Customize your JAMA Network experience by selecting one or more topics from the list below.
Darier-White disease (also known as Darier disease or keratosis follicularis spinulosa decalvans) is a rare dominantly inherited skin disorder characterized by firm, scaly, cutaneous papules and plaques distributed over various regions of the body.1Histopathologic and electron microscopic studies of biopsied skin specimens have revealed a loss of cell to cell adhesion and abnormal differentiation of the epidermis.1Ocular involvement in Darier-White disease has been observed, with eyelid and corneal abnormalities being reported.2-5To date, however, examination of corneal abnormalities in Darier-White disease has been limited to slitlamp observation2-5and microscopic examination of superficial peripheral biopsy samples in cases with confirmed corneal abnormalities.2,3
In this article we use in vivo confocal microscopy to describe the general corneal morphological features present in 5 members (4 affected and 1 unaffected) of a 5-generation, 32-member, Swedish family with Darier-White disease, 15 of whom are affected. All 5 individuals had good vision without ocular symptoms or history of contact lens wear, and no corneal abnormalities were apparent on slitlamp examination. Using in vivo laser-scanning confocal microscopy (HRT3-RCM; Heidelberg Engineering, Heidelberg, Germany), irregularities in the epithelium, nerves, and anterior stroma were observed in all affected individuals. Documenting corneal abnormalities that, on occasion, have been associated with severe photophobia2and corneal clouding3may be useful in elucidating the pathogenesis of corneal changes in this rare disease.
Report of Cases
In vivo confocal microscopy in the central cornea of a 67-year-old affected woman revealed basal epithelial cells with an abnormally dark cytoplasm and reflective nuclei invading the intermediate epithelial layers (Figure 1). Oblique sections indicated an indistinct demarcation between the basal epithelium and the Bowman membrane while thick, beaded, subbasal nerve fibers invaded the epithelial compartment. Numerous reflective punctate deposits were observed in the anterior stroma.
Corneal images of case 1. A, An oblique section of epithelium shows abnormal basal cells and epithelial invasion by subbasal nerves. B, An abnormally tortuous branching subbsal nerve is seen in the basal and wing cell layer (depth, 39 μm from the epithelial surface). C, Bright, punctate, anterior stromal deposits are apparent (depth, 69 μm). D, The epithelium of a healthy, 60-year-old, male subject is shown. Scale bars, 100 μm.
In a 41-year-old affected daughter of case 1, in vivo confocal microscopy revealed a basal epithelial cell layer with abnormally reflective nuclei physically separated from the Bowman layer and folded upwards into the wing cell layers (Figure 2). Thick, beaded, reflective subbasal nerves were observed; however, they did not appear to invade the epithelium. Punctate deposits were observed in the anterior stroma.
Oblique section of corneal epithelium (E) and anterior stroma (S) in a daughter of case 1. The basal epithelium is separated from the Bowman layer and protrudes upward into the epithelium (arrows).
A 33-year-old affected daughter of case 1 exhibited small intercellular inclusions throughout the epithelium (Figure 3). Beaded, abnormally tortuous subbasal nerves were interspersed among basal and wing cells, with regions of abnormally reflective cytoplasm or cell nuclei appearing to be demarcated by the subbasal nerves, as in case 1. In the underlying subbasal plexus, nerves were thickened. As in case 1, punctate deposits were present in the anterior stroma, while oblique sections revealed discontinuities in the basal and wing cell layers. No visible corneal changes were noted on slitlamp examination; however, skin lesions and plaque-like material were observed in the eyelid margin and eyelids.
Daughter of case 1. A, Bright intercellular deposits (arrows) are seen in the epithelial wing cell layer (depth, 36 μm). B, Confocal microscopy shows subbasal plexus with prominent nerves (depth, 57 μm). C, Slitlamp photograph shows cornea without visible changes, but with lesions at the eyelid margin (arrows). D, Keratotic lesions of the lower eyelid are seen. Scale bars, 100 μm.
A 44-year-old unaffected daughter of case 1 exhibited intercellular inclusions throughout the epithelium, as in case 3. Thickened subbasal nerves were present, while the remainder of the cornea appeared normal.
A 51-year-old sister of case 1 exhibited intercellular epithelial inclusions, as in case 3, and fragmented islands of wing and basal epithelial cells with either an abnormally bright cytoplasm or a dark cytoplasm and indistinct cell borders (Figure 4). Subbasal nerves were tortuous, and a large population of dendritic cells was present. Oblique sections revealed discontinuities in the various epithelial cell layers and punctate deposits in the anterior stroma.
Corneal microstructure in a sister of case 1. A, Beaded, subbasal nerves are present in the fragmented basal and wing cell layers (depth, 33 μm). B, The subbasal nerve plexus contains tortuous nerves and dendritic cells (depth, 45 μm). C, Oblique section shows epithelial lesions (dark areas). Note, punctate anterior stromal deposits (arrows) are apparent. Scale bars, 100 μm.
Previously reported slitlamp findings of corneal involvement in Darier-White disease have included punctate epithelial opacities,2,4peripheral intraepithelial opacities,3faint lines of central epithelial irregularity,3and prominent corneal nerves.2Histopathological and ultrastructural analysis of biopsy samples revealed intracellular and extracellular epithelial edema in basal and wing cell layers, separation of basal epithelium from the Bowman layer, a deficit of desmosomes and hemidesmosomes at the basement membrane, cellular debris and a granular substance below the epithelium, and an almost total absence of epithelial basement membrane.2,3
Abnormalities in the cytoplasm, nuclei, and homogeneity of epithelial wing and basal cells as well as morphology consistent with an absent or abnormal epithelial basement membrane were prominent corneal features of Darier-White disease observed by in vivo confocal microscopy. These findings are suggestive of abnormal cellular adhesion and differentiation, which are hallmarks of the condition. The punctate anterior stromal deposits (reminiscent of the microdot deposits seen in long-term contact lens users) may correspond to the cellular debris or granular substance observed by electron microscopy3; however, the origin and composition of this substance remains unknown.
Corneal subbasal nerve involvement was noted in the present family. Perpendicular penetration of thick, beaded, subbasal nerve fiber bundles into the epithelium suggests that in the absence of an intact basement membrane (providing both a physical and biochemical barrier between epithelium and stroma), thicker subbasal nerve fiber bundles may proceed unimpeded into the more superficial wing cell layers before branching into thinner nerve strands. Additionally, nerves observed in the epithelium appeared to follow a course adjacent to areas of basal and wing cells with abnormally reflective cytoplasm; extracellular edema or a breakdown of intercellular adhesion may have provided a further path of decreased resistance to direct aberrant nerve growth. Dendritic cells in the basal epithelium appeared in 2 of 4 affected individuals, indicating possible immune activity. As the small intercellular epithelial deposits observed in the present family were not visible with the slitlamp, it is unclear whether these corresponded to the “punctate epithelial opacities” observed by others.2,4Interestingly, the deposits were also found in the unaffected individual. These deposits may be dendritic cells additionally present within the wing cell layers; however, it is unclear whether their presence is disease related, as a sparse distribution of dendritic cells is sometimes observed in the central cornea of healthy individuals.
Notably, we did not detect peripheral corneal opacities or the “cornea verticillata” observed by Blackman et al3; nevertheless, the epithelial edema and abnormal cellular adhesion they found in biopsy samples is consistent with the (somewhat milder) epithelial pathology and lesions observed in the central and peripheral cornea in the present family.
Correspondence: Dr Lagali, Department of Ophthalmology, Linköping University Hospital, 581 85 Linköping, Sweden (firstname.lastname@example.org).
Financial Disclosure: None reported.
Lagali N, Dellby A, Fagerholm P. In Vivo Confocal Microscopy of the Cornea in Darier-White Disease. Arch Ophthalmol. 2009;127(6):816–818. doi:10.1001/archophthalmol.2009.100
Ophthalmology in JAMA: Read the Latest