Posterior polymorphous corneal dystrophy

Genetics

AD, with variable penetrance and variable clinical presentation between individuals. Some cases are sporadic and unilateral.

Mutation

A heterogeneous hereditary dystrophy with 3 different mutations:

• DCPP 1: 20p11.2-q11.2
• DCPP 2: 1p34.3-p32.3, COL8A2 gene

Recent data — genetics of the late-onset form

Expansion of a CTG repeat triplet (CTG18.1 locus), located within an intron of the TCF4 gene (transcription factor 4), is now recognized as the principal genetic determinant of late-onset Fuchs dystrophy. An expansion (generally ≥ 40 repeats) is found in the majority of patients and increases the disease risk more than 30-fold. Several non-exclusive mechanisms have been proposed: dysregulation of TCF4 expression, toxicity of the repeat-containing RNA (gain of function), RAN translation (independent of the AUG codon), and somatic instability of the locus. This mechanism, shared with other repeat-expansion disorders, opens the way to targeted gene therapies currently under development.

• DCPP 3: 10p11.2, TCF8 gene, transcription factor 8, and ZEB1 gene, zinc-binding domain (Zinc finger E-box binding homeobox 1), which play a role in repressing epithelial cell adhesion genes such as E-cadherin and desmoglein, and a role in the ectopic expression of type IVa3 collagen (present in the central corneal epithelium). A mutation in ZEB1 and TCF8 results in ectopic expression of epithelial genes such as E-cadherin and a decreased expression of mesenchymal genes (mesenchymal-epithelial transition).

Laterality

Bilateral, but some cases are unilateral (sporadic).

Symmetry

yes, but it may be asymmetric.

Associated factors:

• An association between DCPP3 and Alport syndrome has been described. A binding site for TCF8 on the promoter of the COL4A3 gene in Alport disease has been described. The association between posterior polymorphous dystrophy and Alport syndrome is strong enough that it is worthwhile to systematically screen for renal involvement and deafness in any patient presenting with posterior polymorphous dystrophy.
• Peripheral anterior synechiae, present in 25% of cases, ranging from fine adhesions seen on gonioscopy to broad, glass-like-surfaced membranes seen on direct examination.
• The iris may be normal, or show broad areas of iris atrophy and corectopia.
• Glaucoma in nearly 15% of cases. Either angle-closure secondary to the synechiae or open-angle secondary to an anterior insertion of the iris.
• Steepened keratometry readings, especially in DCPP3.

Age of onset

The abnormality is present from birth but rarely diagnosed, since the majority of patients are asymptomatic.

Location

Descemet membrane and endothelial cells, with three types of lesions:

• vesicular
• band-shaped
• diffuse opacities

Appearance:

Direct illumination:

• Vesicular lesions of the cyst type surrounded by a grey halo at the level of the endothelium and Descemet membrane (pathognomonic). These lesions may be isolated, grouped, linear or confluent.
• The bands are often horizontal and parallel, with scalloped edges, and do not taper toward their ends. They are located mainly inferior to the central cornea.
• The diffuse opacities are lesions at the level of Descemet membrane of variable size: small greyish-white macular lesions resembling guttae, and broad, sinuous, geographic lesions. A posterior stromal haze is often found overlying these lesions.
• Corneal oedema is rare in this dystrophy and may range from mild stromal thickening to bullous keratopathy.

Retroillumination:

• The diffuse opacities give an orange-peel appearance, with a size varying from 0.5 to 2 mm.

Pain or recurrent erosion

No

Visual acuity

Often preserved, patients often asymptomatic, rarely associated with a progressive decrease in visual acuity.

Diagnosis:

A brief embryological reminder: Descemet membrane is a true basement membrane divided into two parts:

• An anterior banded portion deposited during fetal life, approximately 3 microns thick, with bands measuring between 110 and 120 nm and formed solely by type VIII collagen. An anterior banded zone indicates good functionality of the endothelial cells between the 4th month and birth.
• A posterior non-banded portion deposited after birth by the endothelial cells.
• Histology: endothelial cells behaving like epithelial cells, with microvilli, positive staining for keratin, rapid and easy proliferation in cell culture, presence of intracellular desmosomes, and a marked proliferative tendency in the cornea. As a result, abnormalities of Descemet membrane are also found: thickening of the membrane, a multilayered appearance, and polymorphous alteration.
• The abnormalities range from generalized thickening of Descemet membrane with foci of enlarged endothelial cells in a double layer, to an irregular Descemet membrane that is absent in places, with 3 to 4 layers of flattened endothelial cells.
• Electron microscopy: focal presence of large squamous epithelial cells with intermediate filaments (tonofilaments), desmosomes and microvilli, and without the tight junctions that characterize endothelial cells.
• The anterior banded zone is often normal in DCPP (indicating that the endothelial cells functioned normally before birth), except in the rare cases where children are born with a white cornea; in this case the endothelial cell abnormality begins very early during fetal life. The posterior non-banded zone, by contrast, is abnormal in these cases, composed of an abnormal mix of collagen with a laminated appearance. The lamellae resemble those found in the anterior banded zone and are sometimes mixed, especially in depth, with the type IV basement membrane collagen, giving a vacuolated appearance.
• These epithelial cells present in multiple layers may extend to cover the trabecular meshwork and the iris.
• Specular microscopy:
• The vesicles appear as well-demarcated round regions that are either of clear content, corresponding to cellular aggregates, or of dark content (black dots that interrupt the normal endothelial mosaic). The vesicles contain fibrillar or collagenous material. The endothelial cells surrounding the vesicles are enlarged and pleomorphic.
• The bands appear as shallow troughs and ridges, arising from a large number of confluent vesicles. The endothelial cells bordering the bands are enlarged and pleomorphic.
• The diffuse opacities take on the appearance of well-demarcated regions with multiple hyper-reflective borders. These regions contain enlarged and pleomorphic cells and are surrounded by endothelial cells of normal size. A double cell population is observed: endothelial cells of normal appearance and large, polymorphous black cells with bright rounded contours (an inverted appearance of the endothelial mosaic). The transition between these two cell populations is abrupt.

Recurrence

Possible