Early stage fibrodysplasia ossificans progressiva - iKnow

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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.

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:[email protected](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

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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 3

Fig.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

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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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Fig.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.

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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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Fig.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-

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shouldbeawareoftheearlyfeatureofFOP.Earlydiagnosis preventscatastrophicharmfuldiagnosticandtreatmentpro- cedures.Theprogressivenatureofthisdiseaseisdifficultto stopbutweshoulddelayitasmuchaspossiblebypreventing muscletrauma,givingdiseasemodifyingagentandlong-term physiotherapytocounterfurtherdisabilitieswhichwilleven- tuallydevelop.

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