2007Wiley-Liss,Inc.AmericanJournalofMedicalGeneticsPartA143A:2886 - PDF document

2007Wiley-Liss,Inc.AmericanJournalofMedicalGeneticsPartA143A:2886–2888(2007)TerminologicalInexactitudeMasonBarr,Jr.*DepartmentsofPediatrics,Pathology,andObstetrics,UniversityofMichigan,AnnArbor,MichiganReceived2April2007;Accepted27May2007Howtocitethisarticle:BarrMJr.2007.Terminologicalinexactitude.AmJMedGenetPartA143A:2886–2888.MytitlecomesfromanappositecoinageofWinstonChurchill’sinaspeechtotheHouseofCommonsonFebruary22,1906.Linguistsandlaymenalikehavearguedforcenturiesabout‘‘growth’’and‘‘degrada-tion’’ofthelanguage,anylanguage.Linguistsdes-cribetwocamps:prescriptivistsandpermissivists.Theformerargueforlawandordertostopcivilization’sslidedownthedrain.Thelatterholdthatthelanguagewillandshouldevolvefreely.Historically,theper-missivistshavealwaysbeenascendant;languageevolutionisliketheweather,itwillchangeandthereisnotmuchonecandoaboutit.Iwaverwithoutceasebetweenthetwocamps.Inthespokenlanguage,mostofusleantothepermissivistview.But,weshouldrecognizethatinsomesituationsmorecareisneeded.‘‘WhenIuseaword,’’HumptyDumptysaid,inaratherscornfultone,‘‘itmeansjustwhatIchooseittomean—neithermorenorless.’’‘‘Thequestionis,’’saidAlice,‘‘whetheryoucanmakewordsmeansomanythings.’’Informalwriting,wetendtobemorecarefulinourchoiceofwords.ItisherethatIndmyselfintheprescriptivistcampandarguethattheuseofproperterminologyisimportantforclearcommunication.Onecasewhereimprecisionoflanguagecausesaproblemishowwelabelinstancesofmultiplemalformationsinasingleindividual.InEnglishwriting,toavoidserialrepetitionofaword,wearetaughttousesynonyms.Sincearebothusedtolabelmultiplemalfor-mationcomplexes,theyaresometimesmistakenlyusedassynonyms.MichaelCohenhassummarizedandextensivelydiscussedtherecommendationsofaninternationalworkinggroupforimprovementsintheterminologyofbirthdefects(hereaftercalledtherecommendedterminology),particularlythenamingofmultipledefectsinthesameindividual *Correspondenceto:MasonBarr,Jr.,TeratologyUnit,DivisionofPediatrics,D5210MPB/Box0718,UniversityofMichigan,AnnArbor,MI48109.E-mail:barr@umich.eduDOI10.1002/ajmg.a.31972 defectsnotidentiedasasequenceorasyndrome.Leftunsaidisthepossibilityof‘‘noneoftheabove.’’Whilethetermwasproposedasastatisticalconcept,thatis,a‘‘nonrandom’’occur-renceofseveralmorphologicaldefects,thedefectsincludedwithinassociationshavenotalwaysbeenestablishedtobenonrandomlyassociated—some-timesthatjudgmentisrathersubjectiveorbasedonasamplesizetoosmalltobegenuinelyvalid.Howeverthatmaybe,Ithinktheterminology,despitebeinglooselyused,servesatleastthreefunctions:(1)itisashorthandlistofndings,(2)itisaremindertolookmorediligentlyforpossiblyconcurrentabnor-malities,and(3)itisacluetotheresearcherthatetiologicinvestigationmaybefruitful.Butplease,anassociationisnotadiagnosisintermsofcausation—itisadescription.Shouldwebothertoreservethedesignationforthoseconditionsofknownorpre-sumedknownetiology?LetmeusetheVACTERL(orVATER)associationasacaseinpoint.Ithasbeencommonforthatlabeltobeappliedwhenthreeormoreofthespecieddefectsarefoundinoneindividual.Butconsiderthatatleast31known-genesissyndromesinSmith’sPatternsofHumanMalformationcouldthusbedescribedasexamplesoftheVACTERLassociation[Jones,1997].Infact,one,trisomy18,mayhaveallsevencomponents.Surelywewouldnotacceptlabelingtheseconditionsas‘‘VACTERLsyndrome.’’Itshouldbenotedthatforanycombinationofmultipleanomalies,justasforisolatedanomalies,theretypicallywillbemultipleConsiderthetransmogricationoftheCHARGEassociation.BasedonoriginalobservationsbyHall[1979]andHittneretal.[1979],thepatternofndingswascategorizedasanassociationbyPagonetal.[1981].Tellieretal.[1998]reportedtheirndingsamong47casesofCHARGEassociationbutappliedthenameCHARGEsyndrome.Vissersetal.[2004]andsubsequentlyLalanietal.[2006]andJongmansetal.[2006]foundthat61%(133of217)CHARGEpatientshadmutationsintheCHD7gene.Becauseacausewasidentied,thisseemedtojustifyanamechangetotheCHARGEsyndrome[Carey,2005].However,the39%withoutthegenemutationswerenowwhat—CHARGEassociationorCHARGEsyndrome?ConsultingtherelevantOMIM[2007]entry(#214800)revealsconfusion.‘‘CHARGEsyn-drome’’isused19times,‘‘CHARGEassociation’’15times,‘‘CHARGE’’(alone)fourtimes,‘‘CHARGEpatients’’twice,and‘‘CHARGEcomplex,’’‘‘CHARGEconstellation,’’‘‘themnemonicCHARGE,’’and‘‘thetermCHARGE’’onceeach.Thereisawayoutofthisdilemma.Whenanetiologyisfoundforsomeofthecasesinitiallyincludedinanassociation,thatgroupshouldberelabeledwithadistinctanddescriptivenamethatclearlyseparatesitfromtheassociation.Tohiscredit,Graham[2001]commentedonthe‘‘recogniz-ablesyndromewithintheCHARGEassociation’’andproposedthenameHall–Hittnersyndrome.Thediscoveryofacauseforsomecasesmeansthatonlyonesyndromehasbeenidentied;therestoftheconglomeratedoesnotbecomeasyndrome,itremainsanassociation.Tousethesamenameforbothisnothelpful.Ithinksomeoftheconfusionarisesbecause‘‘why’’and‘‘how’’arenotthesamequestion.Incommonusagethereisambiguityinthewords‘‘cause,’’‘‘origin,’’‘‘etiology,’’andeven‘‘why.’’Oftenwhenweusethesewordsweincludenotonlytheinitiatingfactorbutalsotheprocessthatfollows.Thereislessambiguityintheword‘‘how.’’Herewearemoreclearlyaddressingthequestionofprocess.Ifwearecarefulinouruseofterminology,‘‘why’’isaqueryaboutcause,and‘‘how’’isaqueryabouttheway(s)thatcauseproducesanabnormality.IrecallJamesG.Wilsonteachingsomeyearsagothatthesequenceinteratologywascause,mechanism,pathogenesis,andmanifestation.Causewastheinitiatingfactor,waswhathappenedatthe(usually)subcellularlevel,waswhatcouldbeobservedoftheprocessmacroscopically,andwaswhatweenduprecognizingasanabnormality.IhavefounditusefultousethissequenceinexploringtheoriginandnatureofApplyingtheseconceptstotheterminologyrecommendedbytheworkinggroup,onlyspeaktocause;dealwiththequestionof‘‘how’’orthemechanism/pathogenesisofdefects.itsaknown(orperhapsstronglysuspected)cause;Iwouldfurtherspecifyitshouldbeacause.Ontheotherhand,suggests,‘‘thesemani-festationsmaybecausallyrelated,butwedonotknowhow,andseveralcausesmaybeoperativewithinthisgrouping.’’IdourgethecarefuluseoftheterminologyrecommendedbySprangeretal.[1982].Inatimewhenwearemakingrealgainsinourknowledgeofthecausationofbirthdefects,Ithinkitisespeciallyimportanttodistinguishbetweenwhatweknowandwhatwehaveyettolearn.Thatwenowknowdifferentmutationsinthesamegenemayresultindifferentphenotypes,whilemutationsindifferentgenesmayresultinapparentlysimilarphenotypes,Itakeasamessagethatcareinnamingiswarranted.Wemaynameaconditionforitsappearance,foritsetiology,foritsfunctionalaberration,foritsrstdescriber,orformoreobscurereasons.Whatevernameischosen,implicitinthequalierIhaveseenitwrittenas‘‘Vatersyndrome,’’suggestingperhapsthatitisaconditionrstdescribedbyEmilLudwigVater(whopresumablylaterchangedhisnametoVacterl).TERMINOLOGICALINEXACTITUDEAmericanJournalofMedicalGeneticsPartA:DOI10.1002/ajmg.a shouldbethenotionthatweknowtheetiology.Ithinkitisusefultohavethequaliersignalthatwedoknowtheetiology.Otherwise,touseforinstancesofassociationsimpliesthatweknowsomethingoftheetiology,orthatallcaseshavemoresimilaritythanmayactuallybethecase.Accordingly,syndromesandassociationsshouldbegivendifferentanddistinctnamestoavoidMy35-yearexperienceofdetailedexaminationsoffetusesandneonatestellsmethattherearemanyinstancesofmultipledefectsthatcurrentlydefyetiologicexplanationormeaningfullabeling.Theyareremindersofhowmuchwehaveyettolearn.IbelievethattheÞelddefectterminologyisuseful,particularlyasitsignalstheextentandlimitationofourknowledge.Iworrythatuseofimpreciseterminologymaylullusorothersintothinkingweknowmorethanwereallydo.Ihavenoillusionsaboutchangingthewaypeopletalk,butataneditoriallevelwecanemendtheliteraturetomaintainmoreprecisionintheuseofourselectedterminology.REFERENCESAmericanHeritageDictionary.3rdedition.1992.Boston:HoughtonMifinCo.CareyJC.2005.CHARGEsyndrome:2005.AmJMedGenetPartACohenMM.1997.Thechildwithmultiplebirthdefects2ndedition.NewYork:OxfordUniversityPress.GrahamJM.2001.ArecognizablesyndromewithinCHARGEassociation:Hall-Hittnersyndrome.AmJMedGenet99:120–HallBD.1979.Choanalatresiaandassociatedmultipleanoma-lies.JPediatr95:395–398.HittnerHM,HirschNJ,KrehGM,RudolphAJ.1979.Colobom-atousmicrophthalmia,heartdisease,hearingloss,andmentalretardation—Asyndrome.JPediatOphthalStrabismus16:122–128.JonesKL.1997.Smith’srecognizablepatternsofhumanmalformation.5thedition.Philadelphia:WBSaundersCo.JongmansMCJ,AdmiraalRJ,vanderDonkKP,VissersLELM,BaasBF,Kaputsal,vanHagenJM,DonnaiD,deRavelTJ,VeltmanJA,GeurtsvanKesselA,DeVriesBBA,BrunnerHG,HoefslootLH,vanRavenswaaaijCMA.2006.CHARGEsyndrome:ThephenotypicspectrumofmutationsintheCHD7gene.JMedGenet43:306–314.LalaniSR,SaullahAM,FernbachSD,HarutyunyanKG,ThallerC,PetersonLE,McPhersonJD,GibbsRA,WhiteLD,HefnerM,DavenportSLH,GrahamJMJr,BacinoCA,GlassNL,TowbinJA,CraigenWJ,NeishSR,LinAE,BelmontJW.2006.SpectrumofCHD7mutationsin110individualswithCHARGEsyndromeandgenotype-phenotypecorrelation.AmJMedGenet78:303–314.NewShorterOxfordEnglishDictionary.1993.NewYork:OxfordUniversityPress.OMIM.2007.(OnlineMendelianInheritanceinMan,2007).OpitzJM.1986.Editorialcomment:Thedevelopmentaleldconcept.AmJMedGenet21:1–11.PagonRA,GrahamJM,ZonanaJ,YoungSL.1981.Coloboma,congenitalheartdisease,andchoanalatresiawithmultipleanomalies:CHARGEassociation.JPediatr99:223–227.SprangerJW,BenirschkeW,HallJG,LenzW.1982.Errorsofmorphogenesis:Conceptsandterms.JPediatr100:160–165.TellierAL,Cormier-DaireV,AbadieV,AmielJ,SigaudyS,BonnetD,deLonlay-DebneyP,Morrisseau-DurandMP,HubertP,MichelJL,JanD,DollfusH,BaumannC,LabruneP,LacombeD,PhilipN,LeMerrerM,BriardML,MunnichA,LyonnetS.1998.CHARGEsyndrome:Reportof47casesandreview.AmJMedGenet76:402–409.VissersLELM,vanRavenswaaijCMA,AdmiraalR,HurstJA,deVriesBBA,JanssenIM,vanderVlietWA,HuysEHLPG,deJongPJ,HamelBCJ,SchoenmakersEFPM,BrunnerHG,VeltmanJA,GeurtsvanKesselA.2004.MutationsinanewmemberofthechromodomaingenefamilycauseCHARGEsyndrome.NatureGenet36:955–957.Webster’sNewCollegiateDictionary.2ndedition.1950.Spring-eld,MA:G&CMerriamCo.AmericanJournalofMedicalGeneticsPartA:DOI10.1002/ajmg.a