Presence of Fleischer ring and prominent corneal nerves in keratoconus relatives and normal controls

P esenceo Fleische ingandp ominen co nealne es inke a oconus ela i esandno malcon ols 窑ClinicalResea ch窑 Depa men o Oph halmology,Uni e si yo Deb ecen ClinicalCen e ,Deb ecen4032,Hunga y Co espondence o: LiliTak觃cs. Depa men o Oph halmology,Uni e si yo Deb ecenMedicalSchool, H4032Deb ecen,Nagye deik ,98,Hunga y.l akacs@med. unideb.hu Recei ed:2014-09-24 Accep ed:2015-02-03 Abs ac ·AIM:Toexamine heoccu enceo commonlyknown clinicalsignso ke a oconus (KC), Fleische ing, p ominen co neal ne es and hinning, among una ec ed amilymembe so KCpa ien sandheal hy con olindi iduals. ·METHODS:Da ao bo heyeso 117 ela i eso KC pa ien s ha ing no mani es disease based on ideoke a og aphy indices (KC ela i es), and 142 con olswe eused o Pea sonco ela ionand - es s a is ics.Co ela iono Fleische ing,p ominen co neal ne esandcen alpachyme yda awe e es edwi h eacho he andwi h ideoke a og aphyindices(KSI, KISA,3and6mmFou ie asymme y,andI-S) ·RESULTS:Amode a eco ela ionwas oundbe ween Fleische ingandallexamined opog aphicalindices. Mos impo an co ela ionwasp esen wi h6mm Fou ie asymme y,andco nealpachyme y(=0.272, < 0.001; =-0.234, =0.027, espec i ely).Simila co ela ions we e oundwi hp ominen co nealne es(=0.234, < 0.001 o 6mmFou ie asymme yand =-0.235, = 0.0265 o pachyme y). KC amily membe s who exhibi edFleische ingo p ominen ne eshad hinne and mo e asymme ic co neas han hose wi hou Fleische ingo p ominen co nealne es ( <0.05 o pachyme yand opog aphicindiceswi h - es and Mann-Whi ney anksum es ).Though a ely,Fleische ingandp ominen co nealne esoccu edamong no malcon ols,indica ing heexis enceo o me us e casesin heno malpopula ion.Con olsubjec s,who hadco nealFleische ingo p ominen ne eshad co neasmo esimila oKC hano he con ols(- es : inc eased KSI and KISA, =0.048 and 0.012, espec i ely). ·CONCLUSION:InKC amilymembe sandheal hy indi iduals,Fleische ingandp ominen co nealne es a eassocia edwi h ea u eso KCandmaysugges a possibili yo o me us eKC.Sea ching o hepossible p esenceo Fleische ingo p ominen ne eson he co neamayhelpin hedecisionwhe he o no o diagnosesubclinicalKCinabo de linecase. ·KEYWORDS: o me us e/subclinicalke a oconus; Fleische ing; co nealne es; co neal hinning; ideoke a og aphicindices;ia ogenicke a ec asia DOI:10.3980/j.issn.2222-3959.2015.05.12 K isz 魣,LosonczyG,Be aA,Tak觃csL.P esenceo Fleische ing andp ominen co nealne esinke a oconus ela i esandno mal con ols. 2015;8(5):922-927 INTRODUCTION Ke a oconus(KC,OMIM#148300)isap og essi e, bila e al,p ima yec a icdiseaseo heco nea, cha ac e izedbynon-in lamma o y hinningandconical p o usion [1].In hegene alpopula ion,i ses ima ed p e alenceliesbe ween50and230pe 100000 [2],bu dependingondiagnos icc i e iaande hnici y,i can each 2.34%[3].KCis equen lyanisola edcondi ion,bu i may associa ewi ho he sys emico ocula diso de s [1,4].The eis awell- ecognisedgene iccomponen oKC,ase idencedby win [5] and amilys udies [1,6-8];howe e , hee iologyo he diseaseiscomplex,mul i ac o ialwi hbo hgene icand en i onmen al ac o splayinga ole[9,10]. Amsle [11] demons a edsimila bu lessp onouncedco neal opog aphicalchangesbyPlacidodiscin ela i eso KC pa ien s,andcalled hisqui e equen phenomenon o me us eKC.Hep o ed ha classicand o me us eKC cons i u ed hesameen i yand ha mus beconside edin gene ics udies.Topog aphicexamina iono ela i eso KC pa ien s e ealedagg ega iono asymme icco nealpa e ns andinc eased ideoke a oscopyindices [7,12].Topog aphic ea u essimila o o me us eKCwe eobse edamong some e ac i esu ge ycandida es,especiallyamong he ones su e ing omp og essi eke a ec asia a e he in e en ion [13].Rela i eso pa ien swi hKCha eahigh p e alenceo undiagnosedKCandKC ai s, he e o e, ke a o e ac i esu ge yshouldbeconside edcau iouslyin heseindi iduals[14,15]. KCse e i ywas ound obeassocia edwi haninc easing a eo sli -lampbiomic oscopicsigns, Vog s iae, Fleische inginke a oconus ela i es 922 陨灶贼允韵责澡贼澡葬造皂燥造熏灾燥造援 8熏晕燥援 5熏Oc .18, 圆园15 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ijop ess岳员远猿援糟燥皂 Fleische ing,p ominen ne es,hazeand hinningo he co nea.Fleische ingisp esen inmos KCco neaswhe eas p ominen ne esa eless equen andspeci ic o KC[1,16]. Diagnosing o me us eo subclinicalKCiss illchallenging inmanycases.Howe e ,iden i yingsuchcasesisnecessa y bo h o gene ics udiesandsc eeningpo en ialhigh isk e ac i esu ge ycandida es.Inou p e iouswo k,we obse ed heoccu enceo Fleische ingandp ominen co nealne esinuna ec edKC amilymembe s [9].Fo me us eKCisknown ooccu equen lyamongKC amily membe s, he e o emanys udiesexamineKC amily membe s ode inesub lecha ac e is icsassocia edwi h o me us eo subclinicalKC [15,17].In hep esen s udy,we in es iga ed heco ela iono co nealFleische ingand p ominen ne eswi h ideoke a og aphicsignso KCbo h amonguna ec ed amilymembe sandheal hycon ol indi iduals o indou i hesesignscanbeused obe e iden i y o me us eKC. SUBJECTSANDMETHODS Subjec s Ou s udy'sdesign ollowed he ene so he HelsinkiDecla a ionwi hins i u ional esea che hicsboa d app o al,in o medconsen o pa ien sandcon olswas ob ainedbe o eexamina ion.KC amilieswe e ec ui edby mailingle e s opa ien s ea edinou depa men o KC, in o ming hemabou heaimso hes udyandasking o pa icipa iono he ela i es, oo.Heal hycon olswe e ec ui ed oms uden s,pe sonnelandpa ien so he depa men wi hheal hyco neas.Allo heen olledsubjec s we eHunga ianpa ien swi hCaucasianances y.Table1 shows heg oupso indi idualsen olledin hes udy. Non-a ec edKC amilymembe swe ede inedasha ing 臆 3Das igma ismo 臆6Dsphe ical e ac i ee o andno ha ingKCbasedonke a oconusse e yindex(KSI)o KISA( aluesbelow30%and100%, espec i ely).Noneo he amilymembe shadanyo heknowngene ic associa ionso KC( Downsynd ome,Ma ansynd ome ).O 142con olindi idualswi hou amilyhis o yo KC andwi hou his o yo co nealdiseaseo eyesu ge ywe e selec ed,wi h 臆3Das igma ismo 臆6Dsphe ical e ac i ee o .Onlyeyes ha hadnop e iousco nealinju y andsu ge y,including pe o a ing ke a oplas y,we e in ol edin hes udy. Me hods Fo eachKCp oband,diagnosiswasbasedon clinicalexamina ion,includingmeasu emen o isualacui y, sli -lampbiomic oscopy,di ec oph halmoscopy, e inoscopy and ideoke a og aphy. AllKC amilymembe sandcon olindi idualsconsen ed co neal opog aphy,sli -lampclinicalexamina ion,and86 consen edul asonicpachyme y(27eyeso 15KCpa ien s, 89eyeso 45 amilymembe sand52eyeso 26con ols; Table1). Bysli -lampbiomic oscopy, hep esenceo Fleische ingin heepi helium,p ominen co nealne eswe esea ched o in amilymembe so KCpa ien sandcon ols.Fleische ingwasconside edasp esen whena leas 2mmcu ed pa acen alsubepi heliali ondeposi (incomple e)o a comple eFleische ingwasde ec ed(Figu e1). Videoke a og aphy Topog aphicexamina ionwas pe o medonbo heyeso eachs udypa icipan ,usinga TMS-4 ideoke a oscope(TomeyCo po a ion,Nagoya, Japan).A leas ou imagespe eyewe e aken,disca ding hose ha we emisaligned,ou o ocuso o poo quali y. Ca ewas aken oa oida i ac sdu ing heexamina ion whichcouldbe esponsible o pseudoke a oconusimages[18]. Da aob ained om hebes imageo eacheye,selec edupon hequali yo heke a oscopymi esby isualinspec ion, we eused.Topog aphicalimagesandpa ame e so ope a ed eyeswe eigno ed. Videoke a og aphyindiceso ke a oconus Videoke a o- g aphyindicesyieldedby heTMS-4so wa eand hose calcula ed om hemwe eselec ed o u he analysis. KISA Valueso KISAabo e100we e aken oindica e mani es KC,below60heal hyeyes,and hein e al be ween he wobeingconside ed o me us ecases[19]. Ke a oconusse e i yindex KSIexp esses hese e i yo hediseaseinpe cen age, KCsuspec >15%,mani es KC>30%[20]. Th eeandsixmilime e Fou ie asymme yindices Decen a ion( i s ha monic)componen ,onmi e ings1-9, Table 1 Cha ac e is ics o he examined 47 KC amilies and con ol indi iduals KC amilies (n=47) KC pa ien s KC amily membe s Heal hy con olsc No. o subjec s 49 (87 eyes) a 117 (233 eyes) a 142 (279 eyes) b Age (a): ( ange) 33.3 ± 11.7 (15-64) 41.3 ± 18.6 (9-81) 35.9 ± 13.7 (14-74) No. o subjec s ha ing addi ional cen al co neal pachyme y measu emen s 15 (27 eyes) 45 (89 eyes) 26 (52 eyes) No. o subjec s ha ing Fleische ing 33 (71.7%) 36 (30.8%) 3 (2.1%) No. o subjec s ha ing p ominen co neal ne es 7 (15.2%) 17 (14.5%) 4 (2.8%) All subjec s unde wen sli -lamp and opog aphic examina ion, and a subpopula ion had addi ional cen al co neal pachyme y measu emen s. a In wo amilies, wo membe s we e a ec ed. Da a o ope a ed eyes we e excluded (3 and 5 p obands unde wen bila e al and unila e al ke a oplas y, espec i ely, and one ela i e had p e ious eye inju y); bFi e eyes ha ing p e ious inju ies we e excluded; cCon ols we e no signi ican ly di e en om he membe s o KC amilies, conce ning age (P=0.11) and gende dis ibu ion (P=0.153). s x ± 923 and ings1-20whichapp oxima ely ep esen hecen al3o 6mmo heco nea[21,22]. I-S Absolu e alueso heI-S (in e io -supe io diop ic asymme y)[23].[I-S]逸1.4wasconside edabno mal. Co nealpachyme y Co nealul asonicpachyme ywas used omeasu e hecen alco neal hicknessonbo heyeso 86indi iduals:15KCp obands,45non-a ec ed ela i es and26con ols(Table1). S a is icalAnalysis Fo calcula ings a is ics,da ao bo h he igh andle eyeso eachindi idualwe eincluded.In KC amilymembe s,3se ieso co ela ions a is icswe e es ed: hep esenceo Fleische ing,cen alco neal pachyme yda aand hep esenceo p ominen co neal ne es,wi honeano he andwi h ideoke a og aphyindices. Co ela ions a is icswe e no pe o medincon ol indi idualsbecause helownumbe o caseswi hFleische ingo p ominen co nealne es.Thep esenceo Fleische ingandp ominen ne esin heco neawe ebina y a iables. Cen alco nealpachyme yda aandall ideoke a og aphyindiceswe econ inuous a iables. Co ela ionbe ween a iableswascalcula edusingPea son co ela ion s a is ic, alueand heco ela ion coe icien ( )we ede e mined.Pa ame e aluesbe ween g oupswe ecompa edwi h - es o Mann-Whi ney ank sum es .Thep og amSigmaS a 3.5 e sionwasused o s a is icsand 琢=0.05was hele elo signi icance. RESULTS Table1shows hecha ac e is icso heexaminedpopula ion. Con olswe eno signi ican lydi e en om hemembe so KC amilies,conce ningage(=0.11)andgende dis ibu ion(=0.153).InKCpa ien s,Fleische ingwas de ec edin71.7%,andp ominen ne eso heco neain 15.2%.InKC amilymembe s,co nealFleische ingwas obse edin30.8%andp ominen ne eswe ede ec edin 14.5%. Amongcon olindi iduals,Fleische ingandp ominen ne eswe eno comple elyabsen bu occu edin2.1%and 2.8%, espec i ely(Table1;Figu e1). Co ela ions a is icsinKC ela i esamongKC amily membe s, he ewasasigni ican nega i eco ela ion be weencen alco nealpachyme yandFleische ing(= -0.234;Table2).Fo each opog aphicindex, he ewasa signi ican posi i eco ela ionwi hFleische ing(Table2). Theseco ela ion esul simply ha Fleische ingoccu edin hinne andmo easymme icco neaso KC ela i es.The e wasasigni ican posi i eco ela ionwi hp ominen co neal ne es o all opog aphicindices,excep o I-S.Signi ican nega i eco ela ionbe weenp ominen ne esandcen al Figu e1Sli -lampand ideoke a og aphicimageso wo heal hycon olindi iduals A:Sli -lamppho og aphyo a39 yea -oldmanwhohasco nealFleische ing(a ows)andp ominen ne es(a owheads);B:Videoke a og aphicimageo hesameman showsasymme icco nealpa e n;C:Sli -lamppho og aphyo a32 yea -oldwomanwhohasco neali ondeposi ion,whichdidno each2mmleng h, he e o ei wasno conside edasFleische ing (a ow),bu shehasp ominen co nealne es(a owheads);D: Videoke a og aphicimageo hesamewomanshowsasymme ic co nealpa e nwi hskewed adialaxis. Table 2 Co ela ion s a is ics in KC ela i es Pea son co ela ion Pa ame e s P Fleische ing Pachyme y -0.234 0.027 KSI 0.169 0.00958 KISA 0.155 0.0178 3 mm Fou ie asymme y 0.214 0.001 6 mm Fou ie asymme y 0.272 0.0000261 I-S 0.229 0.000419 Pachyme y P ominen ne es -0.235 0.0265 KSI -0.377 0.000271 KISA -0.342 0.00104 3 mm Fou ie asymme y -0.425 0.0000328 6 mm Fou ie asymme y -0.427 0.0000303 I-S -0.338 0.00119 P ominen ne es Fleische ing 0.00437 0.947 KSI 0.237 0.000261 KISA 0.246 0.000148 3 mm Fou ie asymme y 0.228 0.000463 6 mm Fou ie asymme y 0.234 0.000308 I-S -0.0287 0.663 The p esence o Fleische ing in KC ela i es showed signi ican co ela ion wi h cen al co neal pachyme y da a and all opog aphic indices. Cen al co neal pachyme y da a displayed signi ican co ela ion wi h he p esence o p ominen ne es and all opog aphic indices. The p esence o p ominen co neal ne es showed signi ican co ela ion wi h all opog aphic indices excep o I-S. : Co ela ion coe icien . Fleische inginke a oconus ela i es 924 陨灶贼允韵责澡贼澡葬造皂燥造熏灾燥造援 8熏晕燥援 5熏Oc .18, 圆园15 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ijop ess岳员远猿援糟燥皂 co nealpachyme yda aindica ed ha p ominen ne es we emo elikely oappea in hinne co neas(=-0.235; Table2). Cen alco nealpachyme y aluesnega i elyco ela edwi h allexamined opog aphicindices(<-0.3 o allindices, co ela ionwas hehighes o Fou ie asymme yindices3 and6mm =-0.425,-0.427, espec i ely). The ewasnosigni ican co ela ionbe weenFleische ing andp ominen ne esin heseco neas,indica ing ha p ominen ne esandFleische ingdidno equen lyoccu in hesameindi iduals(Table2). Inacco dancewi hco ela ions a is ics,sigini ican di e enceswe e oundbe ween ela i esha ingo no ha ingclinicalsignso KC,by - es s.Table3.shows ha ela i eswi hFleische inghadsigni ican ly hinne co neas andhighe alueso each ideoke a og aphyindexcompa ed o hosewi hou Fleische ing.Rela i eswi hp ominen co nealne esdisplayedhighe KSI,3and6mmFou ie asymme yindices han hoseha ingnop ominen ne es (Table3).SinceFleische ingandp ominen co nealne es we eno equen lyconcomi an ,compa isono co neaswi h p ominen ne es oallo he amilymembe co neas includingco neaswi hFleische ing-whichwe e hinne andmo easymme ical-yieldedsigni ican di e encesonly o KSIand6mmFou ie asymme y.Acco dingly,when co neaso ela i eswi hp ominen ne eswe ecompa ed o hosewhohadnei he p ominen co nealne esno Fleische ingsigni ican di e enceswe e ound o allpa ame e s excep o KISA(Table3). Ou o 142con olindi iduals,1hadonlyFleische ing,2 hadbo hFleische ingandp ominen ne es,2hadonly p ominen ne es.Co ea ions a is icsin hisda ase wasno eliablebecauseo lownumbe o cases. Con olindi idualswi hFleische ingandp ominen co neal ne esshowedsigni ican lyhighe alueso KSI(=0.048) andKISA ( =0.012)indices,bu we eno signi icanly hinne hancon olswi hou Fleische ingandwi hou p ominen ne es( >0.1). DISCUSSION Inou da ase o 47spo adicKC amilies,occu enceo Fleische ingandp ominen co nealne eswasobse edon co neaso una ec ed ela i es.O hesepa hognomicclinical signs, hemos ema kableonewas heco nealFleische ing whichwasp esen inalmos e e y hi d amilymembe (30.8%).This esul issimila o heoccu enceo Fleische ingde ec edinmildKC(27.27%in<45Dke a ome y eadings) [24].Inmani es KC,we oundFleische ingin 71.7%o hepa ien s,whichisconsis en wi h he esul so p e iouss udieso 57%-87% [25,26].In heheal hycon ol popula ion,Fleische ing(2.1%),p ominen ne es(2.8%) andco nealasymme ys illoccu ed a ely(Figu e1).In he examinedpopula ion,Fleische ingwasmos ly ain in he co neaso KC amilymembe sandcon ols.To hebes o heau ho s'knowledge, hisis he i s s udyo an examina iono Fleische ingandp ominen co nealne es amonguna ec ed ela i eso KCpa ien s. Basedonou co ela ionand - es esul s, hep esenceo Fleische ingandp ominen ne eswasassocia edwi h ea u eso KC.Familymembe swhoexhibi edFleische ingandp ominen ne eshad hinne andmo easymme ic co neas han hosewi hou Fleische ingandp ominen ne es.Incon olsubjec s,co neasdisplayingaFleische ingandp ominen ne eswe emo esimila oKCco neas (shownbysigni ican lyhighe KSIandKISA alues),bu we eno hinne hano he no malco neas. Table 3 Compa ison o g oups o indi iduals in he s udied popula ion Pa ame e s o KC amily membe s (n) Pachyme y KSI KISA 3 mm Fou ie asymme y 6 mm Fou ie asymme y I-S Wi h Fleische ing (36) 510.87 (±40.23) 6.20 (±15.94) 261.37 (±1497.80) 0.43 (±0.35) 0.67 (±0.54) 2.48 (±4.91) Wi hou Fleische ing (81) 530.17 (±32.90) 2.49 (±9.50) 19.02 (±91.67) 0.30 (±0.23) 0.43 (±0.30) 1.06 (±2.50) P 0.017 0.010 <0.001 <0.001 <0.001 <0.001 Wi h p ominen ne es (17) 506.72 (±48.44) 10.45 (±23.31) 566.07 (±2163.86) 0.50 (±0.43) 0.74 (±0.74) 1.41 (±2.07) Wi hou p ominen ne es (100) 527.96 (±31.79) 2.48 (±8.22) 13.24 (±28.19) 0.31 (±0.24) 0.47 (±0.31) 1.51 (±3.67) P 0.083 0.006 0.467 0.002 0.008 0.349 Wi h p ominen ne es (17) 506.72 (±48.44) 10.45 (±23.31) 15.60 (±2163.86) 0.50 (±0.43) 0.74 (±0.74) 1.41 (±2.07) Wi hou p ominen ne es and wi hou Fleische ing (70) 530.55 (±31.86) 2.02 (±8.17) 12.90 (±31.79) 0.28 (±0.21) 0.41 (±0.26) 1.03 (±1.50) P 0.024 0.001 0.907 <0.001 <0.001 0.029 KC amily membe s ha ing co neal Fleische ing compa ed o hose wi hou Fleische ing ha e signi ican ly hinne co neas ( - es ) and highe alues o all opog aphy indices (Mann-Whi ney ank sum es s). KC amily membe s wi h p ominen co neal ne es compa ed o hose ha ing no p ominen ne es show signi ican ly highe alues o KSI, 3 and 6 mm Fou ie asymme y indices (Mann-Whi ney ank sum es s). KC amily membe s ha ing p ominen co neal ne es compa ed o hose wi hou p ominen ne es and wi hou Fleische ing ha e signi ican ly hinne co neas ( - es ) and highe alues o all opog aphy indices excep o KISA (Mann-Whi ney ank sum es s). 925 In e es ingly,p ominen ne esandFleische ingdidno alwaysoccu oge he in hesameco nea.I iswellknown ha hesesignsoccu wi hunequal equenciesinKC [1].I is belie ed ha KCisacomplexdisease,bo hgene icand en i onmen al ac o splayinga oleini spa hogenesis [9]. Fleische ingissupposed ode elopasaconsequenceo al e ed esponseo KCepi helialcells ooxida i es ess[27]. Recen co neal con ocalmic oscopys udies consis en lyha eshown ha e eninmildKC, hesubbasal ne emo phologyisg osslyabno mal [28].Thismigh be explainedbyal e ed egula iono ne eg ow h ac o ecep o exp essionin heKCco nea [29].Thesedi e en e iological ac o smigh explainwhyFleische ingand co nealne esdono alwaysoccu oge he inKCo o me us eco neas. I wasunexpec ed o indFleische inginno malcon ols. Ne e heless,supposing ha o me us eKCisan incomple ely de elopedKC,i soccu enceinno mal con olsispossible.A ecen s udy epo ed hep esenceo bila e alFleische inginasubjec whohadonlymild opog aphicasymme y,a e agecen alco neal hickness, lowmyopiawi hs able e ac ion,no malbes co ec ed isualacui yandno mal e inoscopic e lexes.Theexample o hispa ien ,whowasconside edas o me us eKC, indica ed ha hiscondi ion, co neali on ingcanoccu wi hou aposi i e amilyhis o yand cha ac e is ic opog aphicsignso KC[30]. Inou amilymembe s,minimal opog aphical e a ionswe e obse edandassocia edwi h hep esenceo Fleische ing and p ominen co nealne es. Oneo heexamined pa ame e sin hiss udywascen alco neal hickness measu edbyul asound pachyme y.Cen alco neal pachyme yaloneisun eliablein hediagnosiso KC, ne e heless,dec eased hicknesscanbeagoodindica o o simila i y oKCand oge he wi h he ideoke a og aphic indices hispa ame e suppo ed ha Fleische ingand p ominen ne es end ooccu inco neasmo esimila o KC.Howe e , heexamina iono hepos e io co neal su aceandpachyme ywi hmode ndiagnos icme hods( Scheimp lugimagingo O bscan)wouldbehelp ulin u u e s udies,since heea lies signso KCcanbemo eaccu a ely de ec edwi h hese echniquesandco ela ionswillbegi en u he impac wi h headdi iono pos e io opog aphical in o ma ion[31,32]. Inspi eo sophis ica edimaging echniques,de ec ing subclinicalKCiss illchallenginginmanycases.Iden i ying subclinical/ o me us ecases,howe e ,isimpo an bo h o gene ics udiesandselec inghigh isk e ac i esu ge y candida es [13,33,34].Basedonou esul s,i canbesugges ed ha a ho oughsea ch o Fleische ingandp ominen ne esin heco neacanhelp odecidewhe he o no o diagnosesubclinicalKCinbo de linecases. ACKNOWLEDGEMENTS Founda ions: Suppo edbyHunga ianNa ionalResea ch FundG an sOTKAF046321andTAMOP-4. 2.1/B-09/1/KONV-2010-0007.Tak觃csLis ecipien o he Szodo ayFellowshipo heUni e si yo Deb ecen. Con lic so In e es :K isz 譧,None; LosonczyG,None; Be aA,None; Tak仳csL,None. REFERENCES 1K achme JH,Fede RS,BelinMW.Ke a oconusand ela ed nonin lamma o yco neal hinningdiso de s. 1984;28(4): 293-322 2Rabinowi zYS.Ke a oconus. 1998;42(4):297-319 3Millodo M,Shneo E,AlbouS,A laniE,Go don-ShaagA.P e alence andassocia ed ac o so ke a oconusinJe usalem:ac oss-sec ionals udy. 2011;18(2):91-97 4Rome o-JimenezM,San odomingo-RubidoJ,Wol sohnJS.Ke a oconus: a e iew. 2010;33(4):157-166;quiz205 5Tu SJ,HassanH,Geo geS,F aze DG,WilloughbyCE,Lisko aP. Ke a oconusin18pai so wins. 2012;90(6):e482-486 6IhalainenA.Clinicalandepidemiological ea u eso ke a oconusgene ic andex e nal ac o sin hepa hogenesiso hedisease. 1986;178:1-64 7Rabinowi zYS,Ga busJ,McDonnellPJ.Compu e -assis edco neal opog aphyin amilymembe so pa ien swi hke a oconus. 1990;108(3):365-371 8WangY,Rabinowi zYS,Ro e JI,YangH.Gene icepidemiological s udyo ke a oconus:e idence o majo genede e mina ion. 2000;93(5):403-409 9K isz A,LosonczyG,Be aA,Ve ebG,TakacsL.Seg ega ionanalysis sugges s ha ke a oconusisacomplexnon-mendeliandisease. 2014;92(7):e562-568 10NielsenK,Hjo dalJ,PihlmannM,Co ydonTJ.Upda eon he ke a oconusgene ics. 2013;91(2):106-113 11Amsle M.Ke a oconeclassiquee ke a ocone us e,a gumen s uni ai es. 1946;111(2-3):96-101 12Le yD,Hu chingsH,RoulandJF,GuellJ,Bu illonC,A neJL,ColinJ, La ocheL,Mon a dM,DelboscB,Ap elI,Ginis yH,G andjeanH, MalecazeF.Videoke a og aphicanomaliesin amilialke a oconus. 2004;111(5):867-874 13Seile T,Quu keAW.Ia ogenicke a ec asiaa e LASIKinacaseo o me us eke a oconus. 1998;24(7):1007-1009 14Ka imianF,A ameshS,RabeiHM,Ja adiMA,Ra a iN.Topog aphic e alua iono ela i eso pa ien swi hke a oconus. 2008;27(8): 874-878 15S eeleTM,FabinyiDC,Coupe TA,LoughnanMS.P e alenceo O bscanIIco nealabno mali iesin ela i eso pa ien swi hke a oconus. 2008;36(9):824-830 16ZadnikK,Ba JT,Go donMO,Ed ing onTB.Biomic oscopicsigns anddiseasese e i yinke a oconus.Collabo a i eLongi udinalE alua ion o Ke a oconus(CLEK)S udyG oup. 1996;15(2):139-146 17Ka aN,Al inkaynakH,BazO,Goke Y.Biomechanicale alua iono co neain opog aphicallyno mal ela i eso pa ien swi hke a oconus. 2013;32(3):262-266 18HubbeRE,FoulksGN.Thee ec o poo ixa iononcompu e -assis ed opog aphicco nealanalysis.Pseudoke a oconus. 1994; 101(10):1745-1748 Fleische inginke a oconus ela i es 926 陨灶贼允韵责澡贼澡葬造皂燥造熏灾燥造援 8熏晕燥援 5熏Oc .18, 圆园15 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ijop ess岳员远猿援糟燥皂 19Rabinowi zYS,RasheedK.KISA%index:aquan i a i e ideoke a og aphyalgo i hmembodyingminimal opog aphicc i e ia o diagnosing ke a oconus. 1999;25(10): 1327-1335 20SmolekMK,KlyceSD.Cu en ke a oconusde ec ionme hods compa edwi haneu alne wo kapp oach. 1997;38(11):2290-2299 21Hjo dalJO,E dmannL,BekT.Fou ie analysiso ideo-ke a og aphic da a.A ool o sepa a iono sphe ical, egula as igma icandi egula as igma icco nealpowe componen s. 1995;15(3): 171-185 22TanabeT,Tomidoko oA,SamejimaT,Miya aK,Sa oM,KajiY, OshikaT.Co neal egula andi egula as igma ismassessedbyFou ie analysiso ideoke a og aphyda ainno malandpa hologiceyes. 2004;111(4):752-757 23Rabinowi zYS,McDonnellPJ.Compu e -assis edco neal opog aphy inke a oconus. 1989;5(6):400-408 24Ag awalVB.Cha ac e is icso ke a oconuspa ien sa a e ia yeye cen e inIndia. 2011;6(2):87-91 25Ed ing onTB,ZadnikK,Ba JT.Ke a oconus. 1995;4(3): 65-73 26ZadnikK,Ba JT,Ed ing onTB,E e e DF,JamesonM,McMahon TT,ShinJA,S e lingJL,Wagne H,Go donMO.Baseline indingsin he Collabo a i eLongi udinalE alua iono Ke a oconus(CLEK)S udy. 1998;39(13):2537-2546 27JosephR,S i as a aOP,P is e RR.Di e en ialepi helialands omal p o einp o ilesinke a oconusandno malhumanco neas. 2011;92(4):282-298 28SpadeaL,Sal a o eS,VingoloEM.Co nealsensi i i yinke a oconus:a e iewo heli e a u e. 2013;2013:683090 29LambiaseA,Me loD,Mollina iC,BoniniP,RinaldiAM,D'Ama oM, Mice aA,CoassinM,RamaP,BoniniS,Ga aciE.Molecula basis o ke a oconus:lacko T kAexp essionandi s ansc ip ional ep essionby Sp3 2005;102(46):16795-16800 30DownieLE.T ansiencyo Fleische 's ingsinFo me-F us e ke a oconus. 2013;120(5):1101.e1-8 31FukudaS,Behe ega ayS,HoshiS,Yamana iM,LimY,Hi aokaT, YasunoY,OshikaT.Compa isono h ee-dimensionalop icalcohe ence omog aphyandcombininga o a ingScheimp lugcame awi haPlacido opog aphysys em o o me us eke a oconusdiagnosis. 2013;97(12):1554-1559 32IshiiR,KamiyaK,Iga ashiA,ShimizuK,U sumiY,KumanomidoT. Co ela iono co nealele a ionwi hse e i yo ke a oconusbymeanso an e io andpos e io opog aphicanalysis. 2012;31(3):253-258 33Moshi a M,SmedleyJG,Mu happanV,Ja s edA,Os le EM.Ra eo ec asiaandincidenceo i egula opog aphyinpa ien swi huniden i ied p eope a i e isk ac o sunde going em osecondlase -assis edLASIK. 2014;8:35-42 34RandlemanJB,T a le WB,S ul ingRD.Valida iono heEc asiaRisk Sco eSys em o p eope a i elase insi uke a omileusissc eening. 2008;145(5):813-818 927