颌骨骨纤维异常增殖症的诊断与治疗

骨纤维异常增殖症（osteofibrousdysplasia）是一种先天性、非遗传性疾病，属骨肿瘤样病损。其骨髓和网状骨被纤维结缔组织和不规则骨所代替，并非真性肿瘤。该病占全身骨肿瘤及瘤样病变的5.89%，颌骨常常受累，占全身病变的27.3%。全面系统地了解该病，对于临床诊断与治疗有很大帮助。骨纤维异样增殖症属于骨发育异常疾病，可累及单骨或多骨，其病因尚未完全明确。综合各种文献资料，骨纤维异样增殖症的发生与基因突变、白细胞介素－6、染色体和形态学异常、骨发育异常、干细胞疾病等有关，其病因及发病机制的研究已经进入基因水平的基础阶段，相信随着各种新技术的运用，骨纤维异样增殖症的病因及发病机制会被逐渐认识。目前的研究认为，Gs蛋白的α亚单位突变，可导致骨纤维发育异常。突变为错意突变，而且是合子后突变，呈体细胞镶嵌体状态。编码Gs蛋白的α亚单位的GNAS1基因第8外显子G→A或C→T突变，导致Gs蛋白的α亚单位第201位氨基酸由精氨酸替换为组氨酸或半胱氨酸。G蛋白为偶联蛋白，是异三聚体，在G蛋白介导的跨膜信号传导中起关键作用；而Gsα亚基由Ras样结构域即GTP酶结构域和α-螺旋区结构域组成。GTP酶结构域由6个β-片层包围5个α-螺旋（α1～α5）组成，其中β2反向平行排列，α-螺旋区结构域由1个长的中心螺旋（αA）及5个短螺旋（αB～αF）组成，并通过2个延伸链与GTP酶结构域相连。GTP酶结构域还包含3个开关元件，GTP是Gsα3个开关元件的组织中心。在GTP水解时，Gsα发生空间结构重排，与开关元件密切相关，并且开关元件与Gsα、β、γ分离，与细胞膜及效应器作用有关。值得注意的是，在Gsα中，Arg201位于开关元件Ⅰ部位4。GNAS1isthegenethatisresponsibleforthealphasubunitoftheGproteinthatactivatesadenylylcyclase.Thisgeneisfoundonchromosome20.Activatingmutationsofthisgeneareresponsibleforcellularproliferationofendocrinetissuesandthebonylesionsoffibrousdysplasia.InactivatingmutationscreateresistancetohormonalsignalsinsuchdiseasesasAlbright'sHereditaryOsteodystrophy.Inresponsetoahormoneligand,thealphasubunitoftheGproteinactivatesadenylatecyclasetoformcyclicampthatthenactivatesanumberofintracellularprocesses.ThemutationofGNAS1foundinfibrousdysplasiaconstitutivelyactivatesthealphasubunit.Dependingontheinvolvedtissuethiscancreateendocrinehyperfunctionorthebonylesionsoffibrousdysplasia.Itisthoughtthatmutationsinthisgenewhichoccurearlyinembryologicaldevelopmentleadtodiffusediseaseandthatlatermutationscausesuchlimiteddisordersasfibrousdysplasiaandmayberesponsibleforsomepituitaryandthyroidtumors.Thismutationhasbeenfoundinblood,liverandheartinsomepatients,and,whileuncommon,cardiacarrhythmiaandhepaticdisordershavebeenreportedinconjunctionwithfibrousdysplasia.1临床分类骨纤维异样增殖症通常分为3型：（1）单骨型（monostotic），单个或多个病损累及一个骨者，颅面骨发病率高；（2）多骨型不伴内分泌紊乱（polyostotic），多个损害累及一个以上的骨，分布在单一肢体或身体一侧；（3）多骨型伴内分泌紊乱（McCuneAlbrightsyndrome，apolyostoticformoffibrousdysplasiathatalsoinvolvesendocrineabnormalities），即Albright综合征。损害散布于全身多个骨，伴皮肤色素沉着，性早熟（disseminatedbonylesions,hyperpigmentedskinlesions,andendocrinedysfunctionwithprecociouspubertyinfemales）。

2临床表现多见于年轻人，病程发展缓慢，男女发病比2∶1～1∶3。颌面部主要表现为局限性、无痛性骨隆起，常偶然发现。如逐渐增大，可致面部畸形，使邻近组织器官受压移位，牙错位、移位，但不松动，语音不清，鼻塞，流泪等。膨胀区的软组织正常，当伴有牙源性感染时，局部可有疼痛。皮肤和黏膜异常的色素沉着是骨纤维结构不良最常见的骨外表现，单骨型偶见，其余两型多见。

3实验室检查3.1X线平片：骨纤维异样增殖症X线表现多种多样，但单骨型和多骨型的表现相似，一般分为4型。（1）毛玻璃样型：最多见，特别是上颌骨病变，上颌窦腔变暗，边界不清，与窦腔各壁融为同一密度，呈均匀一致的中等密度影，似磨砂玻璃状。（2）硬化型：钙化程度高，不均匀，有较致密的絮团状影。（3）囊状型：有单囊，也可见多囊。表现为不规则的似囊腔状透射区，边缘不光滑，与正常骨组织界限不清，囊内可见少数钙化不等的点状致密影。（4）混合型：表现为大小不等的致密片团影和不规则的透射影相间杂。由于病变是渐进性向正常骨过渡，无包膜，故与正常骨分界不清。3.2　CT扫描：CT扫描有助于X线平片不典型病变的诊断，并能准确反映病变范围。二维CT表现：（1）受累骨膨胀增厚；（2）病变密度多样化，密度均匀或不均匀；（3）冠状位扫描能更好地显示牙槽骨、硬腭、颌骨的受累情况。三维CT表现：能立体地显示颌面部的情况，图像形象直观，类似颅骨大体标本的照片。3.3　MRI检查：骨纤维异样增殖症磁共振显像表现为骨轮廓增大，T1相减弱，T2相变化较大，在判断病变范围及骨纤维结构不良恶变、确定手术方案等方面有与X线不可比拟的价值。Theirregular,misshapentrabeculaeformoddgeometricpatternsandaredescribedas"Chineseletters."Threetypesofradiographicappearancehavebeendescribedforfibrousdysplasia.Thefirstandmostcommonis"Pagetoid,"duetoitssimilarityofappearancetoPaget'sdiseaseofbone.Theselesionshaveincommonacharacteristic"GroundGlass"appearancewithcoexistingradiodenseandradiolucentareas.Pagetoidlesionsofteninvolvethecalvarium.Spiculesofnewboneareresponsibleforthewell-known"groundglass"appearanceofthefibrousregiona.Twenty-fivepercentoffibrousdysplasialesionshaveascleroticappearance.CTrevealsanon-homogeneousthickeningofbone,andT1MRIrevealsanon-homogeneouslesionofintermediatesignalintensity.CTisthepreferredmodeofimaginginthesebonylesions.OnT1MRI,fibrousdysplasiaappearsasnon-homogeneouswithintermediatesignalintensity.OnT2weightedMR,thelesionsarenon-homogeneouswithlowtointermediatesignalintensity.Theturbinateswellingisincidental.3.4　核素扫描：放射性核素全身显像对多骨病变的检出有独特价值。骨纤维异样增殖症无论是单骨型还是多骨型，其病变部位都表现为放射性核素异常浓聚区，与X线平片密度增高区相一致。对于多骨型，X线检查需多次拍片才能检出全身多发性病变，患者受照剂量很大，而骨显像仅一次扫描就可获得全身骨骼图像。4鉴别诊断4.1　骨化纤维瘤；主要侵犯下颌骨，多见于女性，发病年龄15～26岁，发展快慢不一，导致面部畸形。X线片上呈轮廓清晰而膨大透明的外观，中心可为斑点状影。病变有包膜，与周围正常骨界限分明。4.2　成釉细胞瘤：多发生于成人，无性别差异，下颌骨多见。生长缓慢，逐渐出现颌骨膨大，面部畸形。与骨纤维结构不良不同的是：肿瘤可使牙松动或脱落，还可突破骨板侵入到软组织内。X线表现为多房透光区，界清，有分叶和切迹，牙根呈锯齿状吸收或有截根现象。4.3　颌骨巨细胞瘤：多发生于30岁以上，无性别差异，以下颌骨前部和前磨牙区多见。其生长缓慢，颌骨肿大畸形，牙松动、移位，咬合错乱，晚期可出现病理性骨折；而颌骨骨纤维结构不良未见有病理性骨折的报道。X线表现病变区呈肥皂泡沫样改变。Numberoneonthedifferentialdiagnosisisossifyingfibroma.However,fibrousdysplasiamayalsoclinicallyorradiographicallyresemblePaget'sdiseaseofbone,aneurysmalbonecyst,giantcelltumor,orthebrowntumorofhyperparathyroidism.Thedistinctionismadebasedonthecombinationofclinicalpicture,radiographicfindings,andhistology.Histologically,ossifyingfibromaischaracterizedbyamixtureofmature-appearinglamellarboneandfibrousstroma,asopposedtotheimmaturewovenboneoffibrousdysplasia.Theosseouscomponentsherearerimmedwithosteoblasts,unlikefibrousdysplasiathatlacksnormalosteoblasticrimming.Plainradiographsdepictanossifyingfibromaoftheleftfronto-orbitalregion.Notethethickhyperostotic"cap."Thislesion'sappearancediffersfromcysticlesionsoffibrousdysplasiainthatthemarginsareseverelyhyperostiticandthecentralportionisisodensewithnormalbone,ratherthanradiolucentasexpectedinfibrousdysplasia.Paget'sdiseaseisanessentiallybenignprocessofdisorderedboneproductionandresorption.Itisfoundwithintheaxialskeletonandoccursin11%ofpersonsover80yearsofage.Itcreatesosteoblasticandosteolyticlesionsthatradiographicallyarevirtuallyindistinguishablefromfibrousdysplasia.Histologicallyitischaracterizedbylamellarbonesurroundedbynumerousosteoblastsandfewosteoclasts.DrRobertFechnerfromthePathologyDepartmentattheUniversityofVirginiaconsidersfibrousdysplasiaandossifyingfibromatobeonacontinuousspectrumofhistopathology.Oftenspecimenswillnotfalleasilyintoacategoryandapathologistwillreturnadiagnosisof"benignfibro-osseouslesion."Clinicalinformationisveryimportantinmakingthedistinction.Ageofonsetisbefore25yearsin90%offibrousdysplasiapatients,andover25in90%ofossifyingfibromapatients.Thereisasignificantfemalepredilectionwithossifyingfibroma,andlesionstendtobesmallerinossifyingfibroma.Mandibularinvolvementismuchmorecommoninossifyingfibroma;however,itisfarfromuncommoninfibrousdysplasia.5治疗骨纤维异样增殖症的治疗取决于患者的年龄、病变部位、范围及严重程度、有无功能障碍等。一般只能采用外科手术的方法，病变小而局限时，可单纯切除；如果范围大，可行目的在于恢复美观和功能的成形手术。对于儿童的手术，尽可能推迟到青春期后进行，此时病变已趋于稳定，过早手术可能导致反复或面部畸形。Radiationiscontraindicatedasithasbeenfoundtoincreasetherateofmalignancyarisingfromfibrousdysplasiaby400times.Expectantmanagementisbasedonthepossibilitythatthediseaseprocesswillsloworsubsideattheonsetofpuberty.Conservativesurgicalmanagementconsistsofshaving,reshapingandexcisinglesionsastheybecomeproblematic.Indicationsareprogressivedeformity,compromiseoffunction,painorsuspicionofmalignancy.Anexamplewouldbeopticcanalunroofingfromcompressionorthreatenedcompressionoftheopticnerve.Radicalresectionisbasedontheprinciplethatthisisalocalizeddiseaseprocess.Theoretically,removalofallinvolvedtissueshouldbecurative.ChenandNoordhoff'sZone1consistsofthefrontal,orbital,nasal,ethmoid,zygomaticanduppermaxillaryareas.Itisthemostevidentpartoftheface.Zone1lesionsareconsideredtobeamenabletoradicalexcisionandreconstructionwithautogenousbonegraft.In1990,ChenreportedsuccessfulresectionforcureandreconstructionofZone1lesionsinfiveof14patients.Zone2isthehair-bearingcranium.Thisareaisalsoamenabletoradicalresection.However,deformitiesofthisregionarelesscosmeticallyobvious,soconservativesurgicalshavingisthemodalityrecommendedbyChen.Zone3comprisesthebaseofskullregionincludingthemastoid,petrousandpterygoidregions.Thisisadangerousareaforexplorationduetothepresenceofcranialnervesandlargevessels.Treatmentisconservative,withsurgeryonlyassymptomsariseorincasesofwheresomestructures,suchastheopticnerveareendangered.Zone4isthetooth-bearingbones,themaxillaryalveolarboneandthemandible.Treatmentisconservative,basedontheprinciplethatresectionwillnecessitatedentures,whicharenotasfunctionalasnaturalteeth.Surgicalshavingisthereforepreferred.近年来，采用降钙素（calcitonin）或帕米膦酸钠（pamidronate）治疗单骨型骨纤维异样增殖症（monostoticfibrousdysplasia），取得了令人振奋的疗效。二磷酸酯是骨破坏的有效抑制剂，其化学结构来源于焦磷酸盐的核心，不同的分子机制导致成熟的破骨细胞失活和脱噬作用增强，从而减少骨溶解。Parisi等对7例FD患者（平均年龄26岁）静滴帕米膦酸钠（每天60mg，共3天），每6个月一次。每2～3个月评估临床症状、血清碱性磷酸酶、尿I型胶原C－末端交联端肽水平。治疗前和12个月时，分别测量全身骨矿物质密度（BMD），并作FD病变区X线检查。发现FD病变区平均BMD较对侧减少11.4%。治疗12个月时，所有患者骨疼痛缓解，骨代谢标志物下降，全身骨平均BMD上升33.3%，FD病变区BMD升高6.8%，而对侧升高2.6%。Isaia等、Chapurlat等也分别报道了相似结果，X线片显示骨皮质增厚。Kos等治疗6例12～19岁青少年患者，静滴帕米膦酸钠1mg/kg，连续3天，间隔4～6个月重复一次。结果，所有患者疼痛缓解，炎症消失；3例病变稳定，3例病变缩小。X线检查显示病变缩小，原骨吸收区有新骨充填，局部骨密度增高，未见病变扩展。除发热（38℃～40℃）外，无其他不良反应。治疗期间，血生化检测指标正常。降钙素和1,25-（OH）2一VD）3已被联合应用于FD的治疗。Yasuoka等发现，手术治疗前应用降钙素使骨局部钙化，可以达到减少术中出血的目的。静滴帕米膦酸钠期间，需同时补充钙和VitD，长期使用安全可靠。具体使用方法：临用前，将帕米膦酸钠用不含钙离子的0.9%生理盐水或5%葡萄糖液稀释，缓慢静滴4h以上，浓度不得超过15mg/125ml，滴速不得大于15～30mg/2h。连续3天为1个疗程，第1天0.5mg/kg，第2天和第3天1mg/kg。以后间隔4～6个月重复使用，每天1～1.5mg/kg，连续3天。一次用量30～60mg。参考文献1.YasuokaT,TakagiN,HatakeyamaD,YokoyamaK.Fibrousdysplasiainthemaxilla:possiblemechanismofboneremodelingbycalcitonintreatment.OralOncol.2003;39（3）:301-5.2.KosM,LuczakK,GodzinskiJ,KlempousJ.Treatmentofmonostoticfibrousdysplasiawithpamidronate.JCraniomaxillofacSurg.2004;32（1）:10-5.3.ChapurlatRD,HuguenyP,DelmasPD,MeunierPJ.Treatmentoffibrousdysplasiaofbonewithintravenouspamidronate:long-termeffectivenessandevaluationofpredictorsofresponsetotreatment.Bone.2004;35（1）:235-42.4.IsaiaGC,LalaR,DefilippiC,MatarazzoP,AndreoM,RoggiaC,PrioloG,deSanctisC.BoneturnoverinchildrenandadolescentswithMcCune-Albrightsyndrometreatedwithpamidronateforbonefibrousdysplasia.CalcifTissueInt.2002;71（2）:121-8.5.ParisiMS,OliveriB,MautalenCA.Effectofintravenouspamidronateonbonemarkersandlocalbonemineraldensityinfibrousdysplasia.Bone.2003;33（4）:582-8.6.ChapurlatRD.Medicaltherapyinadultswithfibrousdysplasiaofbone.JBoneMinerRes.2006;21Suppl2:P114-9.Review.7.MäkitieAA,TörnwallJ,MäkitieO.Bisphosphonatetreatmentincraniofacialfibrousdysplasia--acasereportandreviewoftheliterature.ClinRheumatol.2008;27（6）:809-12.8.LeetAI,CollinsMT.CurrentapproachtofibrousdysplasiaofboneandMcCune-Albrightsyndrome.JChildOrthop.2007;1:3-17.9.PlotkinH,RauchF,ZeitlinL,MunnsC,TraversR,GlorieuxFH.Effectofpamidronatetreatmentinchildrenwithpolyostoticfibrousdysplasiaofbone.JClinEndocrinolMetab.2003;88（10）:4569-75.Intravenousinfusionswiththebisphosphonatecompoundpamidronatedecreasebonepainandreportedlycanleadtorefillingofdysplasticlesionsinadultswithfibrousdysplasia（FD）ofbone.Herewedescribetheeffectsofthistreatmentapproachin18childrenandadolescents（ageatstartoftherapy,6.2-17.5yr;eightgirls）withpolyostoticFD,whoreceivedpamidronatefor1.2-9.1yr（median,3.8yr）.Treatmentcycleswithpamidronate（1-1.5mg/kg.don3consecutivedays）weregivenevery4months.LevelsofserumalkalinephosphataseandurinarycollagentypeIN-telopeptidewereelevatedatbaselineanddecreasedcontinuouslyduringthefirst3yroftherapy.Therewasnoradiographicevidenceoffillingoflyticlesionsorthickeningofthebonecortexsurroundingthelesionsinanypatient.Histomorphometricresultsindysplasticbonetissueofpatientsreceivingpamidronate（n=7;timeoftherapy,1.4-4.8yr）weresimilartothoseofpatientswithoutmedicaltherapy（n=9）.Noserioussideeffectswerenoted.Inconclusion,pamidronatetherapyappearstobesafeinchildrenandadolescentswithpolyostoticFD.However,wefoundnoclearevidencethatpamidronatehasaneffectondysplasticlesionsinsuchpatients.骨纤维结构不良的研究进展（PDF）EffectofPamidronateTreatmentinChildrenwithPolyostoticFibrousDysplasiaofBone（PDF）FibrousdysplasiabyCarrieA.Roller（PDF）Craniofacialfibrousdysplasia（PDF）