case report
Achmad Fauzi Kamal, MD,PhD
∗, Dina Aprilya, MD
DepartmentofOrthopaedicandTraumatologyCiptoMangunkusumoGeneralHospital,FacultyofMedicine UniversitasIndonesia,Jl.DiponegoroNo.71,JakartaPusat,Jakarta,Indonesia
a r t i c l e i n f o
Articlehistory:
Received23September2019 Revised17November2019 Accepted17November2019
Keywords:
Fibrodysplasiaossificans progressiva
Ectopicossification Painfulsoftmass Earlydiagnosis
Preventingmuscletrauma
a b s t r a c t
Fibrodysplasiaossificansprogressivaisaveryrareautosomaldominantgeneticconnective tissuediseasewithaprogressiveectopicossificationofmuscle(intramuscular)orperimus- cularconnectivetissuesuchastendonsorjointcapsules.Theosseousmassesproducedwill formbridgesthatabnormallyconnectsectionsoftheskeleton,causingdisfigurationand normalmotorfunctioninhibition.Wereporteda5-year-oldgirlwithmultiplehardnodules onthebackregionwhichinitiallypresentasapainfulsoftmassontheposteriorneckre- gion.Asthepainsubsided,themasshardenedandalsoappearedinotherpartsofherback.
Wedecidednottodoabiopsyorexcisionalsurgerytopreventflaringupofthedisease.
Earlydiagnosispreventscatastrophicdiagnosticandtreatmentprocedures.Theprogres- sivenatureofthisdiseaseisdifficulttostopbutweshoulddelayitasmuchaspossibleby preventingmuscletrauma,givingdiseasemodifyingagentandlong-termphysiotherapyto counterfurtherdisabilitieswhichwilleventuallydevelop.
© 2019TheAuthors.PublishedbyElsevierInc.onbehalfofUniversityofWashington.
ThisisanopenaccessarticleundertheCCBY-NC-NDlicense.
(http://creativecommons.org/licenses/by-nc-nd/4.0/)
Introduction
Fibrodysplasia ossificans progressiva (FOP) is a very rare autosomaldominantgeneticconnectivetissuediseasewitha progressiveectopicossificationofmuscle(intramuscular)or perimuscularconnectivetissuesuchastendonsorjointcap- sules[1–3].Theosseousmassesproducedwillformbridges that abnormally connect sections of the skeleton, causing disfiguration and normal motor function inhibition [1-3]. MutationsinthecytoplasmicGSdomainofthecellsurface
Acknowledgment:Nothingtodeclare.
CompetingInterests:Nothingtodeclare.
∗ Correspondingauthor.
E-mailaddress:fauzi.kamal@ui.ac.id(A.F.Kamal).
receptorActivinAreceptortypeI(ACVR1)wererecentlyiden- tifiedasthegeneticcauseoftherarehumandiseaseFOP[4]. Theinheritanceisautosomaldominant,butthatmostcases aresporadic.ThemutationinACVR1leadstooveractivation ofthebonemorphogeneticproteinsignalingpathway[4].
Thisconditionusuallybeginsinchildhood,whichclinically presentaspainfulswellingofthemusclesandconnectivetis- sue.Astheswellingsubsides,afterapproximately6months ormore,ossificationstartsatsomesitesatthemeanageof 4-5years.Congenitalmalformationswhicharecharacteristi- callyobservedinthegreattoesatbirthinalmostallcasesof
https://doi.org/10.1016/j.radcr.2019.11.009
1930-0433/© 2019The Authors.Publishedby ElsevierInc.on behalfof UniversityofWashington.Thisisanopenaccessarticleunderthe CCBY-NC-NDlicense.(http://creativecommons.org/licenses/by-nc-nd/4.0/)
168
R a d i o l o g y C a s e R e p o r t s 1 5 ( 2 0 2 0 ) 1 6 7 – 1 7 3Fig.1– Paraspinallesions,notetheincreaseinsizeandnumber.1A-1C10-monthonsetparaspinallesions(1A/B)with largestdiameterof2cm(1C).1D-1F16-monthonsetparaspinallesions(1D/E)withlargestdiameterof4.5cm(1F)
FOParethediagnostichallmark.AchildwithFOPwilleven- tually develop disabilities starting from abnormal gait and jointmovement untiltheyare confinedtoawheel chairat the thirddecade of life.Mortalityis usuallycausedby the restrictedchestexpansionwhichleadstorespiratoryfailure [2,5].
Wearereportinga5-year-oldgirlpresentedwithmultiple hardnodulesonthebackregionwhichinitiallypresentasa painfulsoftmassontheposteriorneckregion.Asthepain subsided,themasshardenedandalsoappearedinotherparts ofherback.Basedontheclinicalandradiologicalexamina- tion,FOPwasthemostpossiblediagnosis.Wedecidednotto doabiopsyorexcisionalsurgerytopreventflaringupofthe disease.
Case report
A5-year-oldgirl wasreferredtoourhospitalwithbilateral periscapularand multipleparavertebral nontendermasses.
Themass wasfirst noticedafter the patient fellfrom bed October2017(10monthsbeforebeingreferredtoourhospi- tal)withaninitialmassontheoccipitocervicalregion.The patientwasbroughttothemasseuseandgotmassagesatthe mass3timesbuttherewasnoimprovement.Shewasbrought tothepediatricianinapublichospitalbecausethereanother massappeared on the left paracervical region. A Mantoux test, blood,and radiological examinations were performed toruleout tuberculosisinfection.Thepatientwas referred
Fig.2– Spinaldeformity.a.Increasedinbody-armdistanceontherightside(1.5cm),plumblineshift2cmtotherightside, and1cmshouldertilt;bandc.Straightlumbar
tothe orthopedicsurgeon inthe same hospital.Acervical radiographwasperformedwhichrevealednobonychanges sothepatientwasinitiallyobservedforfurtherprogression.
Threemonthsafterthefirstmass,othermassesappearedin thescapularregion.Masseswere initiallysmallinsizeand soft,thentheygrewslightlybiggerandconsistentlybecame hardened.Shewasreferredtoacitypublichospitalandwas diagnosedthereasbacktumorandreferredtoourcenter.On physicalexamination,wefoundthat thegeneralcondition was good and no abnormality oforgans was found inthe otherorgan.Thereweremultiplelumpsvaryingfrom5mm to2cmindiameterattheparavertebralregionfromcervical tolumbarandscapularregion(Figs.1and2).
Theconsistencyofeachlumpvariedfromsoftuntilashard asabonyprominence.Bilateralhalluxvalguswas alsoob- served(Fig.3)There wasnopain,and allmasses wereim- mobile.There wasalimitationtodoallneckmotionssuch asforwardflexion,extension,andlateralbending(Fig.4).
Theshouldergirdleandallotherjointshadnormalranges ofmotion.Wehadobservedprogressivenessofclinicalhet- erotopicossification(HO)inapproximately6monthsafterini- tialdiagnosisofFOPwasestablished.Therewere increases inmass’ number and size and in a region other than the paraspinalregion(Figs.1and5).
Weperformedradiographicexaminationinseveralregions relatedtothemassandComputedTomography(CT)Scan.The radiographrevealedossificationsofsofttissueonlateralmar- ginofbothscapularbonesandontheleftsupraclavicularre- gion.TheCTscanindicatedossificationofsubcutaneoussoft tissuemasses onbothsidesofT11-L4 paravertebralregion, extensivedystrophicossificationoffasciaandintramuscular ofbilateralbackmusclesextendingfromsemispinaliscapitis muscleandfasciauntiltothelevelofsacralbone.Thedys- trophicossificationpartlyformed abonybridge fromfascia
Fig.3– Bilateralhalluxvalgus
and intramuscularpart ofbilateral levator scapularmuscle (particularlyontherightside),spinaliscervicismuscle,sple- niuscapitismuscle,trapeziusmuscle,rhomboidmuscle,until erectorspinaemuscle(onthelevelofthesacrum).Therewas nobonedestructionandthealignmentandcurvatureofthe spinewerewithinthenormallimit(Figs.6and7).
Basedonthetypicalclinicalandimagingfindingsforthe earlystageofFOPsuchasthecongenitalmalformationofbi- lateralhalluxvalgusasahallmarkwasenoughforustodi- agnosethepatientasFOPwithoutanunnecessarybiopsy.We hadinformedthepatientregardingthenatureofthisdisease
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R a d i o l o g y C a s e R e p o r t s 1 5 ( 2 0 2 0 ) 1 6 7 – 1 7 3Fig.4– Limitedneckrangeofmotion(normalneckforwardflexionandextensionis0-45°,lateralflexion45°,rotation80°).A andB10monthsonset:Neckflexion60°(A),extension45°(B).4C-H16monthsonset:Neckflexion60°(C),extension60°(D), lateralflexion35°left(F),and30°right(G),rotation45°left(G)and35°right(H)
Fig.5– Newmasseson16monthsonset.a.oncervicalregion;b.onaxillaryregion
whichmayleadtodisabilityandevendeath.Wecloselyob- servedthedevelopmentofthediseaseinthispatientandpre- scribedthepatientnonsteroidanti-inflammatorydrugs.We carefullypreventedflare-upbynotdoinganyiatrogenictrig- gerssuchasbiopsy,excisionalsurgery,oranyintramuscular injection.Wealsoeducatedthe parentstobemorecareful andnottoacceptintramuscularinjection(suchasforimmu- nization)andpreventinjurysincethesemightalsotriggera flare-up.
Discussion
FOP is anentity for progressive muscle ossification which will eventually lead to significant disability. Thisvery rare geneticconnectivetissuediseasewasfirstdescribedbyGay Patinin1648asacasewho“turnedtowood”.Theprevalence
isapproximately 1/2.000.000and over 700 caseshavebeen reported[2,5,6].
FOPisthemostcatastrophicdisorderofheterotopicen- dochondral ossification in humans.The diagnosis is clini- calandit isusuallymadebasedon thepresenceof3ma- jorcriteriathatarenamely;congenitalmalformationofthe greattoes,progressiveheterotopicendochondralossification andprogressionofthediseaseinwell-definedanatomicand temporalpatterns.TheFOPisinitiallydevelopedassofttis- sueswellingwhichspontaneouslysubsides.Intime,thereare episodicflare-upswhichendupinimmobilityandconfines thepatientinawheelchairbythethirddecade[2,5–8].
Ourcasealsostartedwiththeabovedescribedpattern.The firstnoticedmasswason theoccipitocervicalregionwhen thepatientwas5yearsold(meanageofsymptomonset4- 5years).Itwas actuallyanincidental findingafter thepa- tientfellfromthebed.Patientcomplainedofmildpainand thenthemasswasnoticedasshegotamassageinthatarea.
Fig.6– Radiologicalexaminationat10month-onset.HOswereseenonlateralmarginofbilateralscapula,left supraclavicularandsubscapularregion,paravertebralregiononthelevelofT11-L4.6A-6Cparaspinalheterotopic
ossification(HO)observedinspineCTscanincoronalview(A),sagittalview(B),axialview(C).6D-6GparaspinalHOinplain radiograph(arrows):cervicalregion(6D-E),thoracolumbarregion(6F-G)
Othermasseswerenoticed3monthsafterontheperiscapu- larregionuntilthemostrecentontheparavertebralregion.
Thepatientstartedtodeveloplimitationonneckmovement andshouldergirdlemovement.However,otherjointwerestill withinnormalfunctionallimit[8–10].
Otherdisablingfeaturessuchasrapidlydevelopingscolio- sisassociatedwithaunilateralosseousbridgealongthespine priortoskeletalmaturitywhichcausesasymmetricalgrowth ofvertebra and cardiopulmonarydisability associatedwith thoracicinsufficiency syndrome were notidentified in the initialassessment[8–10].In6monthsfollow-up,therewasa slightincreaseinthebodytoarmdistancewhichisonesign ofscoliosis.Thecardiothoracicindex (CTI)alsoslightly in- creasedinthechestradiograph(CTI0.55,normalCTI0.4-0.5) comparedtoinitialradiograph.However,thiscouldhavebeen
causedeitherbyanactualthoracicinsufficiencysyndromeor simplyduetoinadequateinspirationduringtheexamination.
Routineevaluationsofthebonemineralmetabolismwere usuallynormal,althoughtheserumalkalinephosphataseac- tivityand theerythrocytesedimentationratemayincrease, particularlyduringflare-ups.C-reactiveproteinelevationsare amorespecifictestthanerythrocytesedimentationratefor monitoringtheacuteinflammatoryphaseofheterotopicos- sificationafterspinalcordinjuriesbuthavenotbeenstudied inFOP.Inthispatient,whichpresentinouroutpatientclinic, notatthestageofflaringwillbemorelikelytohavenormal valuesoflaboratorymeasurementsowehavetocarryoutany laboratoryexamination[6,8].
Currently,therearenoeffectivetreatmentforFOP.Present managementfocusesonearlydiagnosis,assiduousavoidance
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R a d i o l o g y C a s e R e p o r t s 1 5 ( 2 0 2 0 ) 1 6 7 – 1 7 3Fig.7– Radiologicalexaminationat16month-onset.IncreasedsizeofHOoverthelateralmarginofbilateralscapula, superiormarginofrightscapula,leftsupraclavicular,rightparavertebralcervical,bilateralparavertebralthoracolumbar.
7A-BCervicalradiographAPandlateralview;7C-DThoraco-lumbarradiographAPandlateralview;7E-FLumbo-sacral radiographAPandlateralview
of injury or iatrogenic harm,symptomatic amelioration of painfulflare-ups,andoptimizationofresidualfunction[2,3,8]. Intheearlystage,FOPismostcommonlymisdiagnosedas sarcomaandothercancers,aggressivefibromatosisorvascu- larmasses.ThedefinitivediagnosisofFOPcanbemadeby asimpleclinical evaluationthat associates rapidlyappear- ingsofttissuelesionswithmalformationsofthegreattoes.
Ourpatientpresentedafterclinicalmanifestationoccurredso wepreferredtoproceedwithconventionalradiographandCT scan.BiopsyofFOPlesionsisneverindicatedandmaycause additionalHO.Thus,wedecidednotcarryingoutabiopsyin thispatientsincetheclinicalandradiologicalfindingsinour patientwerepathognomonic[1,8].
Prevention ofsoft-tissue injury and muscle damage re- mainthe hallmark ofFOPmanagement. These includein- tramuscular injections as in immunization. Routine child- hooddiphtheria-tetanus-pertussis immunizationsadminis- tered by intramuscular injection pose asubstantial riskof permanent heterotopic ossification at the site ofinjection, whereas measles-mumps-rubella immunizations adminis- teredbysubcutaneousinjectionposenosignificantrisk.For mostindividualswithFOP,theseriesofimmunizationsatin- fancywillhavebeencompletedbeforethediagnosisofFOP hasbeenmade.However,inthoseinwhomFOPisdiagnosed ininfancy,thereisaconflictregardingintramuscularimmu- nizations.Thepatienthadbothinjectionsatearlychildhood andnoHOwasobservedonsiteofinjections[8,11].
There are many proposed potential treatments for FOP, however,theunpredictablenatureofthisdiseasehasmade controlled trials difficultto perform. According to Interna- tionalClinicalConsortiumonFOP(2011),medicationsaredi- videdinto3classesbasedontheknownmechanismofaction asitrelatestotheproposedFOPpathogenesis,experimental oranecdotalexperiencewiththedrugandalsotheknowledge ofthedrug’ssafetyprofile[8].
The first class is medication to control acute flare up suchasinflammatory-relatedsymptoms(painandswelling).
Drugsincludedinthisclasshavegenerallygoodresultsand
Table1– Classesofmedications[7].
Class Description Drugs
I Havebeenwidelyusedto controlsymptomsofthe acuteflare-upinFOP, withanecdotalreportsof favorableclinicalresults andgenerallyminimal sideeffects
Short-termuseof
high-dosecorticosteroids, anduseofnonsteroidal anti-inflammatorydrugs includingthenew anti-inflammatoryand anti-angiogeniccox-2 inhibitors
II Haveatheoretical applicationtoFOP,are approvedforthe treatmentofother disorders,andhave limitedand
well-describedeffects.
Leukotrieneinhibitors, mastcellstabilizers,and aminobisphosphonates (Pamidronate;
Zoledronate)
III Investigationalnewdrugs Signaltransduction inhibitors,monoclonal antibodiestargeting ACVR1,andretinoicacid receptorgammaagonists (presentlyunder development)
minimal side effects (ie, short-term corticosteroids, nons- teroidal anti-inflammatory drugs, or the newer generation suchasanti-angiogeniccox-2 inhibitors).Thesecond class includesmedicationsthataretheoreticallywillgivepositive effectforFOPthatalsohavebeenusedsafelyforotherdis- easeswithlimitedandwell-describedeffects(ie,leukotriene, amino-bisphosphonates,mastcellstabilizer).Thethirdclass includesdrugswhicharestillunderinvestigationsuchassig- naltransductioninhibitors,monoclonalantibodiestargeting ACVR1,andretinoicacidreceptorgammaagonists[8].
We hadprescribed class Imedication foran acuteflare up and planned to prescribe bisphosphonates as class II medicationbasedonitsavailabilityinourcountry.Thispa-
shouldbeawareoftheearlyfeatureofFOP.Earlydiagnosis preventscatastrophicharmfuldiagnosticandtreatmentpro- cedures.Theprogressivenatureofthisdiseaseisdifficultto stopbutweshoulddelayitasmuchaspossiblebypreventing muscletrauma,givingdiseasemodifyingagentandlong-term physiotherapytocounterfurtherdisabilitieswhichwilleven- tuallydevelop.
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