PelletierGFeingoldMCasereport1SyndromeIdentification1973189Gra - PDF document

PelletierG,FeingoldM.Casereport1.SyndromeIdentification.1973;1:8-9.GraysonBH,WeintraubN,BooksteinFL,McCarthyJG.Acompara-tivecephalometricstudyofthecranialbaseincraniofacialanoma-lies:PartI:Tensoranalysis.CleftPalateJ.1985;22(2):75-87.HoodRL,LinesMA,NikkelSM,SchwartzentruberJ,BeaulieuC,NowaczykMJ,AllansonJ,KimCA,WieczorekD,MoilanenJS,etal.MutationsinSRCAP,encodingSNF2-relatedCREBBPacti-vatorprotein,causeFloating-Harborsyndrome.AmJHumGenet.2012;90(2):308-313.HoulstonRS,CollinsAL,DennisNR,TempleIK.Furtherobserva-tionsontheFloating-Harborsyndrome.ClinDysmorphol.1994;3(2):143-149.JohnstonH,KneerJ,ChackalaparampilI,YaciukP,ChriviaJ.Iden-tificationofanovelSNF2/SWI2proteinfamilymember,SRCAP,whichinteractswithCREB-bindingprotein.JBiolChem.1999;274(23):16370-16376.KehrerM,BeckmannA,WydubaJ,FinckhU,DufkeA,GaiserU,TzschachA.Floating-Harborsyndrome:SRCAPmutationsarenotrestrictedtoexon34.ClinGenet.2014;85(5):498-499.KreiborgS,JensenBL,BjorkA,SkiellerV.Abnormalitiesofthecranialbaseincleidocranialdysostosis.AmJOrthod.1981;79(5):549-557.LacombeD,PattonMA,ElleauC,BattinJ.Floating-Harborsyn-drome:descriptionofafurtherpatient,reviewoftheliterature,andsuggestionofautosomaldominantinheritance.EurJPediatr.1995;154(8):658-661.LeGoffC,MahautC,BottaniA,etal.Notallfloating-harborsyn-dromecasesareduetomutationsinexon34ofSRCAP.HumMutat.2013;34:88-92.MessinaG,AtterratoMT,DimitriP.Whenchromatinorganisationfloatsastray:theSrcapgeneandFloating-Harborsyndrome.JMedGenet.2016;53(12):793-797.MilaniD,ScuveraG,GattiM,TolvaG,BonarrigoF,EspositoS,GervasiniC.Perthesdisease:anewfindinginFloating-Harborsyndrome.AmJMedGenetA.2018;176(3):703-706.MonroyMA,SchottNM,CoxL,ChenJD,RuhM,ChriviaJC.SNF2-relatedCBPactivatorprotein(SRCAP)functionsasacoactivatorofsteroidreceptor-mediatedtranscriptionthroughsynergisticinteractionswithCARM-1andGRIP-1.MolEndocrinol.2003;17(12):2519-2528.NagasakiK,AsamiT,SatoH,OgawaY,KikuchiT,SaitohA,OgataT,FukamiM.Long-termfollow-upstudyforapatientwithFloating-HarborsyndromeduetoahotspotSRCAPmutation.AmJMedGenetA.2014;164A(3):731-735.NieX.Cranialbaseincraniofacialdevelopment:developmentalfea-tures,influenceonfacialgrowth,anomaly,andmolecularbasis.ActaOdontolScand.2005;63(3):127-135.NikkelSM,DauberA,deMunnikS,ConnollyM,HoodRL,CaluseriuO,HurstJ,KiniU,NowaczykMJ,AfenjarA,etal.ThephenotypeofFloating-Harborsyndrome:clinicalcharacterizationof52indi-vidualswithmutationsinexon34ofSRCAP.OrphanetJRareDis.2013;8:63.PattonMA,HurstJ,DonnaiD,McKeownCM,ColeT,GoodshipJ.Floating-Harborsyndrome.JMedGenet.1991;28(3):201-204.QuintanillaJS,BiedmaBM,RodriguezMQ,MoraMT,CunqueiroMM,PazosMA.CephalometricsinchildrenwithDown’ssyn-drome.PediatrRadiol.2002;32(9):635-643.RobinsonPL,ShohatM,WinterRM,ConteWJ,Gordon-NesbittD,FeingoldM,LaronZ,RimoinDL.Auniqueassociationofshortstature,dysmorphicfeatures,andspeechimpairment(Floating-Harborsyndrome).JPediatr.1988;113(4):703-706.SaulRA,WilsonWG.A“new”skeletaldysplasiaintwounrelatedboys.AmJMedGenet.1990;35(3):388-393.SeifertW,MeineckeP,KrugerG,RossierE,HeinritzW,WusthofA,HornD.Expandedspectrumofexon33and34mutationsinSRCAPandfollow-upinpatientswithFloating-Harborsyndrome.BMCMedGenet.2014;15:127.SinghA,BhatiaHP,SoodS,SharmaN,MohanA.Anovelfindingofoligodontiaandankyloglossiaina14-year-oldwithFloating-Harborsyndrome.SpecCareDentist.2017;37(6):318-321.StagiS,GalluzziF,BindiG,LapiE,CecchiC,SaltiR,ChiarelliF.Precociouspubertyinagirlwithfloating-harborsyndrome.JPediatrEndocrinolMetab.2007;20(12):1333-1337.TuysuzB,vanBonBW,AlpZ,GuzelZ,VeltmanJA,deVriesBB.AmicroduplicationoftheRubinstein-Taybiregionon16p13.3inagirlwithabilateralcompletecleftlipandpalateandseverementalretardation.ClinDysmorphol.2012;21(4):204-207.UndiagnosedDiseasesNetwork.DatabaseonSRCAP.2019.https://undiagnosed.hms.harvard.edu/genes/srcap/.AccessedJanuary14,2019.

WhiteSM,MorganA,DaCostaA,LacombeD,KnightSJ,HoulstonR,WhitefordML,Newbury-EcobRA,HurstJA.ThephenotypeofFloating-Harborsyndromein10patients.AmJMedGenetA.2010;152A(4):821-829.WiltshireE,WickremesekeraA,DixonJ.Floating-Harborsyndromecomplicatedbytetheredcord:anewassociationandpotentialcon-tributionfromgrowthhormonetherapy.AmJMedGenetA.2005;136(1):81-83.Koetal5 Clinical/CaseReportCaseReportofFloating-HarborSyndromeWithBilateralCleftLipJaeminKo,DDS,MS1 ,JasonH.Pomerantz,MD1,2,HazelPerry,MS,CGC1,JosephT.Shieh,MD,PhD3,AnneM.Slavotinek,MD,PhD3,SnehlataOberoi,BDS,DDS,MDS1,andOphirD.Klein,MD,PhD1,3AbstractFloating-Harborsyndrome(FHS)isararegeneticdisordercausedbyheterozygousmutationsintheSnf2-relatedCREBBPactivatorprotein(SRCAP)gene.Thesyndromeischaracterizedbyproportionalshortstature,delayedbonematuration,delayedspeechdevelopment,andfacialdysmorphism.SubmucouscleftpalateandcleftliphavebeenreportedinFHS,buttoourknowledgeorofacialcleftinginthisconditionhasnotbeenassessedindetail.Here,wereportonacaseofbilateralcleftlipinapatientwithFHSconfirmedbyexomesequencing.Keywordsgenes,genetics,chromosome,Floating-Harborsyndrome,SRCAP,cephalometry,dentalanomaliesIntroductionFloating-Harborsyndrome(FHS;OMIM#136140)isararegeneticdisordercausedbyheterozygousmutationsintheSnf2-relatedCREBBPactivatorprotein(SRCAP)gene(Hoodetal.,2012).Theconditionwasfirstreportedin1973(Pelletier,1973),andapproximately60caseshavebeenreportedtodate.Thesyndromeischaracterizedbyproportionalshortstature,delayedbonematurationthatnormalizesinearlyorlatechild-hood,delayedspeechdevelopment,andfacialcharacteristics(Robinsonetal.,1988;Whiteetal.,2010;Nikkeletal.,2013).Thefaceistriangularwithdeep-seteyes,longeyelashes,bulbousnose,widecolumella,shortphiltrum,andthinlips(Feingold,2006;Hoodetal.,2012).ThediagnosisofFHSissuspectedwhenindividualsshowtypicalclinicalfindingsandcanbeconfirmedbysequencingofSRCAP(Hoodetal.,2012).SRCAPmutationswerefoundtobelocatedmostlywithinasmallregionbetweencodons2407and2677ofexon34,butalsoinexon33(Kehreretal.,2014;Seifertetal.,2014).SRCAPencodesanATPasethatfunctionsasthecorecatalyticcomponentofamultiproteinchromatin-remodelingcomplex,andithasanimportantroleinregulatingcellgrowthanddivision(Johnstonetal.,1999;Monroyetal.,2003;Messinaetal.,2016).ReportsofdentalanomaliesinFHSaresparse,butmal-occlusion,hypoplasticjaw,high-archedpalate,increasedspacing,agenesisofmandibularincisors,supernumeraryteeth,andoligodontiahavebeendescribedinassociationwiththissyndrome(Robinsonetal.,1988;Houlstonetal.,1994;Ala-MelloandPeippo,2004;DeBenedettoetal.,2004;Hoodetal.,2012;Singhetal.,2017).Althoughsubmucouscleftpalateandcleftliphavebeenrarelyreported(Pattonetal.,1991;Hoodetal.,2012;UndiagnosedDiseasesNetwork,2019),toourknowledgeorofacialcleftinginthisconditionhasnotbeenassessedindetail.Here,wereportacaseofbilateralcleftlipinFHSconfirmedbyexomesequencing,andwedescribethegeneralfeaturesanddentalfindingsinthispatient. 1PrograminCraniofacialBiologyandDivisionofCraniofacialAnomalies,DepartmentofOrofacialSciences,UniversityofCalifornia,SanFrancisco,CA,USA2DivisionofPlasticandReconstructiveSurgery,DepartmentofSurgery,UniversityofCaliforniaSanFrancisco,SanFrancisco,CA,USA3DivisionofMedicalGenetics,DepartmentofPediatrics,andInstituteforHumanGenetics,UniversityofCaliforniaSanFrancisco,SanFrancisco,CA,USACorrespondingAuthor:OphirD.Klein,PrograminCraniofacialBiologyandDepartmentsofOrofacialSciencesandPediatrics,UniversityofCalifornia,SanFrancisco,CA94143,USA.Email:ophir.klein@ucsf.eduTheCleftPalate-CraniofacialJournal1-5ª2019,AmericanCleftPalate-CraniofacialAssociationArticlereuseguidelines:sagepub.com/journals-permissionsDOI:10.1177/1055665619858257journals.sagepub.com/home/cpc CaseReportThepatientpresentedtoourinstitutionasa14-year-oldboywhomovedtotheUnitedStatesfromMo

ngolia.Thepatient’smotherreportedanormalpregnancyanddelivery.Hewasbornattermwithabilateralcleftlipatabirthweightof3.3kg,andhehaddifficultyfeedingduetothecleftlip.LiprepairwasperformedinMongoliaatage6.Uponarrivaltoourinstitution,significantfindingsincludedshortstature,brachydactylyofallfingers,maxillarydeficiency,andfacialfeaturesthatincludedupslantingpalpebralfissures,asimpleandenlargedrightearhelix,statuspostrepair,anddownturnedcornersofthemouth(Figure1).Thepatient’sheightat148.3cmplacedhimbelowthe1stpercentilebasedonCentersforDiseaseControlandPreventiongrowthcharts,andhisboneagewasjustundertheupperlimitof2standarddeviations.Thepatienthadahistoryofsignificantdevelopmentaldelays.Hestartedtowalkwhenhewas4yearsold,didnotspeakuntiltheageof5,andbegantospeak2wordsentencesaftertheageof8.Whenhewas11yearsold,hecouldspeakinsimplesentencesanddressandfeedhimself,buthecouldnotreadorwrite.AfterarrivingtotheUnitedStates,thepatientwasplacedinaspecialeducationprograminhisschoolandhadanIndividualizedEducationPlaninplace.Atthetimeoftheinitialvisittoourinstitution,thepatientwasabletospeakfullsentencesandwriteinhisnativelanguage,buthecouldonlymakesimplesentencestructuresandhadsomedifficultyfol-lowingcomplexconversations.Thefamilyhistorywasnegativeforclefts,lipspits,ormounds,andparentswerenonconsanguineous.Asinglenucleotidepolymorphism(SNP)arraywasperformed,andaninterstitialduplicationwithin2p15wasidentified.However,astheclinicalsignificanceofthisfindingwasunclear,thepatient’sandhismother’sbloodwerecollectedandsentforexomesequencing.Thistestingrevealedapresumeddenovoheterozygousmutationinexon34ofSRCAP,whichisindica-tiveofFHS.ThepatientwasevaluatedbyGenetics,Cardiology,Endocri-nology,Neurology,andtheCraniofacialCenteratourinstitution.Cardiologyexaminationshowedsinusrhythm,first-degreeatrio-ventricularblock,normalintracardiacstructure,slightdilationoftheaorticroot,andatinypatentforamenovale.Endocrinologyevaluationforshortstatureandmatureboneage,includingthyr-oidfunctiontests,revealednosignificantfindings.AbrainMRIwasnormal.ClinicalcharacteristicsinindividualswithFHSincomparisonwithourpatientaresummarizedinTable1.OnexaminationatourCraniofacialCenter,thepatientpre-sentedwithaslightlyconcavefacialprofileandaclassIIImolarrelationshipwith2mmoverjet.Nocentricocclu-sion–centricrelationshipshiftwasnoted.Acephalometricradiographrevealedproclinedmaxillaryandmandibularinci-sorsandaskeletalclassIIIrelationshipwithsella-nasion-Apointangle(SNA)at72.9andsella-nasion-Bpointangle(SNB)at73.1(Figure2A).Hehadaflatcranialbaseangle(sella-nasion-basion)whichwas164.4.ApanoramicX-rayrevealedpresenceofallpermanentteeth,includingdevelopingthirdmolars.Twosupernumeraryteethwerealsodetectedbetweenthemaxillarycentralandlateralincisorsonbothsides. Figure1.Frontal(A)andlateral(B)photographsatage15showingdysmorphicfacialfeatures:upslantingpalpebralfissures,asimpleandenlargedrightearhelix,statuspostrepair,anddownturnedcornersofthemouth. Table1.FrequencyofClinicalCharacteristicsinPreviousStudies(Hoodetal.,2012;LeGoffetal.,2013;Nikkel,etal.,2013;Seifert,etal.,2014)andComparisonWithOurPatient.CharacteristicsPreviousStudiesThisStudyFacialdysmorphism63/63þSpeechdelay63/63þSkeletalanomalies11/11þDelayedboneage33/35?Shortstature50/63þIntellectualdisability44/54þEyeanomalies15/54Earanomalies17/63þGastrointestinalmalformations5/35Cardiacmalformations6/63þ/ Figure2.CephalometriclateralX-ray(A)andpanoramicX-ray(B)atage15showingflatcranialbaseandmaxillaryretrusion.PanoramicX-rayshowssupernumeraryteethandabnormalroots.2TheCleftPalate-CraniofacialJournalXX(X) FurtherexaminationofthepanoramicX-rayshowedbluntedandshortenedroots.Thepatient’smaxillaryandmandibularsecondmolarsdidnotshowbifurcationofroots,andtherootsofthemaxillarycentralincisorsappearedto

beseverelydila-cerated(Figure2B).Intraorally,thepatienthadaposteriorandanteriorcrossbitewithanoverbiteof2mmandoverjetof2mm(Figure3A).Hehadmildcrowdinginthemaxillaryanteriorregionandgeneralizedspacinginthemandibularante-riorregion.Morphologically,thepatient’smandibularsecondpremolarswereshapedmorelikeprimarymolars.Thepatientalsohadmultiplecaries(Figure3BandC).PlasticsurgeryrepairedtheStahl’searbyperforminganotoplasty.Aliprevisionsurgerywasalsorecommendedfol-lowingorthodontictreatment,asacentralnotch/whistlewasdetected.Beforebeginningorthodontictreatment,thepatient’spoororalhygienewasaddressed,andprophylaxiswasperformed.Sixcompositerestorationsand3sealantswerecompleted,and2supernumeraryteethwereextracted.Afan-shapedpalatalexpanderwasplacedforpalatalexpansionbeforecomprehensiveorthodontictreatment.After2yearsoforthodontictreatment,thetreatmentwasdiscontinuedduetopoorpatientcomplianceandpoororalhygiene,andthepatientwasplacedinretention(Figure4AandB).Althoughtheimportanceofmaintaininggoodoralhygienewasemphasized,braceshadtoberemovedearlierthanexpectedbecauseoralhygieneremainedpoor.Afterthecom-pletionoforthodontictreatment,thepatientwasfollowedupbyperiodonticsforscalingandrootplaningduetogeneralized,severe,chronicperiodontitis.DiscussionHere,wereportapatientwithFHSwhohadbilateralcleftlipwithoutcleftpalate.Only2casesofcleftinginFHShavepreviouslybeenreported.Onereportmentionedthatthepatientseemedtohavesubmucouscleftpalate,althoughthiswasnotobservedintraorally(Pattonetal.,1991).Anotherpatientwithaunilateralcleftlipwasalsoreported(Hoodetal.,2012),andourpatientisthefirstcasereportedwithabilateralcleftlip,tothebestofourknowledge.Floating-HarborsyndromeiscausedbymutationsinSRCAP,whichencodesanATPasethatisthecorecatalyticcomponentoftheSRCAPcomplex.ThisATPasefunctionsasatranscriptionalactivatorinCREB-mediatedtranscriptionandinteractswithpartnersofCREB-bindingprotein,encodedbyCREBBP(Johnstonetal.,1999;Messinaetal.,2016).Inter-estingly,Rubinstein-Taybisyndrome(RTS)iscausedbymuta-tionsinCREBBP,andclinicalfindingsofFHSandRTSaresimilar(Eseretal.,2017;Milanietal.,2018).Forexample,patientswiththesesyndromesbothtypicallyshowshortsta-ture,delayedboneage,anddevelopmentaldelay.Ofnote,somepatientswithRTShavecleftlipand/orpalate(Tuysuzetal.,2012).CREBBPisatranscriptionalfactorthathasbeenreportedtoplayessentialrolesinembryonicdevelopment.Therefore,itispossiblethatmutationsinSRCAPthatimpairfunctionofCREBBParethecauseofcleftinginFHS.FuturestudieswillberequiredtodeterminewhycleftingonlyaffectsafractionofpatientswithRTSandFHS,andwhatotherfactorseitherprotectagainstorpredisposetoclefting.InthepatientwithFHSdescribedhere,bothSNAandSNBwerebelowtheaveragevalues,whichare82forSNAand80forSNB.Thecranialbaseanglewas164.4inthispatient.Thenormalvalueofthecranialbaseangleis131.WebelievethattheSNAandSNBangleswereretrognathicduetotheflatten-ingofthecranialbaseangle.Thecranialbaseisanimportantstructureforcraniofacialgrowthanddevelopment,astheante-riorcranialbaseinfluencesfacialgrowth(EnlowandMoyers,1971;Nie,2005).Althoughmanyindividualvariationsofgrowthpatternsandshapesinthecranialbasedonotfollowtheaveragepattern(Graysonetal.,1985),increasedordecreasedcranialbaseangleshavebeenseeninanumberofdevelopmentaldisorders.Acutecranialbaseanglesareoftenseeninmandibulofacialdysostosisandcleidocranialdysostosis(Kreiborgetal.,1981).PatientswithDownsyndromeorTurner Figure3.Frontal(A),upper(B),andlower(C)intraoralphotographsatage15showingdentalanomalies:anteriorcrossbite,2supernumeraryteeth,andabnormalteethshape. Figure4.CephalometriclateralX-ray(A)andpanoramicX-ray(B)afterorthodontictreatmentatage17.Koetal3 syndromehaveashortretrognathicfaceduetoreducedcranialbaselengthandincreasedangulation(Andersenetal.,2000;Quintanillaetal.,2002).Asoursisthefir

streporttoassesscephalometricfindingsinFHS,itisnotcertainwhetheraflatcranialbaseisatypicalskeletalfindinginthesyndrome.Ourpatientalsohadmaxillarydeficiencyandananteriorcrossbite,whichmighthavebeencausedbytherepairedcleftlip,becausescarringcanhindernormalmaxillarygrowth.Itwasreportedthatbothpatientswhohadonlylipclosuresurgeryandpatientswhohadlipandpalatalclosuresurgeryhadsimilardegreeofmaxillarydeficiency(CapelozzaFilhoetal.,1996).MaxillarydeficiencymayalsobeattributabletoFHS.However,itisnotcertainifthemaxillarydeficiencywasduetorepairedcleftlip,FHS,oracombination.Surgerywasnotrequiredtocorrecthisjawsizerelationship,ashisApoint-basion-Bpoint(ANB)anglewas0.2.OneofthetypicalfeaturesofFHSisdelayedbonematura-tion.Inpreviouscases,mostpatientshaddelayedboneagewhenmeasuredbeforetheageof6years(Houlstonetal.,1994;Lacombeetal.,1995;Wiltshireetal.,2005),butsomereportsstatedthatdelayedboneagewasstillseeninpatientsagedbetween6and12years(Lacombeetal.,1995;DeBenedettoetal.,2004).Aftertheperiodofdelay,theboneagewasfoundtobemarkedlyacceleratedandreachnormallevel(Nagasakietal.,2014).Becauseourpatientpresentedtousatage14,wewereunabletodeterminewhetherhehadearlierdelayedbonematura-tion.Furthermore,whenhefirstpresentedtous,hishand/wristX-rayshowedthathehadanadvancedboneagecloseto17yearsaccordingtothestandardsofGreulichandPyle.Despitethepatient’sadvancedboneageusingadigitalhandatlas(Figure5),wefoundthathislateralcephalometricX-rayatage15showedacervicalvertebralmaturationindex(CVMI)ofstage4,andattheageof17,theCVMIwasstage5.TheCVMIstagesatbothageswerebehindhischronologicalages,indicatingthatskeletalmaturitymeasuredbyhandwristima-gingandcervicalvertebralimagingwerediscordant.VariousskeletalanomalieswereobservedinpreviouscasesofFHS;mostcommonly,thesewerebrachydactyly,fifthfingerclino-dactyly,coningandsclerosisofseveralepiphyses,andshortphalanges(Whiteetal.,2010;Nikkeletal.,2013).Anomaliesofthespinehavealsobeenreported,includingmildirregula-ritiesofthevertebralbodies,hypoplasiaoftheodontoidpro-cess,andabnormalcurvatureofthespine(SaulandWilson,1990;Stagietal.,2007;Hoodetal.,2012).ThismaysuggestthatassessingbonematuritywiththevertebralshapesmustbedonewithcautioninFHS.Insummary,wereportapatientwithbilateralcleftlipinFHS.Inadditiontovariouscharacteristicsincludingshortsta-ture,skeletalanomalies,andfacialdysmorphism,screeningfororofacialcleftingshouldalsobeperformedwhenthereisadiagnosisofFHS.DeclarationofConflictingInterestsTheauthorsdeclarenopotentialconflictsofinterestwithrespecttotheresearch,authorship,and/orpublicationofthisarticle.FundingTheauthor(s)receivednofinancialsupportfortheresearch,author-ship,and/orpublicationofthisarticle.ORCIDiDJaeminKo,DDS,MS https://orcid.org/0000-0001-7174-2608ReferencesAla-MelloS,PeippoM.ThefirstFinnishpatientwiththeFloating-Harborsyndrome:thefollow-upofeightyears.AmJMedGenetA.2004;130A(3):317-319.AndersenE,SonnesenL,KjaerMS,FischerHansenB,KjaerI.TheprenatalcranialbasecomplexandhandinTurnersyndrome.EurJOrthod.2000;22(2):185-194.CapelozzaFilhoL,NormandoAD,daSilvaFilhoOG.Isolatedinflu-encesoflipandpalatesurgeryonfacialgrowth:comparisonofoperatedandunoperatedmaleadultswithUCLP.CleftPalateCraniofacJ.1996;33(1):51-56.DeBenedettoMS,MendesFM,HirataS,GuareRO,HaddadAS,CiamponiAL.Floating-Harborsyndrome:casereportandcranio-facialphenotypecharacterization.IntJPaediatrDent.2004;14(3):208-213.EnlowDH,MoyersRE.Growthandarchitectureoftheface.JAmDentAssoc.1971;82(4):763-774.EserM,AyazA,YesilG.AcasewithRubinstein-Taybisyndrome:anovelframeshiftmutationintheCREBBPgene.TurkJPediatr.2017;59(5):601-603.FeingoldM.Thirty-twoyearfollow-upofthefirstpatientreportedwiththeFloating-Harborsyndrome.AmJMedGenetA.2006;140(7):782-784. Figure5.Hand-wristX-rayatage15showingslightlyadvancedboneage.4TheCleftPalate-CraniofacialJournalXX