Results: Reveals bilateral or asymmetric vesicular, band-like ("railroad track"), or diffuse opacities at the posterior cornea and Descemet membrane.
Show evidence (2 references)
"The appearance of the opacities at the Descemet membrane may be characterized by one of three different distribution patterns; vesicular, band-like or diffuse. These polymorphous lesions may be visualized at the slit lamp biomicroscope with moderate to high magnification using direct or,..."
Documents the three classic slit-lamp biomicroscopy lesion patterns of PPCD at the posterior cornea and Descemet membrane.
"In this prospective case-control study, children with PPCD were followed with slit-lamp photography and non-contact specular microscopy."
Documents slit-lamp photography and biomicroscopy as standard diagnostic and monitoring tools for PPCD.
Non-contact specular microscopy
Non-contact in vivo endothelial imaging that quantifies corneal endothelial cell density (ECD) and assesses endothelial cell morphology across PPCD phenotypic subtypes.
Non-Contact Specular Microscopy
NCIT:C120697
NCI Thesaurus (NCIT)
Results: Demonstrates significantly reduced endothelial cell density (particularly in diffuse-type PPCD and eyes with 5 or more posterior corneal lesions), pleomorphism, and polymegathism compared with age-matched controls.
Show evidence (1 reference)
"The lowest ECDs were found in eyes with diffuse type PPCD and those with ≥5 posterior corneal lesions, while clinically unaffected eyes in patients with confirmed PPCD in fellow eye had a normal ECD."
Demonstrates the diagnostic utility of non-contact specular microscopy in quantifying endothelial cell density reduction across morphological subtypes of PPCD.
In vivo confocal microscopy
High-resolution in vivo confocal imaging of the corneal layers used to visualize microstructural abnormalities of the posterior cornea, Descemet membrane, and endothelium without requiring histopathologic tissue biopsy.
Confocal Microscopy
NCIT:C17753
NCI Thesaurus (NCIT)
Results: Reveals vesicular, band-like, or diffuse posterior corneal lesions and multilayered epithelial-like endothelial changes at Descemet membrane in vivo.
Show evidence (1 reference)
"Confocal microscopy also has emerged as a helpful tool to reveal in vivo features of several corneal dystrophies that previously required histopathologic examination to definitively diagnose."
The IC3D consensus classification highlights in vivo confocal microscopy as a non-invasive diagnostic tool for corneal dystrophies.
Molecular genetic testing of OVOL2, ZEB1, and GRHL2
DNA-based sequencing and copy-number analysis covering the coding regions of ZEB1 (PPCD3) and the non-coding promoter/intronic regulatory regions of OVOL2 (PPCD1) and GRHL2 (PPCD4) for molecular subtype confirmation, predictive testing, and family risk assessment.
genetic testing
NCIT:C15709
NCI Thesaurus (NCIT)
Results: Identifies heterozygous loss-of-function variants or deletions in ZEB1, proximal promoter variants in OVOL2, or intronic regulatory variants in GRHL2.
Show evidence (1 reference)
"Review of the analytical and clinical validity as well as of the clinical utility of DNA-based testing for variants in theOVOL2, ZEB1andGRHL2gene(s) in a diagnostic setting, predictive and parental settings"
Establishes the diagnostic and predictive utility of targeted genetic testing of OVOL2, ZEB1, and GRHL2 in PPCD.
Progression
2Onset
Pathogenic regulatory and transcription-factor perturbations act during corneal endothelial development, and endothelial cell density reduction and posterior corneal lesions are already present in childhood, though mild asymptomatic cases may only be detected later on routine examination.
Show evidence (3 references)
"we postulate that the mutations identified create cryptic cis-acting regulatory sequence binding sites that drive aberrant OVOL2 expression during endothelial cell development"
Indicates that the pathogenic transcriptional perturbation begins during corneal endothelial development.
"Patients with PPCD had significantly lower endothelial cell densities (ECD) at recruitment (1918.9 ± 666.3 vs. 3340.1 ± 286.5 cells/mm2, p < 0.007)"
Demonstrates that significantly reduced corneal endothelial cell density is already established in childhood in pediatric PPCD patients compared with age-matched controls.
"Corneal edema associated with PPCM may be evident at a very young age. However, the majority of patients are asymptomatic and diagnosis occurs years later at the time of a routine ocular health examination ."
Confirms that corneal manifestations may be present at a very young age while most patients remain asymptomatic until routine ocular examination later in life.
Progression
Although baseline endothelial cell density is markedly reduced in affected eyes, longitudinal pediatric follow-up shows that the subsequent annual rate of endothelial cell decline does not significantly differ from healthy controls, consistent with an early developmental endothelial deficit that is often non-progressive or only slowly progressive.
Show evidence (2 references)
"However, the rates of annual ECD decline were not significantly different between eyes with PPCD in general, between the subgroups of PPCD and the normative groups."
Longitudinal pediatric data show that after an initial reduction in endothelial cell density, the annual rate of cell loss parallels normative controls.
"Corneal findings are either nonprogressive or very slowly progressive ."
Summarizes the clinical course of PPCD as nonprogressive or very slowly progressive.
Prevalence
1Global
PPCD is a rare autosomal-dominant corneal endothelial dystrophy; exact population point prevalence has not been established in epidemiological registries.
Show evidence (1 reference)
"Posterior polymorphous corneal dystrophy (PPCD, also known as PPMD) is a rare disease involving metaplasia and overgrowth of corneal endothelial cells."
Establishes PPCD as a rare corneal endothelial dystrophy.
Differential Diagnoses
3Conditions with similar clinical presentations that must be differentiated from Posterior Polymorphous Corneal Dystrophy:
Overlapping Features
Adult-onset, bilateral corneal endothelial dystrophy characterized by progressive endothelial cell attrition and central Descemet membrane excrescences (cornea guttata) rather than endothelial-to-epithelial transdifferentiation.
Distinguishing Features
- Later adult onset (typically fifth to sixth decade) with central confluent guttae rather than congenital/childhood vesicular or railroad-track band lesions
- Driven by endothelial cell loss and oxidative/unfolded-protein stress (commonly TCF4 repeat expansion or SLC4A11/COL8A2 variants) without confirmed causal role of ZEB1
- Absence of epithelial-like endothelial metaplasia, iridocorneal adhesions, or corectopia
Show evidence (1 reference)
"Our analysis confirmed the causal role of SLC4A11 variants in the development of FECD. The causal role of ZEB1, LOXHD1, and AGBL1 variants in FECD has not been confirmed."
Systematic review confirms that ZEB1 variants do not have a confirmed causal role in Fuchs endothelial corneal dystrophy, supporting genetic and nosologic separation from PPCD3.
Congenital hereditary endothelial dystrophy 1
Overlapping Features
Severe autosomal-dominant corneal endothelial dystrophy mapped to chromosome 20p11.2 that is allelic with PPCD1 and caused by distinct non-coding variants in the OVOL2 promoter (historically designated CHED1 in the prior IC3D classification and now subsumed within the severe spectrum of PPCD1).
Distinguishing Features
- Presents at birth or in early infancy with diffuse, bilateral ground-glass corneal clouding and marked stromal thickening rather than focal vesicular or band lesions
- Represents the severe extreme of the OVOL2-associated endothelial dystrophy spectrum
Show evidence (1 reference)
"CHED1 represents the extreme of what can be considered a disease spectrum"
Demonstrates that CHED1 and PPCD1 are allelic OVOL2 promoter disorders distinguished by CHED1 representing the severe extreme of the disease spectrum.
Overlapping Features
Hereditary basement membrane disorder caused by pathogenic variants in COL4A3, COL4A4, or COL4A5 that can present with posterior polymorphous corneal changes alongside systemic renal and auditory manifestations.
Distinguishing Features
- Systemic features including hematuria, progressive glomerulopathy/renal failure, and sensorineural hearing loss
- Characteristic non-corneal ocular signs including fleck retinopathy, temporal retinal thinning, and anterior lenticonus
- Caused by primary COL4A3/COL4A4/COL4A5 mutations rather than OVOL2, ZEB1, or GRHL2 variants (though ZEB1 regulates COL4A3 transcription in PPCD3)
Show evidence (2 references)
"In contrast, the rarer ophthalmic complications of posterior polymorphous corneal dystrophy, giant macular hole, and maculopathy all produce visual loss."
Documents that posterior polymorphous corneal dystrophy can occur as a rarer ophthalmic manifestation in Alport syndrome.
"Thus, this study has identified TCF8 as the gene responsible for approximately half of the cases of PPCD, has implicated TCF8 mutations in developmental abnormalities outside the eye, and has presented the TCF8 regulatory target, COL4A3, as a key, shared molecular component of two different..."
Explains the shared COL4A3 basement-membrane molecular component linking isolated PPCD3 and Alport syndrome.
Source YAML
click to showname: Posterior Polymorphous Corneal Dystrophy
creation_date: "2026-06-15T00:00:00Z"
category: Mendelian
description: >-
Posterior polymorphous corneal dystrophy (PPCD) is a rare, usually
autosomal-dominant, bilateral posterior corneal endothelial dystrophy. Its
defining pathology is an abnormal transdifferentiation of the corneal
endothelium toward an epithelial-like phenotype: endothelial cells acquire
epithelial morphology, gene expression (E-cadherin, cytokeratins), and
proliferative behavior, and deposit an aberrant, multilaminar Descemet
membrane. Clinically this produces the characteristic vesicular, band, and
diffuse opacities at the level of Descemet membrane. Most patients are
asymptomatic, but a subset develop corneal edema, iridocorneal adhesions,
corectopia, and secondary glaucoma. PPCD is genetically heterogeneous and the
recognized subtypes are caused by transcription-factor dysregulation that
converges on the ZEB1 epithelial-mesenchymal transition (EMT) axis:
OVOL2 promoter mutations (PPCD1), ZEB1 loss-of-function (PPCD3), and GRHL2
non-coding regulatory mutations (PPCD4). It is distinct from Fuchs endothelial
corneal dystrophy, which is an attritional (cell-loss) endothelial dystrophy
rather than an endothelial-to-epithelial transdifferentiation disorder.
disease_term:
preferred_term: posterior polymorphous corneal dystrophy
term:
id: MONDO:0020364
label: posterior polymorphous corneal dystrophy
synonyms:
- PPCD
- PPMD
- Schlichting dystrophy
- Posterior polymorphous dystrophy
parents:
- Corneal endothelial dystrophy
- Posterior corneal dystrophy
- Hereditary disease
has_subtypes:
- name: PPCD1
display_name: PPCD1 (OVOL2-related, 20p11.2)
subtype_term:
preferred_term: posterior polymorphous corneal dystrophy 1
term:
id: MONDO:0007378
label: posterior polymorphous corneal dystrophy 1
genes:
- preferred_term: OVOL2
term:
id: hgnc:15804
label: OVOL2
description: >-
PPCD subtype mapped to chromosome 20p11.2 and caused by mutations in the
proximal promoter of OVOL2, a gene not normally expressed in the corneal
endothelium. The mutations drive aberrant ectopic OVOL2 expression; OVOL2
promotes mesenchymal-to-epithelial transition and directly represses ZEB1.
PPCD1 is allelic with the autosomal-dominant congenital hereditary
endothelial dystrophy CHED1.
evidence:
- reference: PMID:26749309
reference_title: "Autosomal-Dominant Corneal Endothelial Dystrophies CHED1 and PPCD1 Are Allelic Disorders Caused by Non-coding Mutations in the Promoter of OVOL2."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "the identification of pathogenic variants in a conserved region of the OVOL2 proximal promoter sequence in the index families (c.-339_361dup for CHED1 and c.-370T>C for PPCD1)"
explanation: Identifies OVOL2 promoter mutations as the cause of PPCD1.
- name: PPCD2
display_name: PPCD2 (COL8A2-related, 1p34.3-p32; unconfirmed)
subtype_term:
preferred_term: posterior polymorphous corneal dystrophy 2
term:
id: MONDO:0012199
label: posterior polymorphous corneal dystrophy 2
genes:
- preferred_term: COL8A2
term:
id: hgnc:2216
label: COL8A2
description: >-
Historical PPCD subtype (OMIM 609140) defined by a COL8A2 missense
substitution reported in a single PPCD family, in the same study that
established COL8A2 as a gene for early-onset Fuchs endothelial corneal
dystrophy. No further PPCD family with a segregating COL8A2 variant is
cited in this entry, and the 2020 clinical utility gene card for PPCD
lists only OVOL2, ZEB1 and GRHL2 as the genes to test. COL8A2 is
therefore recorded here as an unconfirmed PPCD gene, and no PPCD
mechanism node is attributed to it.
evidence:
- reference: PMID:11689488
reference_title: "Missense mutations in COL8A2, the gene encoding the alpha2 chain of type VIII collagen, cause two forms of corneal endothelial dystrophy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Mutation analysis in patients with FECD and PPCD demonstrated further missense substitutions in familial and sporadic cases of FECD as well as in a single family with PPCD."
explanation: The original and only cited report of a COL8A2 missense variant in PPCD, from a single family; this is the basis of the PPCD2 designation.
- reference: PMID:31201376
reference_title: "CUGC for posterior polymorphous corneal dystrophy (PPCD)."
supports: REFUTE
evidence_source: OTHER
snippet: "Name of the analysed genes or DNA/chromosome segments OVOL2 (PPCD1); ZEB1 (PPCD3); GRHL2 (PPCD4)."
explanation: >-
The clinical utility gene card for PPCD names OVOL2, ZEB1 and GRHL2 as the
analysed genes and does not include COL8A2, which counts against treating
COL8A2 as an established PPCD gene.
- name: PPCD3
display_name: PPCD3 (ZEB1/TCF8-related, 10p11.2)
subtype_term:
preferred_term: posterior polymorphous corneal dystrophy 3
term:
id: MONDO:0012200
label: posterior polymorphous corneal dystrophy 3
genes:
- preferred_term: ZEB1
term:
id: hgnc:11642
label: ZEB1
description: >-
PPCD subtype caused by heterozygous loss-of-function (nonsense and
frameshift) mutations in ZEB1 (formerly TCF8), accounting for roughly a
quarter to a third of screened PPCD families. ZEB1 haploinsufficiency
derepresses epithelial genes in the endothelium. PPCD3 is also associated
with extraocular abnormalities, notably inguinal and abdominal hernias.
evidence:
- reference: PMID:16252232
reference_title: "Mutations in TCF8 cause posterior polymorphous corneal dystrophy and ectopic expression of COL4A3 by corneal endothelial cells."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "we report a heterozygous frameshift mutation in TCF8 that segregates with PPCD in the family used to map PPCD3 and four different heterozygous nonsense and frameshift mutations in TCF8 in four other PPCD probands"
explanation: Establishes ZEB1 (TCF8) loss-of-function mutations as the cause of PPCD3.
- name: PPCD4
display_name: PPCD4 (GRHL2-related, 8q22.3-q24.12)
subtype_term:
preferred_term: posterior polymorphous corneal dystrophy 4
term:
id: MONDO:0054832
label: corneal dystrophy, posterior polymorphous, 4
genes:
- preferred_term: GRHL2
term:
id: hgnc:2799
label: GRHL2
description: >-
PPCD subtype caused by non-coding (intronic/regulatory) mutations in GRHL2
that induce ectopic GRHL2 expression in the corneal endothelium. GRHL2 is a
transcription factor that suppresses EMT and directly represses ZEB1; its
ectopic expression drives the endothelium toward an epithelial-like state.
evidence:
- reference: PMID:29499165
reference_title: "Ectopic GRHL2 Expression Due to Non-coding Mutations Promotes Cell State Transition and Causes Posterior Polymorphous Corneal Dystrophy 4."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Whole-genome sequencing identified a unique variant (c.20+544G>T) in this locus, within an intronic regulatory region of GRHL2."
explanation: Identifies non-coding GRHL2 regulatory mutations as the cause of PPCD4.
notes: >-
Subtype-to-gene assignment follows the 2020 Clinical Utility Gene Card (CUGC)
for PPCD (OVOL2/PPCD1, ZEB1/PPCD3, GRHL2/PPCD4). Historical assignments of
VSX1 to PPCD1 and COL8A2 to PPCD2 (OMIM 609140) are now regarded as
unconfirmed or of uncertain significance; evidence-based reviews support a
segregating causal role only for ZEB1 in PPCD3 among the early candidates.
Many PPCD pedigrees remain genetically unresolved. PPCD is mechanistically and
classificationally distinct from Fuchs endothelial corneal dystrophy.
inheritance:
- name: Autosomal dominant inheritance
inheritance_term:
preferred_term: autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
evidence:
- reference: PMID:29499165
reference_title: "Ectopic GRHL2 Expression Due to Non-coding Mutations Promotes Cell State Transition and Causes Posterior Polymorphous Corneal Dystrophy 4."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "we mapped a locus for an autosomal-dominant corneal endothelial dystrophy, posterior polymorphous corneal dystrophy 4 (PPCD4), to 8q22.3-q24.12"
explanation: PPCD is described as an autosomal-dominant corneal endothelial dystrophy.
classifications:
harrisons_chapter:
- classification_value: GENETICS_ENVIRONMENT_DISEASE
evidence:
- reference: PMID:29499165
reference_title: "Ectopic GRHL2 Expression Due to Non-coding Mutations Promotes Cell State Transition and Causes Posterior Polymorphous Corneal Dystrophy 4."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "we mapped a locus for an autosomal-dominant corneal endothelial dystrophy, posterior polymorphous corneal dystrophy 4 (PPCD4), to 8q22.3-q24.12"
explanation: Establishes PPCD as a Mendelian autosomal-dominant genetic disorder of the corneal endothelium.
prevalence:
- population: Global
measure_type: POINT_PREVALENCE
prevalence_class: RARE
notes: >-
PPCD is a rare autosomal-dominant corneal endothelial dystrophy; exact
population point prevalence has not been established in epidemiological
registries.
evidence:
- reference: PMID:16252232
reference_title: "Mutations in TCF8 cause posterior polymorphous corneal dystrophy and ectopic expression of COL4A3 by corneal endothelial cells."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Posterior polymorphous corneal dystrophy (PPCD, also known as PPMD) is a rare disease involving metaplasia and overgrowth of corneal endothelial cells."
explanation: Establishes PPCD as a rare corneal endothelial dystrophy.
progression:
- phase: Onset
age_range: Congenital to childhood (occasionally diagnosed in adulthood)
notes: >-
Pathogenic regulatory and transcription-factor perturbations act during
corneal endothelial development, and endothelial cell density reduction and
posterior corneal lesions are already present in childhood, though mild
asymptomatic cases may only be detected later on routine examination.
evidence:
- reference: PMID:26749309
reference_title: "Autosomal-Dominant Corneal Endothelial Dystrophies CHED1 and PPCD1 Are Allelic Disorders Caused by Non-coding Mutations in the Promoter of OVOL2."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "we postulate that the mutations identified create cryptic cis-acting regulatory sequence binding sites that drive aberrant OVOL2 expression during endothelial cell development"
explanation: Indicates that the pathogenic transcriptional perturbation begins during corneal endothelial development.
- reference: PMID:33608638
reference_title: "Endothelial cell density in children with posterior polymorphous corneal dystrophy: a longitudinal case-control study."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Patients with PPCD had significantly lower endothelial cell densities (ECD) at recruitment (1918.9 ± 666.3 vs. 3340.1 ± 286.5 cells/mm2, p < 0.007)"
explanation: Demonstrates that significantly reduced corneal endothelial cell density is already established in childhood in pediatric PPCD patients compared with age-matched controls.
- reference: PMID:28613630
reference_title: "Posterior Polymorphous Corneal Dystrophy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Corneal edema associated with PPCM may be evident at a very young age. However, the majority of patients are asymptomatic and diagnosis occurs years later at the time of a routine ocular health examination ."
explanation: Confirms that corneal manifestations may be present at a very young age while most patients remain asymptomatic until routine ocular examination later in life.
- phase: Progression
age_range: Childhood through adulthood
notes: >-
Although baseline endothelial cell density is markedly reduced in affected
eyes, longitudinal pediatric follow-up shows that the subsequent annual rate
of endothelial cell decline does not significantly differ from healthy
controls, consistent with an early developmental endothelial deficit that is
often non-progressive or only slowly progressive.
evidence:
- reference: PMID:33608638
reference_title: "Endothelial cell density in children with posterior polymorphous corneal dystrophy: a longitudinal case-control study."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "However, the rates of annual ECD decline were not significantly different between eyes with PPCD in general, between the subgroups of PPCD and the normative groups."
explanation: Longitudinal pediatric data show that after an initial reduction in endothelial cell density, the annual rate of cell loss parallels normative controls.
- reference: PMID:28613630
reference_title: "Posterior Polymorphous Corneal Dystrophy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Corneal findings are either nonprogressive or very slowly progressive ."
explanation: Summarizes the clinical course of PPCD as nonprogressive or very slowly progressive.
pathophysiology:
- name: Corneal Endothelial-to-Epithelial Transdifferentiation
description: >-
The central, convergent mechanism of PPCD. Normal corneal endothelial cells
are post-mitotic, neural-crest-derived cells with a hexagonal monolayer
morphology. In PPCD, the endothelium undergoes metaplasia toward an
epithelial-like phenotype, acquiring epithelial morphology, epithelial gene
expression (E-cadherin, cytokeratin 7), microvilli, and an aberrant
proliferative/migratory behavior. These cells can overgrow the trabecular
meshwork and iris. The cell-state switch reflects dysregulation of the
ZEB1 EMT axis: ZEB1 normally maintains the mesenchymal/endothelial state by
repressing epithelial genes, while OVOL2 and GRHL2 are EMT-suppressing
transcription factors that repress ZEB1 and drive
mesenchymal-to-epithelial transition (MET). Loss of ZEB1 (PPCD3) or ectopic
activation of OVOL2 (PPCD1) or GRHL2 (PPCD4) all push the endothelium toward
the epithelial state, explaining the indistinguishable phenotypes.
cell_types:
- preferred_term: Corneal endothelial cell undergoing epithelial-like transdifferentiation
term:
id: CL:0000132
label: corneal endothelial cell
modifier: ABNORMAL
biological_processes:
- preferred_term: Aberrant mesenchymal-to-epithelial transition of the endothelium
term:
id: GO:0060231
label: mesenchymal to epithelial transition
modifier: ABNORMAL
- preferred_term: Dysregulated epithelial-to-mesenchymal transition control
term:
id: GO:0010717
label: regulation of epithelial to mesenchymal transition
modifier: ABNORMAL
evidence:
- reference: PMID:16252232
reference_title: "Mutations in TCF8 cause posterior polymorphous corneal dystrophy and ectopic expression of COL4A3 by corneal endothelial cells."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "a rare disease involving metaplasia and overgrowth of corneal endothelial cells. In patients with PPCD, these cells manifest in an epithelial morphology and gene expression pattern"
explanation: Directly describes the endothelial-to-epithelial metaplasia central to PPCD.
- reference: PMID:29499165
reference_title: "Ectopic GRHL2 Expression Due to Non-coding Mutations Promotes Cell State Transition and Causes Posterior Polymorphous Corneal Dystrophy 4."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "These cells were also positive for epithelial markers E-Cadherin and Cytokeratin 7, indicating they have transitioned to an epithelial-like cell type. We suggest that mutations inducing MET within the corneal endothelium are a convergent pathogenic mechanism"
explanation: Demonstrates epithelial-marker expression in PPCD endothelium and the convergent MET mechanism.
- reference: PMID:31194824
reference_title: "ZEB1 insufficiency causes corneal endothelial cell state transition and altered cellular processing."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Transcriptomic and functional studies support the hypothesis that CEnC undergo a MET-like transition in PPCD, termed endothelial to epithelial transition (EnET)"
explanation: A CRISPR ZEB1-knockout corneal endothelial cell model defines the endothelial-to-epithelial transition (EnET) as the cell-state mechanism of PPCD.
- reference: PMID:31194824
reference_title: "ZEB1 insufficiency causes corneal endothelial cell state transition and altered cellular processing."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "PPCD is characterized by a cadherin-switch and transition to an epithelial-like transcriptomic and cellular phenotype"
explanation: Documents the cadherin switch and epithelial-like transcriptomic phenotype underlying PPCD transdifferentiation.
downstream:
- target: Aberrant Descemet Membrane Deposition
causal_link_type: DIRECT
description: >-
Epithelial-like transdifferentiated corneal endothelial cells secrete
ectopic basement-membrane collagens and deposit an aberrant multilaminar
Descemet membrane.
evidence:
- reference: PMID:16252232
reference_title: "Mutations in TCF8 cause posterior polymorphous corneal dystrophy and ectopic expression of COL4A3 by corneal endothelial cells."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In patients with PPCD, these cells manifest in an epithelial morphology and gene expression pattern, produce an aberrant basement membrane, and, sometimes, spread over the iris and nearby structures in a way that increases the risk for glaucoma."
explanation: Links the epithelial-like endothelial transdifferentiation to aberrant Descemet basement-membrane deposition.
- target: Iridocorneal Adhesion and Anterior Chamber Distortion
causal_link_type: DIRECT
description: >-
Proliferative, epithelial-like endothelial cells migrate across the
iridocorneal angle and onto the iris surface, forming adhesions and
distorting anterior chamber structures.
evidence:
- reference: PMID:16252232
reference_title: "Mutations in TCF8 cause posterior polymorphous corneal dystrophy and ectopic expression of COL4A3 by corneal endothelial cells."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "sometimes, spread over the iris and nearby structures in a way that increases the risk for glaucoma"
explanation: Shows that transdifferentiated endothelial cells spread over the iris and anterior chamber structures.
- target: Abnormal corneal endothelium morphology
causal_link_type: DIRECT
description: >-
Endothelial-to-epithelial transdifferentiation directly alters the
normal hexagonal corneal endothelial monolayer into an epithelial-like
cell layer.
evidence:
- reference: PMID:16252232
reference_title: "Mutations in TCF8 cause posterior polymorphous corneal dystrophy and ectopic expression of COL4A3 by corneal endothelial cells."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "these cells manifest in an epithelial morphology and gene expression pattern"
explanation: Directly connects endothelial metaplasia to abnormal corneal endothelial morphology.
- target: Reduced corneal endothelial cell density
causal_link_type: DIRECT
description: >-
Abnormal endothelial differentiation and lesion formation at the
posterior cornea result in significantly reduced endothelial cell density.
evidence:
- reference: PMID:33608638
reference_title: "Endothelial cell density in children with posterior polymorphous corneal dystrophy: a longitudinal case-control study."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Patients with PPCD had significantly lower endothelial cell densities (ECD) at recruitment (1918.9 ± 666.3 vs. 3340.1 ± 286.5 cells/mm2, p < 0.007)"
explanation: Demonstrates significantly lower corneal endothelial cell density in eyes with PPCD endothelial pathology.
- name: ZEB1 EMT-Axis Transcription Factor Dysregulation
description: >-
PPCD-associated genes encode transcription factors that regulate
cell-state transitions and converge on ZEB1. ZEB1 (PPCD3) loss-of-function
causes haploinsufficiency that derepresses epithelial genes. OVOL2 (PPCD1)
and GRHL2 (PPCD4) are EMT-suppressing factors that directly repress ZEB1
and are normally absent from the corneal endothelium; PPCD mutations cause
their ectopic expression. Transcriptomic and immunohistochemical studies of
PPCD endothelium show decreased ZEB1, increased OVOL2/GRHL2, and aberrant
activation of the Wnt signaling pathway (nuclear accumulation of
phospho-beta-catenin), consistent with a shared GRHL2-OVOL2-ZEB1 axis
disturbance.
genes:
- preferred_term: OVOL2
term:
id: hgnc:15804
label: OVOL2
- preferred_term: ZEB1
term:
id: hgnc:11642
label: ZEB1
- preferred_term: GRHL2
term:
id: hgnc:2799
label: GRHL2
molecular_functions:
- preferred_term: DNA-binding transcription factor activity, RNA polymerase II-specific
modifier: ABNORMAL
term:
id: GO:0000981
label: DNA-binding transcription factor activity, RNA polymerase II-specific
biological_processes:
- preferred_term: Dysregulated RNA polymerase II transcriptional regulation
term:
id: GO:0006357
label: regulation of transcription by RNA polymerase II
modifier: ABNORMAL
- preferred_term: Aberrant Wnt signaling activation
term:
id: GO:0016055
label: Wnt signaling pathway
modifier: INCREASED
evidence:
- reference: PMID:31233731
reference_title: "Alterations in GRHL2-OVOL2-ZEB1 axis and aberrant activation of Wnt signaling lead to altered gene transcription in posterior polymorphous corneal dystrophy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Each of these genes encodes a transcription factor that regulates cell-state transitions."
explanation: Confirms the three PPCD genes are cell-state-transition transcription factors converging on a shared axis.
- reference: PMID:31233731
reference_title: "Alterations in GRHL2-OVOL2-ZEB1 axis and aberrant activation of Wnt signaling lead to altered gene transcription in posterior polymorphous corneal dystrophy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "indicating aberrant activation of Wnt signaling, which was not observed in control corneal endothelium"
explanation: Demonstrates aberrant Wnt signaling activation in PPCD endothelium.
- reference: PMID:26749309
reference_title: "Autosomal-Dominant Corneal Endothelial Dystrophies CHED1 and PPCD1 Are Allelic Disorders Caused by Non-coding Mutations in the Promoter of OVOL2."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "OVOL2 encodes ovo-like zinc finger 2, a C2H2 zinc-finger transcription factor that regulates mesenchymal-to-epithelial transition and acts as a direct transcriptional repressor of the established PPCD-associated gene ZEB1"
explanation: Establishes OVOL2 as a direct repressor of ZEB1, anchoring the convergent axis.
downstream:
- target: Corneal Endothelial-to-Epithelial Transdifferentiation
causal_link_type: DIRECT
description: >-
Loss of ZEB1 function or ectopic repression of ZEB1 by OVOL2 or GRHL2
derepresses epithelial genes and drives mesenchymal-to-epithelial
transition in the corneal endothelium.
evidence:
- reference: PMID:29499165
reference_title: "Ectopic GRHL2 Expression Due to Non-coding Mutations Promotes Cell State Transition and Causes Posterior Polymorphous Corneal Dystrophy 4."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "These cells were also positive for epithelial markers E-Cadherin and Cytokeratin 7, indicating they have transitioned to an epithelial-like cell type. We suggest that mutations inducing MET within the corneal endothelium are a convergent pathogenic mechanism"
explanation: Demonstrates that GRHL2-OVOL2-ZEB1 axis mutations drive endothelial-to-epithelial transition.
- target: Inguinal hernia
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
In PPCD3, heterozygous loss-of-function mutations in ZEB1 (TCF8) are
clinically associated with abdominal and inguinal hernias through an
incompletely defined extraocular mechanism.
evidence:
- reference: PMID:17935237
reference_title: "Posterior polymorphous corneal dystrophy is associated with TCF8 gene mutations and abdominal hernia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "the presence of apparently causative TCF8 mutations is associated with abdominal and inguinal hernias"
explanation: Connects ZEB1 (TCF8) loss-of-function in PPCD3 to extraocular inguinal and abdominal hernias.
- name: Aberrant Descemet Membrane Deposition
description: >-
The transdifferentiated, epithelial-like endothelium produces an abnormal,
thickened, multilaminar basement membrane (Descemet membrane) with
posterior collagenous layers. In ZEB1-related PPCD, loss of ZEB1
transcriptional repression leads to ectopic expression of basement-membrane
collagen COL4A3 (collagen type IV alpha 3) by corneal endothelial cells, a
target shared with the Alport syndrome COL4A3 gene. This aberrant matrix
underlies the characteristic vesicular, band-like, and geographic opacities
at the level of Descemet membrane seen clinically.
cell_types:
- preferred_term: Corneal endothelial cell
term:
id: CL:0000132
label: corneal endothelial cell
biological_processes:
- preferred_term: Aberrant basement membrane assembly
term:
id: GO:0070831
label: basement membrane assembly
modifier: ABNORMAL
evidence:
- reference: PMID:16252232
reference_title: "Mutations in TCF8 cause posterior polymorphous corneal dystrophy and ectopic expression of COL4A3 by corneal endothelial cells."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "produce an aberrant basement membrane"
explanation: PPCD endothelial cells deposit an aberrant basement membrane (Descemet membrane).
- reference: PMID:16252232
reference_title: "Mutations in TCF8 cause posterior polymorphous corneal dystrophy and ectopic expression of COL4A3 by corneal endothelial cells."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "we present immunohistochemical evidence of ectopic expression of COL4A3 in corneal endothelium of the proband of the original PPCD3 family"
explanation: Documents ectopic COL4A3 basement-membrane collagen expression in PPCD3 endothelium.
downstream:
- target: Abnormal Descemet membrane morphology
causal_link_type: DIRECT
description: >-
Ectopic basement-membrane collagen synthesis and multilaminar matrix
deposition directly produce an abnormal Descemet membrane morphology.
evidence:
- reference: PMID:16252232
reference_title: "Mutations in TCF8 cause posterior polymorphous corneal dystrophy and ectopic expression of COL4A3 by corneal endothelial cells."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "produce an aberrant basement membrane"
explanation: Aberrant basement-membrane deposition directly manifests as abnormal Descemet membrane morphology.
- target: Polymorphous posterior corneal dystrophy
causal_link_type: DIRECT
description: >-
Aberrant Descemet membrane deposition together with the metaplastic
endothelium produces the vesicular, band-like, and geographic posterior
corneal lesions characteristic of PPCD.
evidence:
- reference: PMID:16252232
reference_title: "Mutations in TCF8 cause posterior polymorphous corneal dystrophy and ectopic expression of COL4A3 by corneal endothelial cells."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In patients with PPCD, these cells manifest in an epithelial morphology and gene expression pattern, produce an aberrant basement membrane"
explanation: Links aberrant basement-membrane production by metaplastic endothelial cells to the clinical PPCD phenotype.
- target: Corneal opacity
causal_link_type: DIRECT
description: >-
Thickened, aberrant Descemet membrane layers and posterior vesicular and
gray-white plaque lesions directly produce opacification of the posterior
cornea.
evidence:
- reference: PMID:28613630
reference_title: "Posterior Polymorphous Corneal Dystrophy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
directness: DIRECT
snippet: "In PPCD, the Descemet basement membrane laid down by endothelial cells is abnormally thickened. Groupings of blister-like vesicles and gray-white plaques lead to opacification of the posterior cornea."
explanation: Directly connects the abnormally thickened Descemet basement membrane and posterior vesicular/plaque lesions to opacification of the posterior cornea.
- name: Iridocorneal Adhesion and Anterior Chamber Distortion
description: >-
The proliferative, migratory epithelial-like endothelium can extend across
the iridocorneal angle and over the iris surface, secreting abnormal
basement membrane that produces iridocorneal/peripheral anterior synechiae,
corectopia (pupillary displacement), and pupillary ectropion. Overgrowth and
membrane formation across the trabecular meshwork impede aqueous outflow,
increasing the risk of secondary glaucoma.
cell_types:
- preferred_term: Epithelial-like (transdifferentiated) corneal endothelial cell
term:
id: CL:0000132
label: corneal endothelial cell
modifier: ABNORMAL
evidence:
- reference: PMID:16252232
reference_title: "Mutations in TCF8 cause posterior polymorphous corneal dystrophy and ectopic expression of COL4A3 by corneal endothelial cells."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "sometimes, spread over the iris and nearby structures in a way that increases the risk for glaucoma"
explanation: Endothelial overgrowth onto the iris and angle increases glaucoma risk.
- reference: PMID:28613630
reference_title: "Posterior Polymorphous Corneal Dystrophy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Rather than confining themselves to the posterior surface of the cornea, the aberrant endothelial cells can migrate erratically across the chamber angle and onto the peripheral iris surface. Abnormal basement membrane is secreted, creating iridocorneal adhesions and a glass-like appearance that can be appreciated gonioscopically. On the iris surface, this membrane can lead to corectopia and pupillary ectropion."
explanation: Details how aberrant endothelial migration across the chamber angle and secretion of abnormal basement membrane on the iris surface produce iridocorneal adhesions and corectopia.
downstream:
- target: Secondary Glaucoma
causal_link_type: DIRECT
description: >-
Overgrowth of epithelial-like endothelial cells and iridocorneal
adhesions across the trabecular meshwork obstruct aqueous outflow,
causing secondary glaucoma.
evidence:
- reference: PMID:16252232
reference_title: "Mutations in TCF8 cause posterior polymorphous corneal dystrophy and ectopic expression of COL4A3 by corneal endothelial cells."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "sometimes, spread over the iris and nearby structures in a way that increases the risk for glaucoma"
explanation: Connects endothelial spread over the iris and angle structures to secondary glaucoma.
- target: Iridocorneal adhesions
causal_link_type: DIRECT
description: >-
Migration of the abnormal endothelium across the anterior chamber angle
and secretion of abnormal basement membrane directly form peripheral
anterior synechiae and iridocorneal adhesions.
evidence:
- reference: PMID:28613630
reference_title: "Posterior Polymorphous Corneal Dystrophy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
directness: DIRECT
snippet: "Rather than confining themselves to the posterior surface of the cornea, the aberrant endothelial cells can migrate erratically across the chamber angle and onto the peripheral iris surface. Abnormal basement membrane is secreted, creating iridocorneal adhesions and a glass-like appearance that can be appreciated gonioscopically."
explanation: Directly states that aberrant endothelial migration across the chamber angle and secretion of abnormal basement membrane create iridocorneal adhesions.
- target: Corectopia
causal_link_type: DIRECT
description: >-
Migration of aberrant endothelial cells onto the peripheral iris surface
and secretion of an abnormal basement membrane across the iris directly
lead to corectopia and pupillary ectropion.
evidence:
- reference: PMID:28613630
reference_title: "Posterior Polymorphous Corneal Dystrophy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
directness: DIRECT
snippet: "Abnormal basement membrane is secreted, creating iridocorneal adhesions and a glass-like appearance that can be appreciated gonioscopically. On the iris surface, this membrane can lead to corectopia and pupillary ectropion."
explanation: Directly links the abnormal basement membrane secreted on the iris surface to corectopia and pupillary ectropion.
- name: Secondary Glaucoma
description: >-
Obstruction of aqueous humor outflow by the abnormal endothelium and
associated iridocorneal adhesions/membranes raises intraocular pressure,
leading to secondary (often angle-closure or membrane-associated) glaucoma,
a major cause of visual morbidity in PPCD.
evidence:
- reference: PMID:16252232
reference_title: "Mutations in TCF8 cause posterior polymorphous corneal dystrophy and ectopic expression of COL4A3 by corneal endothelial cells."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "spread over the iris and nearby structures in a way that increases the risk for glaucoma"
explanation: Links the endothelial overgrowth mechanism to secondary glaucoma.
downstream:
- target: Glaucoma
causal_link_type: DIRECT
description: >-
Elevated intraocular pressure from angle obstruction by the abnormal
endothelium manifests clinically as secondary glaucoma.
evidence:
- reference: PMID:16252232
reference_title: "Mutations in TCF8 cause posterior polymorphous corneal dystrophy and ectopic expression of COL4A3 by corneal endothelial cells."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "spread over the iris and nearby structures in a way that increases the risk for glaucoma"
explanation: Directly supports the clinical glaucoma phenotype resulting from secondary angle involvement.
phenotypes:
- name: Polymorphous posterior corneal dystrophy
category: Ophthalmologic
description: >-
The defining clinical sign: polymorphous (vesicular, band-like, and
geographic/diffuse) opacities at the level of Descemet membrane and the
posterior cornea, reflecting the abnormal transdifferentiated endothelium
and aberrant Descemet membrane.
phenotype_term:
preferred_term: Polymorphous posterior corneal dystrophy
term:
id: HP:0007915
label: Polymorphous posterior corneal dystrophy
evidence:
- reference: PMID:16252232
reference_title: "Mutations in TCF8 cause posterior polymorphous corneal dystrophy and ectopic expression of COL4A3 by corneal endothelial cells."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Posterior polymorphous corneal dystrophy (PPCD, also known as PPMD) is a rare disease involving metaplasia and overgrowth of corneal endothelial cells."
explanation: Establishes the disease entity defined by the posterior polymorphous corneal lesions.
- name: Abnormal corneal endothelium morphology
category: Ophthalmologic
description: >-
The corneal endothelium shows metaplastic, epithelial-like morphology with
loss of the normal hexagonal monolayer architecture.
phenotype_term:
preferred_term: Abnormal corneal endothelium morphology
term:
id: HP:0011488
label: Abnormal corneal endothelium morphology
evidence:
- reference: PMID:16252232
reference_title: "Mutations in TCF8 cause posterior polymorphous corneal dystrophy and ectopic expression of COL4A3 by corneal endothelial cells."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "these cells manifest in an epithelial morphology and gene expression pattern"
explanation: PPCD endothelial cells show abnormal epithelial-like morphology.
- name: Reduced corneal endothelial cell density
category: Ophthalmologic
description: >-
Quantitative reduction in corneal endothelial cell density (ECD). A
longitudinal pediatric case-control study found markedly lower ECD in PPCD
than in age-matched controls, with the lowest densities in diffuse-type
disease and eyes with many posterior corneal lesions.
phenotype_term:
preferred_term: Reduced corneal endothelial cell density
term:
id: HP:0011491
label: Reduced number of corneal endothelial cells
evidence:
- reference: PMID:33608638
reference_title: "Endothelial cell density in children with posterior polymorphous corneal dystrophy: a longitudinal case-control study."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Patients with PPCD had significantly lower endothelial cell densities (ECD) at recruitment (1918.9 ± 666.3 vs. 3340.1 ± 286.5 cells/mm2, p < 0.007)"
explanation: Quantitatively documents reduced corneal endothelial cell density in PPCD versus controls.
- name: Abnormal Descemet membrane morphology
category: Ophthalmologic
description: >-
Aberrant, thickened, multilaminar Descemet membrane produced by the
transdifferentiated endothelium.
phenotype_term:
preferred_term: Abnormal Descemet membrane morphology
term:
id: HP:0011490
label: Abnormal Descemet membrane morphology
evidence:
- reference: PMID:16252232
reference_title: "Mutations in TCF8 cause posterior polymorphous corneal dystrophy and ectopic expression of COL4A3 by corneal endothelial cells."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "produce an aberrant basement membrane"
explanation: The aberrant basement membrane corresponds to abnormal Descemet membrane.
- name: Corneal opacity
category: Ophthalmologic
description: >-
Posterior and, in severe cases, diffuse corneal opacity from the abnormal
endothelium, Descemet changes, and corneal edema.
phenotype_term:
preferred_term: Corneal opacity
term:
id: HP:0007957
label: Corneal opacity
evidence:
- reference: PMID:28613630
reference_title: "Posterior Polymorphous Corneal Dystrophy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "In PPCD, the Descemet basement membrane laid down by endothelial cells is abnormally thickened. Groupings of blister-like vesicles and gray-white plaques lead to opacification of the posterior cornea."
explanation: Directly documents that thickened Descemet membrane and grouped vesicular/plaque lesions produce posterior corneal opacification in PPCD.
- reference: PMID:26749309
reference_title: "Autosomal-Dominant Corneal Endothelial Dystrophies CHED1 and PPCD1 Are Allelic Disorders Caused by Non-coding Mutations in the Promoter of OVOL2."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
snippet: "CHED1 represents the extreme of what can be considered a disease spectrum"
explanation: PPCD1 lies on an allelic spectrum with CHED1, whose severe extreme presents with diffuse corneal clouding/opacity.
- name: Glaucoma
category: Ophthalmologic
description: >-
Secondary glaucoma arising from endothelial overgrowth across the
iridocorneal angle and iris with impaired aqueous outflow.
phenotype_term:
preferred_term: Glaucoma
term:
id: HP:0000501
label: Glaucoma
evidence:
- reference: PMID:16252232
reference_title: "Mutations in TCF8 cause posterior polymorphous corneal dystrophy and ectopic expression of COL4A3 by corneal endothelial cells."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "spread over the iris and nearby structures in a way that increases the risk for glaucoma"
explanation: Directly links PPCD pathology to increased glaucoma risk.
- name: Corectopia
category: Ophthalmologic
description: >-
Corectopia (displaced/distorted pupil) associated with iridocorneal
adhesions and abnormal basement membrane secretion on the iris surface from
endothelial overgrowth.
phenotype_term:
preferred_term: Corectopia
term:
id: HP:0009918
label: Ectopia pupillae
evidence:
- reference: PMID:28613630
reference_title: "Posterior Polymorphous Corneal Dystrophy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Abnormal basement membrane is secreted, creating iridocorneal adhesions and a glass-like appearance that can be appreciated gonioscopically. On the iris surface, this membrane can lead to corectopia and pupillary ectropion."
explanation: Directly documents that abnormal basement membrane secretion on the iris surface leads to corectopia and pupillary ectropion in PPCD.
- reference: PMID:16252232
reference_title: "Mutations in TCF8 cause posterior polymorphous corneal dystrophy and ectopic expression of COL4A3 by corneal endothelial cells."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
snippet: "spread over the iris and nearby structures"
explanation: Endothelial spread over the iris and anterior chamber structures provides the cellular substrate for iris distortion in PPCD.
- name: Iridocorneal adhesions
category: Ophthalmologic
description: >-
Iridocorneal/peripheral anterior synechiae from migration of the abnormal
endothelium across the angle and onto the iris.
phenotype_term:
preferred_term: Iridocorneal adhesions
term:
id: HP:0011483
label: Anterior synechiae of the anterior chamber
evidence:
- reference: PMID:28613630
reference_title: "Posterior Polymorphous Corneal Dystrophy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Rather than confining themselves to the posterior surface of the cornea, the aberrant endothelial cells can migrate erratically across the chamber angle and onto the peripheral iris surface. Abnormal basement membrane is secreted, creating iridocorneal adhesions and a glass-like appearance that can be appreciated gonioscopically."
explanation: Directly documents iridocorneal adhesions created by migrating aberrant endothelial cells and abnormal basement membrane secretion in PPCD.
- reference: PMID:16252232
reference_title: "Mutations in TCF8 cause posterior polymorphous corneal dystrophy and ectopic expression of COL4A3 by corneal endothelial cells."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
snippet: "spread over the iris and nearby structures"
explanation: Endothelial spread over the iris and angle underlies the formation of iridocorneal adhesions (anterior synechiae).
- name: Inguinal hernia
category: Extraocular
subtype: PPCD3
description: >-
Inguinal/abdominal hernias occur at significantly increased frequency in
individuals with ZEB1 (TCF8)-associated PPCD3.
phenotype_term:
preferred_term: Inguinal hernia
term:
id: HP:0000023
label: Inguinal hernia
evidence:
- reference: PMID:17935237
reference_title: "Posterior polymorphous corneal dystrophy is associated with TCF8 gene mutations and abdominal hernia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "the presence of apparently causative TCF8 mutations is associated with abdominal and inguinal hernias"
explanation: Establishes increased inguinal/abdominal hernia frequency in ZEB1-related PPCD3.
genetic:
- name: OVOL2
subtype: PPCD1
notes: >-
Mutations in the proximal promoter of OVOL2 cause PPCD1 by driving ectopic
OVOL2 expression in the corneal endothelium. OVOL2 promotes
mesenchymal-to-epithelial transition and directly represses ZEB1.
gene_term:
preferred_term: OVOL2
term:
id: hgnc:15804
label: OVOL2
evidence:
- reference: PMID:26749309
reference_title: "Autosomal-Dominant Corneal Endothelial Dystrophies CHED1 and PPCD1 Are Allelic Disorders Caused by Non-coding Mutations in the Promoter of OVOL2."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "we postulate that the mutations identified create cryptic cis-acting regulatory sequence binding sites that drive aberrant OVOL2 expression during endothelial cell development"
explanation: OVOL2 promoter mutations drive aberrant endothelial OVOL2 expression, causing PPCD1.
- name: ZEB1
subtype: PPCD3
notes: >-
Heterozygous nonsense/frameshift loss-of-function mutations in ZEB1
(formerly TCF8) cause PPCD3 via haploinsufficiency, accounting for about a
quarter to a third of PPCD families and associated with extraocular hernias
as well as incomplete penetrance in population cohorts.
gene_term:
preferred_term: ZEB1
term:
id: hgnc:11642
label: ZEB1
evidence:
- reference: PMID:16252232
reference_title: "Mutations in TCF8 cause posterior polymorphous corneal dystrophy and ectopic expression of COL4A3 by corneal endothelial cells."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "this study has identified TCF8 as the gene responsible for approximately half of the cases of PPCD"
explanation: Establishes ZEB1 (TCF8) as a major PPCD (PPCD3) gene.
- reference: PMID:33946386
reference_title: "Non-Penetrance for Ocular Phenotype in Two Individuals Carrying Heterozygous Loss-of-Function ZEB1 Alleles."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "ZEB1 loss-of-function (LoF) alleles are known to cause a rare autosomal dominant disorder-posterior polymorphous corneal dystrophy type 3 (PPCD3)."
explanation: Confirms ZEB1 loss-of-function alleles as the cause of PPCD3; the study also documents reduced/incomplete penetrance.
- reference: PMID:33946386
reference_title: "Non-Penetrance for Ocular Phenotype in Two Individuals Carrying Heterozygous Loss-of-Function ZEB1 Alleles."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "GnomAD (n = 141,456 subjects) was also interrogated for LoF ZEB1 variants, notably 8 distinct heterozygous changes presumed to lead to ZEB1 haploinsufficiency, not reported to be associated with PPCD3, have been identified. The NM_030751.6 transcript has a pLI score ≥ 0.99, indicating extreme intolerance to haploinsufficiency. In conclusion, ZEB1 LoF variants are present in a general population at an extremely low frequency. As PPCD3 can be asymptomatic, the true penetrance of ZEB1 LoF variants remains currently unknown but is likely to be lower than estimated by the familial led approaches adopted to date."
explanation: Documents 8 heterozygous ZEB1 loss-of-function variants across 141,456 gnomAD subjects and high LoF intolerance (pLI >= 0.99), supporting incomplete penetrance of ZEB1 alleles in the general population.
- name: COL8A2
subtype: PPCD2
presence: PRESENT
relationship_type: UNKNOWN
variant_origin: GERMLINE
notes: >-
MONDO defines PPCD2 by COL8A2, but the PPCD association rests on one
missense substitution in a single family reported alongside the
early-onset Fuchs dystrophy COL8A2 variants, and the 2020 PPCD clinical
utility gene card does not include COL8A2. The relationship is recorded as
UNKNOWN rather than CAUSATIVE, and the gene is deliberately not placed on
the ZEB1-axis transdifferentiation node, which describes a different
mechanism. COL8A2 is an established early-onset Fuchs endothelial corneal
dystrophy gene, curated in that entry.
gene_term:
preferred_term: COL8A2
term:
id: hgnc:2216
label: COL8A2
evidence:
- reference: PMID:11689488
reference_title: "Missense mutations in COL8A2, the gene encoding the alpha2 chain of type VIII collagen, cause two forms of corneal endothelial dystrophy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Mutation analysis in patients with FECD and PPCD demonstrated further missense substitutions in familial and sporadic cases of FECD as well as in a single family with PPCD."
explanation: The single-family report on which the COL8A2-PPCD association rests.
- name: GRHL2
subtype: PPCD4
notes: >-
Non-coding (intronic regulatory) mutations in GRHL2 cause PPCD4 by inducing
ectopic GRHL2 expression in the corneal endothelium. GRHL2 suppresses EMT
and is a direct transcriptional repressor of ZEB1.
gene_term:
preferred_term: GRHL2
term:
id: hgnc:2799
label: GRHL2
evidence:
- reference: PMID:29499165
reference_title: "Ectopic GRHL2 Expression Due to Non-coding Mutations Promotes Cell State Transition and Causes Posterior Polymorphous Corneal Dystrophy 4."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "GRHL2 is a transcription factor that suppresses epithelial-to-mesenchymal transition (EMT) and is a direct transcriptional repressor of ZEB1."
explanation: Establishes GRHL2 as a PPCD4 gene acting through the EMT/ZEB1 axis.
treatments:
- name: Observation
description: >-
Most individuals with PPCD are asymptomatic and require only periodic
monitoring of corneal status and intraocular pressure rather than active
intervention.
treatment_term:
preferred_term: watchful waiting
term:
id: NCIT:C15747
label: Supportive Care
evidence:
- reference: PMID:33608638
reference_title: "Endothelial cell density in children with posterior polymorphous corneal dystrophy: a longitudinal case-control study."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "children with PPCD were followed with slit-lamp photography and non-contact specular microscopy"
explanation: Reflects real-world longitudinal monitoring (slit-lamp and specular microscopy follow-up) of PPCD patients, consistent with observation as the baseline management of mild/asymptomatic disease.
- name: Corneal Transplantation
description: >-
For symptomatic PPCD with corneal decompensation/edema, corneal
transplantation (endothelial keratoplasty such as DSEK/DMEK, or penetrating
keratoplasty) replaces the dysfunctional endothelium and Descemet membrane.
treatment_term:
preferred_term: corneal transplantation
term:
id: NCIT:C210959
label: Corneal Transplantation
evidence:
- reference: PMID:29499165
reference_title: "Ectopic GRHL2 Expression Due to Non-coding Mutations Promotes Cell State Transition and Causes Posterior Polymorphous Corneal Dystrophy 4."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "leading to dysfunction of the endothelial barrier and disease"
explanation: PPCD produces endothelial-barrier dysfunction; when this decompensates the cornea, corneal transplantation (endothelial keratoplasty or penetrating keratoplasty) replaces the dysfunctional endothelium and Descemet membrane (clinical-management context).
- name: Antiglaucoma Therapy
description: >-
Medical and/or surgical management of secondary glaucoma to control
intraocular pressure in PPCD patients with angle involvement.
treatment_term:
preferred_term: antiglaucoma agent therapy
term:
id: NCIT:C15986
label: Pharmacotherapy
evidence:
- reference: PMID:16252232
reference_title: "Mutations in TCF8 cause posterior polymorphous corneal dystrophy and ectopic expression of COL4A3 by corneal endothelial cells."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "increases the risk for glaucoma"
explanation: Increased glaucoma risk in PPCD motivates antiglaucoma management of affected patients.
- name: Genetic Counseling
description: >-
Genetic counseling for affected families given autosomal-dominant
inheritance and the availability of diagnostic gene testing for OVOL2,
ZEB1, and GRHL2.
treatment_term:
preferred_term: Genetic Counseling
term:
id: NCIT:C15240
label: Genetic Counseling
evidence:
- reference: PMID:31201376
reference_title: "CUGC for posterior polymorphous corneal dystrophy (PPCD)."
supports: SUPPORT
evidence_source: OTHER
snippet: "DNA-based testing for variants in theOVOL2, ZEB1andGRHL2gene(s) in a diagnostic setting, predictive and parental settings"
explanation: The Clinical Utility Gene Card supports diagnostic/predictive gene testing and counseling for PPCD families.
biochemical:
- name: Ectopic corneal endothelial E-cadherin (CDH1) and Cytokeratin 7 (KRT7) expression
presence: ELEVATED
context: Corneal endothelium immunohistochemistry and transcriptomics
notes: >-
Normal corneal endothelial cells express N-cadherin and lack epithelial
cytokeratins; in PPCD, transdifferentiated endothelial cells undergo a
cadherin switch with immunohistochemical positivity for E-cadherin and
Cytokeratin 7.
evidence:
- reference: PMID:29499165
reference_title: "Ectopic GRHL2 Expression Due to Non-coding Mutations Promotes Cell State Transition and Causes Posterior Polymorphous Corneal Dystrophy 4."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "These cells were also positive for epithelial markers E-Cadherin and Cytokeratin 7, indicating they have transitioned to an epithelial-like cell type."
explanation: Confirms ectopic expression of epithelial biomarkers E-cadherin and Cytokeratin 7 in PPCD corneal endothelium.
- name: Ectopic corneal endothelial COL4A3 expression
presence: ELEVATED
context: Corneal endothelium and Descemet membrane immunohistochemistry
subtype: PPCD3
notes: >-
Loss of ZEB1 repression in PPCD3 derepresses the ZEB1 target gene COL4A3,
leading to ectopic collagen IV alpha 3 expression in the corneal endothelium
and aberrant Descemet membrane deposition.
evidence:
- reference: PMID:16252232
reference_title: "Mutations in TCF8 cause posterior polymorphous corneal dystrophy and ectopic expression of COL4A3 by corneal endothelial cells."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "we present immunohistochemical evidence of ectopic expression of COL4A3 in corneal endothelium of the proband of the original PPCD3 family"
explanation: Demonstrates ectopic COL4A3 protein expression in PPCD3 corneal endothelium.
- name: Corneal endothelial nuclear phospho-beta-catenin (S552) accumulation
presence: ELEVATED
context: Corneal endothelium immunohistochemistry
notes: >-
PPCD corneal endothelium exhibits nuclear accumulation of S552
phosphorylated beta-catenin and cytosolic localization of S33/37/T42
non-phosphorylated beta-catenin, reflecting aberrant activation of canonical
Wnt signaling downstream of GRHL2-OVOL2-ZEB1 axis dysregulation.
evidence:
- reference: PMID:31233731
reference_title: "Alterations in GRHL2-OVOL2-ZEB1 axis and aberrant activation of Wnt signaling lead to altered gene transcription in posterior polymorphous corneal dystrophy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Immunohistochemistry results demonstrated corneal endothelial nuclear accumulation of S552 phos-β-catenin and cytosolic localization of S33/37/T42 non-phosphorylated β-catenin in PPCD, indicating aberrant activation of Wnt signaling, which was not observed in control corneal endothelium."
explanation: Documents nuclear S552 phospho-beta-catenin accumulation in PPCD corneal endothelium as a biomarker of aberrant Wnt pathway activation.
diagnosis:
- name: Slit-lamp biomicroscopy
diagnosis_term:
preferred_term: Slit-lamp Examination
term:
id: NCIT:C75583
label: Slit-lamp Examination
description: >-
Primary clinical examination used to detect and classify the characteristic
polymorphous posterior corneal lesions (vesicular, band-like, or diffuse
geographic opacities) at the level of Descemet membrane and to evaluate for
iridocorneal adhesions or corectopia.
results: >-
Reveals bilateral or asymmetric vesicular, band-like ("railroad track"), or
diffuse opacities at the posterior cornea and Descemet membrane.
evidence:
- reference: PMID:28613630
reference_title: "Posterior Polymorphous Corneal Dystrophy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "The appearance of the opacities at the Descemet membrane may be characterized by one of three different distribution patterns; vesicular, band-like or diffuse. These polymorphous lesions may be visualized at the slit lamp biomicroscope with moderate to high magnification using direct or, preferentially, retro-illumination techniques."
explanation: Documents the three classic slit-lamp biomicroscopy lesion patterns of PPCD at the posterior cornea and Descemet membrane.
- reference: PMID:33608638
reference_title: "Endothelial cell density in children with posterior polymorphous corneal dystrophy: a longitudinal case-control study."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In this prospective case-control study, children with PPCD were followed with slit-lamp photography and non-contact specular microscopy."
explanation: Documents slit-lamp photography and biomicroscopy as standard diagnostic and monitoring tools for PPCD.
- name: Non-contact specular microscopy
diagnosis_term:
preferred_term: Non-Contact Specular Microscopy
term:
id: NCIT:C120697
label: Non-Contact Specular Microscopy
description: >-
Non-contact in vivo endothelial imaging that quantifies corneal endothelial
cell density (ECD) and assesses endothelial cell morphology across PPCD
phenotypic subtypes.
results: >-
Demonstrates significantly reduced endothelial cell density (particularly in
diffuse-type PPCD and eyes with 5 or more posterior corneal lesions),
pleomorphism, and polymegathism compared with age-matched controls.
evidence:
- reference: PMID:33608638
reference_title: "Endothelial cell density in children with posterior polymorphous corneal dystrophy: a longitudinal case-control study."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The lowest ECDs were found in eyes with diffuse type PPCD and those with ≥5 posterior corneal lesions, while clinically unaffected eyes in patients with confirmed PPCD in fellow eye had a normal ECD."
explanation: Demonstrates the diagnostic utility of non-contact specular microscopy in quantifying endothelial cell density reduction across morphological subtypes of PPCD.
- name: In vivo confocal microscopy
diagnosis_term:
preferred_term: Confocal Microscopy
term:
id: NCIT:C17753
label: Confocal Microscopy
description: >-
High-resolution in vivo confocal imaging of the corneal layers used to
visualize microstructural abnormalities of the posterior cornea, Descemet
membrane, and endothelium without requiring histopathologic tissue biopsy.
results: >-
Reveals vesicular, band-like, or diffuse posterior corneal lesions and
multilayered epithelial-like endothelial changes at Descemet membrane in
vivo.
evidence:
- reference: PMID:25564336
reference_title: "IC3D classification of corneal dystrophies--edition 2."
supports: SUPPORT
evidence_source: OTHER
snippet: "Confocal microscopy also has emerged as a helpful tool to reveal in vivo features of several corneal dystrophies that previously required histopathologic examination to definitively diagnose."
explanation: The IC3D consensus classification highlights in vivo confocal microscopy as a non-invasive diagnostic tool for corneal dystrophies.
- name: Molecular genetic testing of OVOL2, ZEB1, and GRHL2
diagnosis_term:
preferred_term: genetic testing
term:
id: NCIT:C15709
label: Genetic Testing
description: >-
DNA-based sequencing and copy-number analysis covering the coding regions of
ZEB1 (PPCD3) and the non-coding promoter/intronic regulatory regions of
OVOL2 (PPCD1) and GRHL2 (PPCD4) for molecular subtype confirmation,
predictive testing, and family risk assessment.
results: >-
Identifies heterozygous loss-of-function variants or deletions in ZEB1,
proximal promoter variants in OVOL2, or intronic regulatory variants in
GRHL2.
evidence:
- reference: PMID:31201376
reference_title: "CUGC for posterior polymorphous corneal dystrophy (PPCD)."
supports: SUPPORT
evidence_source: OTHER
snippet: "Review of the analytical and clinical validity as well as of the clinical utility of DNA-based testing for variants in theOVOL2, ZEB1andGRHL2gene(s) in a diagnostic setting, predictive and parental settings"
explanation: Establishes the diagnostic and predictive utility of targeted genetic testing of OVOL2, ZEB1, and GRHL2 in PPCD.
differential_diagnoses:
- name: Fuchs endothelial corneal dystrophy
disease_term:
preferred_term: Fuchs' endothelial dystrophy
term:
id: MONDO:0005321
label: Fuchs' endothelial dystrophy
description: >-
Adult-onset, bilateral corneal endothelial dystrophy characterized by
progressive endothelial cell attrition and central Descemet membrane
excrescences (cornea guttata) rather than endothelial-to-epithelial
transdifferentiation.
distinguishing_features:
- Later adult onset (typically fifth to sixth decade) with central confluent guttae rather than congenital/childhood vesicular or railroad-track band lesions
- Driven by endothelial cell loss and oxidative/unfolded-protein stress (commonly TCF4 repeat expansion or SLC4A11/COL8A2 variants) without confirmed causal role of ZEB1
- Absence of epithelial-like endothelial metaplasia, iridocorneal adhesions, or corectopia
evidence:
- reference: PMID:37441688
reference_title: "Systematic review of SLC4A11, ZEB1, LOXHD1, and AGBL1 variants in the development of Fuchs' endothelial corneal dystrophy."
supports: SUPPORT
evidence_source: OTHER
snippet: "Our analysis confirmed the causal role of SLC4A11 variants in the development of FECD. The causal role of ZEB1, LOXHD1, and AGBL1 variants in FECD has not been confirmed."
explanation: Systematic review confirms that ZEB1 variants do not have a confirmed causal role in Fuchs endothelial corneal dystrophy, supporting genetic and nosologic separation from PPCD3.
- name: Congenital hereditary endothelial dystrophy 1
description: >-
Severe autosomal-dominant corneal endothelial dystrophy mapped to chromosome
20p11.2 that is allelic with PPCD1 and caused by distinct non-coding
variants in the OVOL2 promoter (historically designated CHED1 in the prior
IC3D classification and now subsumed within the severe spectrum of PPCD1).
distinguishing_features:
- Presents at birth or in early infancy with diffuse, bilateral ground-glass corneal clouding and marked stromal thickening rather than focal vesicular or band lesions
- Represents the severe extreme of the OVOL2-associated endothelial dystrophy spectrum
evidence:
- reference: PMID:26749309
reference_title: "Autosomal-Dominant Corneal Endothelial Dystrophies CHED1 and PPCD1 Are Allelic Disorders Caused by Non-coding Mutations in the Promoter of OVOL2."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "CHED1 represents the extreme of what can be considered a disease spectrum"
explanation: Demonstrates that CHED1 and PPCD1 are allelic OVOL2 promoter disorders distinguished by CHED1 representing the severe extreme of the disease spectrum.
- name: Alport syndrome
disease_term:
preferred_term: Alport syndrome
term:
id: MONDO:0018965
label: Alport syndrome
description: >-
Hereditary basement membrane disorder caused by pathogenic variants in
COL4A3, COL4A4, or COL4A5 that can present with posterior polymorphous
corneal changes alongside systemic renal and auditory manifestations.
distinguishing_features:
- Systemic features including hematuria, progressive glomerulopathy/renal failure, and sensorineural hearing loss
- Characteristic non-corneal ocular signs including fleck retinopathy, temporal retinal thinning, and anterior lenticonus
- Caused by primary COL4A3/COL4A4/COL4A5 mutations rather than OVOL2, ZEB1, or GRHL2 variants (though ZEB1 regulates COL4A3 transcription in PPCD3)
evidence:
- reference: PMID:25649157
reference_title: "Ocular features in Alport syndrome: pathogenesis and clinical significance."
supports: SUPPORT
evidence_source: OTHER
snippet: "In contrast, the rarer ophthalmic complications of posterior polymorphous corneal dystrophy, giant macular hole, and maculopathy all produce visual loss."
explanation: Documents that posterior polymorphous corneal dystrophy can occur as a rarer ophthalmic manifestation in Alport syndrome.
- reference: PMID:16252232
reference_title: "Mutations in TCF8 cause posterior polymorphous corneal dystrophy and ectopic expression of COL4A3 by corneal endothelial cells."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Thus, this study has identified TCF8 as the gene responsible for approximately half of the cases of PPCD, has implicated TCF8 mutations in developmental abnormalities outside the eye, and has presented the TCF8 regulatory target, COL4A3, as a key, shared molecular component of two different diseases, PPCD and Alport syndrome."
explanation: Explains the shared COL4A3 basement-membrane molecular component linking isolated PPCD3 and Alport syndrome.
references:
- reference: PMID:11689488
title: "Missense mutations in COL8A2, the gene encoding the alpha2 chain of type VIII collagen, cause two forms of corneal endothelial dystrophy."
findings: []
- reference: PMID:16252232
title: "Mutations in TCF8 cause posterior polymorphous corneal dystrophy and ectopic expression of COL4A3 by corneal endothelial cells."
findings: []
- reference: PMID:17935237
title: "Posterior polymorphous corneal dystrophy is associated with TCF8 gene mutations and abdominal hernia."
findings: []
- reference: PMID:25564336
title: "IC3D classification of corneal dystrophies--edition 2."
found_in:
- Posterior_Polymorphous_Corneal_Dystrophy-deep-research-falcon.md
findings: []
- reference: PMID:25649157
title: "Ocular features in Alport syndrome: pathogenesis and clinical significance."
found_in:
- Posterior_Polymorphous_Corneal_Dystrophy-deep-research-falcon.md
findings: []
- reference: PMID:26749309
title: "Autosomal-Dominant Corneal Endothelial Dystrophies CHED1 and PPCD1 Are Allelic Disorders Caused by Non-coding Mutations in the Promoter of OVOL2."
found_in:
- Posterior_Polymorphous_Corneal_Dystrophy-deep-research-falcon.md
findings: []
- reference: PMID:28613630
title: "Posterior Polymorphous Corneal Dystrophy."
tags:
- StatPearls
findings: []
- reference: PMID:29499165
title: "Ectopic GRHL2 Expression Due to Non-coding Mutations Promotes Cell State Transition and Causes Posterior Polymorphous Corneal Dystrophy 4."
found_in:
- Posterior_Polymorphous_Corneal_Dystrophy-deep-research-falcon.md
findings: []
- reference: PMID:31194824
title: "ZEB1 insufficiency causes corneal endothelial cell state transition and altered cellular processing."
findings: []
- reference: PMID:31201376
title: "CUGC for posterior polymorphous corneal dystrophy (PPCD)."
found_in:
- Posterior_Polymorphous_Corneal_Dystrophy-deep-research-falcon.md
findings: []
- reference: PMID:31233731
title: "Alterations in GRHL2-OVOL2-ZEB1 axis and aberrant activation of Wnt signaling lead to altered gene transcription in posterior polymorphous corneal dystrophy."
found_in:
- Posterior_Polymorphous_Corneal_Dystrophy-deep-research-falcon.md
findings: []
- reference: PMID:33608638
title: "Endothelial cell density in children with posterior polymorphous corneal dystrophy: a longitudinal case-control study."
found_in:
- Posterior_Polymorphous_Corneal_Dystrophy-deep-research-falcon.md
findings: []
- reference: PMID:33946386
title: "Non-Penetrance for Ocular Phenotype in Two Individuals Carrying Heterozygous Loss-of-Function ZEB1 Alleles."
found_in:
- Posterior_Polymorphous_Corneal_Dystrophy-deep-research-falcon.md
findings: []
- reference: PMID:37441688
title: "Systematic review of SLC4A11, ZEB1, LOXHD1, and AGBL1 variants in the development of Fuchs' endothelial corneal dystrophy."
found_in:
- Posterior_Polymorphous_Corneal_Dystrophy-deep-research-falcon.md
findings: []
References & Deep Research
References
14Missense mutations in COL8A2, the gene encoding the alpha2 chain of type VIII collagen, cause two forms of corneal endothelial dystrophy.
No top-level findings curated for this source.
Mutations in TCF8 cause posterior polymorphous corneal dystrophy and ectopic expression of COL4A3 by corneal endothelial cells.
No top-level findings curated for this source.
Posterior polymorphous corneal dystrophy is associated with TCF8 gene mutations and abdominal hernia.
No top-level findings curated for this source.
IC3D classification of corneal dystrophies--edition 2.
No top-level findings curated for this source.
Ocular features in Alport syndrome: pathogenesis and clinical significance.
No top-level findings curated for this source.
Autosomal-Dominant Corneal Endothelial Dystrophies CHED1 and PPCD1 Are Allelic Disorders Caused by Non-coding Mutations in the Promoter of OVOL2.
No top-level findings curated for this source.
Posterior Polymorphous Corneal Dystrophy.
No top-level findings curated for this source.
Ectopic GRHL2 Expression Due to Non-coding Mutations Promotes Cell State Transition and Causes Posterior Polymorphous Corneal Dystrophy 4.
No top-level findings curated for this source.
ZEB1 insufficiency causes corneal endothelial cell state transition and altered cellular processing.
No top-level findings curated for this source.
CUGC for posterior polymorphous corneal dystrophy (PPCD).
No top-level findings curated for this source.
Alterations in GRHL2-OVOL2-ZEB1 axis and aberrant activation of Wnt signaling lead to altered gene transcription in posterior polymorphous corneal dystrophy.
No top-level findings curated for this source.
Endothelial cell density in children with posterior polymorphous corneal dystrophy: a longitudinal case-control study.
No top-level findings curated for this source.
Non-Penetrance for Ocular Phenotype in Two Individuals Carrying Heterozygous Loss-of-Function ZEB1 Alleles.
No top-level findings curated for this source.
Systematic review of SLC4A11, ZEB1, LOXHD1, and AGBL1 variants in the development of Fuchs' endothelial corneal dystrophy.
No top-level findings curated for this source.
Deep Research
1Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.
Evaluations and curation notes (1)
Review and enhance Posterior Polymorphous Corneal Dystrophy · 2026-10-16T22:55:00Z · View source
Reviewed Posterior Polymorphous Corneal Dystrophy (MONDO:0020364) against the deep-research report (Posterior_Polymorphous_Corneal_Dystrophy-deep-research-falcon.md) and cached PubMed references (including StatPearls PMID:28613630). Added classifications, prevalence, progression, biochemical markers (ectopic E-cadherin/Cytokeratin 7, COL4A3, and nuclear S552 phospho-beta-catenin), separate diagnostic modalities (slit-lamp biomicroscopy, non-contact specular microscopy, in vivo confocal microscopy, and OVOL2/ZEB1/GRHL2 genetic testing), differential diagnoses (Fuchs endothelial corneal dystrophy, congenital hereditary endothelial dystrophy 1, and Alport syndrome), and bibliography references; wired OVOL2, ZEB1, and GRHL2 with GO:0000981 molecular_functions on the ZEB1 EMT-axis node; moved the gnomAD ZEB1 LoF allele frequency snippet (PMID:33946386) from prevalence to genetic ZEB1; and strengthened direct clinical evidence and causal_link_type annotations across downstream phenotype edges.
Falcon
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1. Disease Information
1.1 Concise overview
Posterior polymorphous corneal dystrophy (PPCD) is a rare autosomal dominant corneal endothelial dystrophy characterized by abnormal corneal endothelial cell morphology and posterior corneal/Descemet membrane changes that can be clinically visible as vesicular lesions, band/“snail‑track/rail‑track” changes, and/or diffuse posterior opacities, with variable severity from asymptomatic findings to corneal edema, secondary glaucoma, and need for corneal transplantation. (Human clinical) (fung2021endothelialcelldensity pages 1-2, davidson2016autosomaldominantcornealendothelial pages 1-3, liskova2018ectopicgrhl2expression pages 6-7, davidson2020cugcforposterior pages 1-2)
1.2 Key identifiers
- OMIM disease IDs (PPCD subtypes): 122000; 609141; 618031 (davidson2020cugcforposterior pages 1-2)
- Genes and OMIM gene IDs: OVOL2 (616441), ZEB1 (189909), GRHL2 (608576) (davidson2020cugcforposterior pages 1-2)
- IC3D classification context: IC3D “Edition 3” is a 2024 update that evaluated peer‑reviewed publications from 2014–2023 and provides standardized corneal dystrophy templates and a management table. URL in abstract: https://corneasociety.org/publications/ic3d (Published Feb 2024) (fung2021endothelialcelldensity pages 1-2)
MONDO / MeSH / ICD / Orphanet IDs: Not reliably extractable from the retrieved documents in this session; therefore they are not asserted here.
1.3 Common synonyms / alternative names
- Posterior polymorphous corneal dystrophy
- Often discussed by genetic subtypes: PPCD1, PPCD3, PPCD4 (davidson2020cugcforposterior pages 1-2)
1.4 Source type (aggregated vs patient-level)
- Aggregated resources: IC3D classification (2024) (fung2021endothelialcelldensity pages 1-2)
- Aggregated clinical genetics guidance: CUGC for PPCD (2020) (davidson2020cugcforposterior pages 1-2)
- Patient-level primary data: OVOL2 families (AJHG 2016), GRHL2 families (AJHG 2018), ZEB1 non‑penetrance family (Genes 2021), pediatric longitudinal cohort (Eye 2021), family case report with variants (Frontiers Genet 2025) (fung2021endothelialcelldensity pages 2-4, davidson2016autosomaldominantcornealendothelial pages 6-8, liskova2018ectopicgrhl2expression pages 6-7, dudakova2021nonpenetranceforocular pages 1-2, lin2025polymorphouscornealdystrophy pages 2-3)
2. Etiology
2.1 Primary causes (genetic)
PPCD is predominantly caused by autosomal dominant variants affecting transcriptional regulators of epithelial/mesenchymal cell state: - PPCD1: non‑coding promoter mutations in OVOL2 (gain of promoter activity) (davidson2016autosomaldominantcornealendothelial pages 1-3, chung2017confirmationofthe pages 5-7) - PPCD3: ZEB1 haploinsufficiency / loss‑of‑function variants (dudakova2021nonpenetranceforocular pages 1-2, siddiqui2016geneticanalysisof pages 42-46) - PPCD4: non‑coding regulatory variants in GRHL2 causing increased transcription and ectopic endothelial expression (liskova2018ectopicgrhl2expression pages 1-2, liskova2018ectopicgrhl2expression pages 8-9)
Historically proposed loci such as COL8A2 have shown inconsistent replication across cohorts, suggesting weaker/uncertain evidence for a general PPCD2 mechanism in many populations. (siddiqui2016geneticanalysisof pages 42-46)
2.2 Risk factors
- Genetic risk factors: carrying a pathogenic/likely pathogenic variant in OVOL2 promoter, ZEB1 LoF, or GRHL2 regulatory region (davidson2016autosomaldominantcornealendothelial pages 1-3, liskova2018ectopicgrhl2expression pages 1-2, dudakova2021nonpenetranceforocular pages 1-2)
- Iatrogenic/clinical risk context: Reduced endothelial reserve may increase vulnerability to intraocular surgery; pediatric cohort emphasizes lower baseline endothelial cell density (ECD). (Human clinical) (fung2021endothelialcelldensity pages 2-4)
- Corneal refractive surgery context: A three‑generation family report describes keratoconus aggravation after SMILE in individuals later diagnosed with PPCD3 and carrying ZEB1/ZNF469 variants, supporting caution and pre‑operative corneal evaluation/genetic screening in suspected familial disease. (Human clinical) (lin2025polymorphouscornealdystrophy pages 2-3)
2.3 Protective factors
No specific genetic or environmental protective factors were identified in the retrieved evidence.
2.4 Gene–environment interactions
No PPCD-specific gene–environment interaction studies were identified in the retrieved evidence.
3. Phenotypes (with suggested HPO terms)
3.1 Core corneal/endothelial phenotypes
Posterior corneal lesions / Descemet abnormalities - Clinical lesion patterns: vesicular, band/snail-track, diffuse posterior corneal opacities (fung2021endothelialcelldensity pages 1-2, fung2021endothelialcelldensity pages 2-4) - Suggested HPO (examples): - Abnormality of the cornea (HP:0000481) - Corneal opacity (HP:0007957) - Corneal dystrophy (HP:0001117)
Reduced corneal endothelial cell density (ECD) (key quantitative phenotype) - Pediatric longitudinal case-control study (mean age 10.5 years; follow-up ~3 years): - Baseline ECD: 1918.9 ± 666.3 cells/mm² (PPCD) vs 3340.1 ± 286.5 cells/mm² (controls) - Final ECD: 1793.1 ± 684.6 (PPCD) vs 3265.2 ± 304.3 (controls) - Annual ECD loss: 1.9 ± 3.7% per year, not significantly different from controls (p=0.95) (Human clinical) (fung2021endothelialcelldensity pages 2-4) - Suggested HPO: - Abnormality of the corneal endothelium (no specific code provided here; map at curation time)
Visual impairment / amblyopia risk - PPCD can be asymmetric in children and may contribute to amblyopia via unilateral/asymmetric involvement. (Human clinical) (fung2021endothelialcelldensity pages 5-6) - Suggested HPO: - Reduced visual acuity (HP:0007663) - Amblyopia (HP:0000649)
3.2 Glaucoma and anterior segment abnormalities
- OVOL2-linked families: secondary glaucoma reported at approximately ~30% in one dataset excerpt. (Human clinical) (davidson2016autosomaldominantcornealendothelial pages 6-8)
- GRHL2/PPCD4 Czech series: glaucoma in 25.9% (mean diagnosis ~46 years). (Human clinical) (liskova2018ectopicgrhl2expression pages 6-7)
- Iris abnormalities/adhesions noted in OVOL2-linked disease descriptions (ectropion uveae/corectopia/adhesions). (Human clinical) (davidson2016autosomaldominantcornealendothelial pages 1-3)
- Suggested HPO:
- Glaucoma (HP:0000501)
- Corectopia (HP:0000579)
- Anterior segment dysgenesis (HP:0000591)
3.3 Course, onset, progression
- Disease expression ranges from asymptomatic to severe corneal edema requiring transplantation; infants may rarely present with early corneal edema/haze. (Human clinical) (fung2021endothelialcelldensity pages 1-2, liskova2018ectopicgrhl2expression pages 6-7)
- In pediatric PPCD, no corneal edema or ectasia occurred during ~3 years follow-up, despite lower ECD. (Human clinical) (fung2021endothelialcelldensity pages 1-2)
3.4 Quality of life impact
A prospective case-control study of non-Fuchs corneal dystrophies (2021–2024 recruitment; included 3 PPCD patients) found significantly worse quality of life scores vs controls using VF-14 and NEI-VFQ, correlated with visual acuity and higher-order aberrations. (Human clinical) (elhardt2025 study retrieval; PPCD-specific subgroup results not extractable in retrieved snippets) (lin2025polymorphouscornealdystrophy pages 5-7)
4. Genetic / Molecular Information
4.1 Causal genes (established)
- OVOL2 (PPCD1): promoter mutations (non-coding) (davidson2016autosomaldominantcornealendothelial pages 1-3, chung2017confirmationofthe pages 5-7)
- ZEB1 (PPCD3): LoF/haploinsufficiency (dudakova2021nonpenetranceforocular pages 1-2, siddiqui2016geneticanalysisof pages 42-46)
- GRHL2 (PPCD4): intronic/5′ regulatory mutations (liskova2018ectopicgrhl2expression pages 1-2, liskova2018ectopicgrhl2expression pages 6-7)
4.2 Pathogenic variant classes and examples
- OVOL2 promoter: c.-307T>C segregates in PPCD1-linked family and increases promoter activity in corneal endothelial cells. (Human clinical / in vitro promoter assay) (chung2017confirmationofthe pages 5-7)
- GRHL2 intron 1 regulatory: c.20+544G>T; c.20+257delT; c.20+133delA; all associated with increased transcriptional activity in luciferase assays. (Human genetics / in vitro) (liskova2018ectopicgrhl2expression pages 1-2, liskova2018ectopicgrhl2expression pages 8-9)
- ZEB1 LoF: example c.1279C>T p.(Glu427) reported in non-penetrant carriers; population data suggest extreme rarity but presence of LoF alleles in gnomAD. (Human genetics*) (dudakova2021nonpenetranceforocular pages 1-2)
4.3 Inheritance, penetrance, expressivity
- Inheritance: autosomal dominant (davidson2020cugcforposterior pages 1-2)
- Penetrance: Familial studies for ZEB1 LoF suggest ~95% penetrance, but documented non-penetrance indicates true penetrance may be lower. (dudakova2021nonpenetranceforocular pages 1-2)
- Expressivity: highly variable, ranging from asymptomatic endothelial findings to corneal edema and transplantation. (davidson2016autosomaldominantcornealendothelial pages 1-3, liskova2018ectopicgrhl2expression pages 6-7)
4.4 Modifier genes
A 2025 family report suggests potential interaction of ZEB1 variants with ZNF469 (ECM regulation; brittle cornea syndrome gene) in a family with PPCD3 and keratoconus aggravation; ZEB1 variant allele frequency noted as ~1e-5 in gnomAD EAS. (Human clinical) (lin2025polymorphouscornealdystrophy pages 3-5, lin2025polymorphouscornealdystrophy pages 2-3)
4.5 Epigenetic / chromosomal abnormalities
No PPCD-specific epigenetic signatures were identified in retrieved evidence; however, disease causality is frequently driven by cis-regulatory non-coding variants (OVOL2, GRHL2) (davidson2016autosomaldominantcornealendothelial pages 1-3, liskova2018ectopicgrhl2expression pages 1-2).
5. Environmental Information
No PPCD-specific environmental, lifestyle, or infectious causal factors were identified in the retrieved evidence.
6. Mechanism / Pathophysiology
6.1 Core concept: endothelial-to-epithelial transition (EnET) as a MET-like process
Frausto et al. developed a CRISPR ZEB1+/- corneal endothelial cell model and concluded that PPCD represents an MET-like transition termed endothelial-to-epithelial transition (EnET).
Direct abstract-supported statement (from retrieved abstract excerpt): PPCD is described as being “characterized by a cadherin-switch and transition to an epithelial-like transcriptomic and cellular phenotype” in the context of ZEB1 insufficiency. (In vitro / transcriptomics) (frausto2019zeb1insufficiencycauses pages 1-2)
6.2 Regulatory network: OVOL2 / GRHL2 repress ZEB1
- OVOL2 promoter mutations increase promoter activity and are interpreted as causing ectopic/increased OVOL2 expression; OVOL2 “directly represses ZEB1.” (Human genetics / in vitro promoter assay) (davidson2016autosomaldominantcornealendothelial pages 1-3, davidson2016autosomaldominantcornealendothelial pages 11-13)
- GRHL2 regulatory variants cause ectopic endothelial GRHL2 expression; diseased endothelium can express epithelial markers (E-cadherin, CK7) consistent with MET. (Human ex vivo / in vitro) (liskova2018ectopicgrhl2expression pages 8-9, liskova2018ectopicgrhl2expression pages 7-8)
6.3 Causal chain (variant → phenotype)
1) Non-coding promoter/intronic variants (OVOL2/GRHL2) or ZEB1 LoF → 2) Reduced ZEB1 function/expression (direct LoF or repression by OVOL2/GRHL2) → 3) EnET / epithelialization of corneal endothelium (cadherin switch; epithelial gene expression; stratification) → 4) Abnormal Descemet membrane and endothelial morphology, reduced endothelial reserve → 5) Corneal edema/opacification and angle/iris abnormalities, predisposing to secondary glaucoma and sometimes keratoplasty. (davidson2016autosomaldominantcornealendothelial pages 1-3, liskova2018ectopicgrhl2expression pages 6-7, frausto2019zeb1insufficiencycauses pages 1-2)
6.4 Biochemical abnormalities
Aqueous humor study (ELISA) found active TGF‑β2 significantly higher in PPCD patients (mean 386.98 ± 114.88 pg/mL) vs controls (mean 260.95 ± 112.43 pg/mL; P=0.0001). (Human clinical samples) (chung2017confirmationofthe pages 2-4)
6.5 Suggested ontology annotations
- Cell types (CL):
- Corneal endothelial cell (curation to CL term)
- Corneal epithelial cell (curation to CL term)
- Anatomy (UBERON):
- Corneal endothelium, Descemet membrane, cornea (curation to UBERON terms)
- Processes (GO):
- Epithelial to mesenchymal transition (GO:0001837)
- Mesenchymal to epithelial transition (GO:XXXXXXX; commonly represented as MET/epithelialization processes)
- Cell fate commitment / cell differentiation
- Cell adhesion
7. Anatomical Structures Affected
- Primary: corneal endothelium and Descemet membrane (fung2021endothelialcelldensity pages 1-2, davidson2016autosomaldominantcornealendothelial pages 1-3)
- Secondary/complications: iridocorneal angle/iris (adhesions/corectopia) and glaucoma risk (davidson2016autosomaldominantcornealendothelial pages 1-3, liskova2018ectopicgrhl2expression pages 6-7)
8. Temporal Development
- Onset: can be recognized in childhood; rare infantile onset with edema/haze reported in PPCD4 series; OVOL2 allelic CHED1/PPCD1 can present from infancy with haze. (liskova2018ectopicgrhl2expression pages 6-7, davidson2016autosomaldominantcornealendothelial pages 5-6)
- Progression: variable; pediatric ECD decline similar to controls over ~3 years suggests slow change in childhood despite low baseline ECD. (fung2021endothelialcelldensity pages 2-4)
9. Inheritance and Population
9.1 Epidemiology
- Prevalence estimate: Czech prevalence reported as ~1 per 80,000. (davidson2020cugcforposterior pages 1-2)
- Broader prevalence is poorly defined; PPCD is consistently described as rare. (davidson2020cugcforposterior pages 1-2)
9.2 Population genetics and founder effects
- Founder effects are noted in the CUGC context (details not fully extractable here). (davidson2020cugcforposterior pages 1-2)
- Example allele frequency (illustrative, not definitive for PPCD causality): ZEB1 p.P5A variant reported with gnomAD EAS frequency ~0.00001 in a family study. (lin2025polymorphouscornealdystrophy pages 3-5)
10. Diagnostics
10.1 Clinical and imaging tests used in practice
- Slit-lamp biomicroscopy for posterior corneal lesions (chung2017confirmationofthe pages 5-7)
- Specular microscopy for rail-track/snail-track and endothelial morphology; ECD quantification (fung2021endothelialcelldensity pages 2-4, fernandezgutierrez2022posteriorpolymorphouscorneal pages 1-2)
- In vivo confocal microscopy (posterior lesions; abnormal/absent endothelial cells; hyperreflective deposits) (fung2021endothelialcelldensity pages 5-6)
- OCT / anterior segment imaging including SD‑OCT (posterior reflectivity, Descemet protrusion) (liskova2018ectopicgrhl2expression pages 6-7)
- Corneal tomography (Pentacam) used in complex/overlap phenotypes (e.g., keratoconus) (lin2025polymorphouscornealdystrophy pages 2-3)
10.2 Genetic testing approach (authoritative guidance)
CUGC recommends genome sequencing as the most comprehensive approach because PPCD includes structural and non-coding variants across OVOL2, ZEB1, and GRHL2; Sanger validation and CNV methods may be required to confirm ZEB1 haploinsufficiency and define breakpoints. (davidson2020cugcforposterior pages 1-2)
10.3 Differential diagnosis
Not systematically extractable from retrieved documents; however, PPCD overlaps clinically with other corneal endothelial dystrophies and with anterior segment dysgenesis entities.
11. Outcome / Prognosis
- Many patients remain mildly affected; however, substantial minorities require surgery.
- Keratoplasty proportion:
- OVOL2-linked cohorts: about one-third underwent keratoplasty in an excerpted dataset (davidson2016autosomaldominantcornealendothelial pages 6-8)
- GRHL2/PPCD4 Czech series: 25.9% underwent corneal transplantation (mean first surgery ~35 years) (liskova2018ectopicgrhl2expression pages 6-7)
- Glaucoma: GRHL2/PPCD4 Czech series: 25.9% (liskova2018ectopicgrhl2expression pages 6-7)
12. Treatment
12.1 Current standard management (real-world)
- Observation/monitoring: visual acuity, endothelial reserve, glaucoma surveillance, amblyopia/strabismus monitoring in children. (davidson2020cugcforposterior pages 4-5)
- Glaucoma management: medical drops and/or drainage surgery when needed. (davidson2020cugcforposterior pages 4-5)
- Corneal transplantation: performed for corneal edema/endothelial failure; includes penetrating keratoplasty historically and increasing use of endothelial keratoplasty in endothelial diseases broadly (PPCD infant endothelial keratoplasty reported). (davidson2016autosomaldominantcornealendothelial pages 5-6, fung2021endothelialcelldensity pages 5-6)
12.2 MAXO suggestions
- Corneal transplantation (MAXO: term for keratoplasty)
- Endothelial keratoplasty (MAXO: term for lamellar endothelial keratoplasty)
- Topical intraocular pressure-lowering therapy (MAXO: term for glaucoma medication)
- Glaucoma surgery (MAXO: term for aqueous shunt/trabeculectomy procedures)
12.3 Clinical trials
ClinicalTrials.gov search performed within this session did not retrieve PPCD-specific therapeutic trials among the returned set. (trial search results not PPCD-relevant) (fung2021endothelialcelldensity pages 1-2)
13. Prevention
- No primary prevention strategies exist for Mendelian PPCD.
- Secondary/tertiary prevention: family screening, genetic counseling, monitoring for glaucoma/amblyopia; avoidance of high-risk elective corneal procedures without adequate endothelial evaluation in suspected familial disease. (davidson2020cugcforposterior pages 4-5, lin2025polymorphouscornealdystrophy pages 2-3)
14. Other Species / Natural Disease
No naturally occurring PPCD in non-human species was identified in retrieved evidence.
15. Model Organisms and Experimental Systems
15.1 In vitro models
- CRISPR ZEB1+/- corneal endothelial cell model recapitulates epithelial-like shift, EnET concept, and transcriptomic PPCD signatures; ZEB1 reconstitution rescues phenotype, suggesting therapeutic plausibility in principle. (In vitro) (frausto2019zeb1insufficiencycauses pages 2-3, frausto2019zeb1insufficiencycauses pages 14-16)
15.2 Mouse models
- PPCD1 mouse model (DBA/2J background; D2.Ppcd1): enlarged anterior chamber due to endothelial epithelialization/proliferation and angle blockage; increased IOP and downstream retinal pathology were reported. (Model organism) (shen2017retinalpathologyin pages 11-12)
Key quantitative data highlights (for knowledge base ingestion)
- Pediatric PPCD ECD baseline: 1918.9 ± 666.3 cells/mm² vs controls 3340.1 ± 286.5 (fung2021endothelialcelldensity pages 2-4)
- Pediatric PPCD annual ECD loss: ~1.9 ± 3.7%/year, similar to controls (fung2021endothelialcelldensity pages 2-4)
- GRHL2/PPCD4 series: 25.9% keratoplasty; 25.9% glaucoma (liskova2018ectopicgrhl2expression pages 6-7)
- OVOL2-linked cohorts excerpt: ~30% secondary glaucoma; ~one-third keratoplasty (davidson2016autosomaldominantcornealendothelial pages 6-8)
- Aqueous humor active TGF‑β2: 386.98 ± 114.88 pg/mL (PPCD) vs 260.95 ± 112.43 pg/mL (controls), P=0.0001 (chung2017confirmationofthe pages 2-4)
Visual evidence (ECD by lesion subtype)
Cropped tables/figures from the pediatric longitudinal cohort show ECD stratification by lesion subtype and longitudinal trends. (fung2021endothelialcelldensity media 4fa8c68b, fung2021endothelialcelldensity media 5637544d)
Genetics summary artifact
The following table compares PPCD subtypes, variant classes, mechanisms, and complication frequencies.
| Subtype / OMIM disease ID | Gene (OMIM gene ID) | Variant types / hotspots (example) | Molecular mechanism | Key clinical features / complications | Key supporting citations |
|---|---|---|---|---|---|
| PPCD1 / OMIM 122000 | OVOL2 (OMIM 616441) | Non-coding promoter variants in a conserved proximal promoter region; examples: c.-307T>C, c.-274T>G, c.-370T>C; related severe allelic CHED1 family with c.-339_361dup | Promoter variants increase OVOL2 transcriptional activity, causing ectopic/increased OVOL2 expression in corneal endothelium; OVOL2 is a MET-promoting transcription factor that represses ZEB1, driving endothelial cell-state transition toward epithelial-like phenotype | Typical PPCD posterior corneal lesions (vesicles/bands/gray-white opacities), endothelial dysfunction, corneal edema/haze, iris abnormalities/adhesions, secondary glaucoma risk; ~20–25% of affected individuals may require corneal transplantation in PPCD overall; in OVOL2-linked families, ~30% secondary glaucoma and about one-third underwent keratoplasty; severe early-onset/founder families may present from infancy and need repeated grafting. Czech prevalence estimate for PPCD overall: ~1 per 80,000 | (davidson2016autosomaldominantcornealendothelial pages 1-3, davidson2016autosomaldominantcornealendothelial pages 11-13, davidson2016autosomaldominantcornealendothelial pages 6-8, chung2017confirmationofthe pages 1-2, davidson2020cugcforposterior pages 1-2) |
| PPCD3 / OMIM 609141 | ZEB1 (OMIM 189909) | Predominantly heterozygous loss-of-function variants: nonsense, frameshift, splice, whole-gene/partial deletions; example: c.1279C>T p.Glu427*; rare missense variants also reported in some families | ZEB1 haploinsufficiency causes a MET-like endothelial-to-epithelial transition (EnET) with a cadherin switch (↓CDH2, ↑CDH1), epithelial-like transcriptome, altered adhesion/proliferation/migration, and endothelial stratification | Bilateral often asymmetric PPCD lesions, reduced endothelial cell density, occasional corectopia/iridocorneal synechiae, association with corneal steepening/ectasia in some cases; PPCD3 is often milder than OVOL2-linked disease but variable. Familial studies suggest ~95% penetrance, yet documented non-penetrance exists, so true penetrance may be lower. ZEB1 LoF alleles are extremely rare in population databases | (frausto2019zeb1insufficiencycauses pages 1-2, frausto2019zeb1insufficiencycauses pages 13-14, frausto2019zeb1insufficiencycauses pages 2-3, dudakova2021nonpenetranceforocular pages 1-2, dudakova2021nonpenetranceforocular pages 2-4) |
| PPCD4 / OMIM 618031 | GRHL2 (OMIM 608576) | Non-coding regulatory / intron 1 variants; examples: c.20+544G>T, c.20+257delT, c.20+133delA | Regulatory variants increase GRHL2 transcription, causing ectopic GRHL2 expression in corneal endothelium; GRHL2 promotes epithelial identity and represses/acts upstream of ZEB1, producing MET-like transition with epithelial markers (e.g., E-cadherin, CK7) | Typical PPCD lesions with irregular posterior corneal surface, endothelial multilayering, corneal edema (including infantile onset in some), reduced endothelial cell density, corectopia/band keratopathy; in the large Czech series with recurrent variant, 25.9% underwent corneal transplantation and 25.9% developed glaucoma; mean first keratoplasty ~35 years, mean glaucoma diagnosis ~46 years | (liskova2018ectopicgrhl2expression pages 1-2, liskova2018ectopicgrhl2expression pages 6-7, liskova2018ectopicgrhl2expression pages 9-10, liskova2018ectopicgrhl2expression pages 8-9, davidson2020cugcforposterior pages 1-2) |
Table: This table summarizes the main genetically supported PPCD subtypes—OVOL2/PPCD1, ZEB1/PPCD3, and GRHL2/PPCD4—covering variant classes, mechanisms, clinical complications, and the strongest available evidence. It is useful for quickly comparing subtype-specific diagnostic and counseling implications.
URLs and publication dates (where available in retrieved texts)
- Weiss et al. IC3D Classification of Corneal Dystrophies—Edition 3. Cornea. Feb 2024. https://doi.org/10.1097/ICO.0000000000003420 and online resource: https://corneasociety.org/publications/ic3d (fung2021endothelialcelldensity pages 1-2)
- Davidson et al. Autosomal-Dominant Corneal Endothelial Dystrophies CHED1 and PPCD1… OVOL2 promoter. Am J Hum Genet. Jan 2016. https://doi.org/10.1016/j.ajhg.2015.11.018 (davidson2016autosomaldominantcornealendothelial pages 1-3)
- Liskova et al. Ectopic GRHL2 expression… PPCD4. Am J Hum Genet. Mar 2018. https://doi.org/10.1016/j.ajhg.2018.02.002 (liskova2018ectopicgrhl2expression pages 1-2)
- Frausto et al. ZEB1 insufficiency… EnET. PLoS ONE. Feb 2019. https://doi.org/10.1371/journal.pone.0218279 (frausto2019zeb1insufficiencycauses pages 1-2)
- Davidson et al. CUGC for PPCD. Eur J Hum Genet. Jun 2020. https://doi.org/10.1038/s41431-019-0448-8 (davidson2020cugcforposterior pages 1-2)
- Fung et al. Endothelial cell density in children with PPCD. Eye. Feb 2021. https://doi.org/10.1038/s41433-021-01451-y (fung2021endothelialcelldensity pages 2-4)
- Dudakova et al. Non-penetrance… ZEB1 LoF. Genes. Apr 2021. https://doi.org/10.3390/genes12050677 (dudakova2021nonpenetranceforocular pages 1-2)
Limitations and gaps (explicit)
- MONDO/Orphanet/ICD/MeSH identifiers were not retrieved in the available evidence and are therefore not provided.
- 2023–2024 PPCD-specific primary studies were not prominently retrievable in this run beyond the IC3D 2024 classification update; consequently, “latest” advances are described using the best-available primary mechanistic/genetic sources (2016–2019) plus later clinical genetics guidance.
- Differential diagnosis and formal diagnostic criteria for PPCD (as distinct from FECD/ICE syndrome/anterior segment dysgenesis) require additional targeted retrieval beyond the current evidence set.
References
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(fung2021endothelialcelldensity pages 1-2): Simon Sheung Man Fung, Hamza Sami, Ali El Hamouly, Dishay Jiandani, Sara Williams, Kamiar Mireskandari, and Asim Ali. Endothelial cell density in children with posterior polymorphous corneal dystrophy: a longitudinal case-control study. Eye, 35:3397-3403, Feb 2021. URL: https://doi.org/10.1038/s41433-021-01451-y, doi:10.1038/s41433-021-01451-y. This article has 6 citations and is from a peer-reviewed journal.
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(davidson2016autosomaldominantcornealendothelial pages 1-3): Alice E. Davidson, Petra Liskova, Cerys J. Evans, Lubica Dudakova, Lenka Nosková, Nikolas Pontikos, Hana Hartmannová, Kateřina Hodaňová, Viktor Stránecký, Zbyněk Kozmík, Hannah J. Levis, Nwamaka Idigo, Noriaki Sasai, Geoffrey J. Maher, James Bellingham, Neyme Veli, Neil D. Ebenezer, Michael E. Cheetham, Julie T. Daniels, Caroline M.H. Thaung, Katerina Jirsova, Vincent Plagnol, Martin Filipec, Stanislav Kmoch, Stephen J. Tuft, and Alison J. Hardcastle. Autosomal-dominant corneal endothelial dystrophies ched1 and ppcd1 are allelic disorders caused by non-coding mutations in the promoter of ovol2. The American Journal of Human Genetics, 98:75-89, Jan 2016. URL: https://doi.org/10.1016/j.ajhg.2015.11.018, doi:10.1016/j.ajhg.2015.11.018. This article has 94 citations.
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(liskova2018ectopicgrhl2expression pages 6-7): Petra Liskova, Lubica Dudakova, Cerys J. Evans, Karla E. Rojas Lopez, Nikolas Pontikos, Dimitra Athanasiou, Hodan Jama, Josef Sach, Pavlina Skalicka, Viktor Stranecky, Stanislav Kmoch, Caroline Thaung, Martin Filipec, Michael E. Cheetham, Alice E. Davidson, Stephen J. Tuft, and Alison J. Hardcastle. Ectopic grhl2 expression due to non-coding mutations promotes cell state transition and causes posterior polymorphous corneal dystrophy 4. American Journal of Human Genetics, 102:447-459, Mar 2018. URL: https://doi.org/10.1016/j.ajhg.2018.02.002, doi:10.1016/j.ajhg.2018.02.002. This article has 59 citations and is from a highest quality peer-reviewed journal.
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(davidson2020cugcforposterior pages 1-2): Alice E. Davidson, Nathaniel J. Hafford-Tear, Lubica Dudakova, Amanda N. Sadan, Nikolas Pontikos, Alison J. Hardcastle, Stephen J. Tuft, and Petra Liskova. Cugc for posterior polymorphous corneal dystrophy (ppcd). European Journal of Human Genetics, 28:126-131, Jun 2020. URL: https://doi.org/10.1038/s41431-019-0448-8, doi:10.1038/s41431-019-0448-8. This article has 7 citations and is from a domain leading peer-reviewed journal.
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(fung2021endothelialcelldensity pages 2-4): Simon Sheung Man Fung, Hamza Sami, Ali El Hamouly, Dishay Jiandani, Sara Williams, Kamiar Mireskandari, and Asim Ali. Endothelial cell density in children with posterior polymorphous corneal dystrophy: a longitudinal case-control study. Eye, 35:3397-3403, Feb 2021. URL: https://doi.org/10.1038/s41433-021-01451-y, doi:10.1038/s41433-021-01451-y. This article has 6 citations and is from a peer-reviewed journal.
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(davidson2016autosomaldominantcornealendothelial pages 6-8): Alice E. Davidson, Petra Liskova, Cerys J. Evans, Lubica Dudakova, Lenka Nosková, Nikolas Pontikos, Hana Hartmannová, Kateřina Hodaňová, Viktor Stránecký, Zbyněk Kozmík, Hannah J. Levis, Nwamaka Idigo, Noriaki Sasai, Geoffrey J. Maher, James Bellingham, Neyme Veli, Neil D. Ebenezer, Michael E. Cheetham, Julie T. Daniels, Caroline M.H. Thaung, Katerina Jirsova, Vincent Plagnol, Martin Filipec, Stanislav Kmoch, Stephen J. Tuft, and Alison J. Hardcastle. Autosomal-dominant corneal endothelial dystrophies ched1 and ppcd1 are allelic disorders caused by non-coding mutations in the promoter of ovol2. The American Journal of Human Genetics, 98:75-89, Jan 2016. URL: https://doi.org/10.1016/j.ajhg.2015.11.018, doi:10.1016/j.ajhg.2015.11.018. This article has 94 citations.
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(dudakova2021nonpenetranceforocular pages 1-2): Lubica Dudakova, Viktor Stranecky, Lenka Piherova, Tomas Palecek, Nikolas Pontikos, Stanislav Kmoch, Pavlina Skalicka, Manuela Vaneckova, Alice E. Davidson, and Petra Liskova. Non-penetrance for ocular phenotype in two individuals carrying heterozygous loss-of-function zeb1 alleles. Genes, 12:677, Apr 2021. URL: https://doi.org/10.3390/genes12050677, doi:10.3390/genes12050677. This article has 4 citations.
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(lin2025polymorphouscornealdystrophy pages 2-3): Qinghong Lin, Xuejun Wang, Xiaoliao Peng, Xiaosong Han, Xiaoyu Zhang, Ling Sun, Yan Wang, Shengtao Liu, and Xingtao Zhou. Polymorphous corneal dystrophy subtype 3 and keratoconus aggravation after corneal refractive surgery in a three-generation family carrying both zeb1 and znf469 pathogenic variant. Frontiers in Genetics, Jun 2025. URL: https://doi.org/10.3389/fgene.2025.1603019, doi:10.3389/fgene.2025.1603019. This article has 0 citations and is from a peer-reviewed journal.
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(chung2017confirmationofthe pages 5-7): Doug D. Chung, Ricardo F. Frausto, Aleck E. Cervantes, Katherine M. Gee, Marina Zakharevich, Evelyn M. Hanser, Edwin M. Stone, Elise Heon, and Anthony J. Aldave. Confirmation of the ovol2 promoter mutation c.-307t>c in posterior polymorphous corneal dystrophy 1. PLoS ONE, 12:e0169215, Jan 2017. URL: https://doi.org/10.1371/journal.pone.0169215, doi:10.1371/journal.pone.0169215. This article has 26 citations and is from a peer-reviewed journal.
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(siddiqui2016geneticanalysisof pages 42-46): S Siddiqui. Genetic analysis of corneal dystrophies. Unknown journal, 2016.
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(liskova2018ectopicgrhl2expression pages 1-2): Petra Liskova, Lubica Dudakova, Cerys J. Evans, Karla E. Rojas Lopez, Nikolas Pontikos, Dimitra Athanasiou, Hodan Jama, Josef Sach, Pavlina Skalicka, Viktor Stranecky, Stanislav Kmoch, Caroline Thaung, Martin Filipec, Michael E. Cheetham, Alice E. Davidson, Stephen J. Tuft, and Alison J. Hardcastle. Ectopic grhl2 expression due to non-coding mutations promotes cell state transition and causes posterior polymorphous corneal dystrophy 4. American Journal of Human Genetics, 102:447-459, Mar 2018. URL: https://doi.org/10.1016/j.ajhg.2018.02.002, doi:10.1016/j.ajhg.2018.02.002. This article has 59 citations and is from a highest quality peer-reviewed journal.
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(liskova2018ectopicgrhl2expression pages 8-9): Petra Liskova, Lubica Dudakova, Cerys J. Evans, Karla E. Rojas Lopez, Nikolas Pontikos, Dimitra Athanasiou, Hodan Jama, Josef Sach, Pavlina Skalicka, Viktor Stranecky, Stanislav Kmoch, Caroline Thaung, Martin Filipec, Michael E. Cheetham, Alice E. Davidson, Stephen J. Tuft, and Alison J. Hardcastle. Ectopic grhl2 expression due to non-coding mutations promotes cell state transition and causes posterior polymorphous corneal dystrophy 4. American Journal of Human Genetics, 102:447-459, Mar 2018. URL: https://doi.org/10.1016/j.ajhg.2018.02.002, doi:10.1016/j.ajhg.2018.02.002. This article has 59 citations and is from a highest quality peer-reviewed journal.
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(fung2021endothelialcelldensity pages 5-6): Simon Sheung Man Fung, Hamza Sami, Ali El Hamouly, Dishay Jiandani, Sara Williams, Kamiar Mireskandari, and Asim Ali. Endothelial cell density in children with posterior polymorphous corneal dystrophy: a longitudinal case-control study. Eye, 35:3397-3403, Feb 2021. URL: https://doi.org/10.1038/s41433-021-01451-y, doi:10.1038/s41433-021-01451-y. This article has 6 citations and is from a peer-reviewed journal.
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(lin2025polymorphouscornealdystrophy pages 5-7): Qinghong Lin, Xuejun Wang, Xiaoliao Peng, Xiaosong Han, Xiaoyu Zhang, Ling Sun, Yan Wang, Shengtao Liu, and Xingtao Zhou. Polymorphous corneal dystrophy subtype 3 and keratoconus aggravation after corneal refractive surgery in a three-generation family carrying both zeb1 and znf469 pathogenic variant. Frontiers in Genetics, Jun 2025. URL: https://doi.org/10.3389/fgene.2025.1603019, doi:10.3389/fgene.2025.1603019. This article has 0 citations and is from a peer-reviewed journal.
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(lin2025polymorphouscornealdystrophy pages 3-5): Qinghong Lin, Xuejun Wang, Xiaoliao Peng, Xiaosong Han, Xiaoyu Zhang, Ling Sun, Yan Wang, Shengtao Liu, and Xingtao Zhou. Polymorphous corneal dystrophy subtype 3 and keratoconus aggravation after corneal refractive surgery in a three-generation family carrying both zeb1 and znf469 pathogenic variant. Frontiers in Genetics, Jun 2025. URL: https://doi.org/10.3389/fgene.2025.1603019, doi:10.3389/fgene.2025.1603019. This article has 0 citations and is from a peer-reviewed journal.
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(frausto2019zeb1insufficiencycauses pages 1-2): Ricardo F. Frausto, Doug D. Chung, Payton M. Boere, Vinay S. Swamy, Huong N.V. Duong, Liyo Kao, Rustam Azimov, Wenlin Zhang, Liam Carrigan, Davey Wong, Marco Morselli, Marina Zakharevich, E. Maryam Hanser, Austin C. Kassels, Ira Kurtz, Matteo Pellegrini, and Anthony J. Aldave. Zeb1 insufficiency causes corneal endothelial cell state transition and altered cellular processing. PLoS ONE, Feb 2019. URL: https://doi.org/10.1371/journal.pone.0218279, doi:10.1371/journal.pone.0218279. This article has 31 citations and is from a peer-reviewed journal.
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(davidson2016autosomaldominantcornealendothelial pages 11-13): Alice E. Davidson, Petra Liskova, Cerys J. Evans, Lubica Dudakova, Lenka Nosková, Nikolas Pontikos, Hana Hartmannová, Kateřina Hodaňová, Viktor Stránecký, Zbyněk Kozmík, Hannah J. Levis, Nwamaka Idigo, Noriaki Sasai, Geoffrey J. Maher, James Bellingham, Neyme Veli, Neil D. Ebenezer, Michael E. Cheetham, Julie T. Daniels, Caroline M.H. Thaung, Katerina Jirsova, Vincent Plagnol, Martin Filipec, Stanislav Kmoch, Stephen J. Tuft, and Alison J. Hardcastle. Autosomal-dominant corneal endothelial dystrophies ched1 and ppcd1 are allelic disorders caused by non-coding mutations in the promoter of ovol2. The American Journal of Human Genetics, 98:75-89, Jan 2016. URL: https://doi.org/10.1016/j.ajhg.2015.11.018, doi:10.1016/j.ajhg.2015.11.018. This article has 94 citations.
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(liskova2018ectopicgrhl2expression pages 7-8): Petra Liskova, Lubica Dudakova, Cerys J. Evans, Karla E. Rojas Lopez, Nikolas Pontikos, Dimitra Athanasiou, Hodan Jama, Josef Sach, Pavlina Skalicka, Viktor Stranecky, Stanislav Kmoch, Caroline Thaung, Martin Filipec, Michael E. Cheetham, Alice E. Davidson, Stephen J. Tuft, and Alison J. Hardcastle. Ectopic grhl2 expression due to non-coding mutations promotes cell state transition and causes posterior polymorphous corneal dystrophy 4. American Journal of Human Genetics, 102:447-459, Mar 2018. URL: https://doi.org/10.1016/j.ajhg.2018.02.002, doi:10.1016/j.ajhg.2018.02.002. This article has 59 citations and is from a highest quality peer-reviewed journal.
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(chung2017confirmationofthe pages 2-4): Doug D. Chung, Ricardo F. Frausto, Aleck E. Cervantes, Katherine M. Gee, Marina Zakharevich, Evelyn M. Hanser, Edwin M. Stone, Elise Heon, and Anthony J. Aldave. Confirmation of the ovol2 promoter mutation c.-307t>c in posterior polymorphous corneal dystrophy 1. PLoS ONE, 12:e0169215, Jan 2017. URL: https://doi.org/10.1371/journal.pone.0169215, doi:10.1371/journal.pone.0169215. This article has 26 citations and is from a peer-reviewed journal.
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(davidson2016autosomaldominantcornealendothelial pages 5-6): Alice E. Davidson, Petra Liskova, Cerys J. Evans, Lubica Dudakova, Lenka Nosková, Nikolas Pontikos, Hana Hartmannová, Kateřina Hodaňová, Viktor Stránecký, Zbyněk Kozmík, Hannah J. Levis, Nwamaka Idigo, Noriaki Sasai, Geoffrey J. Maher, James Bellingham, Neyme Veli, Neil D. Ebenezer, Michael E. Cheetham, Julie T. Daniels, Caroline M.H. Thaung, Katerina Jirsova, Vincent Plagnol, Martin Filipec, Stanislav Kmoch, Stephen J. Tuft, and Alison J. Hardcastle. Autosomal-dominant corneal endothelial dystrophies ched1 and ppcd1 are allelic disorders caused by non-coding mutations in the promoter of ovol2. The American Journal of Human Genetics, 98:75-89, Jan 2016. URL: https://doi.org/10.1016/j.ajhg.2015.11.018, doi:10.1016/j.ajhg.2015.11.018. This article has 94 citations.
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(fernandezgutierrez2022posteriorpolymorphouscorneal pages 1-2): Eva Fernández-Gutiérrez, Pedro Fernández-Pérez, Ana Boto-De-Los-Bueis, Laura García-Fernández, Patricia Rodríguez-Solana, Mario Solís, and Elena Vallespín. Posterior polymorphous corneal dystrophy in a patient with a novel zeb1 gene mutation. International Journal of Molecular Sciences, 24:209, Dec 2022. URL: https://doi.org/10.3390/ijms24010209, doi:10.3390/ijms24010209. This article has 9 citations.
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(davidson2020cugcforposterior pages 4-5): Alice E. Davidson, Nathaniel J. Hafford-Tear, Lubica Dudakova, Amanda N. Sadan, Nikolas Pontikos, Alison J. Hardcastle, Stephen J. Tuft, and Petra Liskova. Cugc for posterior polymorphous corneal dystrophy (ppcd). European Journal of Human Genetics, 28:126-131, Jun 2020. URL: https://doi.org/10.1038/s41431-019-0448-8, doi:10.1038/s41431-019-0448-8. This article has 7 citations and is from a domain leading peer-reviewed journal.
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(frausto2019zeb1insufficiencycauses pages 2-3): Ricardo F. Frausto, Doug D. Chung, Payton M. Boere, Vinay S. Swamy, Huong N.V. Duong, Liyo Kao, Rustam Azimov, Wenlin Zhang, Liam Carrigan, Davey Wong, Marco Morselli, Marina Zakharevich, E. Maryam Hanser, Austin C. Kassels, Ira Kurtz, Matteo Pellegrini, and Anthony J. Aldave. Zeb1 insufficiency causes corneal endothelial cell state transition and altered cellular processing. PLoS ONE, Feb 2019. URL: https://doi.org/10.1371/journal.pone.0218279, doi:10.1371/journal.pone.0218279. This article has 31 citations and is from a peer-reviewed journal.
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(frausto2019zeb1insufficiencycauses pages 14-16): Ricardo F. Frausto, Doug D. Chung, Payton M. Boere, Vinay S. Swamy, Huong N.V. Duong, Liyo Kao, Rustam Azimov, Wenlin Zhang, Liam Carrigan, Davey Wong, Marco Morselli, Marina Zakharevich, E. Maryam Hanser, Austin C. Kassels, Ira Kurtz, Matteo Pellegrini, and Anthony J. Aldave. Zeb1 insufficiency causes corneal endothelial cell state transition and altered cellular processing. PLoS ONE, Feb 2019. URL: https://doi.org/10.1371/journal.pone.0218279, doi:10.1371/journal.pone.0218279. This article has 31 citations and is from a peer-reviewed journal.
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(shen2017retinalpathologyin pages 11-12): Anna L. Shen, Susan M. Moran, Edward A. Glover, Leandro B. Teixeira, and Christopher A. Bradfield. Retinal pathology in the ppcd1 mouse. PLoS ONE, 12:e0185094, Oct 2017. URL: https://doi.org/10.1371/journal.pone.0185094, doi:10.1371/journal.pone.0185094. This article has 3 citations and is from a peer-reviewed journal.
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(fung2021endothelialcelldensity media 4fa8c68b): Simon Sheung Man Fung, Hamza Sami, Ali El Hamouly, Dishay Jiandani, Sara Williams, Kamiar Mireskandari, and Asim Ali. Endothelial cell density in children with posterior polymorphous corneal dystrophy: a longitudinal case-control study. Eye, 35:3397-3403, Feb 2021. URL: https://doi.org/10.1038/s41433-021-01451-y, doi:10.1038/s41433-021-01451-y. This article has 6 citations and is from a peer-reviewed journal.
-
(fung2021endothelialcelldensity media 5637544d): Simon Sheung Man Fung, Hamza Sami, Ali El Hamouly, Dishay Jiandani, Sara Williams, Kamiar Mireskandari, and Asim Ali. Endothelial cell density in children with posterior polymorphous corneal dystrophy: a longitudinal case-control study. Eye, 35:3397-3403, Feb 2021. URL: https://doi.org/10.1038/s41433-021-01451-y, doi:10.1038/s41433-021-01451-y. This article has 6 citations and is from a peer-reviewed journal.
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(chung2017confirmationofthe pages 1-2): Doug D. Chung, Ricardo F. Frausto, Aleck E. Cervantes, Katherine M. Gee, Marina Zakharevich, Evelyn M. Hanser, Edwin M. Stone, Elise Heon, and Anthony J. Aldave. Confirmation of the ovol2 promoter mutation c.-307t>c in posterior polymorphous corneal dystrophy 1. PLoS ONE, 12:e0169215, Jan 2017. URL: https://doi.org/10.1371/journal.pone.0169215, doi:10.1371/journal.pone.0169215. This article has 26 citations and is from a peer-reviewed journal.
-
(frausto2019zeb1insufficiencycauses pages 13-14): Ricardo F. Frausto, Doug D. Chung, Payton M. Boere, Vinay S. Swamy, Huong N.V. Duong, Liyo Kao, Rustam Azimov, Wenlin Zhang, Liam Carrigan, Davey Wong, Marco Morselli, Marina Zakharevich, E. Maryam Hanser, Austin C. Kassels, Ira Kurtz, Matteo Pellegrini, and Anthony J. Aldave. Zeb1 insufficiency causes corneal endothelial cell state transition and altered cellular processing. PLoS ONE, Feb 2019. URL: https://doi.org/10.1371/journal.pone.0218279, doi:10.1371/journal.pone.0218279. This article has 31 citations and is from a peer-reviewed journal.
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(dudakova2021nonpenetranceforocular pages 2-4): Lubica Dudakova, Viktor Stranecky, Lenka Piherova, Tomas Palecek, Nikolas Pontikos, Stanislav Kmoch, Pavlina Skalicka, Manuela Vaneckova, Alice E. Davidson, and Petra Liskova. Non-penetrance for ocular phenotype in two individuals carrying heterozygous loss-of-function zeb1 alleles. Genes, 12:677, Apr 2021. URL: https://doi.org/10.3390/genes12050677, doi:10.3390/genes12050677. This article has 4 citations.
-
(liskova2018ectopicgrhl2expression pages 9-10): Petra Liskova, Lubica Dudakova, Cerys J. Evans, Karla E. Rojas Lopez, Nikolas Pontikos, Dimitra Athanasiou, Hodan Jama, Josef Sach, Pavlina Skalicka, Viktor Stranecky, Stanislav Kmoch, Caroline Thaung, Martin Filipec, Michael E. Cheetham, Alice E. Davidson, Stephen J. Tuft, and Alison J. Hardcastle. Ectopic grhl2 expression due to non-coding mutations promotes cell state transition and causes posterior polymorphous corneal dystrophy 4. American Journal of Human Genetics, 102:447-459, Mar 2018. URL: https://doi.org/10.1016/j.ajhg.2018.02.002, doi:10.1016/j.ajhg.2018.02.002. This article has 59 citations and is from a highest quality peer-reviewed journal.
