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SPECIAL ARTICLE
IC3D Classification of Corneal DystrophiesEdition 2
Jayne S. Weiss, MD,* Hans Ulrik Mller, MD, PhD, Anthony J.
Aldave, MD, Berthold Seitz, MD,Cecilie Bredrup, MD, PhD, Tero
Kivel, MD, FEBO,k Francis L. Munier, MD,**
Christopher J. Rapuano, MD, Kanwal K. Nischal, MD, FRCOphth,
Eung Kweon Kim, MD, PhD,John Sutphin, MD, Massimo Busin, MD,kk
Antoine Labb, MD,*** Kenneth R. Kenyon, MD,
Shigeru Kinoshita, MD, PhD, and Walter Lisch, MD
Purpose: To update the 2008 International Classication ofCorneal
Dystrophies (IC3D) incorporating new clinical, histopath-ologic,
and genetic information.
Methods: The IC3D reviewed worldwide peer-reviewed articlesfor
new information on corneal dystrophies published between 2008and
2014. Using this information, corneal dystrophy templates
andanatomic classication were updated. New clinical,
histopathologic,and confocal photographs were added.
Results: On the basis of revisiting the cellular origin of
cornealdystrophy, a modied anatomic classication is proposed
consist-ing of (1) epithelial and subepithelial dystrophies, (2)
epithelialstromal TGFBI dystrophies, (3) stromal dystrophies, and
(4)endothelial dystrophies. Most of the dystrophy templates
areupdated. The entity Epithelial recurrent erosion dystrophies
actually includes a number of potentially distinct
epithelialdystrophies (Franceschetti corneal dystrophy, Dystrophia
Smolan-diensis, and Dystrophia Helsinglandica) but must be
differentiatedfrom dystrophies such as TGFBI-induced dystrophies,
which arealso often associated with recurrent epithelial erosions.
Thechromosome locus of Thiel-Behnke corneal dystrophy is
onlylocated on 5q31. The entity previously designated as a variant
ofThiel-Behnke corneal dystrophy on chromosome 10q24 mayrepresent a
novel corneal dystrophy. Congenital hereditary endo-thelial
dystrophy (CHED, formerly CHED2) is most likely only anautosomal
recessive disorder. The so-called autosomal dominantinherited CHED
(formerly CHED1) is insufciently distinct tocontinue to be
considered a unique corneal dystrophy. On review ofalmost all of
the published cases, the description appeared mostsimilar to a type
of posterior polymorphous corneal dystrophylinked to the same
chromosome 20 locus (PPCD1). Confocalmicroscopy also has emerged as
a helpful tool to reveal in vivofeatures of several corneal
dystrophies that previously requiredhistopathologic examination to
denitively diagnose.
Conclusions: This revision of the IC3D classication includes
anupdated anatomic classication of corneal dystrophies more
accu-rately classifying TGFBI dystrophies that affect multiple
layersrather than are conned to one corneal layer. Typical
histopathologicand confocal images have been added to the corneal
dystrophytemplates.
Key Words: cornea, cornea dystrophy, cornea pathology,
cornea,genetics, genetic disease, hereditary disease, confocal
microscopy,histopathology, epithelium, Bowman membrane, stroma,
Descemetmembrane, endothelium, TGFBI, epithelial and subepithelial
dys-trophies, epithelial-stromal TGFBI dystrophies, stromal
dystrophies,endothelial dystrophies, keratoconus, epithelial
basement membranedystrophy, epithelial recurrent erosion
dystrophies, subepithelialmucinous corneal dystrophy, Meesmann
dystrophy, gelatinousdrop-like corneal dystrophy, ReisBcklers
corneal dystrophy,Thiel-Behnke corneal dystrophy, Lisch epithelial
corneal dystrophy,lattice corneal dystrophy, granular corneal
dystrophy type 1,granular corneal dystrophy type 2, macular corneal
dystrophy,Schnyder corneal dystrophy, congenital stromal corneal
dystrophy,eck corneal dystrophy, posterior amorphous corneal
dystrophy, centralcloudy dystrophy of Franois, preDescemet corneal
dystrophy, Fuchsendothelial corneal dystrophy, posteror
polymorphous corneal dystro-phy, congenital corneal endothelial
dystrophy and Xlinked endothelialdystrophy, histology, confocal
microscopy
(Cornea 2015;34:117159)
Received for publication September 8, 2014; revision received
October 2,2014; accepted October 3, 2014. Published online ahead of
printDecember 14, 2014.
From the *Department of Ophthalmology, Pathology and
Pharmacology,Louisiana State University Eye Center of Excellence,
Louisiana StateUniversity Health Sciences Center, Louisiana State
University, NewOrleans, LA; Department of Pediatric Ophthalmology,
Viborg Hospitaland Aarhus University Hospital, Aarhus, Denmark; The
Jules Stein EyeInstitute, University of California at Los Angeles,
Los Angeles, CA;Department of Ophthalmology, Saarland University
Medical Center,Homburg/Saar, Germany; Department of Ophthalmology,
HaukelandUniversity Hospital, Bergen, Norway; kDepartment of
Opthalmology,Helsinki University Central Hospital, Helsinki,
Finland; **Jules-GoninEye Hospital, Lausanne, Switzerland; Cornea
Service, Wills EyeHospital, Philadelphia, PA; University of
Pittsburgh Medical CenterChildrens Eye Center, Pittsburgh, PA;
Cornea Dystrophy ResearchInstitute, Department of Ophthalmology,
College of Medicine, YonseiUniversity, Seoul, Korea; Department of
Ophthalmology, University ofKansas Medical Center, Kansas City, KS;
kkDepartment of Ophthalmol-ogy, Villa Igea Hospital, Matre de
Confrences des Universits PraticienHospitalier, Forli, Italy;
***Centre Hospitalier National dOphtalmologiedes Quinze-Vingts,
Institut de la Vision, Paris, France; Tufts UniversitySchool of
Medicine, Harvard Medical School, Schepens Eye ResearchInstitute,
New England Eye Center, Boston, MA; Department ofOphthalmology,
Kyoto Prefectural University of Medicine, Kyoto, Japan;and
Department of Ophthalmology, Johannes Gutenberg UniversityMainz,
Mainz, Germany.
Supported by The Cornea Society, Louisiana Lions Eye Foundation,
andResearch to Prevent Blindness.
The authors have no conicts of interest to disclose.Reprints:
Jayne S. Weiss, MD, Department of Ophthalmology, Louisiana
State
University Health Sciences Center, School of Medicine, 2020
Gravier St,Suite B, New Orleans, LA 70112. (e-mail:
[email protected]).
Copyright 2014 Wolters Kluwer Health, Inc. All rights
reserved.
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117
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INTRODUCTION
DedicationWe dedicate this work to the memory of Gordon
K. Klintworth, MD, PhD, a brilliant ophthalmic pathologist,and a
highly esteemed member of the International Committeefor
Classication of Corneal Dystrophies (IC3D), whose legacyof
excellence in corneal research and teaching is legendary.
International Committee for the Classificationof Corneal
Dystrophies
In 2008, the rst IC3D report sought to develop a newclassication
system for corneal dystrophies through inte-gration of the then
current information on phenotype,pathology, and especially
genetics.1 This project was initiallyundertaken to correct the
shortcomings of the century-oldphenotypic method of corneal
dystrophy classication.
Cornea Dystrophy: History and DefinitionIn 1890, the term
corneal dystrophy was introduced into
the literature by Groenouw2 and then by Biber.3 Groenouwreported
2 patients with noduli corneae, although he did notdistinguish
between the one patient having granular cornealdystrophy (GCD) and
the other having macular cornealdystrophy (MCD). Subsequently,
Biber described a patientwith lattice corneal dystrophy (LCD).
Thereafter, Fuchs,4
Uhthoff,5 and Yoshida6 continued to use the term
cornealdystrophy.
The general term corneal dystrophy describes aninherited
disorder that affects, singly or in combination, cells,tissues,
and/or organs.1 In ophthalmology, corneal dystro-phies have
typically referred to a group of inherited disordersthat are
usually bilateral, symmetric, slowly progressive, andnot related to
environmental or systemic factors.7 There areexceptions to each
part of the dystrophy denition. Epithelialbasement membrane
dystrophy (EBMD) and central cloudydystrophy of Franois (CCDF) are
likely degenerative ratherthan hereditary conditions in the
majority of patients. Cornealdystrophies can also be clinically
unilateral, for example,posterior polymorphous corneal dystrophy
(PPCD). Systemicchanges are occasionally seen as in Schnyder
cornealdystrophy (SCD), where hypercholesterolemia is common.
Another challenge is that it is unclear where to draw
thedividing line between hereditary bilateral essentially
stationarycorneal diseases such as cornea plana (from mutations
inkeratocan) and the hereditary bilateral diseases called
cornealdystrophies. This is underscored by the entity,
posterioramorphous corneal dystrophy (PACD) (from deletion
ofkeratocan together with 3 other genes), which is
typicallyminimally progressive and can be associated with iris
abnor-malities. Consequently, many would agree that the termcorneal
dystrophy may have more historic than practicalmeaning. However, we
have chosen to follow custom, and inthis second edition of IC3D, we
have continued to address onlyentities that have been traditionally
included in cornealdystrophies.
KeratoconusIs It a Corneal Dystrophy?Do the corneal ectatic
diseases, keratoconus and pellucid
marginal degeneration, meet the criteria for inclusion in
cornealdystrophies? This is a complex and controversial
discussion.
The choice to include keratoconus in a corneal
dystrophyclassication could be supported by the emerging suggestion
ofa genetic basis. There is a family history in 10% of
cases,increased prevalence in rst-degree relatives of
affectedindividuals, and markedly increased prevalence in
trisomy21. Keratoconus is likely genetically heterogeneous and
mayhave incomplete penetrance and variable expressivity.813
However, most cases of keratoconus are sporadic, andin contrast
to established corneal dystrophies, potentialcausative associations
such as eye rubbing and atopy arenoted. There is still insufcient
evidence demonstrating a cleargenetic basis in the majority of
patients with keratoconus. Forthis reason, the IC3D continues to
support exclusion ofcorneal ectasias from the corneal dystrophy
classication. Asinterest in molecular etiology of keratoconus
continues, weanticipate future new insights into the true genetic
basis ofthis highly prevalent corneal disease.
Shortcomings of the Historic CornealDystrophy Classification
There were numerous aws in the traditional and mostwidely used
corneal dystrophy classication system.14,15 Someof the dystrophies
were named before the advent of the slitlamp, whereas most were
described before the development ofgenetic mapping. Introduction of
genotyping revolutionizedour knowledge base of corneal dystrophies.
Genotypingrevealed both genotypic heterogeneity, that is, a single
dystro-phy such as Meesmann corneal dystrophy is associated
withdifferent genes (KRT3 and KRT12) and with
phenotypicheterogeneity, the TGFBI gene is associated with
multipledistinct allelic dystrophy phenotypes, ReisBcklers
cornealdystrophy (RBCD), Thiel-Behnke corneal dystrophy
(TBCD),granular corneal dystrophy type 1 (GCD type 1),
granularcorneal dystrophy type 2 (GCD type 2), and classic
latticecorneal dystrophy (LCD).1 The IC3D classication
systemattempts to address these critically important
shortcomings.
Dystrophy Versus Degeneration andOther Questions
As noted previously, a number of entities formerlyconsidered as
corneal dystrophies are more likely degener-ations rather than
inherited diseases. For example, themajority of epithelial basement
membrane dystrophy(EBMD) cases have no hereditary basis. Central
cloudydystrophy of Franois (CCDF), although hereditary in a
fewfamilies, is phenotypically identical to posterior
crocodileshagreen. The only distinction is that CCDF is associated
witha family history. There are only a few publications
describingan entire family with CCDF.1618 Hence, in descriptionsof
CCDF patients without a detailed family history, it isimpossible to
exclude the diagnostic possibility of posteriorcrocodile shagreen
degeneration.19
Fuchs endothelial corneal dystrophy (FECD) is a verycommon
corneal dystrophy and has a familial basis.20,21 Stage
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Inc. All rights reserved.
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1 FECD consists of only cornea guttata without
cornealdecompensation. Not all patients with stage 1 FECD
progress.Are nonprogressive corneal guttae evidence of a
cornealdegeneration rather than FECD? The answer is not knownbut
has important clinical implications. Often, the patient withcornea
guttata is informed of having a diagnosis of FECD. Ifthe individual
consults the Internet or other sources, theirresearch will
inevitably suggest that FECD is a disease thatoften progresses to
corneal edema, visual loss, and surgicalintervention. Thus, a
premature diagnosis of FECD in theabsence of a family history,
genetic evidence, or corneal edemacan have important adverse
psychological impact on the patientwho anticipates future visual
loss and need for cornealtransplantation surgery.
Other dystrophies were described decades agowith minimal or
unclear clinical information and no geneticinformation. In
particular, such dystrophies as Grayson-Wilbrandt might be variants
of other well-known dystrophiesor might not even exist.
Misleading dystrophy names have also contributed tomisdiagnosis.
Among individuals with the disease formerlynamed Schnyder
crystalline corneal dystrophy (SCCD), 50%actually have visible
crystalline deposits.22 Correct diagnosisof those affected patients
in the absence of crystals oftenconfounded even seasoned clinicians
who depended on thisawed assumption coupled with erroneous
literature, bothsupporting the notion that crystals were integral
to thediagnosis.23,24 Indeed, the compounded errors of SCD werethe
major impetus to create the IC3D nomenclature revisiongroup in
2005. Because the 2008 IC3D publication observedonce established in
textbooks, it is exceedingly difcult topurge incorrect information
about rare diseases. Many mythsare perpetuated because very few
ophthalmologists have seena substantial number of the unusual
corneal dystrophies.Even experienced corneal subspecialists often
were unable tocorrectly diagnose those with acrystalline SCD24 and
patientswent undiagnosed for decades.
Formation of the IC3D in 2005 Leading toPublication in 2008
Initially, the rst requirement for membership in theIC3D group
was extensive rsthand knowledge and experi-ence in examining
patients with one or more distinct cornealdystrophies. In this way,
each dystrophy could be discussedand analyzed by those who had seen
the disease rather thansolely being informed by published
descriptions, which mightbe erroneous. The group was to critically
assess the publishedliterature to purge errors. The members were
also necessarilyinternational to assess geographically distinctive
foundereffects on globally distinct population. Although SCD
wasextremely common in central Massachusetts in the UnitedStates
and the west coast of Finland, GCD type 2 wasextremely common in
Korea. In some cases, the IC3D wasfortunate to include the
individual who originally describedthe dystrophy, as in Lisch
epithelial corneal dystrophy(LECD) and X-linked endothelial corneal
dystrophy. Thesecond requirement for membership in the IC3D
wasrepresentation from geneticists and ophthalmic pathologists.
The 2008 IC3D publication contained the traditionalanatomic
classication that organized dystrophies accordingto the corneal
layer that was chiey affected.14,15 Templatesfor each dystrophy
were created in a standard format tosummarize clinical,
pathological, and genetic information aswell as representative
clinical photographs.
An evidence-based category system was suggested byProfessor
Gordon K. Klintworth, MD, PhD, to indicate thelevel of evidence
supporting existence of a given cornealdystrophy depending on how
substantive was the knowledgeof its clinical, pathological, and
genetic basis. He postulatedthat existence of a new corneal
dystrophy must begin withidentication of a clinical phenotype and
should progress tocharacterization of the causative gene
mutation.
An example of a monogenic category 1 dystrophy isSCD, which is
caused by mutations in 1 gene, UBIAD1.Another category 1 dystrophy
PACD is caused by deletion ofmultiple genes, keratocan (KERA),
lumican (LUM), decorin(DCN), and epiphycan (EPYC). The genetic
basis of otherdystrophies, such as some types of FECD, may prove to
becomplex and involve multiple genes.
These categories were specied as follows:
Category 1: A well-dened corneal dystrophy in whichthe gene has
been mapped and identied and the specicmutations are known.Category
2: A well-dened corneal dystrophy that has been
mapped to one or more specic chromosomal loci, but thegene(s)
remains to be identied.Category 3: A well-dened corneal dystrophy
in which the
disorder has not yet been mapped to a chromosomal locus.Category
4: This category is reserved for a suspected, new,
or previously documented corneal dystrophy, although theevidence
for it, being a distinct entity is not yet convincing.1
We postulated that with increased knowledge abouta dystrophy,
its category should progress over time from 4 to3 to 2 to 1.
Suspected dystrophies that remain category 4because no further
information ever becomes available maybe eventually removed from
the nomenclature. The group didnot further specify specic criteria
for removal of a category 4dystrophy.
Corneal Dystrophy Purgatory and the Category 4DilemmaWhen Can a
Category 4 DystrophyBe Eliminated?
In some cases, additional information might show thata category
4 dystrophy is not an independent entity. One suchexample is
central discoid corneal dystrophy (CDCD).25,26
This category 4 dystrophy was phenotypically indistinguish-able
from acrystalline SCD. When the causative gene forSCD was found to
be UBIAD1,27,28 genetic testing of CDCDsimilarly demonstrated
mutations in UBIAD1 indicating thatCDCD was not a unique dystrophy.
CDCD was consequentlyremoved before publishing the rst IC3D
classication, inwhich it was reclassied as SCD variant.26
Should elimination also be considered for a category 4corneal
dystrophy in which no further information to prove ordisprove its
unique existence is forthcoming? In such a case,there is no
evidence to substantiate or to disprove the
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existence of the dystrophy. We consider this the equivalent
ofcorneal dystrophy purgatory.
A case in point is Grayson-Wilbrandt, a category 4dystrophy,
which was described in 1 publication in 1966supported only by
artists renditions of phenotype, withoutclinical photographs or
genotyping.29 Over the ensuing 4decades, while no subsequent
articles have disputed theoriginal publication, there also have
been no articles sub-stantiating these ndings. Most members of the
IC3D agreedthat this entity should be eliminated from the
classication. Itis now being consigned to a category of Removed
Dystro-phies (Table 1) so that in the event a future
publicationseems to substantiate the existence of this entity, the
referencepublication remains readily retrievable for future
use.
Has the IC3D Been Accepted?The IC3D 2008 classication system
successfully
integrated the then most currently accurate clinical,
patho-logical, and genetic information regarding corneal
dystro-phies. The nomenclature has been incorporated by theAmerican
Academy of Ophthalmologys widely used Basicand Clinical Science
Course Series,30 which instructs oph-thalmology residents in the
United States and Europe and hasbeen referenced by the National Eye
Institute. Nonetheless,
the recommendations of the IC3D have been incorporatedonly in a
minority of new publications. They had been cited114 times by July
2014, according to Thomson Reuters Webof Science, as opposed to
about 800 articles published oncorneal dystrophies since 2009. It
is unclear whether theeditors and reviewers reject the new
classication, think itunimportant, or remain creatures of habit.
For example,despite the nomenclature revision to GCD type 2, the
nameAvellino is still used, although its prevalence is
seeminglydecreasing. Recognizing that change is an
evolutionaryprocess, such incremental progress is encouraging.
Revising the IC3D NomenclatureThe nomenclature revision was
congured to be user-
friendly and easily accessible to physicians and patients
onwww.corneasociety.org and open access through the journalCornea.
One stated requirement of the original nomenclaturerevision was
that it be easily upgradeable. Six years afterthe original
publication, sufcient new information hadbecome available to begin
our rst revision of the IC3D.
Changes in the 2015 IC3D
Anatomic Classication ChangeThe traditionally accepted anatomic
level corneal
dystrophy classication has limitations,14,15 as dystrophieswere
solely assigned to the single layer most affected. YetRBCD and TBCD
affect not only the subepithelial area withdestruction of the
Bowman layer but also the anterior stromaand later the deeper
stroma. Although categorized anatomi-cally as Bowman layer
dystrophies, TGFBI dystrophiesaffect multiple layers. Other corneal
dystrophies also affectmore than 1 layer. MCD affects both the
stroma andendothelium, and SCD involves epithelium, stroma,
andendothelium. As we understand the primary cell(s) of origin,it
may be less important to categorize dystrophies as beingconned to 1
specic layer. In addition, histopathology,although affording
improved resolution at the cellular level, isalso subject to
individual case and disease stage variation.
In this revision of the original IC3D from 2008, weinclude a
proposed alteration of the century-old anatomiclevel classication
to more accurately reect involvement ofthe cellular layers. We now
exclude the Bowman acellularlayer and Descemet acellular membrane.
Dystrophies are nowdivided into epithelial and subepithelial
dystrophies,epithelial-stromal TGFBI dystrophies, stromal
dystrophies,and endothelial dystrophies (Table 1).
What We Have Removed and AddedThe IC3D elected to remove the
extensive table of gene
loci and genes with specic mutations because this informa-tion
is rapidly changing and can be more easily obtained onthe Internet.
For similar reasons, a table of mutations is notincluded in this
revision although templates still include thegene locus and
gene.
The classic articles on corneal dystrophy classication byWaring,
Rodrigues, and Laibson14,15 included clinical drawingsand
histopathologic photographs. As clinicopathological
TABLE 1. The IC3D Classification (C = Category)
Epithelial and subepithelial dystrophies
1. Epithelial basement membrane dystrophy (EBMD)
majoritydegenerative, rarely C1
2. Epithelial recurrent erosion dystrophies (EREDs)Franceschetti
cornealdystrophy (FRCD) C3, Dystrophia Smolandiensis (DS) C3,
andDystrophia Helsinglandica (DH) C3
3. Subepithelial mucinous corneal dystrophy (SMCD) C4
4. Meesmann corneal dystrophy (MECD) C1
5. Lisch epithelial corneal dystrophy (LECD) C2
6. Gelatinous drop-like corneal dystrophy (GDLD) C1
Epithelialstromal TGFBI dystrophies
1. ReisBcklers corneal dystrophy (RBCD) C1
2. Thiel-Behnke corneal dystrophy (TBCD) C1
3. Lattice corneal dystrophy, type 1 (LCD1) C1variants (III,
IIIA, I/IIIA,IV) of lattice corneal dystrophy C1
4. Granular corneal dystrophy, type 1 (GCD1) C1
5. Granular corneal dystrophy, type 2 (GCD2) C1
Stromal dystrophies
1. Macular corneal dystrophy (MCD) C1
2. Schnyder corneal dystrophy (SCD) C1
3. Congenital stromal corneal dystrophy (CSCD) C1
4. Fleck corneal dystrophy (FCD) C1
5. Posterior amorphous corneal dystrophy (PACD) C1
6. Central cloudy dystrophy of Franois (CCDF) C4
7. Pre-Descemet corneal dystrophy (PDCD) C1 or C4
Endothelial dystrophies
1. Fuchs endothelial corneal dystrophy (FECD) C1, C2, or C3
2. Posterior polymorphous corneal dystrophy (PPCD) C1 or C2
3. Congenital hereditary endothelial dystrophy (CHED) C1
4. X-linked endothelial corneal dystrophy (XECD) C2
Removed dystrophies
Grayson-Wilbrandt corneal dystrophy (GWCD) C4
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correlation remains a hallmark of corneal dystrophy diagnosis,we
have included representative histopathology and electronmicroscopy,
as well as confocal microscopy in some cases.
Findings on the emerging technique of anteriorsegment optical
coherence tomography (OCT) were addedto the templates when
available. We expect that this methodwill rene clinical diagnostics
of several dystrophies,especially the differential diagnosis
between TBCD andRBCD by providing images that are highly similar
tohistopathologic sections.
Reclassied Corneal DystrophiesCongenital Hereditary Endothelial
Dystrophy
One challenge of the dystrophy nomenclature has beenthe tendency
to emphasize a new or rare observation insteadof waiting for a
complete analysis of a new disorder. In the2008 IC3D publication,
we observed that inconsistencies inthe literature have confounded
our understanding of precisendings in specic corneal dystrophies.
Since then, we havelearned more about congenital hereditary
endothelial dystro-phy (CHED). In 2008, we followed convention by
including2 types of CHED: an autosomal dominant (AD) form withless
severe ndings was called CHED1 and an autosomalrecessive (AR) form
with more severe ndings was termedCHED2. Further review of the
clinical and pathologicaldescriptions of the 5 families previously
reported withCHED1 suggests that many and possibly all of these
familieshave PPCD.3133 Consequently, AD CHED (CHED1) hasbeen
eliminated. Autosomal recessive CHED, previouslycalled CHED2, is
now called simply CHED.34
Is the 10q23-24 Dystrophy Distinct or a Variant of
TGFBIThiel-Behnke Corneal Dystrophy?
In 1997, Yee et al35 reported a dystrophy affecting theBowman
layer that mapped to 10q23-24, which they calledThiel-Behnke
corneal dystrophy (TBCD). The article sug-gested that the affected
individual had corneal ndingsconsistent with TBCD. The histological
features of this patientwere subsequently reported by Lohse et
al36; however, therewere different pedigrees in both articles.
Clarication of the10q Thiel-Behnke phenotype37 presented other
challenges.Nakamura et al38 described a mixture of
honeycomb-like,geographic-like, and map-like opacity patterns of
the presentedpatients in their legends, but these were not
compatible with theaccompanying black and white photographs that
did notdemonstrate a typical honeycomb-like pattern.
Consequently,given the genetic heterogeneity, phenotypic
heterogeneity andabsence of corroborating histopathology of the
10q23-24dystrophy, we believe that there is insufcient evidence
toconsider this a variant of TBCD. Is it a distinct
dystrophy?Because this is not presently known, we hope
ongoinginvestigations will resolve this uncertainty before the
nextIC3D revision. The 10q23-24 dystrophy is thus still listed asa
footnote to TBCD and not promoted to a template.
Expanded TemplatesIn 2008, the epithelial recurrent erosion
dystrophy
template included both Franceschetti39 hereditary
recurrenterosion and Dystrophia Smolandiensis (DS),40 which
shared
recurrent erosions as their major and often only clinicalnding.
At that time, it was unclear whether these 2 entitieswere variants
of the same condition or whether these weredistinct dystrophies.
Lisch et al41 observed that the affectedmembers of the original
Franceschettis family showedrecurrent erosions in the rst decades,
as well as diffusesubepithelial opacities in the advanced age. The
authorstermed this entity Franceschetti corneal dystrophy(FRCD). In
2009, another entity, Dystrophia Helsinglandica(DH)42 was published
and has been added to the epithelialrecurrent erosion dystrophys
template. Future information,especially future identication of the
underlying gene(s) willreveal whether these 3 entities are unique
entities or allelicvariants of one and the same disorder.
Diagnosis of a Corneal Dystrophy in thePediatric Patient
Diagnosing corneal dystrophies in the pediatric patientremains a
challenge. Most publications contain photographsof the most classic
advanced cases found in adults. Fewphotographs document the
earliest and most subtle cornealchanges as would occur in children,
and there is no atlas ofcorneal dystrophy ndings in children. This
markedlyincreases the difculty of making the correct diagnosis
inthe pediatric patient.43,44
Sporadic Corneal Dystrophy?It is important to be cautious before
making the
diagnosis of a sporadic corneal dystrophy. It is mandatoryto
obtain the family history and examine the parents and otherfamily
members. For example, paraproteinemic immunotac-toid keratopathy
can mimic SCD, lattice corneal dystrophy, orGCD type 1.45
Mucolipidosis IV can cause a cornea verti-cillata pattern similar
to GCD type 1.
A PLEA TO REVIEWERS AND EDITORS
More Stringent Criteria for Publishing theNew Unique Corneal
Dystrophy
An 8-year-old boy is examined and noted to have anunusual
conguration of bilateral corneal ecks. Is thisa unique new corneal
dystrophy? There is a systematicapproach to determining whether
this is a corneal dystro-phy that has already been described or
rather a unique newentity.
Do other family members have similar cornealndings? If so, the
inheritance is likely AD or X-linked.Even if there is no family
history, family members shouldstill be examined to detect subtle or
previously unappre-ciated corneal changes. If no abnormalities are
evident, theinheritance could be AR or there could be
incompletepenetrance or poor expressivity. Although a
classicalphenotypegenotype correlation facilitates diagnosis,
thisdoes not always occur. Histopathology and genotyping canadd
more information.
If geneticists discover a new mutation, a novel type ofcorneal
dystrophy can be constructed phenotypically. Weadvise peer-reviewed
journals to strengthen the criteria
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required for publication of a new corneal dystrophy.A minimum of
approximately 10 affected members in 3generations is reasonably
convincing to demonstrate a dis-tinct dominant phenotype clinically
and scientically. Sucha rigorous systematic approach also avoids
creation of morecategory 4 dystrophies that may be destined only
foreventual elimination. Corneal photographs with a dilatedpupil
also facilitate diagnosis. When the gene or gene locushas been
identied, it is preferable to include photographswith genetic
conrmation. We have attempted to do bothwhen possible for this
article.
As an example, a 27-year-old woman demonstratedrare bilateral
lattice lines atypical for classic LCD. Genotyp-ing demonstrated
the classical Arg124Cys TGFBI LCD1mutation conrming LCD. This was
not a unique cornealdystrophy but rather an additional example of
phenotypicvariation resulting from variable penetrance or
expressivityof the gene.
Regarding mutations of TGFBI, a phenotype typicalenough to be
clinically recognizable is generally limited toTBCD, RBCD, GCD1,
GCD2, and classic LCD. When anyof these classic mutations is
documented, correspondingterminology should be used without
exception, despite anypossible individual variation in phenotype.
Other TGFBImutations often produce variant, overlapping, or
mixedphenotypes, often with amyloid, and these dystrophies canbe
called variant LCD by IC3D conventions. Also, it is illappreciated
that both Congo red and Masson trichromeoften co-label some
deposits in GCD1 and LCD, suggest-ing a mixed phenotype or GCD2.
Also in these cases, theterminology corresponding to the identied
mutationshould simply be used.
There are frequent submissions to journals of suchnew
dystrophies based on a small change in phenotype.More than a
century away from the original description ofcorneal dystrophies,
the eld has progressed from phenotypeto genotype. In the United
States, support of the National EyeInstitute has made genotyping
more accessible through eye-GENE.46 We implore authors and
reviewers alike to requiregenotyping and phenotypic information
before proposing thediscovery of any new genetic disease.
EPITHELIAL AND SUBEPITHELIAL DYSTROPHIES
Epithelial Basement MembraneDystrophy (EBMD)
Mendelian inheritance in man (MIM) #121820.
Former Alternative Names and EponymsMap-dot-ngerprint
dystrophy.Cogan microcystic epithelial dystrophy.Anterior basement
membrane dystrophy.
InheritanceIsolated familial cases have been reported.
However,
because the majority of cases have no documentedinheritance,
they are considered to be degenerative orsecondary to trauma.
Genetic Locus5q31.
GeneTransforming growth factor betainducedTGFBI in 2
families.
OnsetCommonly present in adult life. Rarely described in
children.
SignsPoor adhesion of basal epithelial cells to abnormal
basal
laminar material is thought to predispose to recurrent
erosions.
MapsIrregular islands of thickened, gray, hazy epithelium
with scalloped, circumscribed borders, particularly affectingthe
central or paracentral cornea. Isolated or combined withother signs
(Fig. 1A).
Dots (Cogan)Irregular round, oval, or comma-shaped,
nonstaining,
putty-gray intraepithelial opacities, clustered like an
archipelagoin the central cornea (Fig. 1B). Typically combined with
othersigns, especially with maps.
Fingerprint LinesParallel, curvilinear lines, usually
paracentral, best
visualized with retroillumination (Fig. 1C). Isolated or
com-bined with other signs, especially maps.
Bleb Pattern (Bron)Subepithelial pattern like pebbled glass,
best seen by
retroillumination (Fig. 1D). Isolated or combined with
othersigns.
SymptomsEBMD can be asymptomatic, associated with painful
erosive episodes and/or may cause decreased vision byinducing
mild irregular astigmatism (monocular diplopia,ghost images).
CourseLocation and degree of pathology can uctuate with
time.
Light MicroscopyMaps
Sheets of intraepithelial, multilamellar, basal laminarmaterial
(Fig. 1F).
Fingerprint LinesRib-like intraepithelial extensions of basal
laminar
material (Fig. 1E).
DotsIntraepithelial pseudocysts containing cytoplasmic
debris.
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Bleb PatternIrregular, subepithelial accumulation of
brillogranular
material.
In contrast to some other supercial dystrophies, theBowman layer
is normal.
Transmission Electron MicroscopyMaps
Thick, multilamellar sheets (26 nm thick) ofepithelial basement
membrane that extend into theepithelium.
FIGURE 1. Epithelial basement mem-brane dystrophy. A, Map-like
changes.B, Intraepithelial dot opacities (Cogancysts) underlying
map-like figures. C,Fingerprint lines, best visualized
withretroillumination. D, Multiple crow-ded blebs (Bron), only
visible in ret-roillumination. E and F, Lightmicroscopy shows
excessive base-ment membrane material (arrow-heads) intervening
betweendistorted epithelium and the intactBowman layer) to form
redundantsheets corresponding to maps (E)and fingerprint lines (F)
(E, Massontrichrome; F, PAS, bar = 200 mm.) G,In vivo confocal
microscopy demon-strates abnormal hyperreflective in-traepithelial
basement membranematerial within suprabasal and basalepithelial
cell layers (400 400 mm).
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Fingerprint LinesFine brillar (17 nm diameter) and granular (8
nm)
substance in addition to undulating waves of the
basementmembrane.
DotsIntraepithelial pseudocysts contain degenerating cells
with pyknotic nuclei and cytoplasmic debris.
BlebsDiscrete noncystic mounds of abnormal granular mate-
rial deposited between the epithelium and Bowman layer
thatindents the overlying basal epithelial cells. May mimic
cystsclinically, but no cysts present on histology.
Confocal MicroscopyMaps
Highly reective tissue in various congurationscorresponds to
abnormal basement membrane extendinginto the intermediate and basal
epithelial cell layers.Adjacent basal epithelial cells appear
distorted. No abnor-malities in supercial epithelial cells or
stroma.
Fingerprint LinesLinear hyperreective structures corresponding
to abnor-
mal basement membrane projecting into the corneal
epithelium(Fig. 1G).
DotsHyperreective structures with sharp border within the
intermediate cell layers.
BlebsCircular or oval hyporeective or hyperreective areas
at the level of the basal epithelium and Bowman layer.
CategoryMost cases are sporadic and may be degenerative.
Category 1 in rare cases.Note: Only 1 publication identies 2
families with EBMDwith TGFBI mutations.
BIBLIOGRAPHY Boutboul S, Black GC, Moore JE, et al. A subset of
patientswith epithelial basement membrane corneal dystrophy
havemutations in TGFBI/BIGH3. Hum Mutat. 2006;27:553557.
Bron AJ, Brown NA. Some supercial corneal disorders.Trans
Ophthalmol Soc UK. 1971;91:1329.
Bron AJ, Tripathi RC. Cystic disorders of the cornealepithelium
II. Pathogenesis. Br J Ophthalmol.1973;57:361375.
Cogan DG, Donaldson DD, Kuwabara T, et al. Microcysticdystrophy
of the corneal epithelium. Trans Am OphthalmolSoc.
1964;62:213225.
Guerry D. Fingerprint-like lines in the cornea. Am JOphthalmol.
1950;33:724726.
Fogle JA, Kenyon KR, Stark WJ, et al. Defective
epithelialadhesion in anterior corneal dystrophies. Am J
OphthalmolSoc. 1964;62:213225.
Hau SC, Tuft SJ. In vivo confocal microscopy of
bleb-likedisorder in epithelial basement membrane dystrophy.Cornea.
2011;30:14781480.
Labb A, De Nicola R, Dupas B, et al. Epithelial basementmembrane
dystrophy: evaluation with the HRT II RostockCornea Module.
Ophthalmology. 2006;113:13011308.
Laibson PR, Krachmer JH. Familial occurrence of
dot(microcystic), map, ngerprint dystrophy of the cornea.Invest
Ophthalmol Vis Sci. 1975;14:397399.
Laibson PR. Microcystic corneal dystrophy. Trans AmOphthalmol
Soc. 1976;74:488531.
Lisch W, Lisch C. Die epitheliale
Hornhautbasalmembran-dystrophie. Klin Monatsbl Augenheilkd.
1983;183:251255.
Munier FL, Korvatska E, Djema A, et al.
Kerato-epithelinmutations in four 5q31-linked corneal dystrophies.
NatGenet. 1997;15:247251.
Rodrigues MM, Fine BS, Laibson PR, et al. Disorders ofthe
corneal epithelium. A clinicopathologic study of dot,geographic,
and ngerprint patterns. Arch Ophthalmol.1974;92:475482.
Vogt A. Lehrbuch und Atlas der Spaltlampenmikroskopiedes
lebenden Auges (1. Teil). Berlin, Germany:
Springer;1930:119121.
Epithelial Recurrent ErosionDystrophies (EREDs)
MIM #122400.
VariantsFranceschetti corneal dystrophy (FRCD).Dystrophia
Smolandiensis (DS).Dystrophia Helsinglandica (DH).
InheritanceAutosomal dominant.
Genetic LocusUnknown.
GeneUnknown.
OnsetEarly childhood.
SignsRecurrent epithelial corneal erosions presenting in the
rst decades of life lasting 1 to 7 days. During
pain-freeintervals, no biomicroscopically evident changes are
present(Fig. 2A). By mid-life, diffuse, central, subepithelial
opacity,subepithelial brosis (Fig. 2B), or protruding
keloid-likeformations develop.
SymptomsSevere epithelial erosive attacks commence in child-
hood and recur throughout life. The attacks often start atnight.
Visual impairment from central corneal opacicationconsequent to
erosions occurs in approximately 50% of cases.
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By age 30 to 40 years, corneal erosions become less severeand
less frequent.
CourseWith advancing age to 30 to 40 years, slow reduction
in
frequency of painful erosive episodes. Slow progression
ofcentral opacities impairs visual acuity.
Light MicroscopyFRCD
Based on supercial perilimbal biopsy, irregular basalepithelium
with enlarged intercellular spaces. Alcian bluepositive deposits
were present both intracellularly andintercellularly. Partial
destruction and absence of the Bowmanlayer with intervening
avascular connective tissue pannusbetween the basal epithelium and
Bowman layer (Fig. 2C).Negative Congo red staining.
DSKeloid-like structure stains positive with Congo red
indicating secondary amyloidosis.
Transmission Electron MicroscopyFRCD
Irregularity in size and shape of the basal epithelial cellsand
enlarged intercellular clefts corresponding to Alcianbluepositive
deposits. Presumably dystrophic mitochon-dria in between basal
epithelial cells. Pannus containsnumerous broblasts (Fig. 2D).
ImmunohistochemistryFRCD
Segmental reduced expression of the tight junctionproteins
claudin and E-cadherin, desmosome components.Decorin expression
seems to be enhanced in the basalepithelial layer compared with the
normal postmortemcornea.
DSAbundant bronectin is present in the central subepi-
thelial stroma, localized in areas of subepithelial
brosis.Keratocytes in these areas are immunoreactive for
S100calcium-binding protein A4 (S100A4).
Confocal MicroscopyDS
Abnormal thinning of the corneal epithelium, absenceof the
Bowman layer with accumulation of pathologicalmaterial at the level
of the Bowman layer. Subepithelialcorneal nerves are sparse and
tortuous.
Category3.
Note: The difference in severity of corneal opacication inFRCD,
DS, and DH could be explained by the presence ofpolymorphism and
difference in expressivity of a commongene. The term Familial
recurrent corneal erosions isdescriptive and not diagnostic as
recurrent erosions frequentlyoccur in other corneal dystrophies.
Future DNA analyses willreveal more information about FRCD, DS, and
DH and assistwith differential diagnosis.
FIGURE 2. Franceschetti cornealdystrophy. A, In first decades of
life,the cornea appears normal withoutany dystrophy-specific signs
afterrecurrent epithelial erosion. B, Withadvancing age, diffuse
central haze ofthe epithelial/subepithelial layer de-velops. C,
Light microscopy: inadvanced age, the Bowman layer(arrowhead) is
partially destroyed andpannus (pan) develops between thebasal
epithelium and Bowman layer(PAS, 200 mm). D, Electron micros-copy
of pannus with numerous fibro-blasts. From Lisch W.41
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Corneal Dystrophies
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BIBLIOGRAPHY Franceschetti A. Hereditre rezidivierende Erosion
der
Hornhaut. Z Augenheilk. 1928;66:309316. Hammar B, Bjrck E,
Lagerstedt K, et al. A new cornealdisease with recurrent erosive
episodes and autosomal-dominant inheritance. Acta Ophthalmol.
2008;86:758763.
Hammar B, Bjrck E, Lind H, et al. Dystrophia Helsingland-ica: a
new type of hereditary corneal recurrent erosions withlate
subepithelial brosis. Acta Ophthalmol. 2009;87:659665.
Hammar B, Lagali N, Ek S, et al. Dystrophia Smolandien-sis: a
novel morphological picture of recurrent cornealerosions. Acta
Ophthalmol. 2010;88:394400.
Legrand J. Dystrophie pithliale cornenne rcidivantefamiliale.
Bull Soc Ophtalmol. 1963;5:384387.
Lisch W, Bron AJ, Munier FL, et al. Franceschettihereditary
recurrent corneal erosion. Am J Ophthalmol.2012;153:10731081.
Remler O. Beitrag zur hereditren rezidivierenden
Horn-hauterosion. Klin Monatsbl Augenheilkd. 1983;183:59.
Shindo S. Familial recurrent corneal erosion. Nippon GankaGakkai
Zasshi. 1968;72:9981004.
Wales HJ. A family history of corneal erosions. TransOphthalmol
Soc NZ. 1955;8:7778.
Subepithelial Mucinous CornealDystrophy (SMCD)
MIM #612867.
Former Alternative Names and EponymsNone.
InheritanceAutosomal dominant inheritance most likely, but
X-linked inheritance not excluded.
Genetic LocusUnknown.
GeneUnknown.
OnsetFirst decade of life.
SignsDiffuse bilateral subepithelial opacities and haze,
most
dense centrally (Fig. 3A).
SymptomsPainful episodes of recurrent corneal erosions,
which
decrease during adolescence (only 1 publication of a
singlefamily).
CourseProgressive loss of vision in adolescence.
Light MicroscopySubepithelial band of eosinophilic, periodic
acidSchiff
(PAS)positive, Alcian bluepositive,
hyaluronidase-sensitivematerial is present anterior to the Bowman
layer (Fig. 3B).
Transmission Electron MicroscopySubepithelial deposits of ne
brillar material.
ImmunohistochemistrySubepithelial deposits react for
chondroitin-4-sulfate
and dermatan sulfate.
Confocal MicroscopyNot reported.
Category4.
BIBLIOGRAPHY Feder RS, Jay M, Yue BY, et al. Subepithelial
mucinouscorneal dystrophy. Clinical and pathological
correlations.Arch Ophthalmol. 1993;111:11061114.
Meesmann Corneal Dystrophy (MECD)MIM #122100.
Former Alternative Names and EponymsJuvenile hereditary
epithelial dystrophy.
VariantStockerHolt variant.
InheritanceAutosomal dominant.
Genetic LociLocus 12q13 (KRT3)Locus 17q12 (KRT12) StockerHolt
variant.
FIGURE 3. Subepithelial mucinouscorneal dystrophy. A, Slit-lamp
bio-microscopy reveals that diffuse sub-epithelial opacities and
haze aredensest centrally. B, Light micros-copy: a band of
increased staining ispresent beneath the epithelium. TheBowman
layer is thin (Alcian blue)(40). Photograph courtesy ofRobert
Feder, MD.
Weiss et al Cornea Volume 34, Number 2, February 2015
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Inc. All rights reserved.
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GenesKeratin K3 (KRT3).Keratin K12 (KRT12) StockerHolt
variant.
OnsetEarly childhood.
SignsMultiple, tiny intraepithelial vesicles extend to the
limbus and are most numerous in the interpalpebral areawith
clear surrounding epithelium. Direct illuminationshows varying
diffuse gray opacities in different patterns,which may have a
distinct border (Fig. 4A). Areas of thecentral or peripheral cornea
may be unaffected. Whorled andwedge-shaped epithelial patterns have
been reported. Thegray opacities appear as solitary transparent
cysts on indirectillumination (Figs. 4B, C). Approximately 85% of
eyesshow microcysts affecting the entire epithelium, while
theremainder are localized in the upper, lower, central, and/or
peripheral cornea. Coalescence of several cysts may result
inrefractile linear opacities with an intervening clear cornea.The
cornea may be slightly thinned and corneal sensationmay be
reduced.
StockerHolt VariantThe entire cornea demonstrates ne grayish
punctate
epithelial opacities that stain with uorescein and ne
linearopacities that may appear in a whorl pattern.
SymptomsPatients are typically asymptomatic or may have
mild visual reduction, although some patients complain ofglare
and light sensitivity. Foreign body sensation ortearing may
escalate to painful recurrent epithelial ero-sions. Rarely, blurred
vision results from corneal irregu-larity and scarring.
FIGURE 4. Meesmann corneal dys-trophy. A, In direct
illumination,diffuse gray, superior opacity witha distinct border
is apparent. B, Withretroillumination, the same eyedemonstrates
that the opacity pat-tern is composed of multiple
solitarytransparent microcysts. C, Multiplesolitary transparent
microcysts inretroillumination. D, Light micros-copy:
intraepithelial cysts sometimesextruding onto the corneal
surface,contain amorphous material probablycomprised of degenerated
epithelialcells. The basement membrane isthickened (Alcian blue and
hematox-ylin and eosin stain, 400). E, Electronmicroscopy:
intracytoplasmic fibrillarpeculiar substance, surrounding tan-gles
of filaments. F, In vivo confocalmicroscopy shows
hyporeflectiveareas corresponding to microcysts inthe basal
epithelial layer and roundhyperreflective structures (400 400 mm).
Figures 4A, B, and C fromFigures 4A and B: Weiss JS, Mller HU,Lisch
W, et al. The IC3D classificationof the corneal dystrophies.
Cornea.2008;27(suppl 2):S1S42.
Cornea Volume 34, Number 2, February 2015 IC3D Classification of
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StockerHolt VariantPatients demonstrate more severe signs and
symptoms
with earlier onset compared with classic Meesmann
cornealdystrophy.
CourseStationary or slowly progressive.
Light MicroscopyThe thickened and disorganized epithelium
always
demonstrates intraepithelial cysts (Fig. 4D) lled with
PAS-positive cellular debris, which uoresces. The cells alsocontain
of PAS-positive and diastase-sensitive material(glycogen). A
thickened multilaminar basement membraneprojects into the basal
epithelium.
StockerHolt VariantVariably thickened epithelium with vacuolated
and
degenerating cells. Variably thickened basement membraneextends
into the epithelium. The Bowman layer and stromaremain normal.
Transmission Electron MicroscopyIntracytoplasmic peculiar
substance represents a focal
collection of brogranular material surrounded by tangles
ofcytoplasmic laments (Fig. 4E). These cysts are round anduniform
(1050 mm). Some lesions with reective points inthe cytoplasm
probably correspond to cell nuclei.
StockerHolt VariantNot reported.
Confocal MicroscopyHyporeective areas in the basal epithelium
ranging
from 40 to 150 mm in diameter, some with reective spotsinside
(Fig. 4F).
Numerous corneal intraepithelial microcysts and hyper-reective
material thought to represent degenerative cellshave been detected
closer to the basal layer of the cornealepithelium in older
patients. Compared with the basalepithelial layer, the supercial
layer contains larger micro-cysts with atrophic changes of the
hyperreective material.Clearly visualized demarcation lines between
the microcystsand normal epithelial cells correspond to the
biomicroscopi-cally visible demarcation between clear and affected
areas.
StockerHolt VariantNot reported.
Category1 including StockerHolt variant.
BIBLIOGRAPHY Allen EH, Atkinson SD, Liao H, et al.
Allele-specicsiRNA silencing for the common keratin 12
foundermutation in Meesmann epithelial corneal dystrophy.
InvestOphthalmol Vis Sci. 2013;54:494502.
Behnke H, Thiel HJ. On hereditary epithelial dystrophy ofthe
cornea (type Meesmann-Wilke) in SchleswigHolstein.Klin Monatsbl
Augenheilkd. 1965;147:662672.
Burns RP. Meesmanns corneal dystrophy. Trans AmOphthalmol Soc.
1968;66:530635.
Cao W, Yan M, Hao Q, et al. Autosomal-dominantMeesmann
epithelial corneal dystrophy without an exonmutation in the
keratin-3 or keratin-12 gene in a Chinesefamily. J Int Med Res.
2013;41:511518.
Clausen I, Duncker GI, Grnauer-Kloevekorn C. Identi-cation of a
novel mutation in the cornea specic keratin 12gene causing
Meesmanns corneal dystrophy in a Germanfamily. Mol Vis.
2010;16:954960.
Cremona FA, Ghosheh FR, Laibson PR, et al. Meesmanncorneal
dystrophy associated with epithelial basementmembrane and posterior
polymorphous corneal dystro-phies. Cornea. 2008;27:374377.
Ehlers N, Hjortdal J, Nielsen K, et al. Phenotypic variabilityin
Meesmanns dystrophy: clinical review of the literatureand
presentation of a family genetically identical to theoriginal
family. Acta Ophthalmol. 2008;86:4044.
Fine BS, Yanoff M, Pitts E, et al. Meesmanns epithelialdystrophy
of the cornea. Am J Ophthalmol. 1977;83:633642.
Hassan H, Thaung C, Ebenezer ND, et al. SevereMeesmanns
epithelial corneal dystrophy phenotype dueto a missense mutation in
the helix-initiation motif ofkeratin 12. Eye (Lond).
2013;27:367373.
Javadi MA, Rezaei-Kanavi M, Javadi A, et al. Meesmanncorneal
dystrophy; a clinico-pathologic, ultrastructural andconfocal scan
report. J Ophthalmic Vis Res. 2010;5:122126.
Meesmann A. ber eine bisher nicht beschriebene domi-nant
vererbte Dystrophia epithelialis corneae. Ber Zusam-menkunft Dtsch
Ophthalmol Ges. 1938;52:154158.
Nielsen K, Orntoft T, Hjortdal J, et al. A novel mutation asthe
basis for asymptomatic Meesmann dystrophy in a Dan-ish family.
Cornea. 2008;27:100102.
Ogasawara M, Matsumoto Y, Hayashi T, et al. KRT12mutations and
in vivo confocal microscopy in two Japanesefamilies with Meesmann
corneal dystrophy. Am J Oph-thalmol. 2014;157:93102.
Seto T, Fujiki K, Kishishita H, et al. A novel mutation inthe
cornea-specic Keratin 12 gene in Meesmann cornealdystrophy. Jpn J
Ophthalmol. 2008;52:224226.
Stocker FW, Holt LB. A rare form of hereditary
epithelialdystrophy of the cornea: a genetic, clinical and
pathologicstudy. Trans Am Ophthalmol Soc. 1954;52:133144.
Sullivan LS, Baylin EB, Font R, et al. A novel mutation ofthe
Keratin 12 gene responsible for a severe phenotype ofMeesmanns
corneal dystrophy. Mol Vis. 2007;13:975980.
Szaik JP, O1dak M, Maksym RB, et al. Genetics ofMeesmann corneal
dystrophy: a novel mutation in thekeratin 3 gene in an asymptomatic
family suggestsgenotype-phenotype correlation. Mol Vis.
2008;14:17131718.
Thiel HJ, Behnke H. On the extent of variation of
hereditaryepithelial corneal dystrophy (Meesmann-Wilke type).
Oph-thalmologica. 1968;155:8186.
Weiss et al Cornea Volume 34, Number 2, February 2015
128 | www.corneajrnl.com Copyright 2014 Wolters Kluwer Health,
Inc. All rights reserved.
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Tuft S, Bron AJ. Imaging the microstructural abnormalitiesof
Meesmann corneal dystrophy by in vivo confocalmicroscopy. Cornea.
2006;25:868870.
Wittebol-Post D, van Bijsterveld OP, Delleman JW.Meesmanns
epithelial dystrophy of the cornea. Biometricsand a hypothesis.
Ophthalmologica. 1987;194:4449.
Yeung JY, Hodge WG. Recurrent Meesmanns cornealdystrophy:
treatment with keratectomy and mitomycinC. Can J Ophthalmol.
2009;44:103104.
Lisch Epithelial Corneal Dystrophy (LECD)MIM #300778.
Former alternative names and eponymsBand-shaped and whorled
microcystic dystrophy of the
corneal epithelium.
InheritanceX-chromosomal dominant.
Genetic LocusXp22.3.
GeneUnknown.
OnsetChildhood.
SignsDirect illumination shows localized gray opacities in
different patterns: whorl-like, radial, band-shaped
ame/feathery, and club shaped (Figs. 5A, B). Indirect
illuminationdemonstrates multiple densely crowded clear cysts (Fig.
5C).Opacities can be minimal or asymmetric with clear surround-ing
epithelium. Similar appearance in males and females.
SymptomsAsymptomatic or blurred vision if the pupillary axis
is
involved.
FIGURE 5. Lisch epithelial cornealdystrophy. A and B, Diffuse
grayishepithelial opacities form radial,feathery or club-shaped
patterns.C, Opacification consists of crow-ded, transparent
microcysts in ret-roillumination. D, Light microscopy:pronounced
vacuolization of theepithelial cells, particularly in outerlayers
(hematoxylin and eosin stain,250). E, Electron microscopy:
dis-closes coalescent intracellular va-cuolization of the wing
cells. Someof these vacuoles coalesce to formempty spaces within
the cytoplasmof the epithelial cells, 4000. F, Invivo confocal
microscopy shows in-traepithelial hyperreflective dystro-phic areas
containing hyporeflectiveround structures, sharply demar-cated from
normal epithelial areas(400 400 mm). Figure 5C fromFigure 5C in
Weiss JS, Mller HU,Lisch W, et al. The IC3D classificationof the
corneal dystrophies. Cornea.2008;27(suppl 2):S1S42.
Cornea Volume 34, Number 2, February 2015 IC3D Classification of
Corneal Dystrophies
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CourseSlow progression of opacities with possible visual
deterioration.
Light MicroscopyEpithelial basal cells are cuboidal with low
nuclear to
cytoplasmic ratio. In the suprabasal and parabasal
layers,vacuolated cells (Fig. 5D) progress to the epithelial
surface,where they adopt elongated at squamous shapes.
Thesevacuoles are PAS positive, diastase labile, Luxol fast blue
andSudan black negative, consistent with glycogen.
Intercellularcysts, parakeratosis, orthokeratosis, and
hyperkeratosis arenot identied.
Transmission Electron MicroscopyBasal epithelial cells with
intact basement membrane
and hemidesmosomes are unremarkable. In the midlevel
andsupercial epithelium, there are cells with myriad vacuolesand
inclusions (Fig. 5E) of 2 forms; vaguely occulent orlamellar
material with or without a circumscribing membrane,and more
electron-dense whorled or membranous structures.
Confocal MicroscopyThere are 4 characteristic features of the
abnormal
epithelial cells: highly hyperreective cytoplasm andhyporeective
nuclei (Fig. 5F); uniform involvement ofall epithelial layers
within the affected areas; well-demarcated borders with adjacent
normal epithelium;involvement of the limbal area. No distinct
intracellulardeposits are present, although the cytoplasm has
granularhyperreectivity.
Category2.
BIBLIOGRAPHY Butros S, Lang GK, Alvarez de Toledo J, et al.
Die
verschiedenen Trbungsmuster der Lisch-Hornhautdystrophie.Klin
Monatsbl Augenheilkd. 2006;223:837840.
Charles NC, Young JA, Kunar A, et al. Band-shaped andwhorled
microcystic dystrophy of the corneal epithelium.Ophthalmology.
2000;107:17611764.
FIGURE 6. Gelatinous drop-like cor-neal dystrophy. A, Band
keratopathytype. B, Mulberry type. C, Fluoresceinstaining shows an
extremely hyper-permeable corneal epithelium, herewithout
superficial punctate keratop-athy or erosion. D,
Kumquat-likediffuse stromal opacity. E, Lightmicroscopy: massive
amyloid ina subepithelial lesion (arrowheads)extending to the
midstromal cornea.Bar = 400 mm (direct fast scarlet[DFS], 10).
Figures 6A, B, andD from Figures 6A, B, and C in WeissJS, Mller HU,
Lisch W, et al. TheIC3D classification of the cornealdystrophies.
Cornea. 2008;27(suppl2):S1S42.
Weiss et al Cornea Volume 34, Number 2, February 2015
130 | www.corneajrnl.com Copyright 2014 Wolters Kluwer Health,
Inc. All rights reserved.
-
Kurbanyan K, Sejpal KD, Aldave AJ, et al. In vivo
confocalmicroscopic ndings in Lisch corneal dystrophy.
Cornea.2012;31:437441.
Lisch W, Bttner A, Offner F, et al. Lisch corneal dystrophyis
genetically distinct from Meesmann corneal dystrophyand maps to
Xp22.3. Am J Ophthalmol. 2000;130:461468.
Lisch W, Steuhl KP, Lisch C, et al. A new, band-shapedand
whorled microcystic dystrophy of the corneal epithe-lium. Am J
Ophthalmol. 1992;114:3544.
Robin SB, Epstein RJ, Kornmehl EW. Band-shaped,whorled
microcystic corneal dystrophy. Am J Ophthalmol.1994;117:543544.
Wessel MM, Sarkar JS, Jakobiec FA, et al. Treatment ofLisch
corneal dystrophy with photorefractive keratectomyand Mitomycin C.
Cornea. 2011;30:481485.
Gelatinous Drop-like Corneal Dystrophy (GDLD)MIM #204870.
Former Alternative Names and EponymsSubepithelial
amyloidosis.Primary familial amyloidosis (Grayson).
InheritanceAutosomal recessive.
Genetic Locus1p32.
GeneTumor-associated calcium signal transducer 2 (TACSTD2,
previously M1S1).
OnsetFirst to second decade.
SignsInitially, subepithelial lesions may appear similar to
band-
shaped keratopathy (Fig. 6A) or there may be groups of
smallmultiple nodules, that is, mulberry conguration (Fig. 6B).They
stain with uorescein (Fig. 6C), indicating
epithelialhyperpermeability. Supercial vascularization is
frequentlyseen. In later life, patients may also develop stromal
opacica-tion or develop larger nodular, kumquat-like lesions (Fig.
6D)although it is uncertain whether there is a transition of the
4different phenotypes from one to the other with time.
SymptomsSignicant decrease in vision, photophobia,
irritation,
redness, and tearing.
CourseProgression of protruding subepithelial deposits and
stromal opacity. Most patients develop recurrence aftersupercial
keratectomy, lamellar keratoplasty, or penetratingkeratoplasty,
typically within a few years.
Light MicroscopySubepithelial and stromal amyloid deposits (Fig.
6E).
Transmission Electron MicroscopyDisruption of epithelial tight
junctions in the supercial
epithelium. Amyloid evident in the basal epithelial layer.
ImmunohistochemistryDeposits stain with antibodies to
lactoferrin.
Confocal MicroscopyEpithelial cells are irregular in shape and
often
elongated. There is a mild disorganization of the
overallepithelial architecture. Large accumulations of brightly
reec-tive material are noted within or beneath the epithelium
andwithin the anterior stroma. No evident abnormalities can
bedetected in the posterior cornea.
Category1.
BIBLIOGRAPHY Fujiki K, Nakayasu K, Kanai A. Corneal dystrophies
inJapan. J Hum Genet. 2011;46:431435.
Ide T, Nishida K, Maeda N, et al. A spectrum of
clinicalmanifestations of gelatinous drop-like corneal dystrophy
inJapan. Am J Ophthalmol. 2004;137:10811084.
Kaji Y, Oshika T, Takazawa Y, et al. Co-localization ofadvanced
glycation end products and D-beta-aspartic acid-containing proteins
in gelatinous drop-like corneal dystro-phy. Br J Ophthalmol.
2012;96:11271131.
Kinoshita S, Nishida K, Dota A, et al. Epithelial
barrierfunction and ultrastructure of gelatinous drop-like
cornealdystrophy. Cornea. 2000;19:551555.
Kitazawa K, Kawasaki S, Shinomiya K, et al. Establish-ment of a
human corneal epithelial line lacking thefunctional TACSTD2 gene as
an in vitro model forgelatinous drop-like dystrophy. Invest
Ophthalmol VisSci. 2013;57015711.
Klintworth GK, Valnickova Z, Kielar RA, et al.
Familialsubepithelial corneal amyloidosisa
lactoferrin-relatedamyloidosis. Invest Ophthalmol Vis Sci.
1997;38:27562763.
Nakaizumi GA. A rare case of corneal dystrophy. Acta
SocOphthalmol Jpn. 1914;18:949950.
Nakatsukasa M, Kawasaki S, Yamasaki K, et al. Tumor-associated
calcium signal transducer 2 is required for theproper subcellular
localization of claudin 1 and 7: impli-cations in the pathogenesis
of gelatinous drop-like cornealdystrophy. Am J Pathol.
2010;177:13441355.
Nakatsukasa M, Kawasaki S, Yamasaki K, et al. Two novelmutations
of TACSTD2 found in three Japanese gelatinousdrop-like corneal
dystrophy families with their aberrantsubcellular localization. Mol
Vis. 2011;19:965970.
Paliwal P, Gupta J, Tandon R, et al. Identication
andcharacterization of a novel TACSTD2 mutation in gelati-nous
drop-like corneal dystrophy. Mol Vis. 2010;16:729739.
Ren Z, Lin PY, Klintworth GK, et al. Allelic and
locusheterogeneity in autosomal recessive gelatinous
drop-likecorneal dystrophy. Hum Genet. 2002;110:568577.
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Corneal Dystrophies
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Tsujikawa M, Kurahashi H, Tanaka T, et al. Identicationof the
gene responsible for gelatinous drop-like cornealdystrophy. Nat
Genet. 1999;21:420423.
Tsujikawa M. Gelatinous drop-like corneal dystrophy.Cornea.
2012;31(suppl 1):S37S40.
Yoshida S, Kumano Y, Yoshida A, et al. Two brotherswith
gelatinous drop-like dystrophy at different stages ofthe disease:
role of mutational analysis. Ophthalmol.2002;133:830832.
EPITHELIALSTROMAL TGFBI DYSTROPHIES
ReisBucklers Corneal DystrophyMIM #608470.
Former Alternative Names and EponymsCorneal dystrophy of Bowman
layer, type I (CDB I).Geographic corneal dystrophy
(Weidle).Atypical Granular Corneal Dystrophy.Granular Corneal
Dystrophy, type 3.Anterior limiting membrane dystrophy, type
1.Supercial Granular Corneal Dystrophy.
InheritanceAutosomal dominant.
Genetic Locus5q31.
GeneTransforming growth factor beta-inducedTGFBI.
OnsetChildhood.
SignsConuent early irregular geographic-like opacities with
varying densities develop at the level of the Bowman layer
and supercial stroma, initially discrete (Fig. 7A)
andsubsequently extending to the limbus and deeper stroma(Fig. 7B).
Can be confused with TBCD especially in the rst2 decades. In this
early stage, RBCD shows more irregulardiffuse opacities with clear
interruptions, whereas TBCDexhibits multiple ecks with reticular
formation.
SymptomsVision is impaired from childhood. Painful recurrent
corneal erosions.
CourseSlowly progressive deterioration of vision. Recurrent
corneal erosions tend to abate with time. Similar butfrequently
more aggressive course than TBCD but may notbe able to distinguish
in an individual case.
Light MicroscopyThe Bowman layer is replaced by a sheet-like
layer of
granular Masson trichromered deposits (Fig. 7C), which canextend
to the subepithelial stroma and, in advanced cases,sparse round
deposits appear in the middle and posterior stroma.
Transmission Electron MicroscopySubepithelial electron-dense,
rod- or trapezoidal-shaped
bodies identical to those in GCD1 (Fig. 7D) replace theBowman
layer and extend from the basal epithelial cell level toanterior
stroma and, sparsely, to deeper stroma. Basal epithelialcells may
contain vesicles with similar rods. Electron micros-copy is
necessary for denitive histopathologic diagnosis todistinguish from
TBCD, which demonstrates curly bers notrod-shaped bodies.
ImmunohistochemistryRod-shaped bodies are immunopositive for
transform-
ing growth factor betainduced protein (keratoepithelin).
FIGURE 7. ReisBucklers cornealdystrophy. A, Confluent
irregular,geographic-like opacities. B, Geo-graphic opacities
extend to the lim-bus and deeper stroma in a moreadvanced case. C,
Light microscopy:Masson trichrome stains keratohyalinintensely red
beneath the epitheliumand between superficial stromallamellae. Note
characteristic destruc-tion of the Bowman layer. Deeper redspots
(asterisk) are artifact of lamellarkeratoplasty (Arg124Leu
TGFBImutation), bar = 200 mm. D, Electronmicroscopy: broad band of
irregularlyarranged, subepithelial rod-shapedbodies (3000). E, In
vivo confocalmicroscopy shows a granular highlyreflective material
without anyshadow within the basal epithelium(Arg124Leu mutation)
(400 400mm).
Weiss et al Cornea Volume 34, Number 2, February 2015
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Inc. All rights reserved.
-
Optical Coherence TomographyA homogenous conuent layer of
hyperreective depos-
its often with serrated anterior border is apparent at the level
ofthe Bowman layer and anterior stroma. It is thickest in thecenter
(72132 mm), becomes thinner in midperiphery, anddisappears toward
the limbus.
Confocal MicroscopyDistinct deposits are found in the epithelium
and
Bowman layer. The deposits in the suprabasal and basalepithelial
cell layer show extremely high reectivity from smallgranular or
amorphous material without shadows (Fig. 7E).The Bowman layer is
replaced by highly reective irregularmaterial, even more reective
than in TBCD. Fine diffuseround or spindle-shaped deposits may be
noted in the anteriorand sparsely even in the posterior stroma.
Category1.
BIBLIOGRAPHY Bcklers M. ber eine weitere familire Hornhaut-
dystrophie (Reis). Klin Monatsbl
Augenkeilkd.1949;114:386397.
Kobayashi A, Sugiyama K. In vivo laser confocalmicroscopy ndings
for Bowmans layer dystrophies(Thiel-Behnke and ReisBcklers corneal
dystrophies).Ophthalmology. 2007;114:6975.
Konishi M, Yamada M, Nakamura Y, et al. Immunohistol-ogy of
keratoepithelin in corneal stromal dystrophiesassociated with R124
mutations of the BIGH3 gene. CurrEye Res. 2000;21:891896.
Kchle M, Green WR, Vlcker HE, et al. Reevaluation ofcorneal
dystrophies of Bowmans layer and the anteriorstroma (ReisBcklers
and Thiel-Behnke types): a light andelectron microscopic study of
eight corneas and a review ofthe literature. Cornea.
1995;14:333354.
Liang Q, Pan Z, Sun X, Baudouin C, et al. ReisBcklerscorneal
dystrophy: a reappraisal using in vivo and ex vivoimaging
techniques. Ophthalmic Res. 2014;51:187195.
Munier FL, Korvatska E, Djema A, et al. Keratoepithelinmutations
in four 5q31-linked corneal dystrophies. NatGenet.
1997;15:247251.
Reis W. Familire, eckige Hornhautentartung. Dtsch MedWochenschr.
1917;43:575.
Ridgway AE, Akhtar S, Munier FL, et al. Ultrastructuraland
molecular analysis of Bowmans layer corneal dystro-phies: an
epithelial origin? Invest Ophthalmol Vis Sci.2000;41:32863292.
Small KW, Mullen L, Barletta J, et al. Mapping of ReisBcklers
corneal dystrophy to chromosome 5q. Am JOphthalmol.
1996;121:384390.
Stone EM, Mathers WD, Rosenwasser GO, et al. Threeautosomal
dominant corneal dystrophies map to chromo-some 5q. Nat Genet.
1994;6:4751.
Streeten BW, Qi Y, Klintworth GK, et al. Immunolocaliza-tion of
beta ig-h3 protein in 5q31-linked corneal dystrophiesand normal
corneas. Arch Ophthalmol. 1999;117:6775.
Weidle EG. Klinische und feingewebliche Abgrenzung
derReis-Bcklersschen Hornhautdystrophie. Klin MonatsblAugenheilkd.
1989;194:217226.
Wittbol-Post D, Pels E. The dystrophy described by Reisand
Bcklers. Ophthalmologica. 1989;199:19.
ThielBehnke Corneal Dystrophy (TBCD)MIM #602082.
Former Alternative Names and EponymsCorneal dystrophy of Bowman
layer, type II (CDB2).Honeycomb-shaped corneal dystrophy.Anterior
limiting membrane dystrophy, type II.Curly bers corneal
dystrophy.WaardenburgJonkers corneal dystrophy.
InheritanceAutosomal dominant.
Genetic Loci5q31.
GeneTransforming growth factor betainducedTGFBI.
OnsetEarly childhood.
SignsInitial signs are solitary ecks or irregularly shaped
scattered opacities at the level of the Bowman layer, followedby
symmetrical subepithelial honeycomb opacities (Figs. 8A,B, Ci) with
peripheral cornea typically uninvolved. In olderpatients, opacities
can progress to deeper stromal layers andthe corneal periphery. It
is difcult to distinguish from ReisBcklers corneal dystrophy (RBCD)
in early or individualcases.
Rare alleles that combine Arg555Gln with other TGFBImutations
lead to variants of TBCD with atypical opacities.
SymptomsRecurrent corneal erosions may be painful in the rst
and second decades. Gradual visual impairment developslater.
Erosions are less frequent, and the onset of visualimpairment is
later than in RBCD.
CourseSlowly progressive deterioration of vision results
from
increasing corneal scarring. Recurrent corneal erosionsdiminish
with time. Similar but frequently less aggressivecourse than RBCD
but difcult to distinguish individualcases.
Light MicroscopyAlternating irregular thickening and thinning of
the
epithelial layer to compensate for ridges and furrows
ofunderlying stroma, with focal absence of the epithelialbasement
membrane (Fig. 8D). The Bowman layer is replaced
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Corneal Dystrophies
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by a supercial brocellular pannus with a pathognomonicwavy
sawtoothed pattern.
Transmission Electron MicroscopyPresence of curly collagen bers
9 to 15 nm in
diameter (Fig. 8E), importantly distinguishes TBCD fromRBCD.
ImmunohistochemistryCurly bers are immunopositive for
transforming
growth factor betainduced protein (keratoepithelin).
Confocal MicroscopyDistinct deposits are found in the epithelium
and
Bowman layer. The deposits in the basal epithelial cell
layershow homogeneous reectivity with round edges accompa-nying
dark shadows (Fig. 8F). The Bowman layer is replacedwith reective
irregular material that is less reective than inRBCD.
Optical Coherence TomographyProminent hyperreective material at
the level of the
Bowman layer extending into the epithelium in a
characteristic
FIGURE 8. Lattice Corneal Dystro-phy, type 1 (LCD). A, Initial
signs ofmild honeycomb appearance. B,Intensive honeycomb opacity
pat-tern in advanced disease(Arg555Gln mutation). C, In a
42-year-old with genetically confirmedTBCD: (i) the cornea displays
hon-eycomb opacity while (ii) confocalmicroscopy demonstrates the
saw-tooth pattern of hyperreflectivematerial in the Bowman layer.
D,Light microscopy: varying thicknessof the epithelium due to a
thickenedabnormal subepithelial fibrous layer(arrowheads) that
replaces theBowman layer and has a characteris-tic sawtooth-like
surface. Massontrichrome, bar = 200 mm. E, Trans-mission electron
microscopy: sub-epithelial curly filaments witha thickness of 10 nm
(50,000). F, Invivo confocal microscopy imageshows abnormal
hyperreflectivematerial with homogeneous re-flectivity, round
edges, and darkshadows within the basal epithelium(400 400 mm).
Weiss et al Cornea Volume 34, Number 2, February 2015
134 | www.corneajrnl.com Copyright 2014 Wolters Kluwer Health,
Inc. All rights reserved.
-
sawtooth pattern (Fig. 8Cii), a major feature in
distinguishingTBCD from RBCD.
Category1.
Note: Linkage to 10q24 has been reported in 1 family. Theinitial
and later descriptions of the phenotype are incompleteand variable,
and light microscopic, immunohistochemical,and anterior segment
optical coherence tomographic evidenceof subepithelial scarring
similar to and consistent with TBCDhas not been published.
BIBLIOGRAPHY Chen YJ, Chen JT, Lu DW, et al. In vivo corneal
confocalmicroscopic ndings and gene analysis of three patientswith
Thiel-Behnke corneal dystrophy. Br J Ophthalmol.2010;94:262264.
Cho KJ, Mok JW, Na KS, et al. TGFBI gene mutations ina Korean
population with corneal dystrophy. Mol Vis.2012;18:20122021.
Kobayashi A, Sugiyama K. In vivo laser confocal microscopyndings
for Bowmans layer dystrophies (Thiel-Behnke andReisBcklers corneal
dystrophies). Ophthalmology.2007;114:6975.
Kchle M, Green WR, Vlcker HE, et al. Reevaluation ofcorneal
dystrophies of Bowmans layer and the anteriorstroma (ReisBcklers
and Thiel-Behnke types): a light andelectron microscopic study of
eight corneas and a review ofthe literature. Cornea.
1995;14:333354.
Lohse E, Stock EL, Jones JC, et al. ReisBcklers
cornealdystrophy. Immunouorescent and electron microscopicstudies.
Cornea. 1989;8:200209.
Munier FL, Korvatska E, Djema A, et al. Keratoepithelinmutations
in four 5q31-linked corneal dystrophies. NatGenet.
1997;15:247251.
Niel-Butschi F, Kantelip B, Iwaszkiewicz J, et
al.Genotype-phenotype correlations of TGFBI
p.Leu509Pro,p.Leu509Arg, p.Val613Gly, and the allelic association
ofp.Met502Val-p.Arg555Gln mutations. Mol Vis.2011;17:11921202.
Nowinska AK, Wylegala E, Janiszewska DA, et
al.Genotype-phenotype correlation of TGFBI corneal dystro-phies in
Polish patients. Mol Vis. 2011;17:23332342.
Ridgway AE, Akhtar S, Munier FL, et al. Ultrastructural
andmolecular analysis of Bowmans layer corneal dystrophies:
anepithelial origin? Invest Ophthalmol Vis Sci.
2000;41:32863292.
Streeten BW, Qi Y, Klintworth GK, et al. Immunolocaliza-tion of
beta ig-h3 protein in 5q31-linked corneal dystrophiesand normal
corneas. Arch Ophthalmol. 1999;117:6775.
Thiel HJ, Behnke H. Eine bisher unbekannte
subepithelialehereditre Hornhautdystrophie. Klin Monatsbl
Augenheilkd.1967;150:862874.
Vajzovic LM, Karp CL, Haft P, et al. Ultra
high-resolutionanterior segment optical coherence tomography in
theevaluation of anterior corneal dystrophies and degenera-tions.
Ophthalmology. 2011;118:12911296.
Weidle EG. Die wabenfrmige Hornhautdystrophie (Thiel-Behnke)
Neubewertung und Abgrenzung gegenber der
Reis-Bcklerschen Hornhautdystrophie. Klin Monatsbl Au-genheilkd.
1999;214:125135.
Wittebol-Post D, Van Schooneveld MJ, Pels E. The
cornealdystrophy of Waardenburg and Jonkers. Ophthalmic Pae-diatr
Genet. 1989;10:249255.
Lattice Corneal Dystrophy, type 1 (Classic)(LCD1) and
Variants
MIM #122200.
Former Alternative Names and EponymsLCD, type
1.Biber-Haab-Dimmer.
InheritanceAutosomal dominant.
Genetic Locus5q31.
GeneTransforming growth factor betainducedTGFBI.
OnsetFirst to second decade.
SignsThe rst signs are central supercial eck-like opacities
that usually develop by the end of the rst decade (Fig. 9A).In
retroillumination, isolated peripheral, few, and subtlelattice
lines in deeper layers are visible initially in thesupercial stroma
of the same patient (Fig. 9B). Thinbranching refractile lines
and/or subepithelial, whitish, ovoiddots also develop by the end of
the rst decade. These linesstart centrally and more supercially,
spreading centrifugallyand deeply, but leaving the far peripheral
stroma, Descemetmembrane and the endothelium uninvolved (Figs. 9C,
D).Diffuse subepithelial ground-glass haze of the central
andparacentral cornea develops concurrently with the lattice
linesin the central and paracentral cornea and
subsequentlyprogresses (Fig. 9C), accompanied by recurrent
erosions.Development of diffuse central haze in the second to
thirddecade may reduce vision sufciently to necessitate
surgicalintervention. The number of lattice lines may differ
betweenthe 2 eyes (unilateral cases are described). Variant LCD,
typeIIIA also shows central thicker lattice lines (Fig.
10A),whereas LCD, type IV is characterized more by deeperdeposits
without epithelial erosion (Fig. 10B).
SymptomsOcular discomfort, pain, and visual impairment,
some-
times start as early as the rst decade as consequent tofrequent
recurrent erosive attacks. Visual impairment withinthe fourth
decade.
CourseProgressive, often with marked visual decrease by the
fourth decade.
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Light MicroscopyEpithelial atrophy and disruption with
degeneration of
basal epithelial cells, focal thinning, or absence of theBowman
layer, progress with age. Eosinophilic amyloidmaterial accumulates
between the epithelial basement mem-brane and Bowman layer. Stromal
deposition of amyloid
distorts the architecture of corneal lamellae. Amyloid
depositscharacteristically stain positive with Congo red (Fig. 9E),
anddisplay birefringence and red-green di rhos under polarizedlight
(Fig. 9F). Also, deposits exhibit metachromasia withcrystal violet
and uorescence with the use of thioavin Tstaining.
FIGURE 9. Lattice corneal dystro-phy, type 1 (classic lattice).
Direct(A) and retroillumination (B) of earlylattice corneal
dystrophy (LCD) withdots and fine lattice lines withgenetic
confirmation of Arg124Cysin TGFBI. C, Subepithelial ground-glass
haze of the central and inferiorcornea, and diffuse lattice lines
inadvanced LCD with genetic confir-mation of Arg124Cys in TGFBI.
D,Dots and paracentral lattice lines inretroillumination with
genetic con-firmation of Arg124Cys in TGFBI. E,Light microscopy:
Congo red (E)prominently stains a continuouslayer of amyloid
(asterisk) that un-derlies and partially destroys theBowman layer
and intrastromalamyloid deposits corresponding tolattice lines
(arrowheads). F, Thissame section viewed with polarizedlight
confirms deposits are birefrin-gent and red-green dichroic,
thusamyloid. Arg124Cys TGFBI muta-tion, bars = 200 mm. G, In
vivoconfocal microscopy image showsfilaments corresponding to
latticelines within the stroma (400 400mm). Figure 9D from Figure
10A, inWeiss JS, Mller HU, Lisch W, et al.The IC3D classification
of the cornealdystrophies. Cornea. 2008;27(suppl2):S1S42.
Weiss et al Cornea Volume 34, Number 2, February 2015
136 | www.corneajrnl.com Copyright 2014 Wolters Kluwer Health,
Inc. All rights reserved.
-
Transmission Electron MicroscopyExtracellular masses of ne,
electron-dense randomly
aligned brils of uniform 8 to 10 nm diameter are character-istic
of amyloid protein. There are fewer keratocytes in theareas of
amyloid deposition: some are degenerated withcytoplasmic
vacuolization, whereas others appear metaboli-cally active.
Descemet membrane and the endothelium arenormal.
Confocal MicroscopyLinear and branching structures (Fig. 9G) in
stroma
with changing reectivity and poorly demarcated margins.Such
lines must be differentiated from other similar images(ie,
fungi).
Category1.
Note: The LCD variants (Figs. 10A, B) are caused by morethan 2
dozen distinct heterozygous amyloidogenic mutations,nearly all of
which are located in the fourth FAS1 domain ofTGFBI. LCD variants
(previously designated type IIIA, I/IIIA,IV, and polymorphic
amyloidosis) have a delayed onsetcompared with classic LCD. The
lattice lines may be larger,with a limbus to limbus ropy appearance
(type IIIA), thinner(type I/IIIA), smaller (type IV) or even absent
(polymorphicamyloidosis), although one has to keep in mind that the
latticepattern is very much dependent on age and mutation.
Somepatients do not have clinically evident lattice lines.
Corneal
epithelial erosions are a typical presenting sign of LCD,
typesIIIA and I/IIIA, but are virtually absent in others (type IV
andpolymorphic corneal amyloidosis). The frequency of
recurrenterosions is more common in subtypes that progress
fromanterior to posterior (types IIIA and I/IIIA) compared
withthose progress from posterior to anterior (type IV).
Althoughclassic LCD has been found in numerous countries,
LCDvariants are mostly geographically restricted. For example,LCD
type IIIA and LCD type IV were reported predominantlyin Japan and
Italy, and the 2 LCD type IV variants werereported to be derived
from solitary founder mutations in Japanand Italy.
Historically, multiple subtypes of lattice were createdon the
basis of phenotypic and genotypic variations. Theso-called lattice
corneal dystrophy type 2 (LCD2) is a mis-nomer, in fact comprising
systemic amyloidosis plus corneallattice lines and should be termed
familial amyloidosis,Finnish type, or gelsolin type. Eponymously,
it is known asMeretoja syndrome (Figs. 11A, B).
BIBLIOGRAPHY Biber H. Ueber einige seltene Hornhautkrankungen:
die
oberaechliche gittrige Keratitis [Inaugural
dissertation].Zurich;1890.
Chiou AG, Beuermann RW, Kaufman SC, et al. Confocalmicroscopy in
lattice corneal dystrophy. Graefes Arch ClinExp Ophthalmol.
1999;237:697701.
FIGURE 10. Lattice dystrophy var-iants. A, Type IIIA with
centralthicker ropy-appearing lattice linesextending to the limbus.
B, Type IVwith minimal findings of centralfleck-like opacities in
deeper corneaand few small lattice lines. Epithelialerosions are
typically absent becausethere is posterior-to-anterior
cornealprogression.
FIGURE 11. Familial amyloidosis(Meretoja syndrome). A, Lax,
mask-like facies consequent to cranialnerve VII palsy. B, Lattice
lines areless numerous than in classic andvariant LCD, start
peripherally, andspread centrally (Images providedfor differential
diagnostic purposes).
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Corneal Dystrophies
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Dighiero P, Drunat S, Ellies P, et al. A new mutation(A546T) of
the big-h3 gene responsible for a French latticecorneal dystrophy
type IIIA. Am J Ophthalmol.2000;129:248251.
Dighiero P, Niel F, Ellies P, et al. Histologic
phenotype-genotype correlation of corneal dystrophies associated
witheight distinct mutations in the TGFBI gene. Ophthalmol-ogy.
2001;108:818823.
Ellies P, Renard G, Valleix S, et al. Clinical outcome ofeight
BIGH3-linked corneal dystrophies.
Ophthalmology.2002;109:793797.
Fujiki K, Hotta Y, Nakayasu K, et al. A new L527Rmutation of the
beta IGH3 gene in patients with latticecorneal dystrophy with deep
stromal opacities. Hum Genet.1998;103:286289.
Fukuoka H, Kawasaki S, Yamasaki K, et al. Lattice
cornealdystrophy type IV (p.Leu527Arg) is caused by a
foundermutation of the TGFBI gene in a single Japanese
ancestor.Invest Ophthalmol Vis Sci. 2010;51:45234530.
Funayama T, Mashima Y, Kawashima M, et al. Latticecorneal
dystrophy type III in patients with a homozygousL527R mutation in
the TGFBI gene. Jpn J Ophthalmol.2006;50:6264.
Hida T, Proia AD, Kigasawa K, et al. Histopathologic
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Granular Corneal Dystrophy, type 1(Classic) (GCD1)
MIM #121900.
Former Alternative Names and EponymsCorneal dystrophy Groenouw
type I.
InheritanceAutosomal dominant.
Genetic Locus5q31.
GeneTransforming growth factor betainducedTGFBI.
OnsetChildhood, as early as 2 years of age.
SignsIn children, a vortex pattern (Fig. 12A) of brownish
granules develops supercial to the Bowman lay