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 Ophthalmology,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,photophobia,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),whileothershavelongsidebranches(type StromalCornealDystrophies 3b,>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