Fuchs dystrophy

The dystrophy is divided into two subtypes according to age of onset:

• Late onset (the most common form, age of onset beyond the 4th decade), considered category 3 since no gene has been identified. The genetics of this form are complex and heterogeneous, with variable expressivity and incomplete penetrance. Various genes have been described but all the mutations share the same clinical appearance. More frequent in women, 2.5 to 3 to 1.
• Early onset (between the 1st and 3rd decades): considered category 1, due to a mutation of the alpha 2 gene of type VIII collagen located on chromosome 1p34.3-p32, a mutation similar to that found in DCPP. No difference between the sexes.

Both forms follow a 4-stage progression but differ in the age of onset of clinical signs (1st decade vs 4th decade) and in the age at which the final stage of the disease appears (3rd–4th decade vs later). Note that not everyone progresses to the final stage 4, and that some remain at stage 1:

• Stage 1: Central guttae (small, round, finely dispersed VS large and distinct).
• Stage 2: Progression of the guttae toward the periphery and coalescence of the lesions, endothelial decompensation, and stromal oedema.
• Stage 3: Bullous keratopathy
• Stage 4: subepithelial fibrosis with possible corneal neovascularization.

Genetics

Variable according to the form: the majority of cases are sporadic but some are AD

Mutation

1p34.3-p32 for FECD 1; FECD 2: 13pter-q12.13; FECD3: 18q21.2-q21.3; FECD 4: 20p13-p12; FECD5: 5q33.1-q35.2; FECD6: 10p11.2; FECD7: 9p24.1-p22.1; FECD8: 15q25

Laterality

Bilateral

Symmetry

No

Associated factors:

Age of onset

Depends on the form of the dystrophy

Location

The endothelial cells produce abnormal material, leading to the formation of a multilamellar Descemet membrane from birth onward and to dysfunction of the endothelial pump.

Appearance:

Direct illumination:

• Guttae, initially of central location: they appear as black dots at the posterior part of the cornea, like an excrescence extending from Descemet membrane toward the endothelium. Presence of pigment dispersion corresponding to phagocytosis of melanin pigments by the endothelial cells.
• Endothelial decompensation: the guttae coalesce, giving a beaten-metal appearance with or without pigment deposits. A grey, irregular and thickened appearance of Descemet membrane, with the beginning of fibrosis that may engulf the guttae and even make them disappear. Corneal oedema begins at the level of the posterior stroma and progressively evolves toward the anterior stroma behind Bowman layer. Sometimes intra- and inter-epithelial microcysts can be identified. During this stage the patient's visual acuity begins to decline, with complaints mainly of blurred vision on waking in the morning.

Retroillumination and sclerotic scatter:

• Guttae: appear like dewdrops.
• Endothelial decompensation: Descemet folds, grey stromal haze, and a stippled appearance of the microcysts, especially seen on sclerotic scatter. In blue light after instillation of fluorescein, the surface appears irregular due to a "pool-out" effect secondary to the subepithelial cysts.

Pain or recurrent erosion

no, except in the case of bullous keratopathy when bullae rupture.

Visual acuity

During stage 1 often preserved; some patients may complain of photophobia, halos, and reduced image quality. After stage 1 vision begins to decline.

Diagnosis:

• Histology: endothelial cells enlarged in size, pleomorphic because of the stretching of the remaining cells and the flattening of the nuclei, which are pushed by the guttae arising from the posterior excrescence of Descemet membrane. Descemet membrane is found to be 2 to 3 times thicker than normal and becomes strongly PAS positive, mainly because of the guttae. In addition to the guttae, a marked synthesis of fibrous tissue appears, within which the guttae disappear.
• Electron microscopy: The anterior banded zone is normal; the posterior non-banded zone is abnormal and thinner than normal, indicating that the abnormality occurs early, around the second decade. In addition, an abnormal posterior collagenous layer is added and is responsible for most of the thickness of Descemet membrane and for the formation of the guttae. It is formed of 100 nm banded fibers similar to the anterior banded zone but more irregular because of the amorphous basement membrane. The endothelial cells become increasingly dedifferentiated and take on the appearance of fibroblasts that secrete almost exclusively fibrous product. The intercellular spaces may be enlarged with an opening of the junctional complexes (zonula occludens).
• Confocal microscopy: The guttae appear as black areas with a bright center, completely masking the endothelial cells overlying them. The endothelial cells show pleomorphism (a decrease in the percentage of hexagonal cells), polymegathism (anisocytosis), and a decrease in their density.
• Confocal microscopy: Descemet membrane is always thickened, with dark bands and guttae. The mean endothelial density is decreased. Once oedema sets in, abnormalities of Bowman layer are found in the form of a diffuse bright reflex and the absence of visible corneal nerves, as well as abnormalities of the anterior stroma and posterior stroma.