Nasal cavity shape in unilateral choanal atresia and the role of fetal ventilation in facial growth

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Nasal cavity shape in unilateral choanal atresia and the role of fetal ventilation in facial growth

S. Ferrier, Q. Hennocq, N. Leboulanger, V. Couloigner, F. Denoyelle, Y.

Heuzé, R.H. Khonsari

To cite this version:

S. Ferrier, Q. Hennocq, N. Leboulanger, V. Couloigner, F. Denoyelle, et al.. Nasal cavity shape in

unilateral choanal atresia and the role of fetal ventilation in facial growth. Journal of Stomatology,

Oral and Maxillofacial Surgery, Elsevier Masson, 2020, �10.1016/j.jormas.2020.05.021�. �hal-02985636�

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Original article

Nasal cavity shape in unilateral choanal atresia and the role of fetal ventilation in facial growth

S. Ferrier

^a,

*, Q. Hennocq

^b

, N. Leboulanger

^a

, V. Couloigner

^a

, F. Denoyelle

^a

, Y. Heuze´

^c

, R.H. Khonsari

^b

aServiced’otorhinolaryngologieetchirurgiecervico-faciale,HoˆpitalUniversitaireNecker–EnfantsMalades,AssistancePublique–HoˆpitauxdeParis, CentredeRe´fe´rencedesMalformationsORLraresMALO,Filie`reMaladiesRaresTeteCou,Universite´ ParisDescartes,Universite´ SorbonneParisCite´, 149,ruedeSe`vres,75015Paris,France

bServicedechirurgiemaxillo-facialeetchirurgieplastique,HoˆpitalUniversitaireNecker–EnfantsMalades,AssistancePublique–HoˆpitauxdeParis, CentredeRe´fe´rencedesFentesetmalformationsfacialesMAFACE,Filie`reMaladiesRaresTeteCou,Universite´ deParis,Paris,France

cCNRS,UniversityBordeaux,MC,PACEA-DelaPre´histoirea` l’Actuel:Culture,EnvironnementetAnthropologie,UMR5199,Pessac,France

1. Introduction

1.1. Choanalatresiaandnasalcavityformation

Choanal atresia (CA) is a complete congenital absence of communicationbetweentheposteriornasalcavity(NC)andthe nasopharynx. Choanal stenosis is a narrowing of the posterior choanawithout complete obstruction. In clinical practice,both anomaliesarereferredtoasCA.TheincidenceofCAvariesbetween 1/5000and1/9000births.CAisacharacterizedconditionsincethe

end of the 18thcentury and wasinitially described by Johann Roedererin1755;CarlEmmertreportedtheﬁrstsurgicalrepairof CAin1851,basedontheperforationoftheatreticplate[1].

CAhasnosexualpredominancebutright-sidedCAmaybemore prevalent,eventhoughthispointisnotconsensual[2–4].Three typesofCAarereportedintheliterature:

membranousCA;

bonyCA;

combinedforms(membranous+bony).

Inthebeginningofthe20thcentury,itwasbelievedthat90%of CAwerebonyandthat10%weremembranous[2–4].Nevertheless, withthedevelopmentofdiagnosesbasedonCT-scans,morerecent

* Correspondingauthor.

E-mailaddress:[email protected](S.Ferrier).

ARTICLE INFO

Articlehistory:

Received3May2020 Accepted19May2020

Keywords:

Choanalatresia

Geometricmorphometrics Craniofacialgrowth Functionalmatrix 3Dimaging

ABSTRACT

Objective:Therespiratorymovementsoffetalamnioticfluidareconsideredbycertainscleftsurgery teamstocontributetothegrowthofthenasalcavities(NC).Toassessthisfunctionalhypothesis,we consideredagroupofpatientswithunilateralchoanalatresia(CA)asamodelofunilateralabsenceof amnioticfluidfluxintheNC,andcomparedtheirNCsshapetoage-matchedcontrols.

Material and methods: Three-dimensional reconstructions of NC were performed using Avizo 9.7 (ThermoFisherScientiﬁc,MA,USA),basedonCT-scansof32patientswithunilateralCAand96age-and gender-matched controls. Landmarks were placed on anatomical structures of NC. Procrustes superimpositionsandprincipalcomponentanalysiswereperformed.AnatomicallyrelevantEuclidean distanceswerecomputedusingthecoordinatesofselectedlandmarks–maxillarylength,piriform oriﬁcewidth,choanalwidth–andtestedusingmultivariateanalysis.Growthratesbetweenpatientsand controlsforthesedistanceswerescreenedforcorrelations.

Results:TheatreticNCwassigniﬁcantly deformedwhencomparedtothecontrolcases:Procrustes distancewas0.28(P<0.0001).Themaxillarylengthandwidthoftheatreticchoanaweresigniﬁcantly decreasedcomparedto controls( 2.95mmand 1.35mmrespectively,P<0.001).Therewereno differencesingrowthratesbetweenCAandcontrols,exceptforthechoanalwidthontheatreticside.

Conclusion:NCsinCAweresigniﬁcantlydifferentfromcontrols.Moreprecisely,themaxillarylengthwas signiﬁcantlyreducedintheCAgroup.TherewasnoothermajorshapedifferencebetweentheNCinCA andcontrols.NCseemstodevelopdespiteabnormalfetalventilation.

C 2020PublishedbyElsevierMassonSAS.

Available online at

ScienceDirect

www.sciencedirect.com

https://doi.org/10.1016/j.jormas.2020.05.021 2468-7855/^C 2020PublishedbyElsevierMassonSAS.

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studies report70% of combined CA vs. 30% of bony CA[2–4].

UnilateralCAs are more frequentlyisolated than bilateral CAs, whichcanbeassociatedwithawiderangeofsyndromes–mostly CHARGEassociationandsyndromiccraniosynostosissyndromes such as Crouzon, but also less common conditions such as Pfeiffer,Antley-Bixler,Marshall-Smith,Schinzel-GiedonandTrea- cherCollinssyndromes[4–6].Interestingly,craniosynostosesare associatedwithchoanalstenosisratherthanwithatresia[6].Asa whole,about51%ofCAsareassociatedwithothermalformations.

Fourdiverselyconvincingtheorieshavebeenproposedinthe literature to account for the occurrence of CA, without much supportfromdevelopmentalbiology[7,8]:

Persistence of the bucco-nasal membrane of Hochstetter, formedbytheolfactiveplate–insidethenasalpitmesoderm –andtheoralcavityepithelium[9];thenormaldehiscenceof thismembraneresultsintheformationoftheprimarychoana;

Persistence ofthebucco-pharyngeal membrane,which is the superior limit of the primary gut, spontaneously rupturing in normal conditions between the 3rdand the 4th week of gestation[10];

Adherencesformedbyanabnormalpersistenceofmesodermal tissue[8];

Migrationanomaliesofneuralcrestcells[8].

Toxicfactorssuchasthioamideshavealsobeenimplicatedin theoriginofCA[2–4,7].In fact,CAisgenerallyconsidered asa componentofcarbimazoleembryopathy:forinstance,inastudy reporting20newbornsexposedtocarbimazole,11presentedwith CA[11].Furthermore,increaseduni-and/orbilateralCAhavebeen reportedin embryosexposed tomethymazolebetween the3rd and7thweeksofembryologicdevelopment[12,13].

SeveralgenesareinvolvedinCA,suchasRaldh3inmiceand CHD7in humans. Inactivation of Raldh3 causesbilateral CA in mousemodels;interestingly,theRaldh3proteinisexpressedin theposteriorandcentralmesodermofthenasalcavityandnostrils andispartoftheretinoicacidsignalingpathway.Raldh3knock-out micedidnotdevelopCAwhenmothersweretreatedwithnon- teratogenicdosesofretinoicacid[14,15].Sevento29%ofCAcases reportedintheliteraturearepartofaCHARGEassociation,and 35to65%CHARGEassociationcaseshaveCA.Themostfrequent geneticanomalyinCHARGEassociationistheCHD7mutation,and this gene is currently the only human candidate for causing CA[16].Themechanism linkingCAand CHD7mutationsis not currentlyunderstood.

1.2. Nasalcavitygrowth

Beyondmorphogenesisissues,severalauthorshaveinvestigat- edtheroleofexternal mechanicalfactorsonthegrowthof the nasalcavities.Forinstance,thefluxofamnioticfluidduringfetal respirationhasbeenproposedtobeamajorcontributortoprenatal maxillary growth [17]. In patients with cleft lip and palate, different pressures in the nasal cavities on both sides of the septum,duringfetalamnioticrespiration,havebeenincriminated inthedeformationoftheseptumandalaenasi[18].Inthiscontext, CAisaninterestingmodeltoassessthesemechanicaltheories:CA shouldtheoreticallyinduceacollapseofthenasalcavity,asthe atreticsideisnotsubjectedtoamnioticliquiddynamicsinatresia, andtoabnormalfluxinstenosis.

The referencefor the diagnosisof CAis 2D CT-scan: atretic cavitieshave a narrowernasalﬂoorand mid-orbitalaxiswhen comparedtothecontralateralside;thevomerissimilarlywideron theatreticside[19,20].Variousmethodshavebeendescribedto quantifytheshapeofthenasalcavities,basedonsegmentationof CT-scan data and 3D landmarking [6], or on statistical shape

modeling[21].Hereweassessedtheshapeofthenasalcavitiesin CAusing3Dgeometricmorphometrics,anddiscussedourresults inthelightofthecurrenttheories relatingexternalmechanical factorsandcentro-facialgrowth.

2. Materialandmethods 2.1. Population

We included allpatients admitted for unilateral CAsurgery between2007and2018,withavailablegoodqualitypre-operative CT-scans. Patient charts were retrospectively reviewed and thefollowingclinicalparameterswerecollected:sex,ageatCT- scan, CA side, type of CA,associated conditions or craniofacial malformations. Patients with craniofacial malformations were excluded(cleftlipandpalate,Crouzonsyndrome).

Age-matched normal CT-scans performed for minor trauma wereusedas controls. Thisstudywas assessedby theNecker- EnfantsMaladesEthics Committeeand compliedwiththelocal ethicalregulations(CNEM2020-12).

2.2. Landmarking

Landmarking wasperformed usingAvizo9.7 (ThermoFisher Scientiﬁc,MA,USA)basedon3Dreconstructionssegmentedbased onasinglethresholdcomprisedbetween140and290Hounsﬁeld units.Twentybonylandmarkswereplaced bya singleobserver (SF,Table1,Fig.1)andthe3Dcoordinatesofthelandmarkswere exported.LeftCAcoordinatesweretransformedintorightCAsin ordertoobtainauniformCAgroupforProcrustessuperimposition (seebelow).

Weassessedintra-andinter-observerreproducibilitybasedon a datasetof 10 normal CT-scans. Twooperators (SF and RHK) landmarkedthese10scansthreeconsecutivetimes.Theconcor- dance correlation coefﬁcient (CCC) agreement of Lin [22] was computedforeachoperatorandlandmark.Anoverallconcordance correlationcoefﬁcient(OCCC)wasalsocomputed[23].

2.3. Morphometricanalyses

Procrustessuperimpositionbasedonthe3Dcoordinatesofthe 20landmarkswasperformedusingMorphoJ[24].LeftandrightCA were grouped together after coordinate transformation of left formsintorightforms.

FiveEuclideanlineardistanceswerecomputed:

distances between landmarks2-3and 2-4(respectivelyright andleftpiriformaperturewidth);

distancesbetweenlandmarks12-13and12-14(respectivelyleft andrightchoanalwidth);

distancebetweenlandmarks2-12(maxillarylength).

2.4. Statisticalanalysis

Principalcomponentanalysis (PCA)basedon thecovariance matrix oftheProcrustesshapecoordinateswasperformed. The Procrustes distances between ‘controls’, ‘right CA’, ‘left CA transformed into right CA’ and ‘right CA+left CA transformed into right CA’ were computed. P-values were computed from permutation tests (10,000 permutation rounds) for Procrustes distancesamonggroups.PCAdeﬁnedamorphospaceintowhich groups were separated by a distance referred to as Procrustes distance(d).ForlargeenoughProcrustesdistances(determinedby permutation tests), groups will be considered signiﬁcantly differentinshape.

S.Ferrieretal./JStomatolOralMaxillofacSurgxxx(2020)xxx–xxx 2

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Amultivariateanalysis basedon a linearmodel adaptedfor each distance was used to compare the Euclidean distances betweenCApatientsandcontrols.Theanalysiswasadjustedon thefollowingvariables:distancevalue(inmm),CAvs.control,and age.Growthratecorrelations wereestimatedfor each of these distances.

3. Results

Thirty-twochildrenwithCAwereincludedintothestudy;sex ratiowas11malesfor21females;ageatCTwas1dayto7yearsof age(451.4647.9days):12/32patientswerelessthan3months ofage;23/32werelessthan24monthsofage,3/32werebetween

Fig.1.Landmarksusedformodelingthenasalcavities.(a,b)anteriorview;(c)posteriorview,controlpatient;(d)posteriorview,combinedchoanalatresia;blackasterix:

atreticplate.

Table1

Anatomicaldescriptionofthelandmarksusedformodelingthenasalcavities.Mid.:midline;Bilat.:bilateral.

Landmark Structure Name Description

1 Mid. Nasion Intersectionofnasalandfrontalbones

2 Mid. Anteriornasalspine Triangularbonyprotrusionextendingfromthemaxillaryincisorcrest 3 Bilat. Infero-lateralangleofrightpiriformaperture Lateralanglesofpiriformapertures

4 Bilat. Infero-lateralangleofleftpiriformaperture

5 Bilat. Rightlachrymalduct,superioropening Antero-superiorangleoflachrymalducts,superioropening 6 Bilat. Leftlachrymalduct,superioropening

7 Bilat. Rightinferiorturbinatehead Inferiorturbinate,mostanteriorpart,onitsmedialside 8 Bilat. Leftinferiorturbinatehead

9 Bilat. Rightmediumturbinatehead Mediumturbinate,mostanteriorpart,onitsmedialinferiorangle 10 Bilat. Leftmediumturbinatehead

11 Mid. Vomerinsertiononsphenoidbone

12 Mid. Posteriornasalspine Bonyprotrusionformedbyposteriorendsofinternalsidesofpalatineplates.

13 Bilat. Postero-lateralangleofleftpalatineplate Onaposteriorview,externalangleofpalatineplates,atthejunctionwiththepterygoids 14 Bilat. Postero-lateralangleofrightpalatineplate

15 Bilat. Superiorangleofleftchoanalarch Atthecenterofchoanalarch,superiorconcavity 16 bilat. Superiorangleofrightchoanalarch

17 bilat. Leftinferiorturbinaterear Inferiorturbinate,mostposteriorpart,onitsmedialside 18 Bilat. Rightinferiorturbinaterear

19 Bilat. Leftmediumturbinaterear Mediumturbinate,mostposteriorpart,onitsmedialinferiorangle 20 Bilat. Rightmediumturbinaterear

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24-36monthsofageand6/32wereover36monthsofage.20/32 (62.5%)hadrightCA,12/32hadleftCA;18/32(56.25%)hadcombined forms,12/32(37.5%)hadbonyCAand6/32(6.25%)hadmembranous CA.Ninety-sixcontrolCT-scanswerealsoincluded.CAandcontrol groupsweresimilarintermsofage:mean439.1673.1daysinCA group,455.5639.5daysincontrolgroup(P>0.05).Thesex-ratioin thecontrolgroupwas0.5.

TheCCCmeasuredforeachlandmarkandtheOCCCwereall above0.99, indicating goodintra- and inter-operatorreproduc- ibility,andthusreliablelandmarking.

TheProcrustesdistancebetweentheleftandrightCAgroupswas notsigniﬁcant(d=0.273,P=0.02).TheProcrustesdistancesbetween

‘leftCAandcontrols’,and‘rightCAandcontrols’werebothsigniﬁcant (d=0.352,P<0.0001;d=0.260,P<0.0001respectively).Wethus Table2

Descriptionofthepopulation.Sd:standarddeviation.

Totalpopulation(n=128) Choanalatresia(right)(n=32) Control(n=96)

Mean Sd Mean Sd Mean Sd

AgeatCT(days) 451.4 647.9 439.1 673.1 455.5 639.5

Maxillarylength(mm) 34.9 5.2 32.7 4.6 35.7 5.1

Rightpiriformaperturewidth(mm) 10.3 1.9 10.0 2.1 10.4 1.8

Leftpiriformaperturewidth(mm) 10.4 2.1 10.7 2.9 10.3 1.7

Leftchoanalwidth(mm) 8.2 1.7 8.3 2.5 8.2 1.4

Rightchoanalwidth(mm) 7.3 1.6 6.2 1.5 7.6 1.5

Table3

Multivariateanalysestakingintoaccounttheage:maxillarylength( 2.95,P<0.001)andrightchoanalwidth( 1.35,P<0.001)weredifferentbetweenCAandcontrols.

Estimate Sd T P

Maxillarylength Atresia 2.95 0.55 5.33 <0.001

Age 0.006 0.0003 17.55 <0.001

Rightpiriformaperturewidth Atresia 0.32 0.26 1.23 0.22

Age 0.002 0.0002 12.2 <0.001

Leftpiriformaperturewidth Atresia 0.43 0.35 1.24 0.22

Age 0.002 0.0002 8.13 <0.001

Leftchoanalwidth Atresia 0.19 0.27 0.69 0.49

Age 0.002 0.0002 8.79 <0.001

Rightchoanalwidth Atresia 1.35 0.25 5.32 <0.001

Age 0.001 0.0002 7.36 <0.001

Fig.2.Age-dependenceofEuclidiandistances.(a)maxillarylength;(b)rightpiriformaperturewidth;(c)leftpiriformaperturewidth;(d)leftchoanalwidth;(e)rightchoanal width.Dots:distributionforeachpatient.Redcurves:choanalatresiagroup;bluecurves:controlgroup.

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clusteredleftandrightCAswithinthesamegroupaftertransforming leftCAsintorightforms.TheglobalshapedifferencebetweenCAand controlpatientswassigniﬁcant(d=0.280,P<0.0001).

MultivariateanalysisonselectedEuclidiandistances(Table2), withage taken into account, showed that the mean maxillary lengthandmeanrightchoanalwidthwerestatisticallyshorterin theCAgroupwhencompared tocontrols(P<0.001).Meanleft choanalwidth,meanrightandleftpiriformaperturesweresimilar inCAandcontrols(Table3).

Logistic regressions were conducted in order to study the growthdynamics of each of the ﬁve distances in both groups (Fig.2).Qualitatively,growthwasdifferentforthemaxillarylength and therightchoanal width.Left choanal width,rightand left piriform aperture widths were similar regarding ontogenetic trajectoriesinboth groups.More precisely,rightchoanalwidth only(thatistheaffectedsideinallpatientsaftermirroringleftCA) showedlowergrowthrates(Table4).

4. Discussion

Oursamplehadawideragerange(0–7years)andwaslarger (32patients)thanpreviousstudieswhohadincluded9[19]and11 [20]patientsunder3yearsofage[19,20,25].Inspiteofarelatively lessbalancedsexratio(10/22vs.1),oursamplewassimilartothe literature data in terms of CA type (bony, membranous or combined)andrightprevalence(63%).

The nasal cavities in CA were significantly different from controls.More precisely,themaxillarylength(orseptallength) wassignificantlyreducedintheCAgroup.Nevertheless,therewas noothermajorshapedifferencebetweenthenasalcavitiesinCA andcontrols,andspecifically,noanteriorcollapse–thepiriform aperturedimensionsweresimilarinbothgroups.Intheliterature, studiesbasedon2Ddistancecomputationshadshownincreased bony septal width [19,20,26] and diminished nasopharyngeal length[19].

We considered CA as a model for assessing the theories implicatingfetalrespirationintheformationofnasalcavities,and couldnotfindsupportforthemechanicalroleofpre-natalfluid flux in this process [19]. Ontogenetic trajectories furthermore indicatedthatalldistancesintheCAgrouphaddynamicssimilarto thecontrolgroupexceptforthechoanalwidthontheaffectedside, which had significantly slower growth rates. These results indicatedthat nasalcavity growthin CAwasnotde-correlated tothegrowthoftherestofthecraniofacialskeleton.Thisdynamic resultfurthersupportedthemostprobablylimitedinvolvementof fetalrespirationinpre-natalmaxillarygrowth.

Previousstudieshaddescribedthespeedofchoanalaperture growthinnormalpatientsthrough2DCT-scansanddemonstrated a linearcorrelation between ageand choanalwidth: themean choanal aperture (mm) responded to the following equation:

(0.20.09)(age)+(6.780.67) (25), or: 4.85+(0.04)(age in weeks)[25].Interestingly,our3Dmeasurementsdidnotfollowlinear growth patterns, and further investigations focused on normal patientsare required,withlarger cohorts,inordertoconﬁrmthe non-linearityofchoanalaperturegrowth.

5. Conclusion

Theatreticnasalcavitywassigniﬁcantlydifferentfromcontrols butwasnotcollapsed.Themaxillarylengthandthechoanalwidth weredecreasedinatreticpatientswhencomparedtocontrolcases.

Therewerenosignificantdifferencesintermsofpiriformaperture width on the atretic side when compared to controls. Growth speedsofatreticandcontrolpatientswerecorrelated,exceptfor thechoanal widthon theaffectedside. Significantnasalcavity growth thus occurred despite absent or abnormal prenatal amnioticflux.

A similarcontrolled approachcouldbeappliedtoassessNC growthafterCAsurgery,andtoothertypesofNCmalformations suchaspiriformaperturestenosis,inordertofurtherinvestigate thepotentialroleofﬂuidﬂuxinmaxillarygrowth.

Funding

Thisresearchdidnotreceiveanyspeciﬁcgrantfromfundingagenciesin thepublic,commercial,ornot-for-proﬁtsectors.

Disclosureofinterest

Theauthorsdeclarethattheyhavenocompetinginterest.

References

[1]FlakeCG,FergusonCF.Congenitalchoanalatresiaininfantsandchildren.Ann OtolRhinolLaryngol1964;73:458–73.

[2]CorralesCE,KoltaiPJ.Choanalatresia:currentconceptsandcontroversies.

CurrOpinOtolaryngolHeadNeckSurg2009;17:466–70.

[3]KwongKM.CurrentUpdatesonChoanalAtresia.FrontPediatr2015;3:52.

[4]RamsdenJD,CampisiP,ForteV.Choanalatresiaandchoanalstenosis.Otola- ryngolClinNorthAm2009;42:339–52[x].

[5]BurrowTA,SaalHM,deAlarconA,MartinLJ,CottonRT,HopkinRJ.Characteri- zation of congenitalanomalies inindividuals withchoanal atresia. Arch OtolaryngolHeadNeckSurg2009;135:543–7.

[6]Lesciotto KM, Heuze´ Y, Jabs EW, Bernstein JM,Richtsmeier JT. Choanal atresiaandcraniosynostosis:developmentanddisease.PlastReconstrSurg 2018;141:156–68.

[7]HengererAS,BrickmanTM,JeyakumarA.Choanalatresia:embryologicanal- ysis andevolution oftreatment,a30-year experience.TheLaryngoscope 2008;118:862–6.

[8]HengererAS,StromeM.Choanalatresia:anewembryologictheoryandits inﬂuenceonsurgicalmanagement.TheLaryngoscope1982;92:913–21.

[9]MugnierA.Embryologieetde´veloppementbucco-facial.Paris:MassonetCie, JulienPre´lat;1964.

[10]W.J.Hamilton,J.D.Boyd,H.W.Mossman.Alimentaryandrespiratorysystems, pleuralandperitonealcavities.In:HumanEmbryology.Cambridge:W.Heffer andsonslimited.

[11]WolfD,FouldsN,DayaH.Antenatalcarbimazoleandchoanalatresia:anew embryopathy.ArchOtolaryngolHeadNeckSurg2006;132:1009–11.

[12]DiGianantonioE,SchaeferC,MastroiacovoPP,CournotMP,BenedicentiF, ReuversM,etal.Adverseeffectsofprenatalmethimazoleexposure.Teratology 2001;64:262–6.

[13]BarberoP,ValdezR,Rodrı´guezH,TiscorniaC,MansillaE,AllonsA,etal.

Choanal atresia associated with maternal hyperthyroidism treated with methimazole:acase-controlstudy.AmJMedGenetA2008;146A:2390–5.

[14]Dupe´ V,MattN,GarnierJ-M,ChambonP,MarkM,GhyselinckNB.Anewborn lethaldefectduetoinactivationofretinaldehydedehydrogenasetype3is preventedbymaternalretinoicacidtreatment. ProcNatl AcadSciUSA 2003;100:14036–41.

[15]MinouxM,RijliFM.Molecularmechanismsofcranialneuralcrestcellmigra- tionandpatterningincraniofacialdevelopment.DevCambEngl2010;137:

2605–21.

[16]SanlavilleD,VerloesA.CHARGEsyndrome:anupdate.EurJHumGenetEJHG 2007;15:389–99.

[17]MooneyMP,SiegelMI,KimesKR,TodhunterJ.Premaxillarydevelopmentin normal and cleftlip and palate human fetuses usingthree-dimensional computerreconstruction.CleftPalateCraniofacJ1991;28:49–53[discussion 54].

[18]TalmantJ-C,TalmantJ-C,LumineauJ-P.Afunctionalapproachintheprimary treatmentoflabial-alveolar-velopalatinecleftsforaminimumofsequels.Rev StomatolChirMaxillofac2007;108:255–63.

[19]AslanS,YilmazerC,YildirimT,AkkuzuB,YilmazI.Comparisonofnasalregion dimensions in bilateral choanalatresia patients and normal controls: a computedtomographicanalysiswithclinicalimplications.IntJPediatrOto- rhinolaryngol2009;73:329–35.

[20]SlovisTL,RenfroB,WattsFB,KuhnsLR,BelenkyW,SpoylarJ.Choanalatresia:

preciseCTevaluation.Radiology1985;155:345–8.

Table4

Growthdynamicsweresimilarinatretricandcontrolpatients.P:interactiontest betweenslopesfromcontrolandatreticpatients.

Maxillarylength 0.23

Rightpiriformaperturewidth 0.35

Leftpiriformaperturewidth 0.37

Leftchoanalwidth 0.14

Rightchoanalwidth 0.023

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[21]KeustermansW,HuysmansT,DanckaersF,ZarowskiA,SchmelzerB,SijbersJ, etal.Highqualitystatisticalshapemodellingofthehumannasalcavityand applications.RSocOpenSci2018;5:181558.

[22]Lin LI. Aconcordance correlation coefﬁcientto evaluatereproducibility.

Biometrics1989;45:255–68.

[23]BarnhartHX,HaberM,SongJ.Overallconcordancecorrelationcoefﬁcientfor evaluatingagreementamongmultipleobservers.Biometrics2002;58:1020–7.

[24]Klingenberg CP. MorphoJ:an integrated software package for geometric morphometrics.MolEcolResour2011;11:353–7.

[25]CorstenMJ,BernardPA,UdjusK,WalkerR.Nasalfossadimensionsinnormal andnasallyobstructedneonatesandinfants:preliminarystudy.IntJPediatr Otorhinolaryngol1996;36:23–30.

[26]FaustRA,PhillipsCD.Assessmentofcongenitalbonynasalobstructionby3- dimensionalCTvolumerendering.IntJPediatrOtorhinolaryngol2001;61:71–5.