UltrasoundObstetGynecol:377 - PDF document

UltrasoundObstetGynecol:377–384PublishedonlineinWileyInterScience(www.interscience.wiley.com).Fetalmicrognathia:almostalwaysanominousÞndingD.PALADINIFetalMedicineandCardiologyUnit,DepartmentofObstetricsandGynecology,UniversityFedericoIIofNaples,Naples,ItalyCorrespondence(e-mail:paladini@unina.it) WHYANEDITORIALONMICROGNATHIA?Thefetalmandibleisacommonsitefordefectsinducedbyalargenumberofgeneticconditionsandadverseenvironmentalfactors.Itscomplexdevelopment,describedbrieybelow,requiresseveralelementsfromdifferentembryoniccomponentstointeractandfuse,bothamongthemselvesandwiththecranialneuralcrestcells;thismultistepprocessishighlysusceptibletoaseriesofmolecularandgeneticinsults.Theseelementsexplain ofthemasticatorymuscles,growthofthetongue,theinferioralveolarnerveanditsbranches,anddevelopmentandmigrationoftheteeth.Animportantroleinthisdevelopmentalprocessisalsoplayedbythecranialneuralcrestcells,acellpopulationthatoriginatesinthedorsal Table1Syndromicconditionsprimarilyinvolvingthemandible OtherfeaturespotentiallyinuteroPrenataldiagnosisreported AcrofacialdysostosisPreaxiallimbdeÞciencies,CHD,CNSanomaliesADYesTreacher–Collins(Franceschetti)typeRodrigueztypePreaxiallimbdeÞciencies,CHDARYesNagertypeMicrocephaly,preauriculartags,CHD,preaxiallimbdefects:radialaplasia,syndactyly,missingtoesSporadicYesMiller(Genee–Wiedemann)Syndactyly,thumbhypoplasia,postaxiallimbdefects:AR—typeorPOADS(postaxial)absenceoffthdigitBranchio-oculofacialS.Microcephaly,earanomalies,hypertelorism,,renalanomalies,polydactyly,vermianagenesisADYesCerebrocostomandibularS.,CHD,smallthorax,abnormalribsrenalectopia,polyhydramniosAD-ARYesMandibuloacraldysplasiaJointcontractures,widecranialsuturesAR—OrofaciodigitalIS.Facialasymmetry,biÞdtongue,polycystickidney,syndactyly,CNSanomaliesX-linkeddominantYesOrofaciodigitalIIS.(Mohr)Hypertelorism,polydactyly,porencephalyARYesOromandibular-limbhypogenesisAcralhypoplasia,syndactylySporadic—OtopalatodigitalS.,TypeIIHypertelorism,omphaloceleX-linkeddominant—Robinsequence(Glossoptosis,cleftpalate)Yes Mostcommonsignsinthefetusareinitalics.AD,autosomaldominant;AR,autosomalrecessive;CHD,congenitalheartdefects;CNS,centralnervoussystem;POADS,postaxialacrofacialdysostosis;S.,syndrome.Table2Skeletalandneuromusculardiseasesfrequentlyassociatedwithmicrognathia OtherfeaturespotentiallyinuteroPrenataldiagnosisreported Achondrogenesis,TypesIAandIBSevere,shortribsARYesAmyoplasiacongenitadisruptiveDiffusejointcontractures,gastroschisis,polyhydramniosSporadicYesAtelosteogenesis,TypeIFrontalbossing,midfacehypoplasia,smallthorax,SporadicYes11ribs,,talipes,CampomelicdysplasiaLargeanteriorfontanel,hypertelorism,CHD,,sexreversalinmales,hydronephrosis,oftibiaeandlesssooffemoraADYesal(COFS)S.Microcephaly,,CHDanomalies,ARYesChondrodysplasiapunctata,X-linkeddominanttypeMicrocephaly,rhizomeliaX-linkeddominantYesDiastrophicdysplasiaHitchhikerthumbs,scoliosis,shortlimbsARYesLangermesomelicdysplasiaARYesMultiplepterygiumS.Pterygiaofneck,axillae,antecubitalregion,poplitealARYesNeu–LaxovaS.Microcephaly,exophthalmos,CNSanomalies,jointcontractures,syndactyly,subcutaneousedemaARYesPena–Shokeirphenotype(FADS)Diffusejointcontractures,cystichygroma,microstomiaARYes Mostcommonsignsinthefetusareinitalics.Micrognathiaoccasionally.AD,autosomaldominant;AR,autosomalrecessive;CHD,congenitalheartdefects;FADS,fetalakinesiadeformationsequence;S.,syndrome.microstomia,duetoparalysisofthemouthorbicularAgnathiaisthemostsevereformofmandibularmaldevelopment.Alsoknownasotocephaly,thisisanexceedinglyrareanomalyinwhichthereiscompletederangementoffacialdevelopment,withagenesisorseverehypoplasiaofthemandible,juxtapositionofthetemporalbonesandabnormalpositionoftheears,whicharehorizontalandmayalsobefused.Thepostulatedpathogeneticmechanismisacompletearrestofmandibulardevelopment,whichwouldinducetheother2010ISUOG.PublishedbyJohnWiley&Sons,Ltd.UltrasoundObstetGynecol:377–384. Table3Chrosomomalsyndromesfrequentlyassociatedwithmicrognathia OtherfeaturespotentiallyinuteroPrenataldiagnosis Cat-eyeS.Preauriculartags,TAPVR,renalagenesisADinvdup(22)(q11)YesDeletion3pS.Microcephaly,malformedears,polydactylyoftheDel3p—Deletion4pS.(Wolf–Hirshhorn)Hypertelorism,preauriculartags,CHD,polydactyly,CNSanomaliesIsolated,4p16.3YesDeletion5pS.(Criducat)Microcephaly,hypertelorism,CHD5p15.2YesDeletion9pS.Trigonocephaly,abnormalears,hypertelorism,CHDAD,isolated—Deletion11qS.Trigonocephaly,microcephaly,jointcontractures—Deletion13qS.Microcephaly,CHD,small/absentthumbsIsolated—Deletion22q11.2S.ConotruncalCHD,thymusaplasiaADYesMonosomyX(Turner)S.Left-sidedCHD,cystichygromaSporadicYesPallister–KillianS.Thinupperlip,CDH,CHD,CNSanomalies,SporadicYesTriploidyS.IUGR,hypotonia,hypertelorism,syndactyly,CHD,CNSanomaliesSporadic,69,XYYYesTrisomy8mosaicS.Hypertelorism,jointcontracturesSporadicYesTrisomy9mosaicS.Jointcontractures,CHDSporadicYesTrisomy13S.IUGR,microcephaly,microphthalmia,cleftlip/palate,CNSanomalies(HPE),CHD,renalanomalies,polydactylySporadicYesTrisomy18S.Clenchedhands,CHD,omphalocele,renalanomalies,CHDanomaliesSporadicYes Mostcommonsignsinthefetusareinitalics.Micrognathiaoccasionally.AD,autosomaldominant;AR,autosomalrecessive;CDH,congenitaldiaphragmatichernia;CHD,congenitalheartdefects;CNS,centralnervoussystem;del,deletion,invdup,inverseduplication;HPE,holoprosencephaly;IUGR,intrauterinegrowthrestriction;S.,syndrome;TAPVR,totalanomalouspulmonaryvenousreturn.MicrognathiaandretrognathiaBothmicrognathiaandretrognathiainvolveabnormal,arresteddevelopmentofthemandible,buttheformerreferstothesizeofthemandiblewhereasthelatterreferstoitspositioninrelationtothemaxilla.Inmostcases,thesetwoabnormalitiesareconcurrent,asasmallmandibleisbydenitionabnormallypositioned.However,theoppositeisnotalwaystrue:thereareraresituationsinwhichthereisretrognathiabutnotNormalfetalmandibleThefetalmandiblecanbestudiedbyultrasoundfrom10weeksofgestationvirtuallyuntilterm,ifthepositionofthefetalheadisfavorable.Axialplanesinparticularareusedtoassessthemandibularbone(Figure1a),thealveolarridge(Figure1b)andtherami(Figure1c);theuppermostplanecorrespondstothemaxilla(Figure1d).Three-dimensionalultrasoundallowsprecisealignmentoforthogonalplanesinwhichaccuratemeasurementscanbemadeandallowscreationofrenderedcastsoftheirregularlyshapedmandibularbone(Figure2).Severalgrowthchartsofthemandiblehavebeenpublishedoverthelast10years,derivingmeasurementsfromtwo-dimensionalandthree-dimensionalimagesTheprenatalultrasounddiagnosisofmicrognathiacanbemadesubjectivelyorobjectively.Subjectivediagnosisiscarriedoutbyevaluatingthemidsagittalviewofthefacialproleandassessingthegeometricrelationshipbetweenthemandibleandtherestoftheprole(Figure3).Toassistinobjectivediagnosis,anumberofstudieshavereportedtheuseofindices,ratiosorfacialangles.Inparticular,thetwomostreportedmethodsaretheinferiorfacialangle(IFA)andthejawindex.Theformerismeasuredinamidsagittalviewofthefetalproleatthecrossingoftwolines:oneorthogonaltotheverticalpartoftheforehead,drawnatthelevelofthesynostosisofthenasalbones;andasecondjoiningthetipofthementumandtheanteriorborderofthemoreprotrusivelip.Itsnormalvalueis65(SD,8.Thejawindexismeasuredonanaxialviewofthefetalmandible.Alineisdrawnconnectingthebasesofthetworami(laterolateraldiameter)andtheanteroposteriordiameteristhenmeasured,drawingasecondlinefromthesymphysismentistothemiddleofthelaterolateraldiameter.Thisvalueisnormalizedtothebiparietaldiametertoderivearatio(thejawindex)whichisindependentofgestationalage.Intheoriginalarticlesdescribingthem,bothratiosprovedeffectiveindiagnosingmicrognathia:sensitivityandspecicitywere100%and98.9%fortheIFAand100%and98.7%forthejawindex.Inmyownrecentseriesof19cases,thetwomethodsshowedfaircorrelation(Figure4).TheadvantageoftheIFAisthatitcanbealsomeasuredretrospectivelyonamidsagittalviewofthefetalprole;however,ifthefetalpositionis2010ISUOG.PublishedbyJohnWiley&Sons,Ltd.UltrasoundObstetGynecol:377–384. Table4Othernon-chromosomalsyndromicconditionsassociatedwithmicrognathia SyndromicconditionOtherfeaturespotentiallyinuteroPrenataldiagnosisreported Aniridia–WilmstumorassociationNephroblastoma(Wilms)AD(11p13)Baller–GeroldS.Hypertelorism,microstomia,CHD,renalanomalies,absentradius,absentthumbsAR—CarpenterS.partialsyndactyly,polydactyly,CHDAR—deLangeS.Microcephaly,CHD,CDH,renalAD,isolated—DubowitzS.Microcephaly,microphthalmiaAR—Femoralhypoplasia-unusualfaciesS.Focalfemoralhypoplasia,cleftlip/palatemaxillaryhypoplasiaSporadicYesFetalaminopterin/methotrexateS.Microcephaly,mesomelia,talipesSporadic—FetalvalproateS.CHD,jointcontracturesSporadic—FrynsS.,microphthalmia,omphalocele,GIanomalies,renalCNSanomaliesARYesHallermann–StreiffS.Microcephaly,microstomia,widecranialSporadic—HydrolethalusS.Microphthalmia,,CDH,polydactylyARYesLenz–MajeweskihyperostosisS.Hypertelorism,macrocephaly,syndactylySporadic—Marden–WalkerS.Microcephaly,widecranialsutures,dextrocardia,kidneyanomalies,jointcontractures,CNSanomaliesAR—Marshall–SmithS.Cataract,hypertelorism,atnasalbridgeAD—Meckel–GruberS.Encephalocele,CNSanomalies,polycystickidneys,polydactylyARYesMelnick–NeedlesS.Largefontanel,omphalocele,bowedmesomelicbones,clubfeetX-linkeddominant—Miller–DiekerS.,CHD,duodenalatresia,omphalocele,renalanomalies,ADYesMoebiussequenceMicrophthalmia,limbdeformitiesADisolated—NoonanS.Cystichygroma,enlargedNT,CHD,abnormalductusvenosusSporadicYesOculo-auriculovertebralspectrumHemifacialmicrosomia(microtia,preauriculartagsSporadicYesOpitzG/BBBS.CHD,renalanomalies,CNSanomaliesAD—Pallister–HallS.IUGR,microphthalmia,microtia,CHD,micropenis,hemivertebrae,polydactylyAD—Peters’plusS.IUGR,rhizomelia,CHDARYesRadialaplasia-thrombocytopenia(TAR)S.Bilateralradialaplasia,hypoplasiaofulnaeARYesRestrictivedermopathyHypertelorism,jointcontracturesrocker-bottomfeet,polyhydramniosARYesRetinoicacidembryopathyMicrotia,CHD,CNSanomaliesSporadic—Roberts-SCphocomeliaIUGR,cleftlip/palate,ARYesRubinstein–TaybiS.beakednose,abductedandlargethumbs/toes,CNSanomaliesSporadicYesSeckelS.Microcephaly,arachnoidcysts,beaked,talipesARYesSmith–Lemli–OpitzS.Microcephaly,syndactyly,genitalandrenalanomalies,CHD,talipesARYesToriello–CareyS.Agenesisofcorpuscallosum,CHDARYesYunis–VaronS.IUGR,microcephaly,largefontanels,agenesisofthumbs/toes,absence/hypoplasiaofclavicle(s)AR—ZellwegerS.CNSanomalies,largefontanels,contractures,hepatomegalyAR— Mostcommonsignsinthefetusareinitalics.Micrognathiaoccasionally.AD,autosomaldominant;AR,autosomalrecessive;CDH,congenitaldiaphragmatichernia;CHD,congenitalheartdefects;CNS,centralnervoussystem;GI,gastrointestinal;IUGR,intrauterinegrowthrestriction;NT,nuchaltranslucency;S.,syndrome.2010ISUOG.PublishedbyJohnWiley&Sons,Ltd.UltrasoundObstetGynecol:377–384. Editorial Figure1Volumecontrastimagingofanormalfetalmandibleat28weeksofgestation:axialviewsatdifferentlevels.(a)Thelowermostplaneisusedtoassesstheacutelyangledmandibularbone;thesymphysisisevident(arrowhead)asaretherami(arrows);(b)aplanejustcranialtothatofthemandibularboneshowsthealveolarridge,withtherami(arrows);(c)ahigherplaneatthelevelofthetongue(T)demonstratestherami(arrows);(d)theuppermostplaneshowsthemaxillaryalveolarridge.notfavorable,theIFAcannotbemeasured.Incontrast,thejawindexcanbemeasuredevenifthefetalproleisnotreadilyvisible,becauseitrequiresonlyanaxialviewofthemandible.However,occasionally,shadowingfromonesidemayreducevisualizationofthewholemandibularbone,makingmeasurementlessprecise.SYNDROMICCONDITIONSASSOCIATEDWITHMICROGNATHIAINTHEFETUSTherearemanysyndromesassociatedwithmicrognathia.AsevidentfromTables1–4,diseasesthatareassociatedwithimpairedmandibulardevelopmentcanbeclassi-edintofourgroups:primarymandibulardisorders(Table1),skeletalandneuromusculardiseases(Table2),chromosomalaberrations(Table3),andavarietyofothernon-chromosomalsyndromicconditions(Table4).TherstgroupofdiseasesincludestheRobin,thevariousformsofacrofacialdysos-tosis(Treacher–CollinsorFranceschetti,Rodriguez,Nager,MillerorGenee–Wiedemann)andorofaciodigitalsyndromes.Amongskeletaldysplasias,duetothexedcontractureofthetemporomandibularjointtherecanbe2010ISUOG.PublishedbyJohnWiley&Sons,Ltd.UltrasoundObstetGynecol:377–384. 382 Figure2Three-dimensionalrendering(maximummode)ofthenormalfetalmandibleat20weeksofgestation.(a)Frontalview,withsymphysisindicatedbythearrowhead;(b)lateralobliqueview,withcoronoid(arrow)andcondylar(arrowhead)processesclearlyvisibleavariabledegreeofmandibularhypoplasiapresentinachondrogenesisandcampomelicdysplasia,occasionallyindiastrophicdysplasia,andintheentiregroupofneu-romuscularconditions.However,thegroupofdiseasesthataccountsformostcasesofmicrognathiainthefetusischromosomalaberrations.Infact,micrognathiahasbeenreportedatautopsyin80%ofcasesoftrisomy18andtriploidyand,conversely,anabnormalkaryotypehasbeenfoundin66%offetuseswithmicrognathiaMygroup’sguresdiffersomewhatfromthosereportedbyNicolaidesetalin1993,possiblyduetothetimeelapsedsincethenandthehigherprenataldetectionratesofthevariousnon-chromosomalconditionsassociatedwithmicrognathia.Combiningthehistoricserieswepub-lishedroughly10yearsagowithcasesdiagnosedoverthelast10yearsinourFetalMedicineUnitgivesatotalof50casesofmicrognathia.Twenty-two(44%)ofthesewereassociatedwithchromosomalaberrations,including17casesoftrisomy18,twocasesoftrisomy13andonecaseeachofdel4p(criduchat),del5p(Wolf–Hirshhorn)andtrisomy16p.Ofnote,theassociationwithanabnor-malkaryotypewas82%inthehistoricseriesof11cases(9/11)and31%inthemorerecentseries(12/39),whereintherewasaprevalenceofneuromusculardiseases(FADSandrelateddisorders)andnon-chromosomalsyndromes(e.g.acrofacialdysostosis,orofaciodigitalsyndrome)inadditiontotheclassicRobinsequence.Alsoofnote,asforotherconditions,withtheincreaseduptakeofnuchaltranslucency(NT)screeningforaneuploidies,themostseverecasesofmicrognathiatendtobediagnosedatthetimeoftheNTscan(Figure5).MAKINGAPROGNOSISThemostimportantstepstotakewhenmicrognathiaisdetectedinthefetusare:1)tocheckwhetherthereareassociatedanomaliesthatmaypointtoanon-chromosomalsyndrome;2)todeterminethekaryotypeinordertoexcludeprimarilytrisomy18butalsotheotherabnormalarrangementsthatmaybeassociatedwithmicrognathia(Table2);3)toconsiderRobinsequenceasalikelydiagnosisonlyifthendingisisolated,andespeciallyifglossoptosisisalsofound.Thisisaconditionthat,ifmanagedappropriatelyafterbirth,isassociatedwithnormallifeexpectancyandgoodqualityoflife.However,priortoconsideringmicrognathiaasanisolatedndingand,consequently,tomakingadiagnosisofisolatedRobinsequence,itshouldbeborneinmind80%ofindividualswithPierre–Robinsequencewillultimatelybediagnosedwithasyndrome.Itisneedlesstounderscorethatthisguremaybeexpectedtobeevenhigherinthefetus,asnotallsyndromicsignsareamenabletoprenatalultrasounddiagnosis.Analissuetoconsideristheriskofrecurrence.AsevidentfromTables1–4,mostconditionsassociatedwithmicrognathiaareinheritedaseitheranautosomaldomi-nantorarecessivetrait.Thisshouldbetakenintoaccountinprenatalcounselingandadetailedautopsyorpostnatalclinicalevaluationiswarrantedinordertoprovidethecouplewithareliableestimateoftheriskofrecurrence.Inconclusion,thereisevidencethatthemandibleandthemaxilla–mandiblecomplexcanbestudied2010ISUOG.PublishedbyJohnWiley&Sons,Ltd.UltrasoundObstetGynecol:377–384. Editorial Figure3Three-dimensionalrenderedimagesoffetuseswithsyndromicmicrognathia.(a)Fetuswithmultipleanomaliesat23weeksofgestation;(b)orofaciodigitalsyndromeat22weeks;(c)fetalakinesiadeformationsequence(FADS)at28weeks;(d)and(e)acrofacialdysostosisinthesamepatientat22and21weeks,respectively;(f)anothercaseofacrofacialdysostosisat19weeks. 01020 Figure4Correlationbetweeninferiorfacialangleandjawindexin19casesoffetalmicrognathia.thoroughlyinthefetus,withbothtwo-dimensionalandparticularlythree-dimensionalultrasound.Inaddition,withthemorerecenthigh-resolutionultrasoundsystems,micrognathiaisoftendetectedatthetimeoftheNTscan.Themandiblerepresentsacommonsitefordefectsassociatedwithgeneticconditions,agoodnumberofwhichcanberecognizedprenatally(Tables1–4).However,differentialdiagnosiscanbeverychallenging,andnotallsubtlesyndromicsignscanbedetectedonprenatalultrasound.Hence,cautionshouldbeadoptedwhendiagnosinganapparentlyisolatedRobinsequenceprenatally,becauseithasbeendemonstratedthatin80%ofcasesasyndromiccomponentwilleventuallybefound,andthiswillaffectthenal2010ISUOG.PublishedbyJohnWiley&Sons,Ltd.UltrasoundObstetGynecol:377–384. 384 Figure5Earlydiagnosisofmicrognathiaatthetimeofnuchaltranslucency(NT)screening.(a)Three-dimensionalsurface-renderedimageat13weeksofgestation.NotetheextrememicrognathiaandtheseverelyenlargedNT(arrow).(b)Three-dimensionalmaximummoderenderedimageinacaseofapparentlyisolatedRobinsequenceat12weeksofgestation;thetwoarrowheadsindicatethemaxillaandthemandibleandthearrowindicatestheenlargedNT.1.OnlineMendelianInheritanceinMan.http://www.ncbi.nlm.nih.gov/PubMed/[Accessed11March2010].2.SmithDW,LyonsJonesK.RecognizablePatternsofHumanedn.WBSaundersCompany;London,2006.3.DixonAD.Prenataldevelopmentofthefacialskeleton.InFundamentalsofCraniofacialGrowth,DixonAD,HoyteDAN,onningO(eds).CRCPress:BocaRaton,NewYork,1997;59–97.4.LeDouarinNM,KalchiemC.TheNeuralCrest.CambridgeUniversityPress:Cambridge,1999.5.RajanPV,WingDA,BocianM,McKeownA.Computedtomographicreconstructionofafetuswiththedysgnathiacomplex(agnathia-otocephaly).PrenatDiagn130–132.6.ChittyLS,CampbellS,AltmanDG.Measurementofthefetalmandible–feasibilityandconstructionofacentilechart.Prenat:749–756.7.RoelfsemaNM,HopCJ,WladimiroffJW.Three-dimensionalsonographicdeterminationofnormalfetalmandibularandmaxillarysizeduringthesecondhalfofpregnancy.ObstetGynecol:950–957.8.ZalelY,AchironR.Thefetalmandible:aninuterosonographicevaluationbetween11and31weeks’gestation.PrenatDiagn:163–167.9.PaladiniD,MorraT,TeodoroA,LambertiA,TremolaterraF,MartinelliP.Objectivediagnosisofmicrognathiainthefetus:theJawIndex.ObstetGynecol:382–386.10.OttoC,PlattLD.Thefetalmandiblemeasurement:anobjectivedeterminationoffetaljawsize.UltrasoundObstetGynecol:12–17.11.RottenD,LevaillantJM,MartinezH,DucouH,LePointeD,VicautE.Thefetalmandible:a2Dand3Dsonographicapproachtothediagnosisofretrognathiaandmicrognathia.UltrasoundObstetGynecol:122–130.12.PiluG,RomeroR,ReeceEA,BovicelliL,HobbinsJC.TheprenataldiagnosisofRobinanomalad.AmJObstetGynecol:630–632.13.BuyseML.TheBirthDefectsEncyclopedia.BlackwellScienticPublications:Boston,MA,1990;1099–1102.14.NicolaidesKH,SalvesenDR,SnijdersRJM,GosdenC.Microg-nathiafetalfacialdefects:Associatedmalformationsandchro-mosomalabnormalities.FetalDiagnTher:1–9.15.BronshteinM,BlazerS,ZalelY,ZimmerEZ.UltrasonographicdiagnosisofglossoptosisinfetuseswithPierreRobinsequenceinearlyandmidpregnancyAmJObstetGynecol1561–1564.16.ShprintzenRJ.PierreRobin,micrognathiaand225airwayobstruction:Thedependencyoftreatmentonaccuratediagnosis.IntAnestClin:64–71.2010ISUOG.PublishedbyJohnWiley&Sons,Ltd.UltrasoundObstetGynecol:377–384.