Clinical Spectrum and Geographic Distribution of Keratitis Fugax Hereditaria Caused by the Pathogenic Variant c.61G>C in NLRP3

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Clinical Spectrum and Geographic Distribution of Keratitis Fugax Hereditaria Caused by the Pathogenic Variant c.61G > C in

NLRP3

ANNAMARIT.IMMONEN,SABITAKAWAN,MINNAVESALUOMA,J.MIIKAELHEISKANEN,CLAUDIATAIPALE, MIRAKOSKINEN,ANNAMAJANDER,TERO T.KIVELÄ,ANDJONIA.TURUNEN

• PURPOSE: Tochartclinicalfindingsinindividualswith keratitisfugaxhereditaria(KFH)andthegeographicdis- tributionoftheirancestors.

• DESIGN: Aprospectivecross-sectionalstudy.

• METHODS: This study took place in a tertiary refer- ralcenterwithacohortof84Finnishpatients(55%fe- male)from 25families with thepathogenic nucleotide- bindingdomain,leucine-richrepeat(NLR)familypyrin domain containing 3 (NLRP3) variant c.61G>C. Ob- servation procedures and main outcome measures were Sangersequencing,clinicalexamination,cornealimaging, andaquestionnaireregardingsymptoms, qualityof life, treatment,andcomorbidities.

• RESULTS: Theoldestmembersineachfamilywereborn in Ostrobothnia in Western Finland or in Southwest- ernFinland with historical tiesto Sweden. Onecarrier wasasymptomatic.Most(77%,46/60)experiencedtheir firstattackbetween age6and 20years.Three-quarters had unilateral attacks 3 to 5 times annually, primarily triggered by cold windor air, or stress. Eighty percent (48/60)reportedocularpain(median,7 onscale1-10), conjunctivalinjection,photophobia,foreignbodysensa- tion,andtearingduringattacks.Visualbluroccurredin 75%(45/60)and91%(55/60)duringandaftertheat- tack,respectively,foramedianof10days(range,1day- 2months).Forty-sevenpercent(39/60)hadcornealoval opacitieswithirregulartomographypatternsandmildto moderatedecrease(20/60orbetter)inbest-correctedvi- sualacuitythatimprovedwithscleralcontactlenses.Ex- ceptforheadache in40%, systemicsymptoms wereab- sentduringtheattacks.

• CONCLUSIONS: Symptoms and signs of KFH are re- stricted to the anterior segment of the eye and vary

SupplementalMaterialavailableatAJO.com. AcceptedforpublicationOctober23,2021.

FromtheDepartment ofOphthalmology(A.T.I.,S.K.,M.V.,C.T., M.K., A.M., T.T.K., J.A.T.), University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Folkhälsan Research Center (S.K.,J.A.T.)BiomedicumHelsinki,Helsinki,Finland;Ophthalmology (J.M.H.),Kanta-HämeCentralHospital,Hämeenlinna,Finland

InquiriestoJoniA.Turunen,DepartmentofOphthalmology,Helsinki University Hospital, Haartmaninkatu 4 C, PL220, FI-00029 HUS, Helsinki,Finland.;e-mail:joni.turunen@helsinki.fi

widelybetweenindividuals.Werecommendscleralcon- tact lenses as the first-line treatment for reduced vi- sion. Allele frequencies suggest that KFH goes un- recognized in Sweden and populations with Scandina- vian heritage. (Am J Ophthalmol 2022;236: 309–

This is an open access article under the CC BY-NC- ND license (http://creativecommons.org/licenses/by-nc- nd/4.0/))

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ⁿophthalmology,^1964, ^Olavidescribed^Valle, ^thenin 10^amembers^Finnishof^resident1familyⁱⁿa recurrentunilateralkeratitisthathenamedkeratitisfu- gaxhereditaria(KFH,MIM148200).¹ThesecondFinnish family wasreported in 1987, whereupon the disease was renamed keratoendotheliitis fugax hereditaria² based on misinterpretationofspecularendothelialmicroscopyfind- ings.³ Werecentlydiscoveredin23affectedFinnishfami- liesthatthisautosomaldominantdiseaseiscausedbyahet- erozygous pathogenic variant c.61G>C, p.(Asp21His)in thenucleotide-bindingdomain,leucine-richrepeat(NLR) family pyrin domain containing 3 (NLRP3) gene, and showedthatendothelialcellswereuninvolved.³^,⁴

Unilateral ocular pain, conjunctival injection, photophobia,andtearingcharacterizetheacuteinflammatoryat- tacks ofKFHthat lastfor1 to 3 daysand leaveablurry visionforseveralweeks.¹^,²^,⁴ Ourconfocal microscopyre- sults suggest influxofleukocytes into thecorneal stroma duringtheattack.³Theattacksbeginatthemedianageof 11yearsandrecur1to6timesayear.Repeatedattacksre- sultinbilateralhorizontallyovalcentralstromalopacities inone-halfofthepatientsthatcanreducevisualacuity.³^,⁴ NLRP3 encodes cryopyrin, a crucial member of the NLRP3 inflammasome.⁵ Pathogenic variants in NLRP3 cause rareautoinflammatorydiseasesknownascryopyrin- associated periodic syndromes (CAPS).⁶ These include neonatal-onset multisystem inflammatory disease (NO- MID),Muckle-Wellssyndrome,and familialcoldautoin- flammatorysyndrome.⁶Theyarecharacterizedbyexcessive interleukin-1β secretion that results in systemic autoin- flammation.⁷ Commonsymptomsincluderecurrentfever, headache,arthritis,urticaria-likerashes,hearingloss,and

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conjunctivitis.⁵^,⁸KFHisthefourthmemberoftheCAPS familywithapparentlylocalizedsymptoms.³^,⁴

ThecornealphenotypeofKFHisnowwelldescribed,^1-4 butafullsystematicdocumentationofthesignsandsymp- toms, including potential mild systemicones, is lacking.

HerewechartanddescribethesymptomsandsignsofKFH in84affectedcarriersofthecommonc.61G>CNLRPvari- antin25families,including32newpatientsfrom10new families.Moreover,wechartedthegeographiclocationof theirancestors.Inadditiontoaclinicalophthalmologicex- amination,thepatientscompletedacomprehensiveques- tionnairetocharttheirsymptoms,qualityoflife,treatment, and comorbidities. Because other pathogenic variants in NLRP3 cause divergent systemic autoinflammatory reac- tions,wepaidspecialattention to anyextraocularsymp- toms and manifestations. Understanding the full clinical spectrumofthiscornealautoinflammatorydiseasewillhelp ophthalmologiststorecognizeit.

PATIENTS AND METHODS

AllpatientsclinicallydiagnosedwithKFHattheHelsinki University Hospital between April 3, 2016, and January 30, 2020, and verified to be carriers of the c.61G>C (rs200154873)NLRP3variantwereeligibleforthestudy.

Everypatientreferred to us foraworkupofKFH wasin- vitedtohaveaclinicalexaminationandgeneticanalysis, andnoneofthemrefused.Familymemberswereofferedthe sameopportunity.Forthisstudy,inadditiontotheclinical examination,apaperquestionnairewasmailedtoallgenet- icallyconfirmedpatients.Patientswereaskedtocomplete thesurveyontheirownandmailitbacktotheinvestiga- torsbefore theduedate. Itwasreturnedby two-thirdsof them(60/84).Weestimatethatapproximately700people inFinlandhaveKFHbasedonallelefrequencydata(Sup- plementalTable1),⁹ofwhich127variantcarriershaveal- readybeenrecognized.

The project was approved by the Hospital Region of HelsinkiandUusimaaInstitutionalReviewBoardandfol- lowedthetenetsoftheDeclaration ofHelsinki. Allpar- ticipantsgavetheirwritteninformedconsent.Theconsent wasgivenbytheparentincaseofpediatricpatients.

• GENETIC ANALYSIS: The NLRP3 variant c.61G>C (rs200154873; GenBank: NM_004895.4) was confirmed bySanger sequencing asdescribed earlier.⁴ Variant allele frequencies were determined from Genome Aggregation Database(gnomAD)version2.1.1.⁹

• CLINICAL EXAMINATION: A comprehensive clinical and genetic evaluation wasperformed (A.I. and J.T.)in allpatients,except one ofveryadvanced age(patient1- 14).Itincludedpersonalhistory,reviewofpatientmedical

recordsforreportedsymptomsandcoexistingdiseases,fam- ilyhistory,apedigree,best-correctedvisualacuity(BCVA, Snellen),intraocularpressure(iCareIC100;IcareFinland Oy),andbiomicroscopicexamination.Cornealabnormali- tieswereclassifiedin4categories:none,mildstromalhaze, central oval opacity,and multiple opacities(Supplemen- tal Table 2).The corneawas imagedby Fourier domain, swept-sourceanteriorsegmentopticalcoherencetomogra- phy(SS-1000CASIA;Tomey).

• QUESTIONNAIRE: Tochartpotentialsystemicsignsand symptoms, we used a questionnaire consisting of open- ended questions, multiple-choice questions, and scaled questions thatweredesignedspecificallyto evaluateKFH asatypeofCAPS.Thequestionscovered4topics:personal information, eye health, general health, and symptoms (SupplementalText1,originalquestionnaire10.5281/zen- odo.5101477).Ocularpainandqualityoflifewereratedon ascalefrom1(nopain/noimpactonqualityoflife)to10 (intolerablepain/maximalimpactoneverydaylife).

• STATISTICALMETHODS: DatawereanalyzedwithSPSS 25-v100software(IBMCorp).Medianwithrangeandin- terquartilerange(IQR)isreportedforcontinuousvariables.

Weusednonparametricteststocomparevariablesbetween groups.Characteristicsbetweengroupswerecomparedus- ingtheSpearmanrankcorrelationandMann-WhitneyU test. Levelofsignificancewassetat.05. Alltestswere2- tailed.

RESULTS

Thestudyenrolledall84patientsdiagnosedwithc.61G>C variantKFHatourhospitalduringthestudyperiod.Partic- ipantscamefrom 25families; 46(55%)were femaleand 38(45%)male(P=.45,binomialtest).Seventy-sevenpa- tients(92%)hadafamilyhistoryofKFH.Theremaining7 (8%)hadincompletegenealogydata.Allparticipantswere nativeFinns.Sixtypatients(71%),ofwhom36(60%)were female and 24 male (40%), returned the questionnaire.

Thosewhodidnotreturnthequestionnaire(24[29%])did notdiffersystematicallybyage,sex,ageofonset,numberof attacks, visualacuity,and cornealopacitycomparedwith therespondents.Theagerangeofthosewhoreturnedthe questionnairewas14to94years(median,54;IQR,35-68 years).

• GEOGRAPHICDISTRIBUTIONOFKFHANCESTORS: Ex- cluding the capital region, the birthplaces of the oldest known members in each KFH family are located in Os- trobothnia in Western Finland or in Southwest Finland (Figure 1). These regions parallel the municipalities in whichthepopulationisofficiallySwedishspeakingorbilin- gualwithaSwedish-speakingmajority.Theallelefrequency

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FIGURE 1. Geographic distributionin Finlandof the birth- placesoftheoldestknownancestorsofkeratitisfugaxheredi- tariapatientsin25families.

of the c.61G>C variant in Sweden (0.011%) is nearly as high as in Finland (0.014%) based on the gnomAD database,⁹ althoughto thebest ofourknowledge, nopa- tients haveyet been reportedfrom Sweden. The variant hasalsobeendetectedinthegnomADpopulationcategory

“other,” whichmeansthattheindividuals didnotcluster withthemajorpopulationsinprincipalcomponentanaly- sis.⁹

• AGEATSYMPTOMONSET: Theageatthetimeofthefirst attacksrangedfrom2to 55years(median,11;IQR,9-15 years).Although46ofthe60patients(77%)experienced theirfirstattackbetweenage6and20years,7patientswere youngerand7wereolderatthetimeoffirstsymptoms,and only1 femalerespondent was olderthan 30years atthe onset ofsymptoms. Forty-five patients (75%) had 3 to 5

attacks per year(Figure2,A). Themaximumnumber of attackswas10peryearin2patients(3%).

• TRIGGERING FACTORS: On the basis of the questionnaire,39patients(65%)reportedenvironmentalorother factorsthattriggeredtheacuteattack,and11(18%)specu- latedaboutsuchfactors.Themostcommonpresumedtrig- gers werepsychologicstressin35 patientsand coldwind and airin 26.Otherreportedtriggering extrinsicand in- trinsic factorsarepresented inadiagram(Figure 3).Two patientsreportedattacksinbotheyeswithinanintervalof afewdays,and28(47%)reportedmildsymptomsatbed- timebeforetheiracuteattackthenextday.

• SYMPTOMS DURING ACUTE ATTACKS:Of the 60 pa- tientswhorespondedtothequestionnaire,morethan80%

(48/60)reportedconjunctivalinjection,ocularpain,photophobia,foreignbodysensation,andexcessivetearingdur- ingacuteattacks(Table1).Wefoundnoevidenceofdif- ferencesbetweenwomenandmenduringtheacuteattacks.

However,thepainintensityvariedbydifferentageatonset (Figure2,BandC).Theoverallhighestmedianpainin- tensitywas7onascalefrom1to10(Figure2,B).Thepain lastedfor2to3days(Figure2,C).

Twenty-eight respondents(47%)felt betterwhile hav- ing theireyeclosed duringtheacute attack;however,14 patients (23%) preferred to keep it open,and 18(30%) reportednodifference.Forty-fivepatients(75%)reported reduced vision during the attack (Table 1), and 55 patients(91%)experiencedblurrinessafter theacute symptoms (Figure 2, D). Two patients experienced blurriness onlyfor 1day, while 5 patientssuffered from it formore than2 months.Whenresultswerecombinedfromallpa- tients, thevisual blurlasted amedian of10days (range, 1-50;IQR,3-25days)betweentheagesof21and60years, butwasreportedtobeshorter(3-5days)whenagedyounger than20years.Itshouldbenotedthat1carrier(1.2%;95%

CI,0%-6%)ofthepathogenicvarianthadnotexperienced anysymptomsbytheageof67years.

• CORNEALOPACITIESANDVISUALACUITY: Altogether, 39 (47%) of the 83 clinically examined patients had a corneal opacity(46% of females55% ofmales; P =.51, Fisherexacttest).TheBCVAof62patients(75%)wasat least20/20intheeyewithbettervisualacuity,7(8%)had aBCVAoflessthan20/40,and2patients(2%)lessthan 20/60(SupplementalTable2).AllpatientswithaBCVA oflessthan20/40hadtypicalKFH-relatedcentralcorneal opacities. In addition, 1 individual each hada historyof centralserouschorioretinopathy,opticneuritis,andpene- tratingkeratoplasty.Thirtyeyeswithacentralovalopacity and5eyeswithamildstromalhazehad20/20visionorbet- ter.

Seventy-fivepatients(89%)underwentswept-sourcean- teriorsegmentopticalcoherencetomography,ofwhich70 (83%)couldbeassignedintheanalysisin2groups(clear

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FIGURE2. (A)Themediannumberofattacksperyear,(B)themedianintensityofocularpainduringtheacuteattack(scale:1 nopainand10intolerablepain),(C)themediandurationofacuteattackindays,and(D)themediandurationofblurryvisionafter theacuteattackindaysbytheageofonsetin60patientswithkeratitisfugaxhereditaria.

TABLE1.SymptomsDuringAcuteAttacks

Symptom

Total Females Males Aged<40Years Aged≥40Years (N=60) (n=36) (n=24) (n=19) (n=41)

Ocularsymptoms

Redeye/conjunctivalinjection 59(98) 36(100) 23(96) 19(100) 40(98)

Eyepain 56(93) 36(100) 20(83) 17(89) 40(98)

Photophobia 55(92) 33(92) 22(92) 18(95) 37(90)

Foreignbodysensation 51(85) 33(92) 18(75) 18(95) 33(80) Wateryeyes/excessivetearing 51(85) 34(94) 17(71) 18(95) 33(80)

Glare 46(77) 30(83) 16(67) 9(47) 36(88)

Reducedvision 45(75) 30(83) 15(63) 11(58) 34(83)

Lightscattering 31(52) 22(61) 9(38) 9(7) 20(49)

Eyestrain 31(52) 22(61) 9(38) 10(53) 21(51)

Burningsensation 22(37) 18(50) 4(17) 6(32) 16(39)

Diplopia 22(37) 17(47) 5(21) 5(26) 18(44)

Itchyeye 21(35) 16(44) 5(21) 9(47) 13(32)

Eyelidswelling 18(30) 15(42) 3(13) 4(44) 14(34)

Shadowsinvision 11(18) 7(19) 4(17) 3(16) 8(20)

Eyedischarge 10(17) 7(19) 3(13) 3(16) 8(20)

Sensationofcrying 1(2) 1(3) 0 0 1(2)

Nonocularsymptoms

Fever 3(5) 2(6) 1(4) 1(5) 2(5)

Other(pulsatingpain,chills) 3(5) 3(8) 0 0 3(7)

Note:Dataarepresentedasn(%).

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FIGURE3. Triggeringfactorspredisposingtoanacuteattackofkeratitisfugaxhereditaria(KFH)reportedby60patients.SetA includesenvironmentalfactorsandsetBendogenousfactors.Overlappingareashowssharedfactors.

corneaorcentralovalopacity).Theremainingpatientsin- cluded 2 with corneal transplants and 3 with borderline mildcornealhaze.Whenthethinnestpachymetryvalues ofrighteyeswithaclearcornea(median,504µm;n=39) werecomparedwiththosewithacentralovalopacity(median, 488 µm; n =31), the latter had lowerpachymetry values,butnodifferencecouldbeconfirmedbetweenthe groups(thinnest:P=.14;apex:P=.26,Mann-Whitney Utest)(Table2).Thethinnestpointsofthecorneaswere notlocatedsystematicallyin thesamedirectionfromthe apex.PatientswithalowBCVAanddensecentralcorneal opacitieshadirregulartomographypatterns.

• TREATMENT: Evidence-basedtreatmentforKFHisun- available.Various medicationshad been usedduring the acute attack (Supplemental Table 3). On the basis of thequestionnaire,33patients(55%)hadreceivedtopical

steroids,14patients(23%)topicaland16patients(27%) oralnonsteroidalanti-inflammatorydrugs(NSAIDs),and 16patients(27%)hadnottakenanymedication.

Fifteenquestionnairerespondents(25%)didnotuseany opticalcorrection.Theothersworespectacles,including8 whoadditionallyworecontactlensesregularly.Onewore soft contactlenses, but the 7 other patients wore scleral contact lenses because of reduced BCVA and presumed higher-order aberrations.Scleral contactlensesimproved BCVA1to5lines(logMAR)inallpatients(Supplemental Table4),andpatientsreportedlessdistortionandblurring ofvision.Thenumberofcontactlenswearerswastoosmall to statisticallyconfirmthatscleralcontactlensesimprove theBCVA.Fourof7patientsreportedthatthenumberof attacksseemedtodecreaseaftertheybegantowearscleral contactlenses, especiallyunderwindyconditionssuch as sailing.

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TABLE2.PachymetryandCylinderPowerMeasurementsbyMainTypeofCorneal Opacity

Measurement PatientsWithNoCornealOpacity PatientsWithCentralOvalCornealOpacity

(n=39) (n=31)

Pachymetryapex

Median(IQR) 514(480-535) 503(479-520)

Range,µm 373-622 387-597

P=.26,Mann-WhitneyUtest Pachymetrythinnest

Median(IQR),µm 504(476-530) 488(468-510)

Range,µm 229-615 326-584

P=.14,Mann-WhitneyUtest Cylinderpower

Median(IQR),D 0.6(0.4-1.0) 1.0(0.5-1.4)

Range,D 0.1-1.7 0.3-4.6

P=.07,Mann-WhitneyUtest

Note:MeasurementswereperformedbyFourierdomain,swept-sourceanteriorsegment opticalcoherencetomography.

• OCULAR COMORBIDITIES: As indicated on the questionnaire,themostcommonreporteddiseasesweredryeye (14patients [23%]), allergickeratoconjunctivitis (11 patients[18%]),andcataracts(11patients[18%]).Addition- ally,13patients(22%)hadbeendiagnosedwithpresumed anterioruveitisand 2patientswithpresumedherpessim- plexkeratitis.Fivepatients(8%)hadahistoryofposterior vitreousdetachment, 4(7%)high intraocular pressure,4 (7%)blepharitis,and2(3%)opticneuritis.Twelvepatients (20%)hadundergoneintraocularsurgery.Penetratingker- atoplasty had been performed in 1 patient with corneal opacity³ andin1 withkeratoconus,after whichacuteat- tacksandothersymptomsofKFHceased.

• GENERAL HEALTH: The most frequently reported systemic conditions (Table 3) were hypercholesterolemia (22%,13/60), historyofcancer (15%, 9/60),high blood pressure(12%,7/60),andatopy(10%,6/60).Mostpatients (55%,33/60)didnotsmoke.Twopatients(3%)werefor- mersmokers.Thefirst3mostcommonsystemicconditions appearedmostlyafterage40years.

Except for headache in 24 patients (40%), other fre- quentlyreportedCAPS-associatedsymptoms, such asur- ticaria,unspecificfever,arthritis,jointpainaftercoldex- posure,abnormalsweating,frequentnausea,hearingprob- lems, or abnormal skin pigmentation, were rare and had beenexperiencedatleast onceduring theirlifetime by2 to13patients,dependingonthesymptom(Table4).The mostcommonsymptoms—headache,arthritis,andabnor- malskinpigmentation—typicallywereassociatedwithun- relatedsystemicdiseasesoroldage.

• QUALITYOF LIFE: The effect of KFH on self-reported qualityoflifewasgreaterifthepatienthadacentraloval

cornealopacity(Spearmanρ=−0.57,P=<.001)orde- creasedBCVA(Spearmanρ=0.45,P=.001),butnocor- relationwasfoundbetweenqualityoflifeandageofonset or currentage.Responsesvariedwidelywhentherespon- dentswereaskedtoquantitatetheimpactofKFHontheir quality oflife(Figure4).Themedianvaluewas5(range, 1-10;IQR,2-7).

DISCUSSION

WefoundawidespectrumofsymptomsfromKFH,ranging from patients whoexperiencedonlyafew attacksduring their lifetime, including1 carrier without anysymptoms, tootherswithsevereandprolongedvisualblur.Currently, thereisnospecifictreatmentforKFH,althoughmostpa- tientshadusedtopicalcorticosteroidsor NSAIDstoalle- viatesymptoms.Theattackisclearlyaninflammatoryre- action,soitislogicalthatcorticosteroidsorNSAIDshave beenprescribed.Becauseoftheself-limitingnatureofthe attacks,almostone-thirdhadnotusedanymedication.

We showthatrigid scleral contactlensescan improve BCVAinpatientswithtypicalcentralovalopacitiesandre- ducedvisionfromKFH.Weconsequentlynowrecommend rigid,especiallyscleralcontactlensesasthefirst-linetreat- mentforreducedvisionfromcornealopacitiesandaberra- tions.Sclerallensesgive,inadditiontobettervisualacuity, protectiontotheeyesurface.^10-13

Tothebest ofourknowledge, KFHhasso farbeenre- ported only in Finland, the population of which has a highallelefrequencyof0.014%forthecommonc.61G>C variant (rs200154873). However, until we recognized it as a surprisingly common cause of acute keratitis, typi-

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TABLE3.NonocularDiseasesandDisordersReportedThroughaQuestionnaire

Disease Total AgeatDiagnosis

(N=60) <40Years ≥40Years

Hypercholesterolemia 13(22) — 13(22)

Cancer^a 9(15) 2(3) 7(12)

Highbloodpressure 7(12) — 7(12)

Atopy 6(10) 6(10) —

Hypothyroidism 5(8) — 5(8)

Mental/behavioraldisorder^b 5(8) 3(5) 2(3)

Cardiacdisease 4(7) — 4(7)

Migraine 4(7) 4(7) —

Osteoarthritis 4(7) — 4(7)

Benignprostatichyperplasia 2(3) — 2(3)

Anosmia 2(3) 1(2) 1(2)

Bronchialasthma 2(3) 1(2) 1(2)

Irritablebowelsyndrome 2(3) 1(2) 1(2)

Juvenileidiopathicarthritis 2(3) 2(3) —

Multiplesclerosis 2(3) 1(2) 1(2)

Psoriasis 2(3) 2(3) —

Actinickeratosis 1(2) — 1(2)

Castlemandisease 1(2) — 1(2)

Complexregionalpainsyndrome 1(2) — 1(2)

Diffuseidiopathicskeletalhyperostosis 1(2) — 1(2)

Discoidlupuserythematosus 1(2) — 1(2)

Hearingloss 1(2) — 1(2)

Hyperparathyroidism 1(2) — 1(2)

Osteoporosis 1(2) — 1(2)

Pleuralemphyema 1(2) — 1(2)

Polymyalgiarheumatica 1(2) — 1(2)

Respiratorypolyps 1(2) — 1(2)

Sleepapnea 1(2) — 1(2)

Acne 1(2) 1(2) —

Addisondisease 1(2) 1(2) —

Breastanduterineinﬂammation 1(2) 1(2) —

Dyslexia 1(2) 1(2) —

Epilepsy 1(2) 1(2) —

Harlequinsyndrome 1(2) 1(2) —

Henoch–Schönleinpurpura 1(2) 1(2) —

Hepatitis 1(2) 1(2) —

Herpessimplex 1(2) 1(2) —

Restlesslegssyndrome 1(2) 1(2) —

Vitiligo 1(2) 1(2) —

aBreastcancer(n=2),prostatecancer(n=2),non-Hodgkinlymphoma(n=2),squamouscellcarcinoma (n=1),cholangiocarcinoma(n=1)andbladdercancer(n=1).

bAnxietydisorder(n=1),depression(n=2),posttraumaticstressdisorder(n=1),andbipolardisorder(n=1).

cally misdiagnosed as mild anterior uveitis, it wasessen- tiallyunknownamongFinnishophthalmologists.Thegno- mADdatabaseindicatesthecorrespondingallelefrequency isnearlyequal(0.011%)in Sweden(SupplementalTable 1),⁹ which stronglysuggests thatKFH currentlygoesun- recognizedinSweden.Furtherevidenceisthatthebirth- placesoftheoldestknownancestorsin thefamilieswith KFHarelocalizedtotheWesternandSouthwesterncoastal regionsofFinlandthathistoricallyhavehadclosecontacts

withSwedenandarestillmainlySwedish-speakingregions inFinland,acountrythathas2officiallanguages,Finnish andSwedish.ThegnomADdatabasefurthersuggeststhat individualfamilies,possiblyofNordicdescent,existoutside FinlandandSweden.

ThepopulationofFinlandiscurrently5.54millionand that of Sweden 10.23 million; thus, according to public exome and genome databases, more than 700 and 1000 NLRP3 c.61G>C variant carriers could live in Finland

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TABLE4.Cryopyrin-AssociatedPeriodicSyndromeSymptomsReportedbyQuestionnaire(N=60)

Symptom Yes Possibly No

Headache 24(40) 2(3) 34(57)

Arthritis 13(22) 6(10) 41(68)

Abnormalskinpigmentation 11(18) 7(12) 42(70)

Abnormalsweating 9(15) 4(7) 47(78)

Urticaria 7(12) 9(15) 44(73)

Arthralgia 6(10) 8(13) 46(77)

Hearingproblem 5(8) 6(10) 49(82)

Nausea 5(8) 3(5) 52(87)

Unspeciﬁcfever 2(3) 2(3) 56(93)

FIGURE4. Theself-reportedqualityoflifereportedby57patientswithkeratitisfugaxhereditaria(scale:1noimpactoneveryday lifeand10maximumimpact).

andSweden,respectively.Thisisconsistentwiththeease withwhich wealreadyhaveidentified 23families within 4 yearsin addition to the2 first families reportedin the 1960s and 1980s. This suggests that KFH is common in Finlandbecauseofafoundermutationthatoccurredmore than 200 years ago in Finland or Sweden. None of our families is knownto be related to theothers duringthis timeframe (SupplementalFigure).Givenclosehistorical maritimeties, suspected of facilitatingthe spread ofrare variants¹⁴betweenNorthernPoland,Sweden,Estonia,and SouthernFinland,countriesalongtheBalticSeaotherthan Sweden,especiallyEstoniaontheothersideoftheGulfof Finland,alsomightsharethec.61G>Cvariant.Moreover,

KFHshouldbeconsideredinthedifferentialdiagnosisofa patientwhoisanimmigrantor adescendantofanimmi- grantfromFinlandorSweden.Mostemigrantsfromthese 2countrieshavemovedovertimetotheUnitedStatesand Canada, andaccordingtotheyear2019AmericanCom- munitySurvey,approximately650,000Americansreported beingofFinnishancestryandapproximately3.5millionof Swedishancestry.¹⁵

Patients with KFH with or without a central corneal opacity showed pachymetry values that corresponded to the lower range of the average thickness of the normal cornea (500-575 µm),¹⁶^,¹⁷ consistent with reported thin and finely vacuolated stromal lamellae in the an-

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terior half of the stroma of a patient who had under- gone penetrating keratoplasty for such opacities in the past.³ Theyhad onlymildcylinder powers.However,to- mographic maps of corneas in KFH also show irregular patternsthatmay havehigher-orderaberrations thatcan causestarburstorglare.^18-20Forty-sevenpercentoftheclin- ically examined patients with KFH have corneal opacities and as a result, permanent irregularities that affect their refraction because of the large differencein refrac- tive index betweenair and cornea.¹⁸ Biomicroscopically visible mild stromal haze or incipient oval opacities do notyetinterferewith theanteriorsurface,leavingBCVA unaffected.

Two-thirdsofourrespondentshadputativefactorstrig- geringanacuteattackofKFHandreportedcoldair,wind, and psychological stressas the mostcommon ones. This suggeststhatcornealepithelialmicrotraumaorasystemic humoral factor might possibly trigger the acute attack.

Our in vivo corneal confocal microscopy did not iden- tify visible abnormalities in the corneal epithelium dur- ingthe attack or betweenattacks ofKFH. However,en- vironmental factors,such as variable humidity and tem- perature, ultraviolet radiation, chemicals, smoking, pol- lutants, toxicgases, other airbornetoxins, endotoxins or lipopolysaccharides, various drugs, and cosmetics, invis- ibly affect the homeostasis of ocular surface.²¹ We hy- pothesize that minor stress altering the homeostasis of the corneal epithelium might activate the NLRP3 in- flammasomethathasbeenrenderedhypersensitivebythe pathogenicvariant.Thiscouldtriggeraninfluxofpolymor- phonuclearleukocytes and causean acute autoinflamma- torystromalkeratitiswithactivationofkeratocytes.Alter- natively,othercomponentsofthecornea,suchasitsnerves, couldbethecellsinitiatingtheinflammation.Furtherstud- ies are needed to elucidate the molecular backgroundof KFH.

ThemostcommonocularcomorbiditiesreportedinKFH weredry eyedisease and presumed anterior uveitisin almostone-quarterofthepatients.However,KFHcaneasily bemisdiagnosed asanexacerbation ofocularsurface dis- easeoranterioruveitis,andpatientsoftenshowamildan- teriorchamberreactionduringtheiracuteattack.Arecent casereportdescribedKFH-likecornealfindingsassociated

withposteriorscleritisinapatientwithanotherpathogenic variantp.(R262W)inNLRP3,causingasystemicCASP.²² Noneofourpatientshadexperiencedposteriorinflamma- tionoftheireyes.

Intheother3systemicCAPSsyndromes(familialcold autoinflammatorysyndrome,Muckle-Wellssyndrome,and neonatal-onset multisystem inflammatory disease/chronic infantileneurological,cutaneousandarticularsyndrome), thepathogenicvariantsinNLRP3arepresumedtobegain- of-functionintypethatenhanceproductionofinterleukin- 1β.⁸^,²³^,²⁴Theircharacteristicsymptomsarerecurrentfever, fatigue, arthralgia, skin rash, and influenza-like muscle ache,butalso chronicmeningitisand sensorineuralhear- ingloss.⁴^,²³^,²⁴Ocularsymptomsareconjunctivitis,episcle- ritis,keratitis,andanteriorandposterioruveitis.Elevated intracranialpressuremaycauseopticdiskedema,followed byatrophyinneonatal-onsetmultisysteminflammatorydis- ease/chronic infantile neurological, cutaneous and artic- ular syndrome.^25-28 Because theNLRP3inflammasome is thought to be abody-wide machinery,⁸^,²⁹ it is surprising thatpatientswithKFHhavenotconsistentlyreportedany other symptomsthanocular ones.⁴ Therefore,wequeried themspecificallyforthesesymptoms.Theydidnothavea convincinghistoryofanysystemicsymptomaticinflamma- tion duringtheirattacks, although5 orfewer individuals reportedpossibleprodromalsymptoms, suchasfever,pulsatingpain,orchills.

Limitationsofourstudyincludethataquestionnairein- troducesrecall biasand one-third ofthepatientsdid not respondtoit.Toreducebias,wealsoreviewedpatientmedi- calrecordsforreportedsymptomsandcomorbiditiestospot anyconflictinginformation.

The aforementioned results are from symptomatic patients, butit is possible thatin the future, asymptomatic variantcarriersmaybefoundaswell,inwhichcasethere- sultsshouldbere-evaluated.

Itisimportanttorecognizethefullclinicalspectrumof KFH because itcontinues to bemisdiagnosed asanterior uveitis or presumedherpetic keratitis.Theavailability of genetictestingnowensuresacorrectdiagnosis.Researchis neededinevidence-basedmanagementofacuteattacksand in elucidating the molecularbackgroundof theapparent cornealspecificityofautoinflammationinKFH.

Acknowledgment:BiostatisticianPaulaBergman,UniversityofHelsinki,providedstatisticaladvice.

Funding/Support:ThestudyreceivedsupportfromTheEyeandTissueBankFoundation,Finland;TheEyeFoundation,Finland;andHelsinkiUni- versityHospitalResearchFund(TYH2019323).

FinancialDisclosures:JoniA.TurunenreceivedlecturefeesfromTheaFinland,SantenFinland,andBlueprintGeneticsFinland,andhasservedon theadvisoryboardofNovartisFinland.MinnaVesaluomaandTeroT.Kivelä receivedlecturefeesfromSantenFinland,unrelatedtothepresentwork.

Theotherauthorsindicatenofinancialsupportorconflictsofinterest.AllauthorsattestthattheymeetthecurrentICMJEcriteriaforauthorship.

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