François Central Cloudy Corneal Dystrophy

Key points at a glance

Highlights of this disease

• Central cloudy dystrophy of François (CCDF) is a rare corneal dystrophy characterized by polygonal gray opacities in the posterior stroma of the central cornea.
• The inheritance pattern is unknown, but familial cases showing autosomal dominant inheritance have been reported.
• Most cases are sporadic, and similarities to degenerative diseases have been noted.
• It is non-progressive and usually asymptomatic, with no effect on visual function.
• Diagnosis is based on slit-lamp microscopy, with confocal microscopy as an adjunct.
• Treatment is unnecessary; management consists only of observation.

1. What is Central Cloudy Dystrophy of François?

Central Cloudy Dystrophy of François (CCDF) is a rare corneal dystrophy characterized by bilateral, symmetrical polygonal gray opacities in the posterior stroma of the central cornea. It is listed as Category 4 in the second and third editions of the IC3D (International Committee for Classification of Corneal Dystrophies) classification ^1,2). Category 4 means “insufficient evidence for a dystrophy,” and because CCDF has familial cases but its phenotype matches posterior crocodile shagreen (PCS), it is considered likely to be a degenerative disease in most cases ²⁾.

The inheritance pattern is not established; although familial cases with autosomal dominant inheritance have been reported, most cases are sporadic ²⁾. The causative gene or locus has not been identified.

The characteristic finding is polygonal gray stromal opacities separated by relatively clear lines ³⁾. The opacities are most prominent in the posterior stroma and become thinner anteriorly. It is non-progressive and does not affect visual function, so no treatment is indicated.

Q How to differentiate CCDF from posterior crocodile shagreen?

A

Posterior crocodile shagreen (PCS) is a corneal degenerative disease occurring in elderly individuals and presents findings very similar to CCDF. Differentiating points: in CCDF, the opacity patches are uniform in size, whereas in PCS, the sizes are variable. Also, CCDF has hereditary cases, while PCS is degenerative and not hereditary. Age of onset also differs: CCDF occurs in younger individuals, while PCS appears with aging.

2. Main symptoms and clinical findings

Subjective symptoms

CCDF is usually asymptomatic. Rarely, changes in corneal sensation or photophobia may be reported. No systemic symptoms have been reported.

Clinical findings

Findings	Characteristics
Opacity morphology	Polygonal gray opacities
Distribution	Central cornea, posterior stroma
Symmetry	Bilateral, symmetric

The opacities consist of small polygonal patches separated by clear crack-like lines. They are densest in the posterior stroma just anterior to Descemet’s membrane. Their number and size decrease toward the anterior. The peripheral cornea remains clear.

It is usually bilateral, but unilateral cases have been rarely reported. Onset is typically within the first 10 years of life, with the youngest reported case at 8 years of age.

3. Causes and Risk Factors

The etiology of CCDF is not fully understood.

Familial cases follow an autosomal dominant inheritance pattern. However, the causative gene or locus has not been identified. The pathogenesis of sporadic CCDF is also unknown, and an association with aging degeneration is suspected.

The greatest risk factor is a family history of CCDF. Since sporadic cases without a clear genetic background account for the majority, established risk factors are few.

Prevention and Daily Care

• CCDF is a non-progressive disease that does not affect visual function. No specific preventive measures have been established.
• If there is a family history, it is advisable to undergo an eye examination during childhood.
• If already diagnosed, regular follow-up should be performed to confirm that there are no changes.

4. Diagnosis and Examination Methods

Slit-Lamp Microscopy

This is the basic examination for diagnosis. Bilateral, symmetrical polygonal gray opacities separated by clear lines are observed in the posterior stroma of the central cornea. Observation using scleral scatter or retroillumination is useful for evaluating the opacities.

Confocal Microscopy

Small highly reflective granules are seen in the anterior stromal layer. Multiple dark striae are observed in the extracellular matrix of the posterior stroma.

Transmission Electron Microscopy of the Cornea

Numerous extracellular granules are present in the stroma. Thickening of the basement membrane and degenerated corneal cells are observed.

Differential Diagnosis

Posterior Crocodile Shagreen

Disease characteristics: Corneal degenerative disease in the elderly

Common features: Bilateral polygonal opacities in the central cornea

Differentiating points: Variable size of opacity patches. Non-hereditary.

Macular corneal dystrophy (MCD)

Disease characteristics: Autosomal dominant stromal dystrophy

Common features: Non-progressive opacities predominantly in the posterior stroma

Differentiating points: Some types involve opacities extending to the periphery

Pre-Descemet corneal dystrophy

Disease characteristics: Polymorphic opacities in the posterior stroma

Common features: Both hereditary and sporadic forms exist

Differentiating points: Hereditary form is X-linked. Associated with skin manifestations.

Congenital stromal corneal dystrophy (CSCD) is also considered in the differential diagnosis, but it presents with diffuse opacities throughout the entire stroma, accompanied by moderate to severe visual impairment and corneal thickening, which distinguishes it from CCDF.

Q Is genetic testing useful for confirming the diagnosis of CCDF?

A

Since the causative gene for CCDF has not been identified, genetic testing cannot currently provide a definitive diagnosis. Diagnosis is based on confirming characteristic findings with slit-lamp microscopy. Confocal microscopy and corneal transmission electron microscopy are useful as adjunctive diagnostic tools.

5. Standard treatment

CCDF is non-progressive and asymptomatic, so there is no indication for treatment. Management consists only of observation.

There are no reports of corneal opacities interfering with visual function, and they do not affect daily life ²⁾. The cornea of a CCDF patient can be treated similarly to a healthy cornea. A case has been reported in which monovision LASIK was performed on an eye with CCDF, and good visual acuity was maintained without worsening of the dystrophy for 5 years postoperatively ³⁾.

Precautions in treatment

CCDF is a disease that does not require treatment, but it is important to carefully perform differential diagnosis to exclude other corneal dystrophies. In particular, it is necessary to reliably differentiate from diseases that can cause visual impairment, such as macular corneal dystrophy and congenital stromal corneal dystrophy.

Q Is refractive surgery possible for CCDF patients?

A

Since CCDF is non-progressive and has limited impact on corneal structure, refractive surgery is theoretically possible. In fact, a case has been reported with good outcomes without exacerbation of dystrophy 5 years after monovision LASIK. However, case reports are limited, so careful evaluation on a case-by-case basis is necessary.

6. Pathophysiology and Detailed Pathogenesis

The pathophysiology of CCDF is not fully understood. The following mechanisms are inferred from morphological studies using electron microscopy.

In the corneal stroma, mucopolysaccharides and lipid-like substances accumulate extracellularly. At the same time, vacuoles form within keratocytes. These deposits disrupt the dense, parallel arrangement of normal corneal stromal collagen, causing opacity.

Histopathologically, sawtooth folds of deep stromal collagen are observed. Extracellular vacuoles containing mucopolysaccharides and lipids are present coinciding with the opaque areas. Irregular collagen arrangement and deposition of extracellular lipid vacuoles are considered the main causes of opacity.

The reason why opacity is prominent in the posterior stroma is not fully explained, but it is speculated that metabolic abnormalities in the deep stroma near Descemet’s membrane are more pronounced ³⁾.

---

7. References

1. Weiss JS, Møller HU, Lisch W, et al. The IC3D classification of the corneal dystrophies. Cornea. 2008;27 Suppl 2:S1-83.
2. Weiss JS, Rapuano CJ, Seitz B, et al. IC3D classification of corneal dystrophies—Edition 3. Cornea. 2024;43(4):466-527.
3. Meyer JC, Quantock AJ, Thonar EJ, Kincaid MC, Hageman GS, Assil KK. Characterization of a central corneal cloudiness sharing features of posterior crocodile shagreen and central cloud dystrophy of François. Cornea. 1996;15(4):347-354.