Best practice management guidelines for fibrous dysplasia ...

Fibrous Dysplasia / McCune Albright syndrome (FD/MAS) represents a wide spectrum of diseases due to somatic gain-of-function mutations of ... Skiptomaincontent Advertisement SearchallBMCarticles Search DownloadPDF Positionstatement OpenAccess Published:13June2019 Bestpracticemanagementguidelinesforfibrousdysplasia/McCune-Albrightsyndrome:aconsensusstatementfromtheFD/MASinternationalconsortium MuhammadKassimJavaid  ORCID:orcid.org/0000-0001-7985-00481,AlisonBoyce2,NatashaAppelman-Dijkstra3,JulingOng4,PatriziaDefabianis5,AmakaOffiah6,PaulArundel7,NickShaw8,ValterDalPos9,AnnUnderhil10,DeannaPortero11,LisaHeral11,Anne-MarieHeegaard12,LauraMasi13,FergalMonsell14,RobertStanton15,PieterDurkSanderDijkstra16,MariaLuisaBrandi13,RolandChapurlat17,NeveenAgnesThereseHamdy3&MichaelTerrenceCollins2  OrphanetJournalofRareDiseases volume 14,Article number: 139(2019) Citethisarticle 44kAccesses 58Citations 23Altmetric Metricsdetails ACorrectiontothisarticlewaspublishedon21November2019 Thisarticlehasbeenupdated AbstractFibrousDysplasia/McCuneAlbrightsyndrome(FD/MAS)representsawidespectrumofdiseasesduetosomaticgain-of-functionmutationsoftheGNASgene.Themutationleadstooveractivityinthetargettissuesandtoawidephenotypeofclinicalfeaturesthatvaryinseverityandageofonset.Therarityofthediseaseanditsvariablepresentationtomultiplespecialitiesoftenleadstomisdiagnosisandinappropriatevariabilityininvestigationsandtreatments.Toaddressthis,ourinternationalconsortiumofclinicians,researchers,andpatients’advocateshasdevelopedpragmaticclinicalguidelinesforbestclinicalpracticeforthedefinition,diagnosis,staging,treatmentandmonitoringforFD/MAStoempowerpatientsandsupportclinicalteamsinbothgeneralandspecialisedhealthcaresettings.Withthelackofstrongevidencetoinformcare,theguidelinesweredevelopedbasedonreviewofpublishedliterature,long-standingextensiveexperienceofauthors,inputfromotherhealthcareprofessionalsinvolvedinthecareofFD/MASpatientsandfeedbackfrompatientsandpatientgroupsacrosstheglobe.Thishasledtotheformulationofasetofstatementstoinformhealthcareprofessionals,patients,theirfamilies,carersandpatientgroupsofthebestpracticeofcare.ItisanticipatedtheimplementationoftheserecommendationswillleadtoimprovementinthecareofpatientswithFD/MASinternationally. BackgroundFibrousdysplasia/McCune-Albrightsyndrome(FD/MAS;OMIM#174800)isararedisordercharacterizedbyskeletallesions,skinhyperpigmentation,andhyper-functioningendocrinopathies[1,2].Itarisesfrompost-zygoticgain-of-functionmutationsintheGNASgene,whichencodestheα-subunitoftheGssignallingprotein[3].ThesemutationsdisrupttheintrinsicGTPaseactivityofGsα,leadingtopersistentstimulationofadenylylcyclaseanddysregulatedproductionofcyclicAMPanddownstreamsignalling[4].Theresultingdiseaseismosaicwithabroadclinicalspectrum,rangingfromatrivialincidentallydiscoveredradiographicfindingtosevereanddisablingdisease.FDmayinvolveone(monostotic)ormultiple(polyostotic)bonesandmayoccurinisolationorincombinationwithextraskeletaldisease[5].WhileFD/MASisclassicallydefinedasinvolvingtheskeleton,skin,andendocrinesystems,giventheubiquitousnatureofGssignalling,multipleothertissuesmayalsobeaffected.Anypartorcombinationoffeaturesmaybepresent.ClinicalmanagementinFD/MASischallenging,andmultiplebarriersexisttoprovidingconsistent,highqualitycare.Someoftheseincludethebroadclinicalspectrumwhichresultsinconsiderablephenotypicvariabilityamongpatients;multisysteminvolvementwhichrequirescoordinationbetweendiversespecialties;anddiseaserarity,whichmakesitchallengingforindividualcliniciansandcentrestogainspecialistexpertiseinthedisorder’subiquitousmanifestations.Thereislittlehigh-qualityevidencetoinformthediagnosisandmanagementofFD/MAS.ThereareasyetsubstantialknowledgegapsaboutFD/MASpathophysiologyandnaturalhistory,andapaucityofhardevidencefromclinicaltrialsfordifferentdiagnosticsandtherapeuticapproaches.Toaddressthesechallenges,aninternationalconsortiumofclinicians,researchers,andpatients’advocatesconvenedtodevelopstandardofcareguidelinesfordiagnosisandmanagementofFD/MASbasedonbestavailableevidenceandexpertopinion[6].TheaimofdevelopingbestclinicalpracticecareguidelinesfordiagnosisandmanagementofFD/MASistoharmonizethecareofFD/MASinternationally,toprovidestandardsofcareforthedevelopmentandevaluationofpatient-relatedoutcomemeasures,toprovideauniformcross-borderstandardofcareforinclusionofpatientsintoclinicaltrials,andtoenablecomparisonofcollectedclinicalcareandresearchFD/MASdatabetweencentresandstudies.MethodsTheseguidelineswereco-developedbyclinicalexpertsinthemanagementofFD/MASfromtheFD/MASconsortiumandpatientadvocacygroups[6].TheFD/MASConsortiumconsistedof51FD/MASclinicalandpatientexpertsfrom13countriesfromEurope,theUnitedStatesofAmericaandAsia.TheGuidelineDevelopmentGroup(GDG)consistedofasubgroupofexpertsfrompaediatricandadultrheumatology,endocrinology,orthopaedics,maxillofacialsurgery,radiology,dentistry,apainspecialistandexpertrepresentativesformnationalFD/MASpatientgroups.TheGDGwasformedataconsensusmeetingheldinOxfordinOctober2015[6].ThisfirstmeetingidentifiedkeyquestionsforthedevelopmentofclinicalcareguidelinesandamodifiedDelphiapproachwasselectedtoaddressthesequestions.TheGDGreviewedthepast30 years’publishedevidenceusingtheMeSHterm“FibrousDysplasiaofBone”onMedline.GiventherarityofFD/MASthereareveryfewpublishedrandomisedcontroltrials,andmarkedheterogeneityincasedefinitions,interventionsandoutcomesused.TheGDGthereforeusedthebestoftheexistingdatatogetherwithpersonalexpertiseandexperienceinFD/MAS.TheGDGdevelopedafirstdraftoftheclinicalcarepathwaythatwascirculatedtothebroadermembershipoftheConsortiumforcomment.TheresponseswerereviewedatthesecondconsensusmeetingoftheFD/MASConsortiuminLyoninDecember2016.Theconsensusdraftoftheclinicalcarepathwayswasrecirculatedtomembersoftheinternationalconsortiumforfinalcomments.Thecommentsandsuggestionsfortheclinicalpathwaywerethenreviewedbythewritinggroupandformulatedstatementswithover70%consensuswereincludedinthefinalreport.Thepatientgrouprepresentativesthenindependentlydevelopedaseparatepatientchecklisttogivecontexttotheclinicalpathway,includingquestionspatientsmaywanttoasktheirdoctorandquestionstheirdoctormayaskthem.Thewritinggroupchosetosubmittheguidelinesforpublicationinanopenaccessjournalinordertomakeitfreelyaccessibletoawidereadershipofclinicians,basicscientistsandpatients,alsousingthecreativecommonslicenceonpatientgroupwebsites.TheConsortiumwillreviewtheguidelinesatleastevery5 yearsorsoonerifrequiredbybreakthroughfindingsfrompublishedliterature.TheguidelinesweredevelopedwithoutexternalfinancialsupportfromindustriesinvolvedintherapiesforFD/MAS.Competinginterestsofmemberswererecordedanddocumentedinthepathway.DefinitionAdiagnosisofthesubtypesofFD/MAScanonlybemadeafterathoroughevaluationofa)theextentofskeletaldisease:monostotic/polyostoticandb)thepresenceofextra-skeletalmanifestations.Monostoticfibrousdysplasiaisdefinedasthepresenceoffibrousdysplasiainoneskeletalsiteonly.Polyostoticfibrousdysplasiaisdefinedasthepresenceoffibrousdysplasiainmorethanoneskeletalsitewithoutextra-skeletalmanifestations.McCune-AlbrightsyndromeisdefinedasthecombinationofFDandoneormoreextraskeletalfeature,ORthepresenceoftwoormoreextraskeletalfeatures.NotrequiringFDforthediagnosisofMASreflectsbetterunderstandingofthemolecularpathogenesisofthedisorder.MazabraudSyndromeisthecombinationofFDwithintramuscularmyxoma(s).Themyxomaisdefinedasanextra-skeletalmanifestationofFD/MASandmayoccurinassociationwithanytypeofthedisease(monostotic,polyostoticorMAS).Otherextra-skeletalfeaturesinclude: 1.Café-au-laitskinmaculeswithcharacteristicfeaturesofjagged,irregularborders(CoastofMaine)andadistributionshowingtheso-called“respectof”themidlineofthebody(Fig. 1);2.Gonadotropin-independentsexsteroidproductionresultinginprecociouspuberty,recurrentovariancystsingirls(Fig. 2a)andwomenorautonomoustestosteroneproductioninboysandmen(Fig.2b).ThisincludestesticularlesionsconsistentwithFD/MASwithorwithoutassociatedgonadotropin-independentprecociouspuberty.3.ThyroidlesionsconsistentwithFD/MASwithorwithoutnon-autoimmunehyperthyroidism(Fig.2c)4.Growthhormoneexcess(Fig.2d)5.Neonatalhypercortisolism Fig.1Representativeimagesofcafé-au-laitmaculesinpatientswithMcCune-Albrightsyndrome.Photographsoftheshoulder(a),back(b),andlegs(c)fromthreepatientsdemonstratingcharacteristichyperpigmentedlesionswithjaggedborders,andtendencytoeitheroccurorreflectaround(“respect”)themidlineofthebody.ImagesAandCshowlargelesions,whilethepatientinimageBhastwosmalllesionsinaclassiclocation,demonstratingthebroadpotentialspectrumofinvolvementFullsizeimage Fig.2RepresentativeradiographicfeaturesofendocrineinvolvementinMcCune-Albrightsyndrome.aPelvicultrasonographyina5-year-oldgirlwithclinicalsignsofprecociouspubertydemonstratingalargeunilateralovariancyst.bTesticularultrasonographyinapatientwithmacro-orchidismdemonstratingadiscrete,mixedhyper-andhypoechoiclesion(redarrowheads).cThyroidultrasonographyshowingdiffuse,bilateralinvolvementwithmultiplehyper-andhypoechoicnodules.dApituitaryMRIinapatientwithgrowthhormoneexcessrevealingapituitarymacroadenoma(redarrow)andfibrousdysplasiainvolvementthroughouttheskullbase(whitestar)FullsizeimageOfnote,FGF-23-associatedhypophophataemiaisnotconsideredafeatureofMASbutratheramarkeroftheseverityofskeletalFD.DiagnosisInmostcases,thediagnosisofFD/MAScanbemadeclinicallyafteracompletestagingevaluationforskeletal,endocrine,softtissueanddermatologicfeatures[7,8].Isolatedmonostoticbonelesionswithoutaccompanyingskinorendocrinefindingsincludeawidedifferentialdiagnosisanddiagnosticuncertaintyandusuallyrequirehistologicalconfirmation(Table 1).Insomecasesamoleculardiagnosisofaffectedtissuesisindicatedwhenclinical,radiologicalandhistologicalanalysisfailstoconfirmthediagnosisofFD. Table1PotentialmimicsoffibrousdysplasiabyskeletalsiteFullsizetableRadiologicalcharacterisationAnumberofradiologicaltechniquesarerecommendedforthediagnosisofFD/MASandspecialistradiologicalexpertiseisrequiredtodifferentiateFD/MASfromothermimics.GeneralradiologicfeaturesofFD/MASonconventionalradiographyinclude:ground-glassappearance;completelyradiolucent(cystic)lesions,scleroticlesionsormixedcysticandscleroticlesions;well-circumscribedmargins(geographicpattern),withorwithoutascleroticborder;andexpandedlesionswithashellthatisthick,thin,orshowingsmallperforationsand/orendostealscalloping[9].AsofttissuemassisnotaradiologicalfeatureofFDandshouldbefurtherinvestigated(Fig. 3a–e).ThespecificradiologicalfeaturesofFDaredescribedinTable 2. Fig.3Representativeradiographicfeaturesoffibrousdysplasia.aFemoralX-raydemonstratingdiffuseinvolvementwithfibrousdysplasiaandacoxavara(“shepherd’scrook”)deformity(redarrow).Notetheirregularappearanceofthedistalfemoralmetaphyses(yellowarrowhead)resultingfromFGF-23-mediatedrickets.bHumeralX-raydemonstratingcharacteristicfeaturesoffibrousdysplasia,includinghomogenous“groundglass”appearanceandcorticalthinning.Bowinghasoccurredatapreviouslyfracturedsiteinthemidshaft(redarrowhead).cX-rayfromapatientwithdiffusespinalFDandresultingthoraco-lumbarscoliosis.Notethepresenceofbilateralintramedullaryfemoralrods.dTechnetium-99scintigraphyscanshowingincreasedtraceruptakeinareasoffibrousdysplasia,includingtheskull,spine,righthumerus,andrightlowerextremity(redarrowheads).Diffusebilateraltraceruptakeisalsoobservedintheepiphysesofthisgrowingadolescent.eT2-weightmagneticresonanceimagingofthelowerextremitiesshowingwell-demarcatedlesionsofintermediatetohighsignalintensityinthebilateralfemurs(redarrows),correspondingtofibrousdysplasialesions.fComputedtomographyoftheskullshowingdiffusehomogenous,“groundglass”involvementcharacteristicofcraniofacialfibrousdysplasia.Thebilateralopticcanalsareinvolvedwithfibrousdysplasiaandwidelypatent(redarrows)Fullsizeimage Table2Specificradiologicalfeaturesdependentonbodysite[10]FullsizetableCTisusefulforassessingregionswithcomplexanatomyofskeletalstructuree.g.face,pelvis,spine,andfordetectingsubtleun-displacedfractures.Thepresenceofextra-osseoussofttissuemasswithbonydestructionwouldsuggestmalignanttransformation.AlthoughFDhasnon-specificfeaturesonMRI,thisimagingtoolallowsdifferentiationofFDfromacystlesion.Thelesion(s)maycontainfluid/fluidlevelsbutthereshouldnotbeasofttissuemass.LesionsarepatchywithlowtointermediatesignallingonT1andT2-weightedimagesandmayshowhighsignallingonT2-weightedimagesinchildren.Inversionrecoverypulsesequencesgiveahighsignalandthereispatchycontrastenhancement.Nuclearmedicineimagingstudiessuchas99mTc-MDP,usuallycombinedwithsingle-photonemissioncomputedtomography(SPECT)togivebetteranatomicalresolution,or18FNaFPET/CTdemonstrateincreasedtraceruptakeatthefociofskeletaldisease[10].HistologicalandgeneticcharacterisationBiopsywithhistologicalevaluationofsuspectedbonediseaseisusuallyonlynecessaryinunusualorquestionablecases,and/orifmalignancyissuspected.Therisksandbenefitsofabiopsyshouldbeclearlyexplainedtopatients,includingthatabiopsydoesnottypicallyleadtoregrowthofFD.Thebenefitofgenetictestinginpatientswithaclearclinicaldiagnosisisuncertain.Ageneticdiagnosisisrecommendedwherethediagnosisisinquestion.Thisespeciallyappliestoisolated/monostoticlesionsintheskull,afterexclusionofotherassociatedskeletaland/orextraskeletalfeatures-e.g.otherbones/skinfeatures/endocrinopathies.DiagnosticbiopsiesshouldbeprocessedasfreshorfreshfrozenmaterialtoenablegenetictestingforGNASmutation.Falsenegativesmayoccurifthebiopsycontainsnormaltissueandthebiopsymayneedtoberepeated.Mutationanalysiscanalsobeperformedinparaffin-embeddedsamplesalthoughfalsenegativesarethenmorelikely[11].Nextgenerationsequencing(NGS)hasalowerfalsenegativeoutcomethanSangersequencing.FalsepositiveshavenotbeendescribedusingNGSandthissequencingtechniquecanbeusedtodifferentiateFD/MASfromosteosarcomas[12].UseofbloodformutationanalysiscannotexcludethediagnosisofmonostoticFD,butapositiveresultisinformative.StagingofFD/MASThepurposeofstagingofFD/MASistodeterminethefullextentandimpactofdiseaseatdiagnosistoguidetestsandtreatmentsandtominimizeriskofcomplications.StagingshouldbeconsideredatthetimeofpresentationwithsuspectedFD/MAStakingintoaccountageandclinicalpresentation.Thekeycomponentsofstagingarelistedbelow.Evaluationoftheskeletalsystem(SeeAdditionalfile2:Flowchart:SkeletalevaluationFDlesion(s))Assessmentoftheskeletalsystemrequiresafullmedicalhistory,physicalexamination,laboratoryinvestigationsandradiologicalandnuclearimaging.Assessmentofskeletalsymptomsshouldincludeaskeletalmapwithareasmarkedforbonepain(seebelow),jointpainandbone/jointdeformity;afracturehistoryincludingsite,date,leveloftrauma(e.g.spontaneous,fragility,severetrauma)andfracturehealing(complete/incomplete/non-healing);previousorthopaedicprocedures(typeanddate)includingdetailsofmetalworkinsertion(locationandtype).Thefollowinginformationshouldbecollectedonprevioususeofbonespecifictherapy:everuse,genericnameofdrug,dateoffirstandlastuseandtotalnumberofyearsofuse.Previousorcurrentparticipationinclinicaltrialsshouldberecordedandincludethedateofthetrial(s)andtreatment(s)testedshouldbedocumented.AssessmentofseverityofpainshouldincludeaVAS0–10andBriefPainInventory[13]foradultsorWongBakerFacies[14]forchildren.Thepresenceofnightpainshouldraisearedflagforpossiblecomplicationssuchasimminentfracture,bleedingintoacystorveryrarelymalignanttransformation.ApotentialneuropathiccharactertopainshouldbeassessedusingthePainDetectquestionnaire[15].Thecontributionofpainfromsurgicalscars,referredpainfromadjacentjoints,localtendinosis,chronicpaindisorders/fibromyalgiashouldalsobeevaluated.Inthepresenceoffocaland/oracuteonsetpain,acuteorimpendingfracture,aneurysmalbonecystorstressfractureespeciallyinadeformedlongboneshouldbeconsidered.Mechanicalpaincanbeprovokedusingtherotationalstresstest,forinstanceinlesionsoftheproximalfemur.TheFABERtest:motionhipinFlexion,ABductionandExternalRotation,isalsorecommended.Althoughveryrare,sarcomatouschangeshouldbeconsideredinthepresenceofdiffuseand/orchronicpain,especiallyifprogressiveandunrelentingandalsopresentatnight.ThisshouldbefurtherevaluatedusingCT/MRimaginganddiscussedwiththelocalsarcomateam.Mechanical/weightbearingbonepaincansignalastressorimpendingfracture.Thisshouldtriggerconsiderationforcorrectionofalignment,and/orconsiderationforthenecessityofasurgicalprocedure,possiblyinvolvingtheuseofanintramedullarytitaniumnailorcustom-madetitaniumangledbladeplate,basedonthe‘bridgingthedefect’principles,tostabilizetheinvolvedbone.Physicalexaminationoftheskeletalsystemshouldincludegait,deformityincludingleglengthdiscrepancytoinformpotentialcomplications,areasoftendernessandrangeofmovementofadjacentjointsandpresenceofspinalkyphosisandscoliosis[16,17,18].Bone-relatedlaboratorytesting[19,20,21,22]shouldincludeastandardbiochemistryscreenofrenalprofile,totalalkalinephosphatase,bicarbonate,albumin-adjustedserumcalcium,phosphate(seebelow),25OH-vitaminDandparathyroidhormone.Abnormalphosphatehomeostasis,specificallyrenalphosphatewastingleadingtohypophosphatemia,isimportanttodiagnoseasitisanimportantpredictoroffuturefracturerisk,aswellasothercomplications[20,22,23].Inallsubjectswithsuspectedpolyostoticdisease,baselineovernightfastingphosphatelevelsshouldbechecked.Incaseofuseofphosphatesupplements,serumphosphateshouldbemeasuredwhilstthepatientisoffsupplementsforatleastaday.Valuesshouldberelatedtoagespecificreferenceranges.Phosphatehomeostasisisideallyassessedinthefastingstatebyconcomitantlycollectingserumphosphateandcreatinineandsecondvoidurinephosphateandcreatinine.Thiswillenablecalculationofthetubularreabsorptionofphosphate(TmP/GFR)andcalculatedvaluesshouldagainberelatedtoage-relatedreferenceranges[http://members.iinet.net.au/~bill/java/tmp_gfr.html].Itisimportanttoexcludeothercausesofrenalphosphatewastingsuchashyperparathyroidismandrenaltubularacidosis.Thiscanusuallybedonethroughhistory,examinationandbiochemicalassessmente.g.dipstickurinalysisforglycosuria,measurementofserumbicarbonateandurinaryaminoacids.Itshouldbenotedthathypophosphataemiamaybeepisodicandassessmentmayneedtoberepeatedifskeletalsymptomschangeandduringlineargrowth.IfserumFGF-23istobemeasuredthebloodsampleshouldbecollectedatleast7 daysoffphosphate/vitaminDsupplements,usinganaccreditedassay/laboratoryifavailable.Totalalkalinephosphatase(ALP)istheminimumrecommendedbiomarkerforboneturnover.Otherboneturnovermarkersareoptionalandincludebone-specificALP(withagerelatedreferenceranges),procollagenType1 N-terminalpropeptide(PINP),C-terminaltelopeptide(CTX-I).Ifthesearenotavailable,considerstoringserumat− 20 °Cforlateranalysis.Skeletalimagingistheinvestigationofchoicetodetermineskeletalburdendependingontheclinicalpresentation[24,25,26].Allskeletalburdenisdetectablebyage15 yearsandclinicallysignificantlesionsbytheageof5 years[24].ToevaluatetheextentofFD,wholebodyimagingusingbonescintigraphy,wholebodyMRorlow-dose2D/3Dradiography(e.g.EOS),todeterminethepresenceandextentofskeletalinvolvementshouldbeconsideredforallpatients≥age5 years.ItshouldbenotedthatskullbaselesionsarelikelytobemissedbytheEOS.Duetothepossibilityoffalsenegativeresults,wholebodyimagingshouldbedelayedinasymptomaticchildrenuntilage5[24]andwhenthechildcantolerateanMRIwithoutgeneralanaesthesia.Wholebodyortargetedskeletalimagingpriortoage5shouldbeconsideredwhenthebenefitsofearlydiagnosisoutweightherisksofwaitingtillthechildisolder.ScoringoftheskeletalburdenshouldbeperformedusingtheCollins’validatedmethod[25].AreasofclinicallysignificantaxialandappendicularFDidentifiedonbonescintigraphyshouldbeimagedwithconventionalradiographsintwoplanesofthewholebone.AlocalizedfinecutCTscanispreferredincaseofclinicalevidenceofnerveentrapment.SpecificrecommendationsforspinalFD(Fig.3c)Evidenceofscoliosisonphysicalexaminationshouldbeconfirmedwithconventionalradiographs.Onceestablished,progressionofscoliosisshouldbeassessedwithregular,periodicradiographsandpulmonaryfunctiontesting.Theperiodicityoftheseexaminationsshouldbeadjustedbasedontheseverityandrateofprogression,orlackthereof,inagivenindividual.EarlyconsultationwithspinalteamandtherapistsisrecommendedandsurgicalfixationshouldbeconsideredifCobbangleisabove30degreesdependingontherateofprogressionandlocationofthecurve.[18,27,28].CraniofacialFD(FlowchartCraniofacialFD)Theaimofstagingcranio-faciallesionsistodefineandrecordtheextent,distributionandimpactofFDinthecraniofacialskeleton.Followingahistoryandphysicalexaminationthefollowingtestsarerecommendedwhereclinicallyrelevant:objectiveassessmentoffacialasymmetryusingclinicalphotographyand3DphotographyandassessmentofpsychologicalimpactincludingusingtheCraniofacialExperienceIndex[29].RadiologicalassessmentincludesstandardradiologicalfacialandorthognathicseriesandfinecutCT1 mmorlessslicethickness.Ifcraniofaciallesionsareadjacenttorelevantstructuresornervepathways,referralsshouldbeconsideredtothefollowingspecialties:craniofacialsurgery,plasticsurgery,ophthalmology,ENT&audiology,maxillofacialsurgeryandneurosurgery.Areferraltoaspecialisedcraniofacialserviceshouldbeconsideredifthereisevidenceofnerveimpairmentoffunctionalimpairment.DentalFDIncaseofdentalinvolvement,panoramicradiographsandintraoral(periapicalandbitewing)radiographswillprovideassessmentofbotharches,aswellasadjacentanatomicstructuresincludingmaxillarysinuses,nasalcavity,mentalforaminaandmandibularcanals.Inaddition,usefulinformationwillbeprovidedregardingthepresenceofcariouslesions,periodontaldisease,orperiapicaldisease,allimportantriskfactorsforosteonecrosisofthejaw(ONJ).Moreadvancedimagingtechniquesincludetheuseofconebeamcomputerizedtomography(CBCT)assessingcorticalandcancellousarchitecturewithlowerradiationexposure,magneticresonanceimaging(MRI),99mTc-methylenediphosphonatebonescintigraphy,andpositronemissiontomography,(PET).ExtraskeletalsystemEndocrinesystem Ovarianassessment (SeeAdditionalfile4:FlowchartEndocrinemanagement:GonadalEvaluationinGirls) Atargetedhistoryandphysicalexaminationincludinghistoryofbreastdevelopment,vaginalbleedingand/orsignsofestrogenization(e.g.belowage8 years),ovariancysts(Fig.2a),andirregularmensesasdefinedasmenstrualcyclesthatareshorterthan21 daysorlongerthan35 days). Allchildrenshouldhaveareviewoftheirgrowthcurveforlineargrowthaccelerationordecelerationandastandardisedboneageexamination[30].Ifsymptomatic,girlsshouldhavearandombloodFSH,LH,estradiolandpelvicultrasound. Testicularassessment (SeeAdditionalfile4:FlowchartEndocrinemanagement:GonadalEvaluationinBoysandMen) Atargetedhistoryincludinghistoryofpubertaldevelopment,andphysicalexaminationincludingTannerstagingincludingtesticularvolume[31,32].Allmalesshouldhaveatesticularultrasoundatbaseline(Fig.2b)andafterage5tocharacterisesubclinicalinvolvementconsistentwithMAS.Ifsymptomatic,boysshouldhavemeasurementsofFSH,LHandfreetestosterone. Thyroidassessment (SeeAdditionalfile4:FlowchartEndocrinemanagement:ThyroidEvaluation) Allpatientsshouldhaveatargetedhistoryandphysicalexamination,measurementofTSH,freeT4&totalorfreeT3andthyroidultrasoundtocharacterisesubclinicalinvolvementconsistentwithMAS(Fig.2c)[33,34].Ofnote,inFD/MAS,hyperthyroidismisaT3drivendiseaseduetoincreaseddeiodinaseactivity[33]sothatmeasurementofT3/T4ratiosishelpful,witharatioof> 20beingindicativeofdisease. Pituitaryassessment (SeeAdditionalfile4:FlowchartEndocrinemanagement:GrowthHormoneExcessEvaluation) Allpatientsshouldhaveatargetedhistoryandphysicalexaminationincludingheightmeasurementandcomparisonwithmid-parentalheight[35,36].AllchildrenshouldhaveareviewoftheirgrowthcurveinrelationtoageandstageofpubertaldevelopmentandheadcircumferenceSDS.Evaluationofgrowthvelocitymaybeconfoundedbybonediseaseand/oradditionalendocrinopathies.Allchildrenshouldhavetheirboneageevaluated,withdeterminationofpredictedadultheightandcomparisonwithTannerstageandmid-parentalheight(e.g.BayleyN&PinneauSR[37].Evaluationofboneagemaybeconfoundedbybonedisease. AllpatientsshouldhavearandombloodtestforIGF-1,growthhormone(GH)andprolactinmeasurements.Inchildrenbiochemicaltesting,especiallyofserumGH/IGF-1,maybemisleadinginthepresenceofprecocious(ornormal)pubertyaslikelytobewelloutsidethenormalage-relatedrange.IfthereisalaboratoryabnormalityorclinicalconcernregardingGH-excess,therecommendationistoinvestigatefurtherbymeasuringIGF-1.Suchcasesmayrequireaglucosetolerancetestand/orovernightgrowthhormonesamplingtoconfirmthediagnosis.PituitaryMRIisindicatedincaseofabnormalbiochemistry(Fig.2d),althoughanormalpituitaryMRIdoesnotruleoutthepossibilityofGHexcessastheaffectedtissuemaynotbedetectablebyMRI[36]. Patientswithendocrinopathiesshouldcomplywithadditionaldisease-specificscreeningprogrammesasperpublishedguidelines,e.g.acromegalyandscreeningforcolonicneoplasia[38]. Adrenalassessment (SeeAdditionalfile4:FlowchartEndocrinemanagement:AdrenalEvaluation(children)) Hypercortisolismpresentsexclusivelyinthefirstyearoflifeandmayspontaneouslyresolve[39,40].Atargetedhistoryandphysicalexaminationshouldbeperformed,toincludeahistoryofinfantileillness,developmentaldelay,poorlineargrowthwithexcessiveweightgain.Incaseofclinicalsuspicionofcurrenthypercortisolism,24-hurinaryfreecortisol,lowdosedexamethasonesuppressiontest,diurnalcortisolandadrenalCTshouldbeperformed.Itisofnotethatadrenalinvolvementmaypresentasadrenalinsufficiencyinlaterlifereflectingprevious(resolved)hypercortisolism.TheACTHstimulationtestshouldbeperformedinallpatientswithaknownorsuspectedhistoryofneonatalhypercortisolism. Dermatologicallesions(Fig.1)Aphysicalexaminationshouldbeperformedinallpatientsfortypicalcafé-au-laitmacules(anysizeanddarknesswithcharacteristicjaggedborders(CoastofMaine)[41,42]Figure.Thedistributiontypicallyrespectsthemidlineofthebody).Inadults,brownmacularlesionsmaydeveloponthelips.Extracareshouldbetakentoidentifylesionsinpatientswithdarkerskins.EvaluationofqualityoflifeinFD/MASTheevaluationofqualityoflifeinpatientswithFD/MASshouldbeperformedwithlanguagespecificversionsoftheEQ5D-5 L[43]andSF36[44]inadultsandthePEDS-QL[45]inchildren.Additionalmeasuresofanxietyanddepression,e.g.usingtheHospitalAnxietyandDepressionscale[46]andsleep,e.g.usingtheEpworthSleepinessScale[47]orPittsburghSleepQualityIndex[48]couldbeconsidered.InCFFDassessmentofpsychologicalimpactincludingusingtheCraniofacialExperienceIndex[29]couldbeconsidered.ManagementofFD/MASGeneralmeasuresProvisionofinformationaboutthediseaseProvisionofsufficientinformationaboutthediseasetothepatientandfamiliesisofoutmostimportanceforthisraredisease,whichmaybeassociatedwithdebilitatingmanifestations,andforwhichthereisnocureandnoapprovedtreatment.Theaimistoempowerpatientsandsupportthemtodeveloptothebestoftheirabilities.Patientsandtheirfamiliesshouldbeinformedofthenon-inheritedgeneticnatureofdiseaseandthatwhilemalignanttransformationcanveryrarelyoccur,FD/MASlesionsarealmostinvariablybenign.TheyshouldalsobeinformedthattherearenoknownexposuresthatcauseFD/MAS.PatientsandtheirfamiliesshouldbegivenwritteninformationmaterialaboutFD/MASandinformedofthelocalregional/national/internationalpatientgroupsincludingthosebasedonsocialmediaforadditionalsupport.Patientsshouldalsobegivendetailsof“Expert”patientsandspecialistclinicalcentres/networks(e.g.EuropeanReferenceNetworks).GiventhegapsinourknowledgeofFD/MAS,researchishighpriorityandpatientsshouldbegiveninformationaboutlocalresearchstudiesortrials. Lifestyleadvice Adviceshouldbegiventooptimizelifestylefactorswhichareassociatedwithoptimalbonehealth.Patientsshouldbeadvisedtoachieveappropriatedietarycalciumintakeperageandachievesufficient25-OHvitaminDlevelsaspernationalguidelines,especiallyifpharmacologicaltreatmentwithanti-resorptivesiscontemplated.Smokingcessation,alcoholmoderationto 3/10.ItremainsunclearwhetherbisphosphonatesreduceFDlesionsizeorprogressioninchildrenoradults.Theirabilitytoincreaselocalbonedensityorpreventingcomplicationshasnotbeenestablished.Priortotheiruse,ensurethatthepatientisnormo-calcaemic,hasanadequatedietarycalciumintakeandanadequate25OHvitaminDlevel(accordingtonationalguidelines)andthatthecreatinineclearanceis≥35 ml/min.Importantly,hypophosphatemiashouldbecorrectedasbestapossibleforleast6 monthspriortoinitiatingbisphosphonates.TreatmentprotocolsforthemostcommonlyusedbisphosphonatesareshownintheTable 3.Thereisnoevidencetosupportuseofalendronateorrisedronatefortreatmentofpaininfibrousdysplasia.Highdosealendronate,40 mgdaily,doesnotimprovepaininacontrolledtrial[53].Oralbisphosphonates,atanydose,arethereforenotrecommendedforthetreatmentofbonepain. Table3Exampleofintravenousbisphosphonateregimensusedforthemanagementofbonepaininpatientswithfibrousdysplasia/McCuneAlbrightSyndromeFullsizetable Intravenouslyadministeredpamidronateandzoledronatecanbeequallyconsidered(Table3).Theaimofinitialdosingistoestablishwhetherbisphosphonatesareeffectiveinprovidingpainrelief.Severaldosesmayberequiredinitiallytoestablishwhethertheyareeffectiveinprovidinganalgesia.Subsequentdosingintervalsshouldbedeterminedaccordingtoneedforanalgesiaandresponsetopreviousdoses.Ingeneral,oneshouldaimtoincreasetheintervalbetweendosesovertime. Patientsandfamiliesshouldbecounselledaboutshortandlong-termrisksandconcernspossiblyassociatedwiththeuseofbisphosphonates.Considerationshouldbegiventoappropriatemonitoringofbonehealthaccordingtodoseanddurationoftherapywhichmayincludetheserummeasurementofboneturnovermarkersandbonedensity.Dentalevaluationisrecommendedpriortotreatmenttominimizetheriskofosteonecrosisofthejaw.Therehavebeennoreportsofatypicalfemurfracturesdespitethehighcumulativedosesusedlong-terminsomeofthereportedlargecaseseries[52]. Ifthereisaninadequateclinicalimprovement,asmeasuredbynoorinsufficientchangeinpainscore,othernon-bonecausesofpainshouldbeexcludedbeforeswitchingtotheotherparenteralbisphosphonate.Ifthereisstillnoimprovementinpain,thendonotcontinuewithbisphosphonatetherapyandreviewothercausesofpainandconsiderotheranalgesicstrategies. Evidenceforthedosage,efficacyandsafetyofotheranti-resorptiveagentssuchasdenosumabiscurrentlyscarceandtheuseofthisagentisnotrecommendedoutsidespecialistcentres,preferablyinthecontextofaclinicalstudyortrial.ThemainconcernraisedsofarwiththeuseofthisagentinFDistheapparentincreasedriskofsignificanthypercalcaemiafollowingcessationoftherapyinchildren[58]andreboundincreaseinfracturerateinadultstreatedwithdenosumabforosteoporosiswhentherapyisdiscontinued[59]. ManagementofMazabraudsyndromeMoreoftenthannotmyxomasofMazabraud’ssyndromeareasymptomatic,andrequirenointervention.However,surgicalexcisionisrecommendediftheybecomepainful,.Theremaybealocalrecurrenceriskofupto25%.Follow-upscanningwithMRIisdependentonclinicalsymptoms.Longertermsurveillanceandtestingforotherextra-skeletalmanifestationsisrecommendedinpolyostoticFDandinthepresenceofotherfeaturesofMAS.ManagementofEndocrinopathies Ovarianpathology[52,53,54,55,56,57] (SeeAdditionalfile4:FlowchartEndocrine:Managementofprecociouspubertyingirls) Ingeneral,ovariansurgeryforcystsshouldbeavoided,asdiseaseisusuallybilateral.Ovariectomyshouldonlybeperformedwhenthereisariskoftorsionandafterexpertconsensus.Patientsshouldbeinformedthattheriskoftorsionissmall. Treatmentforprecociouspubertyisindicatedifboneageisadvancedandthereisfrequentbleeding.Psychologicaldistressandthepatient’sageneedtobetakenintoaccountastheheightoutcomeisonlyimprovedinthose<6ysatonseti.e.theveryyounggroup.Firstlinetherapyisletrozole,withtamoxifenorfulvestrantassecondlineoradjuvants.Patientsshouldbemonitoredforcentralpubertyandtheneedtoaddagonadotropin-releasinghormoneanalogue(GnRHa),e.g.leuprolide. Adultwomenshouldbemonitoredfordysfunctionaluterinebleeding.ForcontraceptionandHRTitmaybeprudenttoavoidadditionalestrogeniccompoundstoavoidapossibleincreaseintheriskforbreastcancer,sincepatientswithMASmaybeatanincreasedriskofestrogenpositivebreastcancer[60],andpatientswithprecociouspubertyhavebothlongerexposureaswellascontinuedintermittentautonomousproductionofhighlevelsofestrogenupuntilthemenopause. Testicularpathology[31] (SeeAdditionalfile4:FlowchartEndocrine:Managementofprecociouspubertyinboys&men) Ingeneral,surgeryshouldbeavoided.Structurallesionsarerarelyofclinicalsignificance.Treatmentforprecociouspubertyisindicatedincaseofanassociatedelevatedserumtestosteroneand/orboneageadvancement.Combinationoftestosteronereceptorblockerandaromataseinhibitorareneededaswellasmonitoringforcentralpreciouspuberty,inwhichcaseGnRHamayneedtobeadded. Testicularlesionsshouldbeexaminedannuallyandmalesinformedtoperformself-examinations.Annualultrasonographyisindicatedforpalpablelesionsorforlesionscausinganoverallincreaseinthesizeofthetestes(relativetoothertestisorstageofpuberty).).Inadulthoodnoroutineultrasoundsareadvised,unlesslesionsarechanging.Considerbiopsyforlesionsthatarechanginginsize. Thyroidpathology[33,34,61] (SeeAdditionalfile4:FlowchartEndocrine:Managementofhyperthyroidism) Intheshort-term,carbimazoleormethimazolearerecommendedforhyperthyroidism,whereasthyroidectomyorradio-ablationarerecommendedforlongstandinghyperthyroidismofmorethan5 years..PatientscanbetreatedwithI-131butconsideringtheevaluationofthyroidnodulesoneshouldperformfullevaluationofthenodulebeforetreatingwithI-131. Annuallong-termmonitoringisadvisedduetothepossibilityofregrowth.For,childrenagedlessthan10 yearswithanabnormalUSandnormalthyroidfunctiontests(TFTs),physicalexamination,growthvelocity,andTFT’sshouldbemonitoredevery6to12 month.Incaselesionsarefound,followupofpatientswithFD/MAS-relatedthyroiddiseaseshouldbeperformedaccordingtocurrent(inter)nationalguidelines[62,63,64]. Growthhormoneexcess[36,65,66,67,68,69] (SeeAdditionalfile4:FlowchartEndocrine:Managementofgrowthhormoneexcess) Somatostatinanaloguesarefirstlinetherapieswithsecondlineoptionsincludingpegvisomant,aloneorincombinationwithoctreotideorlanreotideatthediscretionofthetreatingphysician.Pituitarysurgeryisrecommendedforpatientsresistanttomedicaltherapy.Totalhypophysectomyisrequiredasthewholeglandisusuallyinvolvedandremovingjusttheadenomaisnotenoughtocontroltheexcessproductionofgrowthhormone.Surgeryisalmostuniversallycomplicatedbyco-existentcraniofacialFD,andsoalwayschallenging.Maximalmedicaltherapyisstandardofcare,andpituitaryradiationshouldbeafinalrecourseduetotheriskofmalignanttransformationofskullbaseFD[36,70].ThetreatmentgoalsaretoachieveanIGF-1Z-scorebetween− 2and + 1.Treatmentshouldbemonitoredbyannualgrowthvelocity,headcircumference,andIGF-1inallgrowingchildren.Assessmentofadditionalpituitaryhormonedeficienciesisrecommendedafterhypophysectomyand/orradiationtherapy. Adrenalpathology[39,40] (SeeAdditionalfile4:FlowchartEndocrine:Managementofhypercorticolism) Metyraponeisthepreferredfirst-lineagentwithetomidateforcriticallyillpatients.Otheroptionsincludemitotaneandketoconazole.Ketoconazoleshouldbeusedwithcautionasitisfrequentlyassociatedwithhepatictoxicity.However,bilateraladrenalectomyisusuallyrequired.Unilateraladrenalectomymaybeconsideredinstablepatientswhohavetheappearanceofunilateraldisease.Ofnote,spontaneousresolutionoccursinupto1/3ofpatients.Instablepatients,adrenalectomycouldbedeferredwithclosemonitoringforresolution.Thebenefitsandrisksofmedicaltherapyshouldbebalancedwiththepotentialdevelopmentalrisksofcontinuedhypercortisolism.Assessmentofadrenalinsufficiencyisrecommendedafterresolutionofhypercortisolism. ManagementofotherextraskeletalmanifestationsofFD/MAS Haematologicalmanifestations[71] Plateletfunctionactivationtestingshouldbeperformedifthereisahistoryofbleeding.Ifabnormal,thiscanbecorrectedpre-operativelybyplatelettransfusion. Gastrointestinalmanifestations[72,73,74,75] GastrointestinalpolypsandhepatobiliaryneoplasmshavebeenreportedinFD,althoughtheirclinicalsignificanceisunclear.Pancreaticdisease,includingintraductalpapillarymucinousneoplasms,havealsobeendescribedandasinglecaseofmalignanttransformationhasbeenreported.Pancreaticpathologymaybeassociatedwithacuteorchronicpancreatitisandserumamylaseshouldbemeasuredifthereishistoryofabdominalpain.Itisrecommendedthatallpatientsareevaluatedforgastrointestinalsymptomsandimagingconsideredforsymptomaticpatientsandthosewithahistoryofpancreatitis. Malignancies[4,31,61,76,77,78,79] Thereisalikelysmallincreasedbaselineriskofdevelopingmalignanciesinmutation-bearingtissueaswellasinlesionswithhighturnover.Patientsshouldbeencouragedtobecompliantwithexistingcancerscreeningprogrammesforthegeneralpopulationsuchasscreeningforbreastandprostatecancer,asanincreasedriskforthesemalignancieshasbeenobservedinpatientswithFD.Patientswithendocrinopathiesshouldcomplywithadditionaldisease-specificscreeningprogrammesasperpublishedguidelines,e.g.acromegalyandscreeningforcolonicneoplasia[38]. Patientsshouldbeadvisedtoavoidadditionalriskfactors(excessiveradiationexposure,smoking,excessivealcohol,etc.) SurgicalmanagementofFD/MASManagementoforthopaedicissuesrequiresworkingwithinamultidisciplinaryteamtoensureoptimalphosphatestatusandexclusionofendocrineabnormalitiesthatexacerbateskeletaldisease(e.g.GHexcessandT3thyrotoxicosis).Reviewbyaspecialistorthopaedicsurgeonisneededforfracture,potentialmechanical/tumourbonepainorlimbdeformity.Limbdeformityrequiresearlyassessmentforprophylacticsurgerytopreventworseningdeformity,painandfracture[80].Leglengthdiscrepancyrequiresassessmentfortheneedfororthoticsandcorrectivesurgery.Thepresenceofjoint-basedpainmayrequirereferralforphysiotherapy,analgesics,osteotomy(especiallyifthereisdeformity)and/orarthroplasty.Whereascurettagemaybeeffectiveinaverylowvolumebonelesion,curettagefilledwithbone(autoorallogenic)graftsisnotrecommendedasitisineffectiveandmaybeassociatedwithcomplications.Ingeneral,externalfixationisonlyusedfortemporarycorrectionand/orfixation,whilewaitingforamoredefinitivecustom-madeprintedimplant.Preferredinternalfixationiswithatitaniumintramedullarynail,bridgingtheinvolvedbonewherepossible.Inspecialcircumstancesplatefixationcanbeconsidered.Internalfixationusingconventionaltitaniumplatesorcustom-madetitaniumplatesbybridgingtheinvolvedboneisanotheroption.Thereappearstobeahigherrateoffractureaftersteelplatingvs.titaniumplatingandthismayberelatedtothebetterelasticmodulusoftitaniumcomparedwithsteel.Thestabilizationprocedureisoftenfacilitatedbyperformingacorrectionosteotomy.Allogeneiccorticalstrutgrafting(tibiaorfibula)hasbeenusedforbridgingtheinvolvedbone,forsmallFDlesions,butisnotrecommendedafterincompleteorcompletefractures.GiventhatFDlesionsarevascular,bloodlosscanbesignificantandstagedproceduresarethereforerecommendedifmultiplesurgeriesareplannedinordertominimizetheneedfortransfusions.Considerinterventionalradiologicalcontrolwitheitherembolizationorballooncatheterforveryhighflowlesions.ThereissofarnoevidenceforaddedvalueofusingofbisphosphonatestodecreasevascularityofFDlesionspre-operativelyalthoughthiswarrantstestingformallyinfuturestudies.Forchildrenorseverelyaffectedadults,activefollow-upisneededinthemediumandlongtermasthedeformitymayrecurandrequirefurthersurgery.Rehabilitationincludingphysiotherapy,hydrotherapyandmobilityaidsshouldbeavailableasneededaftersurgery.Alsosee:(SeeAdditionalfile5:FlowchartSurgicalmanagementofFDoftheproximalfemur)ManagementofCraniofacialFD(CFFD)[51,81,82,83,84,85,86](SeeAdditionalfile6:Flowchart:ManagementofCFFD)FDofthecraniofacialskeletonisvariableinitsbehaviourandthemultidisciplinaryteamcaringforpatientswithCFFDneedsitscombinedexpertisetocaterforalltreatmentoptions.Anyplannedsurgicaltreatmentshouldbecarefullycoordinatedwithotherspecialistsinvolvedinthepatient’scare.Workingwithinamultidisciplinaryteam,thusensuresamongotheraspectsofmanagement,optimalphosphatestatus,adequatevitaminDandpreoperativecorrectionofendocrineabnormalities,suchasGHexcessandT3thyrotoxicosis,thatmayexacerbateskeletaldisease.Thebalanceofrisksandbenefitsofextensiveresectionand/orreconstructionneedstobecarefullyoutlinedingreatdetailinpatientswithCFFD.Activewatchandwaitpoliciesareoftenthepreferredmanagementstrategy,aslong-termoutcomesintermsofregrowthandpainareveryvariableandgenerallypoorlypredictable.IfCFFDisidentifiedatbaselineoratsubsequentmonitoringevaluations,thepatientshouldbereferredforaformalassessmenttoacraniofacialservicewithexperienceinthecareofpatientswithCFFD.Thegoalsoftreatmentare:a)Preventionoffunctionalloss–especiallyhearingandvision;b)Arrestorreductionofphysicaldisfigurement;c)Preventionofsecondarydeformity;d)Minimisationoflong-termmorbidityfromCFFDanditstreatment.ThestructureoftheindividualisedpackageofcareofCFFDisbasedontheextentofcraniofacialinvolvementandonthefollowingconcepts.Ifpossible,careistobeprovidedlocally,butanydecisionsregardingsurgicalinterventionshouldbetakenbyamultidisciplinaryspecialisedteamincludingphysiciansandsurgeonswithexperienceinmanagingCFFD.SchedulingofperiodicevaluationsshouldbeorganisedbythecentralcoordinatingCFteamwithCFFDpatientsbeingreviewedatleastannuallyormorefrequentlydependingontheextentoftheirdiseaseandriskofcomplications.BaselineandperiodicCTscansoftheheadshouldbeperformedinchildren,usuallyevery2 yearsorlessfrequentlybasedonthelocalisationandseverityofthelesion(s).RegularimagingisnotindicatedInadults,andtimingofthescansshouldbebasedonsymptoms,atmostevery5 yearsinthosewithoutsymptoms.Althoughtheprimaryaimoftreatmentshouldalwaysbetopreservefunction,treatmentofprimarydeformityandpreventionofsecondarydeformityarealsoimportant.Advancedimagingtechniquesand3-dimensionalanalysisofscanstogetherwithvirtualsurgicalplanningandcomputer-aidedmanufacturinganddesignofpatient-specificimplantsshouldberegardedasthestandardofcareinsurgeryofFDofthecraniofacialskeleton.Simplecurettageisnotrecommendedasitisineffectiveandmayincreasetheriskofcomplications. SpecificCFFDmanagementrecommendations Lesionsofthecranialvaultusuallypresentasamass,asymmetryorotherformofphysicaldeformityandtreatmentoptionsinclude:burringofthelesiontoreducebulkandachievesymmetry;subtotalexcisionandreconstruction;completeexcisionofthelesionandreconstructionofthecalvarialdefect. Lesionsoftheskullbaseshouldbemonitoredbyperiodicevaluationbythecraniofacialteam.Anyevidenceoffunctionalembarrassmentofthestructuresexitingtheskullbaseshouldpromptareviewbyaskullbasesurgeon.Surgeryshouldbeavoidedintheabsenceoffunctionaldeficits.Anassessmentofhearingshouldbeperformedannuallyinallpatientswithskullbasedisease. Lesionsofthefrontalboneusuallypresentasaphysicaldeformityorasymmetry.Theselesionsoftenalterorbitalmorphology,affectthepositionoftheglobeandcancausesignificantdeformity.AlthoughdiplopiaisnotacommonsymptomofCFFD,surgicalinterventionmaybeassociatedwiththisdisablingcomplication.Pre-operativeophthalmologicalevaluationisessentialtoestablishthelikelihoodofpost-operativediplopiaandthefusionrange.Surgicaloptionsinclude:burringofthelesiontoreducebulkandachievesymmetry;subtotalexcisionandreconstruction;excisionofCFFDlesionandreconstructionofthefronto-orbitaldefectandcorrectionoftheglobe’sposition.Prophylacticopticnervedecompressionisnotrecommended.Provenvisualdeteriorationwithsequentialophthalmologicalevaluationwarrantsanurgentevaluationbyacraniofacialsurgeonwithexperienceinthemanagementoffibrousdysplasia. Lesionsofthenaso-ethmoidregioncanaffecttheairwayandglobeoftheeye’sposition.AnENTevaluationisrecommendedinadditiontoadetailedophthalmologicalevaluation.Treatmentstrategiesareaimedat:reducingairwayobstruction;correctingglobepositionandvisualfunctionandcorrectingphysicaldeformity.Surgicaloptionsinclude:subtotalexcisionvialimitedaccess/endo-nasalapproachandradicalexcisionwithreconstructionoftheskullbaseandorbits. Maxillarylesionsaffectbothorbitalmorphologyandcontentsaswellasdentalocclusion.Surgicalstrategiesinclude:preservingocclusalfunctionanddentition(includingtoothbudsaswellaseruptedteeth);correctingglobepositionandvisualfunction;reducingsecondarydeformityandusingstealthincisionstominimisesurgicalmorbidity.Surgicaloptionsinclude:burringoflesionstoachievesymmetryandreducebulk;subtotalexcisionandreconstructionoforbitalfloorandmaxillaasrequired;radicalexcisionandreconstructionoftheorbitandmaxillaryarchtoenabledentalrehabilitation. Mandibularlesions:AlthoughCFFDofthissiteoftenpresentswithamassinthelowerborderofthemandible,diseaseprogressionwillleadtodysfunction.Likethemaxilla,surgicalstrategiesshouldbedirectedat:preservingocclusalfunctionanddentition(includingtoothbudsaswellaseruptedteeth),reducingsecondarydeformity;andusingstealthincisionstominimisesurgicalmorbidity.Surgicaloptionsinclude:burringoflesionstoachievesymmetryandreducebulk;subtotalmandibularexcisionandreconstruction;andradicalexcisionandreconstruction. OralanddentalmanagementinFD/MAS[84,87,88,89] PatientswithFD,includingCFFD,donotrequirespecialdentalmanagementandareabletoundergoroutinedentalandorthodontictreatmentswithoutexacerbatingtheircraniofaciallesions.However,malocclusion,dentalcrowdingandsmokingcontributetopooreroralhygiene[82]. Dentalanomaliessuchasoligodontia,enamelhypoplasia,dentindysplasia,taurodonticpulp,odontoma,toothdisplacement,malocclusion,andhighcariesactivityhavebeenreportedin28%ofpatientswithcraniofacialFD.Forthisreason,allpatientswithCFFDshouldbecarefullymonitoredfortheappearanceofthesedentalanomaliesduringgrowth TheriskofONJisdiscussedinthesectiononoralbisphosphonates.ManagementofONJisbasedonthestageofthedisease,sizeofthelesions,andthepresenceofcontributingdrugtherapyandcomorbidity[88].Animportantpreventativestrategyincludesmaintenanceofgoodoralhygiene,eliminationorstabilizationoforaldiseasepriortoinitiationoftreatmentwithananti-resorptiveagentandasfaraspossibleavoidanceofinvasivedentalproceduresduringtreatment.Frequentrecallsmayberequiredforscalingandrootplanningtocontroldentalplaqueaccumulation.OrthodontictoothmovementtendstoberapidinjawswithfibrousdysplasiaandrelapseismorecommonasteethtendtoreturntotheiroriginalpositionafterremovaloforthodonticappliancesduetopoorqualityofFDbone. Orthodontictreatmentmustbeprecededbyradiologicalevaluationtodetectremodeledareastoinformorthodontictherapy.Functionalremovableappliancetherapyshouldbepreferredwheneverpossible.Fixedappliancetherapyrequiresthemaintenanceofexcellentoralhygieneconditions.InthevastmajorityofcasesofcraniofacialFD,orthognaticsurgeryisnotneeded,andobservationisthecorrectapproach.Indicationsforsurgeryincludedocumentedprogressive,severepain,orseveredisfigurement.Resultshavebeenshowntobestablewithnorecurrenceaftersurgeryinadults. Orthognaticsurgeryhelpstorestorestableocclusionandgoodfacialaesthetics,butshouldbeavoidedingrowingpatientsasinyoungpatientsasabnormalfacialgrowthhasbeendescribedinyoungpatientsoperatedduringtheactivephaseofgrowth. ConclusionThesebestpracticeguidelineshavebeendevelopedbyaninternationalcollaborationbetweenmultipleclinicalspecialities,patientsandpatientadvocacygroups,usingthebestevidenceavailable.TheFD/MASguidelinesareintendedtoimprovetheclinicalcareofpatientsacrosstheworldbyaddressingdiagnosis,staging,treatmentandmonitoringaspectsoftheircaregiventhepotentialseriousriskstopatientoutcomeswithlatediagnosis[90].TheprovisionofaPatientChecklist(SeeAdditionalfile1:FibrousDysplasiaandMcCune-AlbrightSyndrome:AChecklistofPatientsandDoctors)isaimedatinformingandempoweringpatientstoseekexcellenceofhealthcarefortheirdisease.Describingstandardsacrosstheclinicalcarepathwayenablesclinicalservicestobeaudited,helpsintheidentificationofareasofthepatientpathwaythatrequireserviceimprovementandfacilitatescross-bordersharingofbestclinicalpracticebetweenclinicalservicesindifferentcountries.TheseguidelineshaveadditionallyhighlightedimportantgapsinourknowledgeaboutFD/MASandraisetheimportanceofimplementinginternationalregistriesandcohortstudieswithactivecollaborationofpatientsandfamilies.Currently,suchinitiativesincludetheFibrousDysplasiaFoundationRegistry(https://fibrousdysplasia.org),RUDYstudy(www.rudystudy.org)[91],JamesLindAlliancePrioritySettingPartnershipforRareMusculoskeletalDiseasesinAdulthood(http://www.jla.nihr.ac.uk/)andEuropeanReferenceNetworksforrarebone(http://ernbond.eu/)andendocrinediseases(https://endo-ern.eu).TheFD/MASconsortiumcommitstodevelopinganaudittoolofkeyperformanceandexperiencemeasurestoaninternationalauditofpracticeandtoreviewingtheserecommendationsatleastevery5 yearstoreflectnewevidenceinFD/MASnaturalhistoryandmanagement. Availabilityofdataandmaterials Notapplicable. Changehistory21November2019Theoriginalversionofthisarticle[1]unfortunatelyincludedanerrortoanauthor’sname.PaulArundelwasinadvertentlypresentedasPaulArunde.AbbreviationsCBCT: ConeBeamComputerizedTomography CFFD: CraniofacialFibrousDysplasia CT: ComputerisedTomography FD: FibrousDysplasia FD/MAS: FibrousDysplasia/McCuneAlbrightSyndrome GDG: GuidelineDevelopmentGroup MRI: MagneticResonanceImaging NGS: NextgenerationSequencing ONJ: OsteonecrosisoftheJaw PET: PositronEmissionTomography ReferencesAlbrightF,etal.SyndromecharacterizedbyosteitisFibrosaDisseminata,areasofpigmentationandendocrinedysfunction,withprecociouspubertyinfemales.NEnglJMed.1937;216(17):727–46.Article  GoogleScholar  LIchensteinL.Polyostoticfibrousdysplasia.ArchSurg.1938;36:874–8.Article  GoogleScholar  WeinsteinLS,etal.ActivatingmutationsofthestimulatoryGproteinintheMcCune-Albrightsyndrome.NEnglJMed.1991;325(24):1688–95.CAS  PubMed  Article  GoogleScholar  LandisCA,etal.GTPaseinhibitingmutationsactivatethealphachainofGsandstimulateadenylylcyclaseinhumanpituitarytumours.Nature.1989;340(6236):692–6.CAS  PubMed  Article  GoogleScholar  BoyceAM,CollinsMT.FibrousDysplasia/McCune-AlbrightSyndrome.In:PagonRA,etal.,editors.GeneReviews(R).Seattle:UniversityofWashington;1993.UniversityofWashington,Seattle.Allrightsreserved.:Seattle(WA). 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DownloadreferencesAcknowledgementsWeacknowledgethecontributionofthefollowingfortheircommentaryonthepathway:FAhmed,RABerengere,JBubbear,CBurren,MCheung,SClarke,RDuncan,CFairchild,SGallacher,NGittoes,R-MJavier,AJawad,LLeiden,MMcKenna,SMalochet,POrcel,SEPapapoulos,KPoole,CSPvanRijswijk,MAJvandeSande,MStone,STakenaka,DTerssaris,STuck,AWainwright,AAVerrijnstuart,LWatts,HWehje,MZacharin,PYZambelli,FundingMKJissupportedbytheNationalInstituteofHealthResearch(NIHR)OxfordBiomedicalResearchCentre,UniversityofOxford.AMBandMTCaresupportedbyfundingfromtheNationalInstituteofDentalandCraniofacialResearch,NIH,Bethesda,MD.TheInternationalOsteoporosisFoundationandKyowaKirinHakinco-fundedtheOxfordworkshopbuthadnoroleinthedesign,collectionofinformation,analysis,interpretationorwritingofthemanuscript.AuthorinformationAffiliationsNuffieldDepartmentofOrthopaedics,RheumatologyandMusculoskeletalSciences,UniversityofOxford,Oxford,UKMuhammadKassimJavaidSkeletalDisordersandMineralHomeostasisSection,NationalInstituteofDentalandCraniofacialResearch,Bethesda,MD,USAAlisonBoyce & MichaelTerrenceCollinsDepartmentofMedicine,DivisionofEndocrinology&CenterforBoneQuality,LeidenUniversityMedicalCenter,Leiden,TheNetherlandsNatashaAppelman-Dijkstra & NeveenAgnesThereseHamdyDepartmentofPlasticSurgery,CraniofacialCentre,GreatOrmondStreetHospitalforChildrenNHSTrust,London,UKJulingOngSectionofPaediatricDentistry,UniversityofTurin,Turin,ItalyPatriziaDefabianisDepartmentofOncology&Metabolism,UniversityofSheffield,Sheffield,UKAmakaOffiahMetabolicBoneTeam,SheffieldChildren’sHospital,Sheffield,UKPaulArundelEndocrineDepartment,BirminghamWomen’sandChildren’sNHSFoundationTrust,Birmingham,UKNickShawEuropeanAssociationofFriendsofMcCune-AlbrightSyndrome(TO),Turino,ItalyValterDalPosFibrousDysplasiaSupportSociety,Birmingham,UKAnnUnderhilFibrousDysplasiaFoundation,Grandville,USADeannaPortero & LisaHeralDepartmentofDrugDesignandPharmacology,UniversityofCopenhagen,Copenhagen,DenmarkAnne-MarieHeegaardDepartmentofSurgeryandTranslationalMedicine,UniversityofFlorence,Florence,ItalyLauraMasi & MariaLuisaBrandiPaediatricOrthopaedicandTraumaSurgery,UniversityHospitalsBristolNHSFoundationTrust,Bristol,UKFergalMonsellDepartmentofOrthopaedicSurgery,NemoursChildren’sHospital,Orlando,Florida,USARobertStantonDepartmentofOrthopaedicSurgery,LeidenUniversityMedicalCenter,Leiden,TheNetherlandsPieterDurkSanderDijkstraINSERMUMR1033andUniversitédeLyon,Lyon,FranceRolandChapurlatAuthorsMuhammadKassimJavaidViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarAlisonBoyceViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarNatashaAppelman-DijkstraViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarJulingOngViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarPatriziaDefabianisViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarAmakaOffiahViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarPaulArundelViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarNickShawViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarValterDalPosViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarAnnUnderhilViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarDeannaPorteroViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarLisaHeralViewauthorpublicationsYoucanalsosearchforthisauthorin 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PubMed GoogleScholarContributionsMKJ,NA,LM,MLB,RC,NH,MCprovidedadultexpertise.MC,AB,PAandNSprovidedpaediatricexpertise.JOprovidedmaxillo-facialexpertise,PDprovideddentistryexpertise.AOprovidedradiologicalexpertise.VDP,AU,LHandDPprovidedpatientandpatientadvocacyexpertise,AMHprovidedpainexpertise.FM,RSandPDSDprovidedorthopaedicexpertise.Allauthorsreadandapprovedthefinalmanuscript.CorrespondingauthorCorrespondenceto MuhammadKassimJavaid.Ethicsdeclarations Ethicsapprovalandconsenttoparticipate Notapplicable. Consentforpublication Consentformsforpatientimagesavailable. Competinginterests FinancialMKJhasreceivedconsultancyfeesfromAmgenforworkunrelatedtothismanuscript. AdditionalinformationPublisher’sNoteSpringerNatureremainsneutralwithregardtojurisdictionalclaimsinpublishedmapsandinstitutionalaffiliations.Theoriginalversionofthisarticlewasrevisedtocorrectatypoinanauthor'ssurname.Additionalfiles Additionalfile1:FibrousDysplasiaandMcCune-AlbrightSyndrome:AChecklistforPatientsandDoctors.(DOCX35kb)Additionalfile2:FlowchartsSkeletalEvaluation.(PPTX47kb)Additionalfile3:FlowchartsManagementofBonePain.(PPTX45kb)Additionalfile4:FlowchartsMASEndo.(PPTX64kb)Additionalfile5:FlowchartsSurgicalManagementofProximalFemur.(PDF34kb)Additionalfile6:FlowchartsManagementofCFFD.(PPTX36kb)Rightsandpermissions OpenAccessThisarticleisdistributedunderthetermsoftheCreativeCommonsAttribution4.0InternationalLicense(http://creativecommons.org/licenses/by/4.0/),whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedyougiveappropriatecredittotheoriginalauthor(s)andthesource,providealinktotheCreativeCommonslicense,andindicateifchangesweremade.TheCreativeCommonsPublicDomainDedicationwaiver(http://creativecommons.org/publicdomain/zero/1.0/)appliestothedatamadeavailableinthisarticle,unlessotherwisestated. ReprintsandPermissionsAboutthisarticleCitethisarticleJavaid,M.K.,Boyce,A.,Appelman-Dijkstra,N.etal.Bestpracticemanagementguidelinesforfibrousdysplasia/McCune-Albrightsyndrome:aconsensusstatementfromtheFD/MASinternationalconsortium. OrphanetJRareDis14,139(2019).https://doi.org/10.1186/s13023-019-1102-9DownloadcitationReceived:07February2019Accepted:21May2019Published:13June2019DOI:https://doi.org/10.1186/s13023-019-1102-9SharethisarticleAnyoneyousharethefollowinglinkwithwillbeabletoreadthiscontent:GetshareablelinkSorry,ashareablelinkisnotcurrentlyavailableforthisarticle.Copytoclipboard ProvidedbytheSpringerNatureSharedItcontent-sharinginitiative KeywordsFibrousdysplasiaMcCuneAlbrightsyndromeGuidelinesDiagnosisManagement DownloadPDF AssociatedContent Section Rarebonediseasesandskeletaldysplasias Advertisement OrphanetJournalofRareDiseases ISSN:1750-1172 Contactus Submissionenquiries:AccesshereandclickContactUs Generalenquiries:[email protected]