Central cloudy dystrophy of François (CCDF) is a non-progressive corneal dystrophy presenting with faint gray, cloudy opacities with ill-defined edges in deep stroma.1,2 The condition is usually bilaterally symmetric and presumed to be autosomal dominant. Stromal corneal dystrophies with similar clinical appearance include anterior and posterior crocodile shagreen (PCS) and posterior amorphous corneal dystrophy.2,3
In this report we present the in vivo confocal microscopic findings in a patient with phenotypic CCDF, but without any history suggesting autosomal dominant inheritance. To the best of our knowledge, this is the second report of the in vivo confocal microscopy findings in presumed CCDF.3
A 70-years-old woman without any visual complaints was referred to our institution for further evaluation of corneal opacities, which were incidentally detected on a routine eye exam. She did not report any history of using drugs potentially toxic to the cornea. She had no systemic disease, except for medically controlled idiopathic hypertension. Family history was non-contributary. Ophthalmological examination of her 49-years-old daughter did not reveal any evidence of corneal pathology.
Ophthalmological examination revealed uncorrected visual acuities of 20/100 in both eyes and best-corrected visual acuities of 20/40 in both eyes with a manifest refraction of +1.50 diopter (D) in the right eye and +1.25(−0.75 × 90) D in the left eye. By non-contact tonometer, intraocular pressures were 18 mm Hg and 19 mm Hg in the right and left eyes, respectively. Both corneas showed multiple polygonal stromal opacities separated by clear lines that were more prominent in the central two-thirds of the cornea and distributed throughout the full thickness of the stroma (Figs. 1 and 2). No epithelial involvement was seen. Opacities were easily detected by scleral scatter or oblique, broad slit illumination against the dilated pupil. They displayed a symmetric distribution in both eyes. The patient had lenticular 1+ nuclear sclerosis and peripheral cortical opacities in both eyes. Dilated fundus examinations were unremarkable. A diagnosis of presumed CCDF was made.
Figure 1. Biomicroscopic Images of the Corneal Opacities by Broad-Beam Illumination
Figure 2. Biomicroscopic Images of the Corneal Opacities by Slit-Beam Illumination
Slit-scanning corneal topography (Orbscan IIz, Bausch & Lomb, software version 3.00; Orbtek, Salt Lake City, UT) revealed central corneal thickness of 480 and 477 μm in the right and left eyes, respectively, along with mild flattening of the central cornea (Fig. 3).
Figure 3. Orbscan Corneal Topography Images of the Right and Left Eyes, Respectively.
Contact confocal microscopy was performed on both eyes with Nidek Confoscan 4 (Nidek, Vigonza, Italy) using 40 × lens and Z-ring attachment. The surface epithelium appeared normal with typical dark and light cells in addition to the basal layer including polygonal cells. Anterior stromal layers showed small highly refractile granules and deposits that seemed to be embedded within the sub-Bowman’s nerve plexus. Hyper-refractile granules seemed to persist in mid and deep stroma, and gave way to multiple dark acellular striae towards various directions among extracellular matrices with increased intensities. No stromal layer with keratocytes was observed. In the right eye, the corneal endothelial cell density was 3,319 cells/mm2, polymegathism was 52.9%, and pleomorphism was 34.3%. In the left eye, endothelial cell counts could not be performed because of high stromal reflectance intensity (Fig. 4).
Figure 4. Confocal Microscopic Images of the Anterior, Middle, Posterior Stroma and Endothelium.
CCDF was originally described as faint, deep central stromal opacifications occuring in two siblings and 6 additional unrelated patients.1 An autosomal dominant inheritance mode was presumed.4,5 Typical findings consist of faint, cloudy, gray-white, polygonal opacities separated by relatively clear thin spaces with indistinct edges in the central cornea.3,6 The stroma is of normal thickness. Although there is epithelial involvement, foreign body sensation or evident photophobia are distinctly atypical; variant cases have been reported.6
Similar clinical features are also seen in PCS, but most commonly limited to the posterior stroma.6 Distinction by degree of encroachment into the stroma may be difficult. Therefore, diagnosis of PCS is considered if there is no strong autosomal dominant inheritance pattern.6,7 As the dystrophy involved full-thickness stroma but heritage could not be demonstrated, our case could be regarded as representing either CCDF or PCS. Differential diagnosis also includes posterior amorphous corneal dystrophy, which results in peripheral involvement and corneal thinning. Ichthyosis, which is known to cause bilateral cloudy cornea,8 pre-descemet’s dystrophy, and cornea farinata have discrete lesions, dissimilar to those in CCDF.2
By light microscopy and tissue electron microscopy (TEM) studies on CCDF corneas, Karp et al. reported that extracellular vacuoles filled with mucopolysaccharide and lipid-like material were present throughout the stroma, most notably in the mid and deep stroma. They proposed that the increased intensity of the extracellular matrices caused by mucopolysaccharide and lipid-like material may correspond to clinical corneal opacities. Additionally, fibrillogranular materials were deposited near the thickened epithelial basement membrane as well as adjacent to keratocytes.9 On the other hand, Krachmer et al. reported TEM findings of concurrent PCS and polymorphic amyloid degeneration, where they noted irregular vertical sawtooth-like configurations of the stromal collagen lamellae, interspersed with patches of 100 nm widely spaced collagen, which they concluded to be corresponding to central cloudy opacities at the slit-lamp. They did not find extracellular fibrillogranular vacuoles or the presence of acid mucopolysaccharides.7
Meyer et al. histopathologically proved the presence of numerous vacuoles in corneal stroma and sawtoothed pattern of collagen lamellae in a case with full-thickness stromal mosaic pattern-sharing features of PCF and CCDF.6 They argued that stromal lacunae, which measured upto 2 μm across, could be responsible for some corneal opacification, because they were almost one-half the wavelength of visible light (~250 nm).
When compared with slit-lamp biomicroscopy, in vivo corneal confocal microscopy allows better lateral resolution and microscopic examination of all corneal layers.10 Woodward et al. reported in vivo confocal microscopy findings of combined polymorphic amyloid degeneration with PCS, where although the mosaic tile pattern of stromal haze interrupted by clear jagged lines was clinically distinguishable only in deep stromal layers, confocal microscopy showed that this pattern extended throughout the corneal stroma.11 In our case, the mosaic pattern of corneal clouding is seen to affect the whole thickness of the corneal stroma by both slit-lamp and confocal microscopy (Figs. 2 and 4). Woodward et al. also suggested that the area of stromal haze has a clumped, non-uniform appearance on confocal microscopy and, thus, areas of haze could correlate with the irregular sawtooth lamellae seen on histopathology.11
Kobayashi et al. reported that subepithelial and anterior stromal hyperreflective granules corresponded to fibrillogranular materials or localized aggregates of acid mucopolysaccharide beneath the Bowman’s layer. These hyperreflective deposits were seen to a lesser extent in the posterior stroma by confocal microscopy.3 They also noted that midstromal layers of the cornea showed normal keratocytic nuclei with a typical coffee bean-like appearance. In our case, however, hyperreflective deposits extended towards posterior stroma, where they merged with multiple dark striae with increased intensities of extracellular matrices. Additionally, there were no stromal layers, where keratocytes could be observed; and this was found to be the most important difference when compared with the previous observations.3 It might be postulated that in more advanced stages of the dystropy, a large number of extracellular vacuoles filled with mucopolysaccharide and lipid-like material are present in full-thickness corneal stroma. These changes in the extracellular environment might be the cause for the death of keratocytes and subsequent compaction of the stroma, with no increase in corneal thickening, as in our case.
Multiple microstriae among extracellular matrices with increased intensities in deep stromal layers have been thought to reflect the clear spaces interspersed between the opacities, as they are acellular and optically lucent.3 Kobayashi et al. explained their appearance by a similar mechanism to that in the case of anterior crocodile shagreen,12,13 which proposed that micro-folds are caused by reduced tension of the Bowman layer. Similarly in CCDF, when tension in Descemet’s membrane is released, collagen lamellae inserting obliquely might create a reproducible polygonal ridge pattern.3
In our case, unlike the previous report,3 the endothelium revealed prominent polymegathism and pleomorphism, bilaterally. No endothelial accumulations or guttae were seen. The endothelial changes could be secondary to the advanced stage of the disease or an incidental finding in this patient. So far, there have been no reports of endothelial decompensation, which required penetrating keratoplasty.
Full-thickness involvement of the corneal stroma, presence of hyperreflective granules with microstriae throughout the stroma with no layer of keratocytes, and changes in endothelial morphology may represent a more advanced stage of the dystrophy.
- François J. Une novelle dystrophie hérédo-familiale de la cornée. J Genet Hum. 1956;5:189–196.
- Krachmer JH, Mannis MJ, Holland EJ. Cornea: Fundamentals, Diagnosis and Management, 2nd ed., vol. 1. Elsevier Health Sciences; 2004: 920.
- Kobayashi A, Sugiyama K, Huang AJW. In vivo confocal microscopy in patients with central cloudy dystrophy of François. Arch Ophthalmol. 2004;122:1676–1679. doi:10.1001/archopht.122.11.1676 [CrossRef]
- Strachan IM. Cloudy central dystrophy of François: five cases in the same family. Br J Ophthalmol. 1969;53:192–194. doi:10.1136/bjo.53.3.192 [CrossRef]
- Bramsen T, Ehlers N, Baggesen LH. Central cloudy corneal dystrophy of François. Acta Ophthalmol (Copenh). 1976;54:221–226. doi:10.1111/j.1755-3768.1976.tb00435.x [CrossRef]
- Meyer JC, Quantock AJ, Thonar EJ-MA, Kincaid MC, Hageman GS, Assil KK. Characterization of a central corneal cloudiness sharing features of posterior crocodile shagreen and central cloudy dystrophy of François. Cornea. 1996;15:347–354. doi:10.1097/00003226-199607000-00003 [CrossRef]
- Krachmer JH, Dubord PJ, Rodrigues MM, Mannis MJ. Corneal posterior crocodile shagreen and polymorphic amyloid degeneration. Arch Ophthalmol. 1983;101:54–59.
- Kempster RC, Hirst LW, de la Cruz Z, Green WR. Clinicopathologic study of the cornea in X-linked ichthyosis. Arch Ophthalmol. 1997;115:409–415.
- Karp CL, Scott IU, Green WR, Chang TS, Culbertson WW. Central cloudy corneal dystrophy of Francois. A clinicopathologic study. Arch Ophthalmol. 1997;115:1058–1062.
- Cavanagh HD, Petroll WM, Alizadeh H, et al. Clinical and diagnostic use of in vivo confocal microscopy in patients with corneal disease. Ophthalmology. 1993;100:1444–1454.
- Woodward M, Randleman JB, Larson PM. In vivo confocal microscopy of polymorphic amyloid degeneration and posterior crocodile shagreen. Cornea. 2007;26:98–101. doi:10.1097/01.ico.0000240103.47508.c4 [CrossRef]
- Bron AJ, Tripathi RC. Anterior corneal mosaic:further observations. Br J Ophthalmol. 1969;53:760–764. doi:10.1136/bjo.53.11.760 [CrossRef]
- Tripathi RC, Bron AJ. Secondary anterior crocodile shagreen of Vogt. Br J Ophthalmol. 1975;59:59–63. doi:10.1136/bjo.59.1.59 [CrossRef]