Central Cloudy Corneal Dystrophy of Francois by ghkgkyyt


									Central              Cloudy Corneal Dystrophy of Francois
A   Clinicopathologic Study
Carol L. Karp, MD;  Ingrid U. Scott, MD, MPH; W. Richard Green, MD;
Tom S.   Chang, MD; William W. Culbertson, MD

                       cloudy corneal dystrophy of Francois was first described in 1955 by J. Francois;
               its pathophysiology remains unknown. An 80-year-old woman with bilateral central cloudy
               corneal dystrophy of Francois was examined after having undergone a combined pen-
               etrating keratoplasty and cataract extraction. The corneal button was obtained. Light
microscopy revealed stromal staining for acid mucopolysaccharide. Transmission electron micros-
copy revealed extracellular vacuoles, some of which had fibrillogranular material and electron-dense
deposits. Fibrillogranular material was present in and around some keratocytes. Numerous endothe-
lial vacuoles contained light-staining fibrillogranular material and round electron-dense granules. Our
findings suggest that the opacities in patients with central cloudy corneal dystrophy of Francois are
due to the extracellular accumulation of mucopolysaccharide and lipidlike material. Further studies
are needed to elucidate the nature of these deposits.            Arch Ophthalmol. 1997;115:1058-1062

                                    Central    cloudy   corneal    dystrophy     of   unremarkable. Her family history was
                                    Francois(CCDF) was first described in             negative for ocular disease, and family
                                    1955 by J. Francois.1 He described 8              members were unavailable for examina¬
                                    patients, ranging  in age from 35 to 76           tion.
                                   years, who had corneal lesions consist¬                    An initial examination   by the refer¬
                                   ing of central cloudy gray areas with              ring ophthalmologist revealed a best-
                                   polygonal stromal opacities and crack¬             corrected visual acuity of 20/60 OD and
                                   like zones primarily in the posterior half         20/50 OS. A     slit-lamp   examination   was
                                   of the corneal stroma. Although central            notable for symmetric, polygonal, stro¬
                                   and bilateral, these lesions typically do          mal opacities separated by clear crack¬
                                   not affect visual acuity. A review of the          like zones in a mosaic pattern through¬
                                   literature reveals few reports of this dys¬        out the full thickness of both central
                                   trophy, and the pathophysiology of the             corneas (figure I). The opacities
                                   condition remains unknown.2"12 We                  appeared denser in the posterior stroma
                                   report the findings of a clinicopatho-             (Figure 2). A moderate nuclear scle¬
                                   logic study of CCDF.                               rotic cataract was present in the right
                                                                                      eye, and a well-positioned posterior
                                                REPORT OF A CASE                      chamber intraocular lens was present in
                                                                                      the left eye. A dilated funduscopic
                                   An  80-year-old white woman with a his¬            examination revealed mild macular pig¬
                                   tory of CCDF and a visually significant            ment epithelial mottling in both eyes.
                                   cataract was examined after having                       The clinical impression was bilat¬
                                   undergone a combined penetrating                   eral CCDF and cataract in the right eye.
                                   keratoplasty and cataract extraction in            The patient reported limited visual
                                   her right eye. Her medical history was             improvement after cataract extraction in
                                                                                      the left eye. Her referring ophthalmolo¬
From the Department of Ophthalmology, Bascom Palmer Eye Institute, University of      gist believed that the residual visual loss
Miami School of Medicine, Miami, Fla (Drs Karp, Scott, Chang, and Culbertson); and    was due to her corneal opacity, and
the Departmentof Pathology, The Johns Hopkins Medical Institutions, the Wilmer        he, therefore, performed a combined
Ophthalmological Institute, Baltimore, Md (Dr Green).                                 penetrating keratoplasty and cataract

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extraction with posterior chamber
intraocular lens implantation in
the right eye.
      The patient was first seen by
us (C.L.K. and W.W.C.) 20
months after undergoing surgery
in her right eye. An ocular exami¬
nation revealed a visual acuity of
20/200 in both eyes. The right eye
had a clear graft. The left eye dem¬
onstrated classic CCDF, with cen¬
tral polygonal stromal opacities in
a mosaic pattern. Both maculae
had significant retinal pigment
                                              Figure 1. Symmetric, polygonal, stromal opacities separated by clear cracklike zones in a mosaic pattern
epithelial degeneration.                      in the central corneas of the right (left) and left (right) eyes.
     The original clinical photo¬
graphs were requested and re¬
viewed. The pathology specimen was
retrieved for réévaluation (by


The   patient's clinical picture    was
consistent with CCDF.       However, to
exclude other      causes   of bilateral
cloudy corneas, the following labo¬
ratory studies were performed:
steroid sulfatase, cholesterol sulfa¬
tase, lecithin cholesterol acetyltrans-
ferase and ß, and lipid profile. The
patient also underwent a complete
examination   by a dermatologist at
the   University   of Miami School of
Medicine, Miami, Fla,        to investi¬
gate for evidence of ichthyosis.
      The right corneal button was            Figure 2. 777« opacities extend throughout the full thickness of the stroma but appear most dense in the
retrieved and reprocessed for light           posterior stroma.
microscopy. Sections were stained
with hematoxylin-eosin, periodic
acid-Schiff, Verhoeff-van Gieson,
Congo red, Alcian blue, and Mas-
son trichome. A portion of the cor¬
nea was removed from the paraffin
block and prepared for transmis¬
sion electron microscopy (TEM).



A complete dermatologie examina¬
tion revealed no evidence of ich¬

The results of all laboratory studies         Figure 3. The area shows a pool of extracellular mucopolysaccharide in the corneal stroma (Aldan blue,
performed were normal.                        340).

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Figure 4. Top, The basement membrane zone is 1.8 pm thick and consists of a       Figure 5. Top, Superficial stroma with a degenerated keratocyte containing
darker external layer (1.4 pm) composed of multiple fragments of basement         fibrillogranular material (asterisk) and numerous linear and curvilinear
membrane (between arrowheads) and a layer of fibrillogranular material (0.4       extracellular deposits (arrowheads) ( 8100). Bottom, A view of the stromal
pm) (between arrows) ( 8100). E Indicates epithelium. Bottom, A higher-power      deposits (asterisks) with fibrillogranular material and some electron-dense
view of a more electron-dense layer (between arrows), aggregates of anchoring     material ( 30 000).
fibrils (AE), and the layer of fibrillogranular material (asterisks) ( 60 000).

                                                                  LIGHT MICROSCOPY                            brane material intermingled with fi¬
                                                                                                              brillogranular material (Figure 4).
                                                          Light microscopy revealed an unre¬                  In some areas, numerous vacuoles of
                                                          markable epithelium. The epithe¬                    various shapes and sizes measuring
                                                          lial basement membrane was                          50 to 300 nm were located between
                                                          mildly thickened throughout. Bow¬                   the thickened epithelial basement
                                                          man's layer was intact. The corneal                 membrane zone and Bowman's layer.
                                                          stroma was 0.4 mm thick and was                     Some of these vacuoles contained a
                                                          unremarkable except for a faint                     light fibrillogranular material. Bow¬
                                                          undulating appearance of the deep                   man's layer was unremarkable.
                                                          lamellae. Descemet's membrane                             Numerous extracellular vacu¬
                                                          and endothelium were unremark¬                      oles of various shapes and sizes
                                                          able. The corneal stroma stained                    (round, oval, linear, and curvilin¬
                                                          positive for acid mucopolysaccha¬                   ear) with a diameter of 250 nm to 6
                                                          ride throughout, most notably in                    pm were present in the stroma. These
                                                          the basement membrane zone of                       vacuoles were located throughout the
                                                          the epithelium and in the pre-                      stroma (Figure 5) but were most
                                                          Descemet's area (Figure 3). Con¬                    numerous in the mid and deep
                                                          nective tissue stains      were unre¬               stroma (Figure 6). Most vacuoles
                                                          markable, and the Congo red stain                   contained a light fibrillogranular or
                                                          was negative for amyloid.                           granular material. Some vacuoles
                                                                                                              contained round, dense osmio-
Figure 6. A posterior portion of the cornea with
                                                             TRANSMISSION ELECTRON                            philic structures measuring 200 to
a degenerated keratocyte (asterisk) and
                                                                  MICROSCOPY                                  250 nm in diameter (Figures 5 and
numerous vacuoles in stroma (arrowheads) that                                                                 6). Many keratocytes were degener¬
are especially concentrated just anterior to              Transmission electron microscopy                    ated (Figures 5 and 6). Intact kera¬
Descemet's membrane (arrows). The
endothelium has numerous vacuoles that
                                                          demonstrated a thickened epithe¬                    tocytes contained or were partially
contain electron-dense globules (circles)                 lial basement membrane zone                         surrounded by fibrillogranular
( 7300).                                                  with reduplicated basement mem-                     material     (Figure 7).        Descemet's

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Figure 7. A deposit of dense fibrillogranular material (asterisk) adjacent to a     Figure 8. 777e endothelium has numerous non-membrane-bound inclusions
keratocyte ( 30 000).                                                               (arrows) that contain a light-staining fibrillogranular material and
                                                                                    electron-dense globules (asterisks) ( ß ).

   Complete Differential Diagnosis*
                                                                                       Corneal Histopathologic
   Variable                                            Ocular Findings                          Findings                             Systemic Findings
   CCDF                                       Polygonal central cracklike          Mostly extracellular vacuoles in        No    systemic abnormalities
                                                opacities in the mid to             the posterior stroma with                   identified
                                                posterior stroma                    fibrillogranular material
                                                                                     (probable MPS), lipid and
                                                                                     light staining with Alcian blue
   Ichthyosis                                 Superficial corneal erosions and     Intracellular and extracellular         Some forms with skin changes,
                                                punctate opacities in the deep        membrane- and                          steroid sulfatase deficiency and
                                                stroma or pre-Descemet zone           non-membrane-bound                     high cholestorol sulfate levels
                                                and ectropion and ichthyosis          vacuoles in the superficial            in the serum and skin, and
                                                of the eyelids                        stroma                                 various inheritance patterns
   LCAT deficiency                            Numerous minute grayish dots         Multiple anterior stromal               LCAT deficiency; and kidney
                                                throughout the stroma, often          vacuoles containing                    dysfunction, anemia, and
                                                concentrated in the peripheral        unesterified cholesterol               hyperlipidemia
                                                 cornea in arcuslike form
  Francois-Neetens speckled corneal           Subtle gray specks in all layers     Intracellular vacuoles with acid        No systemic abnormalities and
    dystrophy                                   of the stroma                         MPS and lipid                          autosomal dominant
  Grayson-Wilbrandt dystrophy                 Asymptomatic, axial and              Intracellular vacuoles with             No systemic abnormalities
                                                para-axial findings, and              fibrillogranular material and          identified
                                                farinatalike deposits                 lipid in the pre-Descemet zone
  Systemic mucopolysaccharidoses              Punctate corneal opacifications      Extensive intracellular vacuoles        Lysosomal enzyme deficiency
                                                and diffuse stromal haze,             with MPS, associated with the          affecting the degradation of
                                                minimal corneal involvement          Golgi complex                           MPS; and, depending on type,
                                                in types IIA and III, and may                                                may have notable skeletal or
                                                have optic nerve or retinal                                                  neurologic manifestations or
                                                degeneration or both                                                         both
  MCD                                         Hazy "ground glass" lesions          Intracellular and extracellular         MCD 1, lack of keratan sulfate in
                                                involving the central and             accumulation of MPS likely             the cornea and serum; MCD 2,
                                                 peripheral cornea                    produced by RER                        normal levels of keratan sulfate;
                                                                                                                             autosomal recessive

 * CCDF indicates central
                          cloudy corneal dystrophy of Francois; LCAT, lecithin cholesterol acetyltransferase; MCD, macular corneal dystrophy; MPS,
mucopolysaccharides; and RER, rough endoplasmic reticulum.

membrane        was    unremarkable and                   to   470 nm in diameter (Figure 6 and                  OD and 1/200 OS at the last fol¬
was   8.5 pm thick. The endothelium                       Figure 8).                                             low-up (4 years after surgery). The
had numerous round, non-mem¬                                                                                     graft in the right eye remained clear.
brane-bound cytoplasmic vacuoles                                     CLINICAL COURSE
that measured 153 nm to 1.4 pm in                                                                                                  COMMENT
diameter and contained a fine fibril¬                     Progressive macular degenerative
logranular material and some dense                        changes developed in the patient, and                  Central cloudy corneal dystrophy of
osmiophilic structures measuring 100                      her visual acuity declined to 7/200                    Francois is       an uncommon            mosaic

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corneal dystrophy, the cause of               ported had atypical features of CCDF            York, NY; the International Order of
which is unknown. It has been de¬             in that the patient had epithelial in¬          Odd Fellows, Winston-Salem, NC; and
scribed in patients ranging in age            volvement and foreign body sensa¬               the Florida Lions Eye Bank, Miami.
from 8 to 89 years,1"8 and no sexual          tion. Histopathologic examination re¬                    We thank        Scheffer Tseng, MD,
or racial predilection is known. Al¬          vealed a thinned epithelium and an              PhD, and Reva Hurtes for their assis¬
though only 2 of the 8 cases Fran¬            amorphous, periodic acid-Schiff                 tance.
cois described were related,1 2 in¬           stain-positive layer containing in¬                      Corresponding author: Carol L.
vestigators have described families           flammatory cells between the epithe¬            Karp, MD, Bascom Palmer Eye Insti¬
with multiple affected members and            lium and Bowman's layer. Similar to             tute, 900 NW 17th St, Miami, FL
have postulated a dominant mode of            our case, TEM demonstrated numer¬               33136.
inheritance.7·8 Isolated cases have           ous lacunae (0.5-2.0 pm in diam¬
been reported in association with             eter) in the corneal stroma. A saw-
                                              toothed pattern of collagen lamellae                             REFERENCES
pseudoxanthoma elasticum,4 flecked
                                              was evident in some areas of the
(speckled) dystrophy of the cor¬
nea,2 pre-Descemet's dystrophy,6 and          stroma. Soybean agglutinin, a lectin             1. Francois J. Une nouvelle dystrophie heredo-
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                                              similar in size and distribution to the          2. Francois J, Neetens A. Nouvelle dystrophie heredo-
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These ultrastructural abnormali¬              staining with Alcian blue and the                     phies corneennes chez deux soeurs. Bull Soc
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of acid mucopolysaccharide. Fur¬              ase    and ß deficiency,15 Francois-                575-579.
                                              Neetens speckled corneal dystro¬                 7. Strachan IM. Cloudy central corneal dystrophy of
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represent lipid droplets.                     dystrophy, can be excluded based on              8. Bramsen T, Ehlers N, Baggesen LH. Central cloudy
      Previous investigators have             clinical features and complete sys¬                 corneal dystrophy of Francois. Acta Ophthalmol.
noted the similar clinical appear¬            temic and serological evaluations.                    1976;54:221-226.
                                                                                               9. Ansons AM, Atkinson PL. Corneal mosaic pat-
ances of CCDF, anterior and poste¬            Our patient had no systemic evi¬
                                                                                                  terns: morphology and epidemiology. Eye. 1989;
rior crocodile shagreen, and arcus            dence of mucopolysaccharidosis or                   3:811-815.
senilis.2·3 These conditions have             ichthyosis; blood test results for ste¬         10. KrachmerJH, Dubord PJ, Rodriguez MM, Man-
been referred to as the corneal               roid sulfatase, cholesterol sulfate,                 nis MJ. Corneal posterior crocodile shagreen and
mosaic patterns9 and may repre¬               lecithin cholesterol acetyltransfer-                 polymorphic amyloid degeneration. Arch Oph-
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mer et al10 described the histo-              completely normal.                                  Hageman GS, Assil KK. Characterization of a cen-
pathologic findings     in   a   patient            Our morphological findings sug¬               tral corneal cloudiness sharing features of pos-
                                                                                                  terior crocodile shagreen and central cloudy dys-
with posterior crocodile shagreen             gest that the opacifications in pa¬                 trophy of Francois. Cornea. 1996;15:347-354.
and polymorphic amyloid degen¬                tients with CCDF are due to the ac¬
                                                                                              12. Starck T, Hersh PS, Kenyon KR. Corneal dysgen-
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arrangement of stromal collagen               presence of some intracellular vacu¬                 Ophthalmology. Philadelphia, Pa: WB Saunders
lamellae in a sawtoothlike configu¬           oles and degenerated keratocytes sug¬               Co; 1994:chap 3.
                                                                                              13. Kempster RC, Hirst LW, de la Cruz Z, Green WR.
ration. We considered the slight              gests that the stromal deposits might               Clinicopathological study of the cornea in x\x=req-\
undulating arrangement of the                 be derived from keratocytes. Fur¬                   linked ichthyosis. Arch Ophthalmol. 1997;115:
deep corneal lamellae to be an arti¬          ther studies are needed to elucidate                409-415.
fact in our case. Unlike our case of          the nature of these deposits and to de¬         14. Teng CC. Macular dystrophy of the cornea: a his-
                                              termine if the deposits are a local phe¬            tochemical and electron microscopic study. Am
CCDF, Krachmer et al10 found no                                                                   J Ophthalmol. 1966;62:436-454.
extracellular fibrillogranular vacu¬          nomenon or related to a systemic
                                                                                              15. Bethell W, McCulloch C, Ghosh M. Lecithin
oles and no staining for excessive            metabolic abnormality.                              cholesterol acetyltransferase deficiency: light
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                                                                                                  corneas. Can J Ophthalmol. 1975;10:494-501.
    A clinicopathologic study of a            Acceptedfor publication February 21,            16. Nicholson DH, Green WR, Cross HE, Kenyon KR,
patient with central corneal cloudi¬          1997.                                               Massof D. A clinical and histopathological study
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scribed by Meyer et al.11 The case re-        by Research to Prevent Blindness, New               phy. Am J Ophthalmol. 1977;83:554-560.

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