Characteristicsofcornealdystrophies 窑Review窑 Characteristicsofcornealdystrophies:areviewfrom clinical,histologicalandgeneticperspectives

DepartmentofOphthalmology,ShanghaiEastHospital, mechanismsremainunclearinmanycases.AlthoughCDs TongjiUniversitySchoolofMedicine,Shanghai200120, arestillenigmatic,ourknowledgeaboutthemhasbeen China expandedgreatlyinrecentyearsduetothedevelopmentof Correspondence to: Hong-PingCui.Departmentof genesequencingtechniquesand ophthalmological ,ShanghaiEastHospital,TongjiUniversity examinationadvances[ high-definitionopticalcoherence SchoolofMedicine,Shanghai200120,China.hpcui@vip. tomography(OCT),confocalmicroscopy].Thisreview 163.com highlightstheadvancesinourunderstandingofCDsbasedon Received:2015-07-19Accepted:2015-08-16 researchesinrecentyears. MATERIALSANDMETHODS Abstract SearchStrategy Toidentifytherelevantstudies,we searchedPubMedforpapersinvestigatingtheclinical · Cornealdystrophyisacommontypeofhereditary manifestations,histologyorgeneticsofCDs.Thesearchwas cornealdiseases.Itincludesmanytypes,whichhave throughMay2015withnolanguagerestrictions.Each variedpathology,histologyandclinicalmanifestations. subtypeofCDswassearchedseparately.Forexample,the Recently,theexaminationtechniquesofophthalmology andgenesequencingadvancegreatly,whichdobenefit searchingkeyitemsofABMDinclude:ABMD,epithelial toourunderstandingofthesediseases.However,many basementmembranedystrophy(EBMD),Coganmicrocystic aspectsremainstillunknown.Andduetothepoor dystrophy,map-dot-fingerprint(MDF)dystrophy,clinic, knowledgeofthesediseases,theresultsofthetreatments histology,genetics,genemutation.TheotherCDswere arenotsatisfactory.Thepurposeofthisreviewwasto searchedwiththesamemeans.Inaddition,wemanually summarize the clinical, histological and genetic reviewedthereferencelistsfromtherelevantarticles. characteristicsofdifferenttypesofcornealdystrophies. StudySelection Weaimedtoidentifyalltherelevant · KEYWORDS: cornealdystrophy;clinic;histology;gene studiesthatinvestigatetheclinical,histologicalorgenetic mutation aspectsofeachtypesofCDs.Weappliedthefollowing DOI:10.18240/ijo.2016.06.20 exclusioncriteria:1)editorialsorletters;2)caseseriesor casereports;3)studiesnotinvestigatingtheclinic,histology LinZN,ChenJ,CuiHP.Characteristicsofcornealdystrophies:a orgeneticsofCDs;4)studiesnotconductedinhumansor reviewfromclinical,histologicalandgeneticperspectives. mice.Thefirsttwoauthorsindependentlyreviewedall 2016;9(6):904-913 searchedresultstogettheeligiblearticles.Discrepancies betweenthetwoauthorswereresolvedbytheconsensusofthe INTRODUCTION thirdauthorofthisreview.Intheend,weidentified99relevant ornealdystrophies(CDs)areagroupofcommonly- articles,whichwereusedasreferencearticlesinourreview. C occurringprimary,progressivecorneal diseases. Anterior(EpithelialandBowman'sMembrane) Dependingontheanatomicalsites,CDscanbeclassifiedinto Anteriorbasementmembranedystrophy ABMD[online 3subtypes:1)anteriorCDsincludeanteriorbasement mendelianinheritanceinman(OMIM)121820]isalso membranedystrophy (ABMD)andMeesman'sepithelial knownasEBMD,CoganmicrocysticdystrophyorMDF dystrophy;2)stromalCDsincludeReis-Bueckler'sdystrophy, dystrophy.ABMDischaracterizedbysubepithelialbleb-like honeycombdystrophy,latticedystrophy,granulardystrophy, microcysts,fingerprintlines,geographicmap-likelines,and Avellinodystrophy,maculardystrophy,Schnydercrystalline epithelialmicrocystsordots,whichareallbilateraland dystrophy,Fleckdystrophy,andcongenitalhereditarystromal frequentlyasymmetric,revealedbyslit-lampexamination. dystrophy;3)endothelialCDsincludeFuch'sdystrophy, About10%ofABMDpatientsdeveloppainfulrecurrent congenitalhereditaryendothelialdystrophy,andposterior epithelialerosions [1].Thecause of ABMD remains polymorphousdystrophy.MostCDsarecharacterizedwith controversial.Thoughitismorelikelytobeage-related,the variedshapesofcornealopacities. CDshavebeen hereditarypathwaysinsomecasesareseeminglyautosomal investigatedbymanyophthalmologistsworldwide,buttheir dominantorX-chromosome-related[2-3]. 904 陨灶贼允韵责澡贼澡葬造皂燥造熏灾燥造援 9熏晕燥援 6熏 Jun.18, 圆园16 www.ijo.cn 栽藻造押8629原愿圆圆源缘员苑圆 8629-82210956 耘皂葬蚤造押ijopress岳员远猿援糟燥皂 ABMDishistologicallycharacterizedbythethickened epithelialbasementmembrane(EBM)whichduplicates and/orinsinuatesintothecornealepithelium,andthe presenceofhyperreflectivedots,whichresultintheclassical manifestationofMDFopacitiesinthecorneaonslit-lamp examination.Morerecently,amorefinestultrastructureof ABMDinsomecaseswasstudiedwithconfocalmicroscopy [4] andstandard-definition(SD)-OCT [2].TheABMDlesions havevariableshapes( map-,dot-,fingerprint-or bleb-like).Inthesuperficial/basalepitheliumandBowman's membraneundermicroscopy,themap-likelesionofthe corneapresentsadifferent shapeofhigh-reflective extracellular deposits,whilethe fingerprint-likelesion Figure1Gelatinousdrop-likedystrophy,courtesyofDr.GK [4] presentsmultipledarkstriae .Bothlesionsshowathickened Klintworth. EBM,whichinvaginatesintotheepitheliumintheformof multi-sheetfibrogranularmaterial [5-8].Thedot-likelesionhas Histologicalbiopsyrevealsathinnedcornealepitheliumwith 2subtypes:CogancystsandthecystsreportedbyBronand anincompletelydestroyedBowman'smembraneand Brown [7].Cogancystsarethecelldegenerationproductsthat subepithelialandstromalamyloiddeposits,partiallyarranged [12] aggregateintheformofcystunderneathanintraepithelial inaband-shape .Immunohistochemicalandproteomic sheet.Thesecondsubtypeisasheetoffibrogranularmaterial analysesrevealthatamyloidfibrilformationmaybe intheEBMandBowman'smembrane.Besidestheclassical attributedtoabnormalaccumulationoflactoferrinand [18-19] MDFtype,therearealsosomeothersubtypes,suchas transforminggrowthfactorbeta-inducedprotein(TGFBIp) . Band-shapedandwhorledmicrocysticdystrophy.Underlight Amyloidnodulesinthesubepitheliallayerandtheanterior corneal stromaarestainedwithCongo redtoform microscopy,thescrapedepitheliumshowsatransitionof apple-greenbirefringencewhencombinedwithpolarized normalcornealepitheliumintothezonewherethecytoplasm light[20]. isdistendedwithabundantfinevacuoles.Swollencellsare Despitethediscoveryofmanygenemutations,the presentatalllevelsofepithelium,andneitherperiodic mechanismofamyloidformationremainsunclear [11].As acid-Schiff(PAS)norAlcianblueacidmucopolysaccharide reported,theabnormalproteinsfoundintheamyloidlesions stainshowscytoplasmicpositivity[3]. ofGDLDarerichinadvancedglycationend(AGE)products Gelatinousdrop-likedystrophy(GDLD)(OMIM204870),or andD-b-asparticacid.Itisproposedthattheamyloidfibril familialsubepithelialcornealamyloidosis,whichhasan formationsinGDLDmaybecausedbythenon-enzymatic autosomalrecessivehereditarypattern,wasfirstreportedin post-translationalmodificationsofproteins,includingAGE 1914 [9].Thoughtheincidenceratewasabout1in30000in formationandisomerisationofaspartylresidues[21]. Japan,itisveryrareinothercountries [10].GDLDis Meesmann'sepithelialcornealdystrophy Meesmann's characterizedbyanaccumulationofamyloidsubstancesin epithelialcornealdystrophy(MECD)(OMIM122100)isa thesubepithelialregionofthecornea,whichhaveseveral rarebilateraldisorderconfinedtothecornealepithelium.Its shapes(yellowish-white,mulberry-like,gelatinous)(Figure1). symptomaticintraepithelialmicrocystsappearinthefirstfew Inthefirstdecadeoflife,theaccumulationofthese yearsoflifeandcanbeseenunderaslitlamp [22].Under substances leadstovisiondisturbance,foreign-body slit-lampbiomicroscopy,thelesionsappearaspunctate, sensation,,andlacrimation.Inthelaterstages, bubble-like,roundorovalopacitiesinthecornealepithelium[23]. neovasculationmayoccurinthesubepithelium and Nevertheless,visionisusuallynotaffected [24].MECDis [11] superficialstroma .Surgicalinterventionistemporally mostlyconsideredasanautosomaldominantinherent effective,butrecurrencewithinafewyearshasbeen disease,butanautosomalrecessiveformisalsoreported [23]. [12-13] reported . MECDhasbeenlinkedtogenemutationinK3andK12, GDLDiscorrelatedwiththegenemutationsonthe whichareexpressedinthecornealepithelium[25-26]. tumor-associatedcalciumsignaltransducer2(TACSTD2)[14]. Thedystrophicepitheliumishistologicallycharacterizedby TheTACSTD2-encodedproteinisamonomericcellsurface cellularswelling,cyst-likeinclusions,andcytoplasmic glycoproteinexpressedinthecornea,trophoblasts,andmost vacuoles.ThecystscontainPAS-positivedegeneratedcell carcinomas [15-16].Todate,morethan20mutationsin debris [27] andareadenseintracellularsubstanceofunknown TACSTD2havebeenidentified [11].InJapan,themajor composition [28].Electronmicroscopyhas revealedan mutationidentifiedinGDLDcasesisQ118XinTACSTD2[17]. electron-denseandamorphous"peculiarsubstance"inthe 905 Characteristicsofcornealdystrophies cytoplasmofepithelialcells.Depositionofthepeculiar trunksarewellbelowtheBowmanlayerandappeardense substanceintheepitheliumleadstocystformationandcell andwhite;3)somedepositshaveshortsidebranches(type death,followedbyrapidepithelialregrowth[27]. 3a,trunkwidth) [34]. Reis-B俟cklercornealdystrophy Reis-B cklercorneal CentralcloudydystrophyofFrancois Centralcloudy 俟 dystrophy(RBCD)(CornealDystrophyofBowman'sI, dystrophyofFrancois (CCDF),firstreportedin1955 [37],is CDB1,OMIM608470)wasfirstreportedin1917byReis characterizedbypolygonalcloudygraystromalopacities andelaboratedin1949byB cklers[29-30].Theaffectedpatients separatedbyrelativelyclearlines,whichcreatesa 俟 experiencerecurrentpainfulerosionsofcornealepithelium leather-likecrocodileappearanceinthecentralcornea.Under withinthefirstfewyearsandmoderateimpairmentofvisual theslitlamp,CCDFislargerandmorenumerousinthe loss.Withaging,however,map-likeandring-likeopacities posteriorpartofthestromaandbecomessmallerandless appearinBowman'smembrane,andtheselesionsbecome frequentintheanteriorpart.Theanteriorlayersare denserandirregular.Aftertheseconddecade,patientsmay unaffectedinsomecases,butthegreypatchesreachthe feellesspainduetothedecreaseofcornealsensitivity [31]. Bowman'smembraneinothercases.Thecorneal RBCDisassociatedwiththeR124Lmutationintransforming endotheliumandepitheliumareunaffected[38].Thiscondition growthfactor,beta-induced(TGFBI)geneorwithatypical ispresumablyanautosomaldominance,butitsdetailed casesofF540,H626R,G623DorR124Cmutations[32].However, mechanismisunknown [39].Incontrast,similarcorneal therearerarereportsonRBCDinChinesepatients. opacitieslocatedateitherthecentralorperipheralcorneain Thematerialsintheopacitiesareeosinophilic,congophilic thedeepstromallayerareknownas"posteriorcrocodile andarenotstainedwithPASon histopathological shagreen"andareusuallyconsideredasage-relatedcorneal examination [30].Lightmicroscopyrevealsrod-shapedand degenerations.Thedistinctionbetweentwoentitiesisan trapezoidaldepositsintheBowman'slayerandbetween inheritantpattern[40]. epithelialcells[32].Thispathologicalfindingisconsistentwith Histologically,lightmicroscopyrevealsstromalstainingfor thesuperficialgranulardystrophy[31]. acidmucopolysaccharide [39].Transmissionelectron AvellinoDystrophy Avellinodystrophy,alsoknownas microscopy(TEM)identifiesextracellularvacuoles,someof GranularcornealdystrophytypeII(GCD2,OMIM607541), whichhavefibrillogranularsubstancesandelectron-dense wasfirstreportedinpatientsfromAvellino,Italy [33].GCD2 deposits.Theopacitiesresultfromthe extracellular belongstothestromalCDs,whichalsoincludeGCDand accumulationofmucopolysaccharideandlipid-likematerial[39]. latticecornealdystrophy(LCD).Theclassicalmanifestations Schnyder's central crystalline dystrophy Schnyder's ofGCD2combinethecharacteristicsofGCDandLCDwith centralcrystallinedystrophy(SCCD)(OMIM121800),first discretegranularandlatticeopacities.Thegranularopacities describedbySchnyderandvanWent,hasanautosomal appearearlierandmorecommonlythanthelatticeopacities[34]. dominantinheritedpattern.SCCDischaracterizedbya Theopacitiescouldleadtothedisturbanceofvisualacuity, bilateralcloudingofthecentralcornea,arcuslipoidesand/or buttheirlocationandseveritydecidethefinaloutcomes [34]. visiblecrystallinedepositsofcholesterolinthestroma.There Theonsetseemstobeearlierinhomozygotethanin isaccumulationofphospholipid,unesterifiedcholesteroland heterozygotepatients [35].GCD2isassociatedwithArg124His cholesterolesterinthecornealstroma [41].Theprecise mutationinTGFBI,mappedtochromosome5q,andhasan mechanismremainsunclear.Genemutationsareconsidered autosomaldominantpattern [34].Itisproposedthatthe tobelocalizedat1p34.1-p36intervalandinsomecandidate pathogenesisofGCD2maybecriticallyrelatedtodefective genes: , , , and autophagy [36].However,itsmechanismisstillpoorly [41].Todate,mutationsof havebeen understood. identifiedin28unrelatedfamilieswithSCCD [42-45].Common Histologically,GCD2patientshavebothhyalinegranular systemicfindingsassociatedwithSCCD include deposits,whicharelocatedsuperficially,andamyloidlattice hypercholesterolemiaandhyperlipidemia,buttheirpresence deposits,whichappearatdeepersites [35].Thehyaline isnotmandatoryforthepathogenesisofSCCD. granulesandamyloidlatticelinesarestainedwithCongored Histologically,diagnosisofSCCDisconfirmedbythelipid andMasson'strichrome,respectively.Dependingonthe andcholesteroldepositsinthecornealstromaonoilredO shapes,GCD2lesionscanbedividedinto3types:1)type1, stainingundercornealbiopsy.Under confocal diffusehazydepositsaresuperficiallylocatedinanirregular microscopy,superficialepithelialcellsappearinnormal softpattern;2)type2,granulardepositsaresubdividedinto limits,whilethebasalcelllayerispoorlyvisualizedand superficialroundgranulardeposits(type2a)andsuperficial presentscrystallinedepositsextendingfromtheanterior roundspiculatedones(type2b).InGCD2linear(lattice) stroma.Moreover,largeormultipledepositsofbrightly deposits,thebranchesradiatedoutfromthemaindepositor reflectivecrystallinematerialextendfromtheanteriorstroma 906 陨灶贼允韵责澡贼澡葬造皂燥造熏灾燥造援 9熏晕燥援 6熏 Jun.18, 圆园16 www.ijo.cn 栽藻造押8629原愿圆圆源缘员苑圆 8629-82210956 耘皂葬蚤造押ijopress岳员远猿援糟燥皂 tothemiddlepart,whiletheregularityanddensityof keratocytesareremarkably decreased.Althoughpoorly visualizedbecauseoftheincreasedreflectivityoftheanterior ,theposteriorstromashowsfineneedle-shaped depositsinthe posterior stromalmatrix,butnumber decreaseswithdepthandthebrightnessisreducedcompared withthedepositsintheanteriorstroma[46]. Congenitalstromalcornealdystrophy Congenitalstromal cornealdystrophy(CSCD)(OMIM610048)isveryrare.Its clinicalmanifestationsincludethediffused,bilateraland cornealcloudingofflake-likewhitishopacitiesthroughout thestroma.Thelesionsappearshortlyafterbirthandprogress withage.Someaffectedpatientsalsosufferfromstrabismus Figure2Granularcornealdystrophy(GroenouwtypeI). ornystagmus.Most patients undergoapenetrating keratoplastyinearlyadulthoodwithgoodoutcomes[47].CSCD istheonlyknownhumandiseaseassociatedwiththemutated geneofdecorin,asmallleucine-richproteoglycan(SLRP)[48]. Decorinisinvolvedinthecontroloffibrillogenesisandfibril organization,whichcontributetocornealtransparencyand refractivestability [49].ItisproposedthatatruncatedSLRP proteincoreisretainedandaccumulatesintracellularly.This processtriggersendoplasmicreticulumstress,whichleadsto abnormalsynthesisandsecretionofSLRPandultimatelyto impairmentofstromalstructureandcornealtransparency [48]. Histologically,epithelialcellsarenormalunderconfocal microscopy,butthereflectivityisincreasedthroughoutthe stromallayer.InCSCDpatients,thelamellarstromal Figure3LightmicroscopyofGCDI.MassonTrichrome structureisdisrupted,whichismoresevereintheanterior stain,courtesyofDr.GKKlintworth. andposteriorcentralstroma.TheFourier-domainOCT imagesalsoshowhigherdiffusereflectivityinthestroma materialinrelativelylargeintracytoplasmicvacuoles,while thaninthenormalcornea.Underelectronmicroscopy,the somekeratocytescontainpleomorphicelectron-denseand electron-lucentzonesinthecornealstromaarelocated membranousintracytoplasmicinclusions [56].Thematerials betweenthenormallamellaeofcollagenfibrilswiththinned were predictedtocontainlipidsandacid filamentsinhaphazardarrangement[47]. mucopolysaccharides[54]. Francois-NeetansFleckcornealdystrophy Fleckcorneal GCDI(GroenouwtypeI)belongstotheTGFBI-associated dystrophy(FCD),alsocalledFrancois-NeetensFCD(OMIM CDs,whichalsoincludeRBCD,Thiel-Behnkecorneal 121850),isveryrareandfirstdescribedin1956[50].Slit-lamp dystrophy(TBCD),LCD,andGCD II. GCD Iis examinationrevealsbilateral,flat,gray-white,ovalorround characterizedbythediscreteopacitiesinthecornealstroma, discreteopacitiesthroughoutthecornealstroma.Nosystemic whichareirregularlycrum-orflake-likeandappearslightly abnormalityhasbeenreported[51].FCDoccursearlyinlifebut whitishorglassy(Figure2).Thoughmostpatientsare thenprogressesslowly,andvisualacuityisnotgreatly asymptomatic,somepatientsdeveloprecurrenterosions.The disturbed.Thus,treatmentisnotnecessaryinmostcases. lesionsbecomemorenumerousandseverewithtime,leading Recurrencewasnotreportedina10-yearfollow-upafter tovisualacuityimpairment.Somepatientsmayrequire penetratingkeratoplasty [52].FCDiscausedbymutationsin keratoplastyinthefifthdecadeorlater[31].GCDIisautosomal PIP5K3andhasanautosomaldominantpattern [53-54].PIP5K3 dominantandassociatedwiththemutationsonTGFBI.The gene isresponsibleforintracellularaccumulationand predominantoneofthevariedmutationsisArg555Trp [57]. engorgementandthereportedmutationsresultintruncation TheArg555Trp mutationwillleadtotheabnormal ofPIP5K3proteinbeforeitsstructureisformed,leadingto degradation/turnoverofcornealTGFBIp,andfinallytothe theabnormalactivityofPIP5K3protein.Furtherstudiesare accumulationandincreasedpropensitytoaggregatethrough neededtoelucidatethefunctionofPIP5K3proteininFCD electrostaticinteractions[58]. patientsandnormalpersons[55]. HistologicfindingswithMassonTrichromeredstainingand Histopathologically,somekeratocytescontainfibrillogranular withoutCongoredstainingweretested(Figure3).Electron 907 Characteristicsofcornealdystrophies microscopy showseletron-denserod-likedepositsand Macularcornealdystrophy Macularcornealdystrophy microfibrilsinkeratocytesandepithelialcells.Thematerials (MCD)(OMIM217800)isveryrareandhasanautosomal areascribedtophospholipid [31].Thoughthelesionsaffect recessiveinheritancepattern.Itsprevalenceratevaries mostlythestroma,theydooccurwithinthewholedepthof amongdifferentcountries [63].MCDbeginsinearlyyearsof thecorneainsomecases. lifewithsuperficialgray-whiteopacitiesconcentratedinthe Latticecornealdystrophy LCDsareasubgroupofstromal middlecornea.Withaging,thelesionsspreadtothe CDs.AllLCDshaveamyloidaccumulationinthestromaand peripheryandinvolvetheentirecornealstroma.Another areoftenarrangedinabranchingpattern [31].LCDshavean characteristicmanifestationiscornealthinning [64].The autosomaldominantpatternandisrelatedtothemutationson opacitiesandabnormalstructureofthecorneacanleadto theTGFIgene,whichencodes keratoepithelin,an severevisualimpairment [65].MCDisassociatedwiththe extracellularmatrixthatmediatescelladhesion [59].LCDsare mutationsontheCHST6gene,whichencodescorneal classifiedinto3subtypes:LCDI(OMIM122200),LCD Ⅱ N-acetylglucosamine6-O-sulfotransferase(C-GlcNAc6ST), (OMIM105120),andLCD Ⅲ andLCD Ⅲ A(OMIMs anenzymethattransferssulfatetotheunsulfatedkeratan 204870and608471).LCDIismostcommonly-seen.The chainsonlumican.Lumicanhelpstomaintainthecrucialsize abnormalitiesofLCDIoccurinthefirstorseconddecadeof andorderedstructureaswellascornealtransparency.Italso lifeandprogressovertime.Itsanteriorstromahasrod-likeor influencescornealhydrationandthereforecorneal linearopacities.Recurrenterosionsarecommonandcentral transparency [66].MCDcanbeclassifiedintosubtypesIand anteriorstromalhazemaydevelopwithage.Thelesions II,definedbytheabsenceorpresenceofsulfatedkeratan usuallyaffecttheanteriorandcentralcorneas,leavinga sulfate(KS)intheserum.Athirdsubtype,typeIA,withKS relativelynormalperipherycornea.Themutationatcodon presentinthekeratocytesbutabsentinthecorneaandthe 124ofTGFBI,wheretheaminoacidarginineisreplacedby serum,hasbeendescribedinMCDpatientsfromSaudi cysteine,ispreviouslyconsideredasthemostfrequentdefect Arabia[65]. ofLCDI.LCD Ⅱ isassociatedwithsystemicamyloidosis Histologically,thecorneainMCDischaracterizedbythe typeV(Meretojasyndrome/Finnishtype),whichisan accumulationofextracellulardepositsinthestromaandDM autosomaldominantsystemicdisease.LCD Ⅱ occursinthe aswellasbyintracellularstorageofsimilarmaterialinthe earlyadulthoodandaffectscornea,skin,andcranialnerves [60]. keratocytesandcornealendothelium.Thedepositsstainwith LCD Ⅲ isclinicallymanifestedasthepresenceofthickropy Alcianblueandotherhistochemicalmethods for latticelinesinthecorneacomparedwithothersubtypes. glycosaminoglycans(GAGs).Biochemicalstudiesbasedon LCD Ⅲ hasanautosomalrecessiveinheredancepatternand organculturesofcorneasaswellasserumanalysesofMCD rarecornealerosions.Itslesionsappearusuallyinthefourth patientssuggestthatthebasicdefectinMCDliesina decadeoflife.LCD Ⅲ Ahasalmostthesamechanges, sulfotransferase,whichisspecificforsulfationofKS exceptthatithasrecurrenterosionsandadominant proteoglycan.MoleculargeneticstudiesonMCDcontribute inheritancepattern[31]. tothe mappingoftheMCDgeneandthentothe Histologically,LCDIisconsideredtoaffectboththestroma identificationofthecarbohydrate6-sulfotransferase( ) andtheepithelium[61].Thestromashowdensedeposits,which gene,which codescorneal N-acetylglucosamine canbestainedwithCongored,PAS,and Masson's 6-sulfotransferase,asthecauseforMCD[67]. trichrome. Dichorismandbirefringenceappear under Pre-Descemet's corneal dystrophy Pre-Descemet's polarizedlight,andfluorescenceoccurswiththioflavin-T [31]. cornealdystrophy(PDCD),ordeepfiliformdystrophy,is InLCD Ⅱ ,theamyloidmarker,Congored,willshow veryrare.PDCDwasfirstdescribedandcalledascornea materialdepositionunderBowman'slayerandsometimesat farinatain1923 [68].Todate,littleresearchisdoneinPDCD. theEBMlevel [60].Histopathologically,amyloiddepositsof Itischaracterizedwithfinemorphologicalopacitiesinthe LCD Ⅲ arelocatedinthemiddleandsuperficialstromata posteriorstroma.Thelesionsarecomposedoflipids [69]. beneaththeBowman’smembrane [31].InLCD Ⅲ A,the PDCDisage-related,butthepathologyremainsunclear [70]. depositscanbestainedbyCongoredanddisplayred-apple Theaffectedpatientsareusuallyasymptomatic,andtheir greenbirefringenceunderpolarizedlight,thusshowingan visualacuityisveryrarelyaffected [71].Theonsettimeis amyloidcomponent.Theyarealsostainedpartiallypositive usuallythefourthto seventhdecade.PDCDcanbe withMassontrichrome,suggestingthepresenceofhyaline subdividedintodeepfiliformdystrophy,deeppunctiform componentsinthe deposits.Thelatticedepositsare dystrophy,polychromaticdystrophy,andcornealfarinata. immunoreactivewiththe anti-TGFBIpantibody.The Thesedystrophieshavesimilaressentialcharacteristics,but epitheliumshowsdehiscencefromtheBowmanlayer.No theydifferincolorunderdirectandindirectslit-lamp abnormalityisfoundinDescemet'smembrane (DM)orthe illumination.Sincethedepositsareuniformthroughoutthe endothelium[62]. cornea,theypresentavarietyofcolorsthatareconstant[68]. 908 陨灶贼允韵责澡贼澡葬造皂燥造熏灾燥造援 9熏晕燥援 6熏 Jun.18, 圆园16 www.ijo.cn 栽藻造押8629原愿圆圆源缘员苑圆 8629-82210956 耘皂葬蚤造押ijopress岳员远猿援糟燥皂 Histopathologicexaminationofone PDCD patient demonstratesthatthepathologicfindingsarelimitedtothe keratocytesoftheposteriorstroma [72].Thekeratocytesare cytoplasmicvacuolescontaininglipid-likematerials,which onelectronmicroscopyconsistoffibrillogranularand electron-denselamellarinclusions.Noextracellular depositionofasimilarmaterialwasnoted.Thesefindings suggestthattheaccumulatedmaterialsaremostlikely lipofuscin,adegenerativepigmentthataccumulatesinaged cells[70]. PosteriorCornealDystrophies Congenitalhereditaryendothelialdystrophy Congenital hereditaryendothelialdystrophy (CHED)isarareinherited Figure4Fuchsendothelialcornealdystrophy,courtesyofDr. disorderofthecornealendotheliumandcharacterizedby GKKlintworth. cornealopacificationandnystagmus.Theonsettimeof CHEDisusuallyatbirthandshortlythereafter.The malfunctionanddegenerationofthecornealendothelium leadtocornealedema,especiallythestroma,andmakethe corneaappearasgroundglass.Theconditionisknownto occurintwogeneticforms:autosomaldominant(CHED1, OMIM121700)andautosomalrecessive(CHED2,OMIM 217700).CHED1ismorerareandhassomeclinical similaritieswiththe posteriorpolymorphousdystrophy (PPMD) [73],whileCHED2ismoresevereandusuallymore common.CHED1andCHED2havebeenmappedto chromosome20attwodistinctloci:20p11.2-q11.2for CHED1[74] and20p13forCHED2[75]. Histopathologicalanalysisidentifiedamarkedlythickened Figure5LightmicroscopyofFECD,PASstain.Courtesyof DMandanatrophiedendotheliuminCHED2patients. Dr.GKKlintworth. Additionally,thepatient'scorneaalsohadamyloiddeposition Histologically,someendothelialcells(ECs)areassumedto andspheroidaldegeneration.Thepresenceofamyloidwas befibroblast-like,includingswollenmitochondria,dilated confirmedbasedonthepresenceofapplegreenbirefringence endoplasmicreticulumwithgranularmaterial,increased [76] viewedunderapolarizingfilter . numberofcytoplasmicfilaments,andphagocytosedpigment Fuchs endothelialcornealdystrophy(FECD) (OMIM granules [81-83],especiallywhentheposteriorfibrillarlayer 136800)isthemostcommontypeofendothelialCD. (layer4)ofDMcoverestheguttaeintheposteriorbanded Bilateral, non-inflammatoryandprogressivelossof layer(layer3)[83].TEMandSEMpresentmicrovilli,increased endotheliumresultsinvisualloss.FECDischaracterizedby numberofhemi-desmosomes,andthepositiveimmune- guttatawithincornea(Figure4),stromaledema,and labellingofpancytokeratinandcytokeratin-7,whichare microcysticepithelialedema.Theprimarydefectiscorneal markersusuallypresentinalmostallcellsofepithelialorigin endothelialdegeneration,andthesecondarydefectiscorneal [82].SomeFECDspecimenshadECswithextremelylong edema.Associatedmanifestationsincludeprominentcorneal filopodiaupto100mmlongthatwereimmuno-positivefor nerves,stromalopacification,recurrentcornealerosions, KSandorientatedinthesameplane,givingtheimpressionof open angle ,femalegender, andfamilial masscellmigrationinonedirection(Figure5)[84]. [77] predisposition .Mostcasesaresporadic,andautosomal Posterior polymorphous corneal dystrophy Posterior dominantinheritancehas beenrecognized infamilial polymorphouscornealdystrophy(PPCD)isararecorneal cases [78-79].Insummary,mutationsinFECDhavebeenfound disease andmainlyaffectstheDMandthecorneal intwotranscriptionfactors (TCF4/E2-2andTCF8/ZEB-1), endothelium.PPCDischaracterizedbytheasymmetric onecollagensubunit(COL8A2),andtwomembraneproteins patchesofgroupedvesicles,scallopedbands,geographic (LOXHD1andSLC4A11/NaBC1).ExceptLOXHD1,these grayhazyareas,andepithelial-likeendothelium(lossof mutationsappeartoconvergeonthecollagensecretionand contactinhibitionwithproliferationandgrowthoverangle waterpumpfunctionsofcornealendothelium[80]. andiris).Somepatientsmaydevelopstromaledema. 909 Characteristicsofcornealdystrophies Moreover,irisandpupilmaychangesimilarlytothosein PIP5K3,UBIAD1,K3,K1,TACSTD2 .Accordingtothe iridocornealendothelialsyndrome.Broadperipheralanterior findingsofhistologyandgenesequencing,thehypothesisof synechiaeandglaucomaarealsocommon.Patientsmayhave somespecialCDswereproposedbyophthalmologists.For symptomsofpains,foreign bodysensation,tearing, example,Underhaug [58] thoughtthatthegenemutations photophobia,anddecreasedvision.PPCDisclassifiedinto3 oftheTGFBImayresultinreductionoftheproteolytic subtypes:PPCD1(OMIM122000),PPCD2(OMIM609140), susceptibilityofthemutatedTGFBIpleadingtotheabnormal andPPCD3(OMIM609141),whichareassociatedwiththe depositionsoftheTGFBIpinGCD.Morever,Choi [36] genemutationsonVSX1,COL8A2andZEB1,respectively[85-89]. consideredthatautophagymayplayanimportantroleinthe Histologically,thelesionsofPPCDarelocatedatthelevelof accumulationoftheTGFBIpinGCD.However,theexact theendotheliumandDM.Thelesionshave3types: detailedmechanismsofmostCDsremainunclear. vesicle-typelesions,bandlesionsanddiffuseopacities.The BecauseofthepoorunderstandingofCDs,thereareno former2typesaremorecommonthanthelastone[90-95].Under efficienttreatmentmethods.Amongthetreatments, slit-lamp,vesiclesappearasblisterorbleb-like,withan keratoplastyistheultimatechancetoimprovethevisual opticallyclearcentreandasmallhaloofgrey-whitehaze [93]. acuityofseverepatients.However,manypatientsundergoing Previousstudiesshow"epithelium-like"multilayeredcells keratoplastymaysufferfromrecurrencewithinafewyears. scatteredinareasofnormalendotheliumanddepositionof Becausethegenemutationsplayanimportantroleinmost abnormalcollagenmaterialonDM,forminganabnormal typesofCDs,generesearchwouldgreatlycontributetothe posteriorcollagenouslayer[90,94,96-97].The4typesofcellsshown understandingofCDs,leadingto anewevolutionary ontheposteriorcornealsurfaceinPPCDarenormalECs, treatmentmethod.Inrecentyears, genetherapy [98] attenuatedordegeneratingECs,fibroblast-likecells,and experimentshavealreadybeendone andtheresultsgiveus epithelial-likecells[95]. aperspectivevisiontocureCDs. 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