PART XIXraniofacial and Orthopedic ConditionsC 100

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100 Craniofacial MalformationsKELLY N. EVANS, ANNE V. HING, AND MICHAEL L. CUNNINGHAM

PART XIX Craniofacial and Orthopedic Conditions

Theneonatologist is often thefirst point of contact for achildbornwithacraniofacialmalformation.Abnormali-tiesofthefaceandheadcanbedistressingtoanewparent,

whoisimmediatelywondering,“Ismychildgoingtolook,feel,and develop normally?” Having a basic understanding of therelationship between craniofacial abnormalities and feeding,breathing,hearing,vision, speech,andoveralldevelopmentwillhelptheneonatologistbegintocounselafamily.Airwaycompro-mise is well described in multiple craniofacial syndromes, andearly identification can be lifesaving. Prompt recognition of aconstellationofanomaliespointingtowardasyndromeordiag-nosiswill result in better targeted evaluations and therapies forthatpatient.(Tables100.1–100.2containaconcisepresentationofpotentialintensivecareunit[ICU]issuesthatmaybeencoun-tered with certain craniofacial malformations and syndromes.)Thischapterhighlightsthemostrelevantcraniofacialmalforma-tions that a neonatologistwill encounter.We describe here theepidemiology,genetics,diagnosis,phenotype,andpotentialICUissues as well as basic management recommendations to helpguidetheneonatologist incaringforaninfantwithcraniofacialmalformations.

Micrognathia/Robin Sequence

EpidemiologyThetriadofmicrognathia,glossoptosis,andairwayobstruction,originallydescribedin1923byPierreRobin,isknownasRobin

sequence(RS)orPierre Robin sequence.WhethercleftpalateisanobligatoryfeatureofRSisdebatable.Approximatelyone-quarterof infantswith cleft palate (CP)were found to haveRS in amultisite,population-based, case–control study (Genisca etal.,2009).Thetremendousheterogeneityandlackofuniformlyaccepteddiagnosticcriteria for,ordefinitionsof,RSmake itchallengingtoknowthetrueprevalence.However,estimatesofbirthprevalencerangefrom1in8500to1in14,000births(BushandWilliams,1983;PrintzlauandAndersen,2004).

PhenotypeRSisanetiologicallyandphenotypicallyheterogeneousdisorder.MorethanhalfofchildrenwithRShaveanassociatedsyndrome,withSticklersyndromebeingthemostcommon.Whilethereisgreatvariation in severity,RS is characterizedby the followingphenotypicfeatures:micrognathia(smallandsymmetricallyrecededmandible),glossoptosis(tongueofvariablesizefallsbackwardintothepostpharyngealspace),andresultantupperairwayobstruction,oftenwithacleftpalate(Breugemetal.,2016;Fig.100.1A–B).Caouette-Labergeetal.(1994)describedCP(U-shapedCPmorecommonthanV-shapedCP)in90%of125individualswithRS.InfantswithRSoftenhaveairwayobstruction,feedingdifficulties,and challenges gainingweight, and theymay have associatedanomalies, including hypotonia and limb reduction defects.Congenitalheartdefectsarepresentinupto25%ofbabieswithRSwhodieinearlyinfancy(Hennekametal.,2010a).IthasbeenreportedthataportionofindividualswithRSexperiencedevel-opmentaldelay,cognitiveimpairment,andpoorerschoolachieve-ment;overallmorbidityandmortality arehigher in syndromicRSorRSwithassociatedanomaliescomparedwith isolatedRS(Caouette-Laberge etal., 1994;Persson etal., 2013).Clinicaljudgmentcanbemadeaboutwhetherthepatientrepresents“isolatedRS,”“RSplus,”ora syndromic formofRS,andthediagnosticwork-upshouldincludeinvestigationofthecommonassociatedanomaliesandsyndromes(Tanetal.,2013;Gomez-OspinaandBernstein,2016).

Intensive Care Unit ConcernsIninfantswithRSthetongueisdisplacedtowardtheposteriorpharyngealwallorup into thecleft, resulting inupperairway

KEY POINTS

• Craniofacialmalformationscanimpactswallowing,breathing,hearing,vision,speech,anddevelopmentandforsomeneonatescanresultinlife-threateningairwaycompromise.

• Earlyrecognitionandassessmentofcraniofacialconditionsthatincludeappropriatediagnosticstudies,identificationofassociatedhealthconcerns,andfamilyeducationcanhaveapositiveimpactonthecareofthenewborn.

• Timelyreferralofthenewbornwithacraniofacialconditionformultidisciplinarycraniofacialteamcareisanimportantstepintheprovisionofcoordinatedmedicalandsurgicalmanagement.

1418 PART XIX Craniofacial and Orthopedic Conditions

Syndrome Phenotype ICU Issues OMIM

Robinsequencea Micrognathia,glossoptosiswithupperairwayobstruction,cleftpalate

Airwayobstruction,feedingdifficulties

na

Sticklersyndromea Cleftpalate,micrognathia,glossoptosis(Robinsequence),highmyopia,riskofretinaldetachmentandblindness,midfacehypoplasia,hearingimpairment,arthropathy,pectus,shortfourthandfifthmetacarpals

Airwayobstruction,feedingdifficulties

180300,604841,184840,614134,614284

22q11.2deletionsyndrome(velocardiofacialsyndrome,DiGeorgesyndrome)a

Cleftpalateandsubmucouscleftpalate,smallmouth,myopathicfacies,retrognathia,prominentnosewithsquared-offnasaltip,hypoplasticnasalalae,shortstature,slendertaperingdigits

Cardiacanomalies,airwayobstruction,feedingdifficulties,aspiration

192430,188400,611867

Opitzoculogenitolaryngealsyndrome(OpitzBBB/Gsyndrome)a

Hypertelorism,telecanthus,cleftlipand/orpalate,dysphagia,esophagealdysmotility,laryngotracheoesophagealcleft(aspiration),hypospadias,bifidscrotum,cryptorchidism,agenesisofthecorpuscallosum,congenitalheartdisease,mentalretardation

Laryngotracheoesophagealclefting(stridor,feedingdifficulties,choking,aspiration)

145410,300000

Pallister–Hallsyndromea Cleftpalate,flatnasalbridge,shortnose,multiplebuccalfrenula,microglossia,micrognathia,malformedears,hypothalamichamartoblastoma,hypopituitarism,postaxialpolydactylywithshortarms,imperforateanus,genitourinaryanomalies,intrauterinegrowthrestriction

Laryngotracheoesophagealclefting(stridor,feedingdifficulties,choking,aspiration),panhypopituitarism

146510

IRF6-relateddisorders(includingVanderWoudeandpoplitealpterygiumsyndrome)

Cleftlipwithorwithoutcleftpalate,cleftpalateonly,lowerlippitsorcysts,ankyloglossia;poplitealpterygiumsyndromewillalsohavepoplitealpterygia,bifidscrotum,cryptorchidism,fingerand/ortoesyndactyly,abnormalitiesoftheskinaroundthenails,syngnathiaandankyloblepharon

Notanticipated 119300,119500

CHARGEsyndromea Colobomaoftheeye,heartmalformations,choanalatresia,growthretardation,genitalanomalies,earabnormalitiesand/ordeafness,facialpalsy,cleftpalate,dysphagia

Airwayobstructioninbilateralchoanalatresia,cardiacanomalies,feedingdifficulties,aspiration

214800

Smith–Lemli–Opitzsyndromea

Cleftpalate,micrognathia,shortnose,ptosis,highsquareforehead,microcephaly,hypospadias,cryptorchidism,ventricularseptaldefect,tetralogyofFallot,hypotonia,mentalretardation,postaxialpolydactyly,2–3toesyndactyly,defectincholesterolbiosynthesis

Cardiacanomalies,airwayhypotonia,andairwayobstruction

270400

Ectrodactyly,ectodermaldysplasia,andcleftingsyndrome

Cleftlipand/orpalate,split-hand/split-foot,ectodermaldysplasia(sparsehair,dysplasticnails,hypohidrosis,hypodontia),genitourinaryanomalies

Notanticipated 129900,604292,129400

Ankyloblepharon,ectodermaldysplasia,andcleftingsyndrome

Cleftlipwithorwithoutcleftpalate,cleftpalateonly,intraoralalveolarbands,maxillaryhypoplasia,ankyloblepharon(eyelidfusion),ectodermaldysplasia(sparsehair,dysplasticnails,hypohidrosis,anodontia)

Notanticipated 106260

Orofaciodigitalsyndrome Mediancleftofupperlip,cleftpalate,accessoryoralfrenula,lobulatedtonguewithhamartomas,broadnasalroot,smallnostrils,syndactyly,brachydactyly,postaxialpolydactyly,polycysticrenaldisease,agenesisofthecorpuscallosum


Kabukisyndromea Cleftpalate,archedeyebrow,longpalpebralfissures,eversionoflateralthirdoflowereyelid,brachydactyly,shortfifthmetacarpal,cardiacanomalies,postnatalgrowthdeficiency/dwarfism,mentalretardation

Cardiacanomalies 147920,300867

Frynssyndromea Cleftlipwithorwithoutcleftpalate,micrognathia,coarsefacies,diaphragmatichernia,distallimbhypoplasia,malformationsofthecardiovascular,gastrointestinal,genitourinary,andcentralnervoussystems

Congenitaldiaphragmatichernia,pulmonaryhypoplasia;cardiacanomalies

229850

Craniofacial Syndromes Commonly Associated With Cleft Lip and/or Cleft PalateTABLE 100.1

CHAPTER 100 Craniofacial Malformations 1419

Craniofacial Syndromes Commonly Associated With Cleft Lip and/or Cleft Palate—cont’dTABLE 100.1

Syndrome Phenotype ICU Issues OMIM

Millersyndrome(postaxialacrofacialdysostosis)a

Cleftpalate(morethancleftlip),malarandmandibularhypoplasia,downslantingpalpebralfissures,lowereyelidcoloboma,microtia/atresia,conductivehearingloss,postaxiallimbdeficiency,absentfifthdigit

Airwayobstruction 263750

TreacherCollinssyndrome(mandibulofacialdysostosis)a

Cleftpalate,malarandmandibularhypoplasia,downslantingpalpebralfissures,lowereyelidcoloboma(missingmediallowereyelidlashes),microtia/atresia,conductivehearingloss

Airwayobstruction 154500,613717,248390

Aarskogsyndrome(faciodigitogenitalsyndrome)

Hypertelorism,widow’speak,ptosis,downslantingpalpebralfissures,strabismus,maxillaryhypoplasia,broadnasalbridgewithantevertednostrils,occasionalcleftlipand/orpalate,floppyears,brachydactyly,clinodactyly,jointlaxity,shawlscrotum


Wolf–Hirschhornsyndrome(4pdeletionsyndrome)a

Cleftlipandpalate,coloboma,hypertelorism,growthdeficiency,microcephaly,mentalretardation,cardiacseptaldefects

Congenitaldiaphragmatichernia,cardiacanomalies,seizures,airwayhypotonia/obstruction

194190

Amnionrupturesequencea Cleftlipandpalate,obliquefacialclefts,focalareasofscalpaplasia,constrictionbandswithterminallimbamputationsandsyndactylies,occasionalanencephaly,encephalocele,andectopiacordis

Encephalocele,oropharyngeal/airwaydeformation

217100

aPotential ICU issues.ICU, Intensive care unit; OMIM, online mendelian inheritance in man.

A

C

B

• Fig. 100.1 (A) Infant with Robin sequence and significant micrognathia. (B) U-shaped cleft palate. (C) Infant with Robin sequence and a nasopharyngeal tube in place.


modifiedsothatitcanbepassedthroughthenaresintothehypo-pharynxabovetheepiglottis,allowingoxygenation/ventilationbybypassingtheobstructionatthebaseofthetongue(Parhizkaretal.,2011).TheNPairwaymayprevent theneed formore invasiveproceduresandallowstheteamtoaddressoral skillsandfeeding(Wageneretal.,2003).InsomeinstitutionstheinfantisdischargedhomewithanNPairwayinplace(Abeletal.,2012).Infantsaremonitoredwithoximetry,andparentsaretaughtNPairwaymain-tenance(suctioning)andreplacement.TheNPtubeistypicallyinplacefor3to6monthsorlessifsymptomsresolveorotherinterven-tionsbecomenecessary.Airwaycompromiseandstabilityareassessedbyphysicalexamination,CO2levels,oxygenation,overnightsleepstudies,andgrowth,monitoredovertime(Evansetal.,2011).

Whenairwayobstructionis localizedtothetonguebaseandpositioninghasnotimprovedbreathingandfeeding,aTLAmaybeatemporizingmeasuretominimizeobstructionwhileallowingformandibular growth (Schaefer andGosain,2003). In someinstitutions,TLAhasbeenshowntohaveahigh initial successrateforcorrectionofairwayobstructioninaneonate.However,long-termfollow-upindicatesthatmanyinfantsrequiresecondaryinterventions tomanagetheir feedingandairway(Dennyetal.,2004).

The infant’s clinical status, perceived need for long-termrespiratorysupport,andfailureoflessinvasiveinterventionswill

obstruction.Thetonguecanactasaballvalve,leadingtoinspira-toryobstruction.Inadditiontoglossoptosis,othermechanismsmay contribute to airwayobstruction in individualswithRS,such aspharyngealhypotonia and airway inflammation fromassociated gastroesophageal reflux.The principal physiologicsequelaeofRSare the inability to effectively feedandbreathedue to airwayobstruction. In the immediateneonatalperiod,patientswithRSmayhaveincreasedinspiratoryworkofbreathing,cyanosis,andapnea.Obstructionismorecommoninthesupineposition and canbe exacerbatedduring feeding and in sleeporinanystatewherethereis lossofpharyngealtone.Chronicobstructioncanleadtofailuretothrive,carbondioxideretention,pulmonaryhypertension,andeventuallyright-sidedheartfailure(corpulmonale).

Airwayobstruction is themaincauseof feedingandgrowthissuesininfantswithRS.Feedingproblemscanalsoberelatedtoabnormal coordination, primary swallowingdysfunction, andpharyngealhypotonia,andsuctionmechanicsarecomplicatedbythepresenceofacleftpalate.Increasedenergyexpendituresbecauseoftheincreasedworkofbreathingmayleadtofailuretothriveiftheinfantisnotreceivingadequatecaloricintake.GastroesophagealrefluxiscommonininfantswithRS,asitisinotherinfantswhohaveincreasedworkofbreathing.

ManagementFirstandforemost,theairwaymustbeaddressed.Placementofanasopharyngeal(NP)airwayorendotrachealtubemayberequiredinanemergency,and it is important to realize that severe, life-threateningairwayobstructioncanpresentinthedeliveryroom.Althoughuncommon,aprenataldiagnosisofmicrognathiaallowsthe involvementofneonatologists andotolaryngologists in thedeliveryroom(Costelloetal.,2010).

AnumberoftherapeuticmaneuverscanbeusedtostabilizetheupperairwayinRS,rangingfrompositioningtosurgery.Placingthebabyintheproneorlateraldecubituspositionwilloftenopenuptheairwayanddecreasethedegreeofobstruction.Thismayimproveairwaypatencyandairexchange,whichdecreases theworkofbreathingandmayalsoimprovetoleranceoforalfeeding.Whenpronepositioningfailstostabilizetheairway,alternativeapproachesincludetheuseofanNPairway,noninvasivepositivepressure,treatmentwithtongue–lipadhesion(TLA),andman-dibularadvancementthroughdistractionosteogenesis.Childrenwithisolatedairwayobstructionatthebaseoftonguewithoutothermedicalcomorbiditiesmaybeconsideredformandibulardistractionosteogenesis(MDO)(Paesetal.,2013).Thesurgeryconsistsofsurgicalosteotomyandplacementofdistractiondevicethat slowly increasesmandibular lengthand ramusheightandbringsthebaseofthetongueforward,therebyincreasingtheairwayspace.Thisprocedurewillnotachieverespiratorystabilizationinpatientswithconcomitantairwayanomalies,lungdisease,centralapnea,ortheneedforpositivepressureventilation.Tracheotomymaybenecessary toprovidea safe and secure airway in someinfants.Treatmentprotocolsdifferacrossinstitutions(Bookmanetal.,2012),andanexampleoftheinitialevaluationandclini-cal teamdiscussion for theneonatewith tongue-based airwayobstruction isprovided inBox100.1.While the threshold forinterventionand themanagementoptionsdiffer substantially,mostprovidersagreethatmostneonateswithRScanbetreatednonsurgically.

AnNPairwayprovidesatemporarywaytobypasstheinfant’sairwayobstruction(seeFig.100.1C).Anendotrachealtubecanbe

Initial Evaluation in the Neonatal ICU:Physicalexamination(supinevsprone):attentiontocraniofacialfeatures,

respiratorystatus,cardiacandlimbdifferencesEvaluationforpresenceofglossoptosis,stertor,obstructiveapnea,andworkof

breathingCapillarybloodgasandtotalCO2levelOxygensaturationmonitoringGrowthparametersDysmorphologyevaluationCraniofacialandotolaryngologyconsultationsConsidergeneticsevaluationiftherearemultipleanomaliesoraconcerning

familyhistory(micrognathia,cleftpalate,childhoodhearingloss/myopia/jointproblems)

Considerairwayendoscopy(guidedbyairwayseverityandresponsetointerventions)

Considerairwayimaging(guidedbyairwayseverityandresponsetointerventions)

Multidisciplinary Team Treatment Discussions May Address:Doesthepatientneedescalationincaretotreatairwayobstruction?Haveappropriatesubspecialtyconsultsandevaluationsbeenobtained?(Varies

byinstitution,butcanincludespecialistswithexpertiseinneonatalintensivecare,craniofacialandpediatriccare,airwayevaluations,airwaysurgery,jawsurgery,parent/familysupport)

ShouldthepatientundergoCTtoassessthepossibilityofcraniofacialskeletonandMDO(ifso,whenandhowtoproceedsafely)

Hasthedistalpartoftheairwaybeenevaluatedtolookforotherlevelsofairwayobstruction?

Doesthepatientneedatracheostomytube,orishe/sheacandidateformandibulardistraction?

Whatisthefamilyandsocialcontext?Whatwillthedispositionbeonceairwayhasbeenstabilized?

CT, Computed tomography; ICU, intensive care unit; MDO, mandibular distraction osteogenesis.

Evaluation and Decision Making for Neonates With Tongue-Based Airway Obstruction

• BOX 100.1


syndrome are found to have amutation in eitherCOL2A1(Stickler syndrome type I,OnlineMendelian Inheritance inMan[OMIM]108300)orCOL11A1(SticklersyndrometypeII,OMIM604841)(Robinetal.,2017).ThediagnosisshouldalsobeconsideredinanynewbornwithafamilyhistoryofRSorSticklersyndromefeatures.

Inadditiontoappropriatemanagementoffeeding,breathing,andgrowth(asdescribedearlierinRS),managementofSticklersyndrome includesactivedetectionof theocular featuresof thesyndrome,suchasmyopia.Thisisbecausetheassociatedriskofretinal detachment and blindness are preventable. An initialophthalmologyevaluationisrecommendedforallchildrenwithRSagedbetween6and12monthsoratthetimeofadefinitivemoleculardiagnosisofSticklersyndromeandthenroutinesurveil-lancethereafter.

Orofacial Clefting

EpidemiologyOrofacialcleftsof theprimaryandsecondarypalateareamongthemostcommoncongenitalanomalies.ClassifiedaseithercleftlipwithorwithoutCP (CL±P)orCPonly (CPO), these twophenotypesarethoughttobedistinctinorigin.Onecaseoforofacialcleftoccursinapproximatelyevery500to550births,andonanaverageday in theUnitedStates,20 infants arebornwith anorofacialcleft(TolarovaandCervenka,1998).Cleftlipandpalateisthemostcommontypeoforofacialclefting,followedbycleftlip,thenCPO,andlessprevalentareatypicalclefts(macrostomiaor lateral cleft,obliqueandmidlineclefts).UnilateralCL±P ismorecommonthanbilateralinvolvement(Geniscaetal.,2009).Abifiduvula canbeanormalvariant, found in2%to4%ofbirths,butcanalsobea signof anassociated submucouscleftpalate,whichcanhavethesamefunctionalimpactasanovertCP(Hennekametal.,2010a,Ch21).

The causes of most orofacial clefts are unknown and arenonsyndromic(isolated)in70%–75%ofinfantswithCL±Pandapproximately50%ofthosewithCPO(TolarovaandCervenka,1998;LeslieandMarazita,2013).Neonateswithorofacialclefting

determinewhethermore invasive surgery is indicated (Evansetal.,2011;Cieloetal.,2016).Forsomeneonates,mandibulardistractionosteogenesismaybeanalternativetotracheostomy.Airway endoscopyhelps todelineate the level of obstruction,andcomputedtomography(CT)ofthefacialskeletonprovidesoptimalunderstandingofjawanatomyandtoothbudpositionbeforedistraction.Recognitionof other airway anomalies orissues, such as laryngotracheomalacia, subglottic stenosis, andpoor secretionhandling,will affectdecisionmaking regardingairwaymanagement.ChildrenwithRSassociatedwithsyndromes,skeletaldysplasia,orneurologicconditionsmayhavemorethanonefactorcontributingtotheirairwayobstructionsuchthatatracheostomymaybethebestapproachtoalleviaterespiratorycompromise.ThusinfantswithRSwhohaveairwayobstructionunresponsivetopositionaltechniques(sideorprone)forwhomsurgical options arebeing considered (mandibulardistractionversustracheostomy)shouldhaveacomprehensiveairwayevalu-ationaswellasadiagnosticevaluationforanunderlyingsyndromeorassociatedmalformationsthatmightimpactrespiratorystatusandresponsetotherapies.

Nutrition canbemaintainedwith a hypercaloric formulaand/or fortifiedbreastmilkgivenby side-lying feedingusingacleftfeeder,viaanasogastricfeedingtube,orviaagastrostomytube.Oral feeding can and should be introducedwhen theairwayisstable.Oralstimulationisimportanttopreventoralaversion.As tone improves, the child gainsbetter control ofthe tongue,andgrowthensues, feedingwillbecome lessofaproblem.Closeobservationforsymptomsofgastroesophagealrefluxwithproactivepharmacologic treatment canminimizeairwayinflammation.

Given theassociationwithcognitiveandmotordelay, closemonitoring of development and referral to early interventionservices,suchasaBirthtoThreeprogram,arerecommended.

Stickler SyndromeThemostcommonsyndromeassociatedwithRSisSticklersyn-drome.Between20%and30%ofindividualswithRSwillhaveSticklersyndrome(Izumietal.,2012).Sticklersyndromeismostcommonlyanautosomaldominant (withvariable expressivity)connective tissuedisorderwithophthalmic,orofacial, auditory,andarticularmanifestationsandhasbeendividedintosixtypes(SticklersyndrometypesIandIIhaveocularfindings,typeIIIisnonocular, and types IV toVIare recessiveconditions) (Robinetal.,2017).

Sticklersyndromeischaracterizedbycleftpalate,hearingloss,arthropathy,jointhypermobility,reducedheight,andeyeabnormali-ties,includingmyopia,cataracts,glaucoma,andretinaldetachment.ThemyopiaofSticklersyndromeisusuallycongenital,nonprogres-sive,andofhighdegree.Facialfeaturesincludeflatmidfacewithdepressednasalbridge,shortnose,antevertednares,andmicro-gnathia, telecanthus, andepicanthal foldswithaconcave facialprofile(Fig.100.2).SensorineuralhearinglossismorecommonintypeIISticklersyndrome.

ThediagnosisofSticklersyndromeshouldbeconsideredinanyneonatewithRSoracleftpalate,especiallywhenassociatedwithmyopiaorhearing loss. Spondyloepiphysealdysplasia isnotusuallyapparentinthenewbornperiod.Mutationsaffect-ingoneofsixgenes(COL2A1,COL9A1,COL9A2,COL9A3,COL11A1,andCOL11A2)havebeenassociatedwithSticklersyndrome,andclinicalmoleculartestingbysequenceanalysisisavailableforalltypes.Morethen90%ofindividualswithStickler

• Fig. 100.2 Infant with Stickler syndrome, showing a flat face, depressed nasal bridge, and epicanthal folds. This infant also has Robin sequence and required tracheostomy.


AA BB CC

DD EE FF

• Fig. 100.3 (A) Infant with a unilateral incomplete cleft lip. (B, C) Infant with bilateral complete cleft lip and palate. (D) Infant with midline cleft and hypertelorism. He also has a frontonasal encephalocele. (E) Infant with premaxillary agenesis and holoprosencephaly. (F) Infant with Van der Woude syndrome with unilateral complete cleft lip and a lip pit (arrow).

foramen) and secondarypalate (posteriorhardpalate and softpalate).Cleftsoftheprimaryandsecondarypalatecanbeunilateralorbilateralandcompleteorincomplete.Acompletecleftoftheprimarypalateleavesnoresidualtissuebetweenthealarbaseandthelip,whereasanincompletecleftdoesnotextendthroughthefloorofthenose(Fig.100.3A–C,F).

PhenotypeThecleftof theprimaryand secondarypalatewill affect facialshapeandgrowth(seeFig.100.3A–C).ChildrenwithCPareatincreasedriskofeustachiantubedysfunction,recurrentotitismedia,andacquiredhearingloss,aswellasspeechissueslaterinchildhood.Associateddentalfindingsincludehypodontiaand,lesscommonly,natalteeth.Feedingdifficulties,nasalregurgitationoffeeds,anddifficultygainingweightmayoccurininfantswithaCP(submucousandovertcleftsofthepalate).

Lateralfacialcleftingormacrostomiaispathogenicallydistinctfromisolatedcleftlip/palateandisoftenassociatedwithsyndromes,includingcraniofacialmicrosomia (CFM)andTreacherCollinssyndrome(TCS).Amniotic rupture sequencecanbeassociatedwithobliquefacialcleftsandmaybeassociatedwithunderlyingcentralnervoussystem(CNS)malformationsandtransverselimbanomalies.

Atruemediancleftoftheupper lip is theraresttypeoffacialclefting(seeFig.100.3D).Midlinecleftingcanbeassociatedwithothercongenitaldefectsascanbeseeninorofaciodigitalsyndromeandfrontonasaldysplasia(FND),andCNSmalformationsarecommoninchildrenwithmidlineclefts.Somemidlinecleftsarenottruecleftsbutrepresenthypoplasiaoragenesisoftheprimarypalateorpremaxil-laryagenesis,whichcanbeassociatedwithholoprosencephaly(HPE)sequence(seeFig.100.3E).InfantswithHPEoftenhaveadepressednasaltipandashortcolumellaandappearhypoteloric(comparedwithFNDorfrontonasalencephalocele,wheremidlinecleftingmay

whoarebornprematurelyorhave lowbirthweightmayhaveahigherincidenceofassociatedcongenitalmalformations(Mileradetal.,1997).Racialandethnicvariationintheprevalenceofcleftshasbeendescribed,withthehighestprevalenceofCL±PfoundinNativeAmericans,followedbywhitesandHispanics,andthelowest overall prevalence of CL±P demonstrated in AfricanAmericans(Croenetal.,1998).Thecauseofnonsyndromiccleftsis complexandmultifactorial, likely resulting from interactionbetweenenvironmentalandgeneticfactors.Knownenvironmentalrisk factors include maternal tobacco smoking, alcohol use,anticonvulsanttreatment,andnutritionalstatus.RecognitionofcontributinggeneticfactorssuchasamutationinIRF6resultinginVanderWoudesyndromeisincreasing,andtheimpactoffolatesupplementationasanenvironmentalmodulatorisunderinvestiga-tion(Mosseyetal.,2009;WehbyandMurray,2010).Althoughmanycandidategeneshavebeendescribed,thereisnoroutinelyrecommendedgenetic testing forachildwith isolatedCL±P intheabsenceofa familyhistory.Recurrencerisk informationfortheparentsofachildwithCL±Porfortheaffectedindividualisdependenteitheron the specific syndrome/geneticdiagnosisoronempiricrisksforthosewithnonsyndromicclefting.Forafamilywith just one child affectedwithCL±P, the recurrence risk is2%–5%forasubsequentchild,increasingto10%–15%ifthereareotherfamilymemberswithclefts.TherecurrenceriskisslightlylessifthechildhasCPO(Harper,2011).

AnatomyTheembryologicdevelopmentoftheprimarypalatebeginsveryearly in gestation, and theupper lip andprimarypalatehaveusuallyfusedbytheseventhweekofgestation.AfailureoffusionofthemedialandlateralnasalprocesseswiththemaxillaryprocessproducesCL±P.Cleftscanaffecttheprimarypalate(lip,alveolus,oranteriorportionofthehardpalatethatextendstotheincisive


recommendedteamcare forpatientswithcleft lip/palatecanbeaccessedelectronically(AmericanCleftPalate-CraniofacialAssociation,2009;TheCenterforChildrenwithSpecialNeeds,2010).

Ontheinitialassessment,theprovidershouldassessthecleftandexaminetheinfantfordysmorphicfeaturesandotheranomalies.Hearingshouldbeevaluatedbyevokedotoacousticemissionsorbybrainstemauditoryevokedresponseifthenewborndoesnotpasstheinitialhearingscreen.Aneonatewithacompletecleftlipshouldbeevaluatedbyacraniofacialorcleftteaminthefirst2weeksoflife,andsomecentersoffertapingorpresurgicalmolding(nasoalveolarmolding)thatcanbeinitiatedinthisperiod.

Manymotherswillbeabletobreastfeedaninfantbornwithanisolatedcleftlip.BreastfeedingababywithCP(withorwithoutcleftlip)willproveextremelychallengingbecausetheopenpalatewillnotgeneratethenegativepressureneededforsucking.ThusinfantswithCPwithorwithoutcleftlipshouldbeofferedexpressedbreastmilkorinfantformulawithuseofaspecializedcleftfeeder.A variety of cleft nipples/bottles have been devised to alloworalfeeding,includingtheCPnurser(squeezebottle),Habermanfeeder, Pigeon bottle, and Dr. Brown bottle with a cleftvalve (http://www.cleftline.org/who-we-are/what-we-do/feeding-your-baby/). InfantswithCPtend to swallowmoreairduringfeedings.Thechildshouldfeedinanuprightposition,asgravitywillhelppreventnasal regurgitation. If thechild is stillhavingdifficultyfeeding,afeedingspecialistshouldbeconsulted.Adequateweightgainisimportantforoverallhealthandreadinessfor the surgical procedures that occur in thefirst year of life.Newbornswithcleftsareconsiderednutritionallyhighrisk,andadietitian shouldbeconsulted tohelpdeterminecaloricneedsandtocloselymonitorgrowth.

Ingeneral, surgical closureof the lipandnasaldeformity isdonewithinthefirst6monthsoflife.Palatoplastytypicallyoccursbetween9and12monthsofagetooptimizespeechandlanguagedevelopment.

Ifthereareconcernsaboutairwaycleftingoranomaliesofthelarynxortrachea,achestX-rayshouldbeobtainedandtheairwayevaluated, in addition to appropriate evaluation of associatedanomalies.Microlaryngoscopywith thepatient under generalanesthesiaremainsthegoldstandardinthediagnosisofalaryngealcleft (Johnstonetal.,2014).Given the riskofgastrointestinalmanifestations suchasgastroesophageal reflux,dysmotility,andaspiration, antirefluxprecautions shouldbe initiated in infantswith suspectedor confirmedLTEdefects.Earlydiagnosis andproperrepairofthelaryngealcleftareessentialtopreventinjuryto the lungs.SignificantLTEdefectswillneed tobemanagedsurgically,andtracheostomymaybenecessaryinitiallytoensureairwaystabilityandsafety.

Inthepresenceofamidlinecleft, it is importanttoevaluatethepatientforunderlyingCNSmalformationssuchasHPE.Inanychildwithamidlinecleftor facial featuresconsistentwithpremaxillaryagenesis/hypoplasia,CNSimaging(CTorMRI)isrecommended.Consultationwithageneticistorgeneticcounselormayprovideinsightintothegenetics,moleculartestingoptions,andrecurrenceriskofHPE.TreatmentofHPEissupportiveandbasedonsymptoms.TheoutcomedependsontheseverityofHPEandtheassociatedmedicalandneurologicmanifestations.

Syndromes Associated With Cleft Lip and/or PalateItisestimatedthattherearemorethan400syndromesassociatedwithorofacial clefts (Hennekamet al.,2010a).The frequency

bepresent,buttheinfanthasabroadnasaltipand/orcolumellaandhypertelorism).

Orofacialcleftingisrarelyassociatedwithcleftingoftheairwaystructures, suchascleft larynxorextensionofclefting into thetrachea.OpitzG/BBBsyndromeisamultiplecongenitalanomalysyndromecharacterizedbyfacialanomalies(100%willbehyper-teloric and50%willhaveCL±P),genitourinaryabnormalities(90%willhavehypospadias),andlaryngotracheoesophageal(LTE)defects (present in70%)(Meroni,2011).Autosomaldominant(OMIM145410)andX-linkedrecessive(OMIM300000)formsofOpitzG/BBBsyndromearerecognized.Pallister–Hallsyndrome(PHS;OMIM146510)ischaracterizedbyaconstellationoffindingsthatincludehypothalamichamartoma(resultinginseizuresandpituitary dysfunction), polydactyly, airway clefting, andotheranomalies(genitourinary,renal,pulmonary,andimperforateanus).BifidepiglottisisthemostcommonairwaymanifestationinPHS,althoughLTEcleftshavebeenreported.LTEdefectsmayrangefromLTEdysmotilityinmildformstolaryngealortracheoesopha-gealcleftsinmoresevereforms.

ICU ConcernsMostinfantswithCL±PdonotrequireICUcare.ThusaninfantwithanapparentlyisolatedcleftwhodevelopssignificantrespiratoryorelectrolyteabnormalitiesrequiringICUcareshouldbeconsideredsyndromicuntil proven otherwise. In these infants a geneticsconsultationshouldbeconsidered.

Thenewbornwithamidlinecleftorpremaxillaryagenesis isatriskofseriousunderlyingCNSanomalies,includingHPE.InthepresenceofHPE,detectionof associatedmedical issues isimportant.Endocrineabnormalitiescanarisebecausethemidlinemalformationaffects thedevelopmentof thehypothalamusandthepituitarygland.Clinicalmanifestationscan includegrowthhormonedeficiency,adrenalhypoplasia,hypogonadism,diabetesinsipidus,andthyroiddeficiency.Neurologicmanifestationsthatwarrant close attention include seizures,hypotonia, spasticity,autonomicdysfunction,anddevelopmentaldelays.

WithanLTEcleft,thereislongitudinalcommunicationbetweentheairwayandtheesophagus,allowingtrachealaspirationoforalcontents, including salivaand feeds.Cleftingof the larynxmayresultinstridor,ahoarsecry,respiratorydistress,swallowingdysfunc-tion, feedingdifficulties, regurgitation,andaspiration,hypoxia,recurrentpneumonias,andeventuallysevererespiratorycompromiseifunrecognized.Aninfantboywithhypertelorism,hypospadias,orofacialclefting,andsymptomsofairwayobstructionoraspirationshouldbeevaluatedforOpitzsyndrome.InfantswithPHSmayalsohaverespiratorydistressduetoairwayclefting,aswellasotherpotentiallylife-threateningclinicalmanifestationssuchasseizuresandseverepanhypopituitarism.GeneticevaluationandconsiderationofmoleculartestingforOpitzsyndromeandPHScanbecoordi-natedthroughageneticist.

ManagementThespecificsofmanagementoforofacialcleftingarecenterspecific.Becauseofthepotentialimpactoftheorofacialcleftonbreathing,eating,hearing,speech,facialgrowth,anddentalhealth,itisrecom-mendedthatinfantsandchildrenwithcleftsbereferredtoamul-tidisciplinarycareteamforlong-termmanagement.Inremoteareas,thenearestcleft teammaybefoundthroughtheAmericanCleftPalate-CraniofacialAssociation (ACPA) team listings (AmericanCleft Palate-Craniofacial Association, 2017). Overviews of

http://www.cleftline.org/parents/feeding_your_baby

http://www.cleftline.org/parents/feeding_your_baby


psychiatricillness.Inthissection,wefocusontheevaluationofinfantswithcraniofacialcharacteristicssuggestiveof22q11.2DS.

Severalcraniofacialfeatureshavebeenobservedinindividualswith22q11.2DS;however,manyofthesearesubtleandmaynotbeapparentinthenewbornperiod.Commonfeaturesidentifiedonthenewbornphysicalexaminationincludecleftpalate,small,overfoldedhelices,andtaperedfingers.Othercluestothediagnosisincludedysphagiaand/ornasalregurgitation(evenintheabsenceofanovertcleftpalate),congenitalheartdisease(mostcommonlyconotruncalanomalies),andhypocalcemia.

Anestimated8%ofinfantswithCPhave22q11.2DS(Hennekametal.,2010b).Forthisreason,recommendationsdifferregardingroutine testingof infantswith isolatedcleftpalate.Mostagree,however,thatmoleculartestingisindicatedforchildrenwithaCPincombinationwithanyoftheotherfeaturesthatcanbeobservedin22q11.2DS.Theaccurate identificationof22q11.2-associateddisordersimpactsmedicalsurveillance,management,andcounseling.Clinicaltestingwithchromosomalmicroarrayormultiplexligation-dependentprobeamplificationwillcapturedeletions,duplications,andsmallerchanges including those thatwouldnotbedetectedwithfluorescenceinsituhybridizationfor22qdeletion.

Evaluation and ManagementFamiliesofinfants,forwhomthereisahighclinicalsuspicionandthosetestingpositiveforthisdeletion,shouldreceivegeneticcounseling.Individualswith22q11.2DSshouldundergostudiestoidentifyassociatedhealthconcerns.Thesescreeningevaluationsincludeatotallymphocytecount(lowabsolutelymphocytecountnecessitates evaluationofT-cell andB-cell subsets and referraltoanimmunologist),hematocrit,plateletcount,andtotalandionized calcium levels to screen the infant forhypocalcemia.Additionalstudiesincludeechocardiogramtoevaluatetheinfantfor congenitalheartmalformationsand renalultrasonography.Newborns shouldhaveapalatalexaminationtoevaluate themforovertorsubmucousclefting,aswellasadiagnostichearingtest.Infantswithevidenceofdysphagia(evenintheabsenceofapalatalcleft)benefitfromanevaluationbyafeedingspecialisttodetermine if a swallow study isneededor if a cleft bottlewouldbehelpful.Additional recommendations for screeningevaluationsandmanagementhavebeenoutlinedbyMcDonald-McGinnetal.(2015).

Craniosynostosis

Definitions/EpidemiologyCraniosynostosis refers to thepremature fusionofoneormorecranialsutures(metopic,sagittal,rightorleftcoronal,orrightorleftlambdoid)thatnormallyseparatethebonyplatesofthecranium.Thebirthprevalenceofallcraniosynostoses isestimatedtobe1in2500livebirths(Bouletetal.,2008).

Typically,patentsuturesallowthecalvariatoexpandasthebraingrows,producingthenormalheadshapeandsize.Ifoneormoresuturesfuseprematurely,thereisrestrictedgrowthperpendiculartothefusedsuturesandcompensatorygrowthinthepatentsutures,producinganabnormalheadshape.Craniosynostosis isahetero-geneousdisorderwithsignificanthealthconsequences thatrangefromanabnormalheadshapeandincreased intracranialpressure(ICP) to secondaryvisualand intellectual impairments.Knowncausesofprimarycraniosynostosisincludemonogenicandchromo-somalabnormalitiesaswellasenvironmentalfactors.Nonsyndromicsinglesuturecraniosynostosisaccountsfor85%ofpatients.Syndromic

withwhichassociatedmalformationsareencounteredwithCL±Pis approximately25% (Genisca etal., 2009). In approachingdiagnosisofasyndrome,oneshouldcategorizethetypeofcleft(CL±P,U-shaped orV-shaped cleft palate, ormore atypicalorofacial cleft) and look for any othermalformations.Table100.1describesthesyndromesmostcommonlyassociatedwithcleftingandthekeyfeatures,potentialICUissues,andOMIMdatabase classification.TheOMIMdatabase at theNationalLibraryofMedicineisacomprehensivecollectionofmorethan15,000humangenes andgeneticphenotypes.A referral to aclinicalgeneticistisrecommendedwhenanunderlyingdiagnosisissuspectedbutnotestablished.

22q11.2 Deletion SyndromeEpidemiology and Genetics22q11.2deletionsyndromeisageneticconditionwithanestimatedprevalenceof1 in1000births inwhichaffected individualsaremissingaregion(typically3Mb,encompassingapproximately40genes) onone copyof chromosome22 (Carlson etal., 1997;McDonald-McGinnetal.,2015).Beforetheavailabilityofgenetictesting for this condition, individualswith clinical featuresof22q11.2DSwereclassifiedunderarangeofotherclinicalsyndromes,such asDiGeorge syndrome, velocardiofacial syndrome, andShprintzen syndrome.Subsequently, a subsetof childrenwithoverlappingfeaturesintheseconditions(suchascongenitalheartdisease andcleftpalate)werealsonoted to shareadeletiononchromosomearm22q.ItwaslaterdiscoveredthatthemostchildreninwhomeitherDiGeorgesyndromeorvelocardiofacialsyndromehasbeenclinicallydiagnosedshare thedeletionononecopyofchromosome22. Ithasbeenestimated thatmore than90%ofindividualswith“classic”featuresof22q11.2DShaveadetectable22qdeletion (McDonald-McGinnetal.,2013).22q11.2DS isassociatedwithmorethan180clinical features,andphenotypicvariationisahallmarkofthisgeneticcondition(McDonald-McGinnetal.,2015).

PhenotypeInneonates,22q11.2DSpresentsinvariousways.Insomeinfantsthisconditionisdiagnosedprenatally.Testingmayoccuraspartof the evaluation for fetuseswith congenitalheartdisease orbecauseofaparentalhistoryof22q11.2DS.Theclinicalindicationsforgenetictestingforthisconditioninneonatesfrequentlyincludecongenitalheartmalformations(particularlyconotruncalanoma-lies),seizuressecondarytohypocalcemia,dysphagia,cleftpalate,and/orrespiratorydistresssecondarytoupperairwayobstruction.22q11.2DS commonly hasmultiorgan system involvement,includingcardiacandpalatalabnormalities,immunedifferences,endocrineandgastrointestinalproblems,andlater-onsetconditionsacross the life span, including variable cognitive deficits and

PediatricsNursingSocialworkGeneticsNutritionFeedingSpeechpathologyAudiology

OtolaryngologyPlasticsurgeryNeurosurgeryOphthalmologyOralsurgeryDentistryOrthodonticsPsychology

Specialties of the Members of a Craniofacial Team

• BOX 100.2


andmaternalsmoking.Althoughuncommon,themostfrequentlyencounteredassociatedanomaliesincludecongenitalheartdefectsandgenitourinarytractmalformations.Syndromeswithsynostosisinvolvingonlythesagittalsuturearerare.Prematureunionofthesagittal suture hinders normal calvarial expansion, leading toscaphocephaly,anelongated,narrowcalvarium,decreasedbitemporaldiameter,andfrontalandoccipitalbossing(Fig.100.4).Prematurefusionofthesuturebeforebirthleadstoabnormalheadshapeinthe newborn period. A breech-positioned neonate can havescaphocephalyordolichocephalythatmaymimicsagittalsynostosis.However, in sagittal synostosis, frontal bossing andbiparietalnarrowingprogress,whereastheheadshapeinabreech-positionedinfantwillnormalizeinthefirstmonthoflife.ThereisaconcernthatchildrenwithsinglesuturesynostosisareatriskofelevationsinICP,localbraininjury,andlaterdevelopmentaldelays.Althoughschool-agechildrenbornwithsinglesuturecraniosynostosishavebeen foundtohaveevidenceofmilddevelopmentaldelays, thepathogenesisanddirectrelationshiptosynostosishavenotbeendetermined(Speltzetal.,2015).

craniosynostosismay involve single ormultiple fused sutures,additional anomalies (suchas limb,cardiac,CNS,and trachealmalformations),anddevelopmentaldelay.Multiplesutureinvolvementisusuallyconsideredhereditaryevenwhenitdoesnotfitaclassicpatternofanomalies.Advances inmoleculargeneticsandnext-generationsequencinghave ledto the identificationofcausativemutationsandgeneticpathwaysintheserelativelycommoncongenitalanomalies(TwiggandWilkie,2015a,2015b).Thegeneticcauseofcraniosynostosisinhumansisonlypartiallyunderstood.However,formost syndromic forms, identificationof theprimarygeneticcauseandcontributingfactorsispossiblewithuseofclinicallyavailablegenetictests(Agochukwuetal.,2012).

Single Suture SynostosisSagittal synostosis is themost common single suture synostosis(50%–60%),withaprevalenceof1.5per10,000livebirths(Bouletetal.,2008).Knownrisk factors includemale sex, intrauterineheadconstraint,twingestation,thyroidhormonedysregulation,

Syndrome Key Features Tracheal Abnormalities Midface Hypoplasia OMIM

Apertsyndromea Craniosynostosis(coronal>lambdoid>sagittal),acrobrachycephaly(steep,wideforeheadandflatocciput),proptosis,hypertelorism,exotropia,trapezoid-shapedmouth,prognathism,invariablesymmetricsyndactylyofhandsandfeet,variableelbowfusion,cognitiveimpairment,narrowpalatewithlateralpalatalswellings,widelypatentsagittalsutureconnectinganteriorandposteriorfontanels

Tracheoesophagealfistula,trachealcartilaginoussleevelesscommon

Significantmaxillaryhypoplasia,obstructivesleepapneasyndrome

101200

Crouzonsyndromea Craniosynostosis(coronal>lambdoid>sagittal),brachycephaly,prognathism,exophthalmos,papilledema,hypermetropia,divergentstrabismus,atresiaofauditorycanals,Chiaritype1malformationandhydrocephalus

Solidcartilaginoustracheaortrachealcartilaginoussleeve


123500

PfeiffersyndrometypesI,II,andIIIa

Craniosynostosis(coronal>sagittal>lambdoid),brachycephaly,hypertelorism,proptosis,broadfirstdigitswithradialdeviation,variablesyndactylyandelbowfusion,cloverleafskull

Solidcartilaginoustracheaortrachealcartilaginoussleeve


101600

Muenkesyndrome Unilateralorbilateralcoronalcraniosynostosis,brachydactyly,downslantingpalpebralfissures,thimble-likemiddlephalanges,conedepiphysis,carpalandtarsalfusions,sensorineuralhearingloss,Klippel–Feilanomaly

Mildmaxillaryhypoplasia,noairwaycompromiseanticipated

602849

Saethre-Chotzensyndromea

Unilateralorbilateralcoronalcraniosynostosis,acrocephaly,brachycephaly,lowfrontalhairline,hypertelorism,facialasymmetry,ptosis,characteristicear(smallpinnawithaprominentcrus),fifthfingerclinodactyly,partial2–3syndactylyofthefingers,duplicatedhalluces

Maxillaryhypoplasia 101400

Carpentersyndrome Craniosyvnostosis(coronal>lambdoid>sagittal),hypertelorism,proptosis,brachycephaly,brachydactyly,preaxialpolysyndactyly,mentalretardation


Jackson–Weisssyndrome

Craniosynostosis(coronal),acrocephaly,hypertelorism,proptosis,midfacehypoplasia,radiographicabnormalitiesofthefootincludingfusionofthetarsalandmetatarsalbones,2–3syndactyly,broadshortfirstmetatarsalsandbroadproximalphalanges


aSignificant risk of airway morbidity.OMIM, Online mendelian inheritance in man.

Craniosynostosis Syndromes and Potential Airway CompromiseTABLE 100.2


craniosynostosissuchasApertsyndrome,Crouzonsyndrome,orMuenkesyndrome,somehavechromosomeaberrationsorpatternsof craniosynostosis with associated anomalies not previouslydescribed.With20knownhereditaryformsofcraniosynostosis,geneticconsultationandcounselingareofcriticalimportanceinthemanagementoftheseconditions(TwiggandWilkie,2015a,2015b).Herewe briefly discuss selectmajor syndromeswithcraniosynostosis thatmayhavemedical issues in thenewbornperiod.SeeTable100.2foradescriptionofkeyphenotypicfeaturesandpotentialairwaycompromise.

Apert syndrome (OMIM101200)was initiallydescribedasacrocephalywith four-limb syndactyly. It accounts for4.5%ofall craniosynostosis (Hennekametal.,2010c;Fig.100.5). It isinheritedasanautosomaldominant traitand isassociatedwithadvancedpaternal age.Neurocognitive outcomesdiffer, but amoderatetoseveredegreeofcognitiveimpairmentismostcommon.Fourmutations inFGFR2 causingApert syndromehavebeenidentified.

Crouzonsyndrome(OMIM123500)isanautosomaldominantconditionthatdemonstrateswidephenotypicvariability.Shalloworbitswithproptosisareanimportantdiagnosticfinding,althoughthisfeaturemaybesubtlerinthenewborn(Fig.100.6).Significantabnormalities involving theCNS include the frequentpresenceofaChiaritype1malformation,withprogressivehydrocephalusresulting in intracranial hypertension.Comparedwith Apertsyndrome,Crouzonsyndromeisassociatedwithmoreextensivesuture involvement, smaller cranial volume, andmore severeintracranialconstraint;however,cognitivedevelopmentisusuallynormal.LikeApert syndrome,Crouzonsyndrome is causedbymutationsinFGFR2.AlesscommonformofCrouzonsyndromewithacanthosisnigricansskinfindingsdevelopinginthefirst2yearsoflifeiscausedbyatransmembranemutationinFGFR3(OMIM612247).

Pfeiffersyndrome(OMIM101600)isahereditarycranio-synostosisthatsharessignificantoverlap,bothphenotypicallyand genetically,withCrouzon syndrome. It is an autosomaldominantinheriteddisorderwithcraniosynostosisaccompaniedby proptosis, broad anddeviated thumbs and big toes, and

Coronal synostosisisthesecondmostcommonsinglesuturesynostosis (20%–30%),with a prevalence of 0.7per 10,000livebirths(Bouletetal.,2008).Theskullisnotableforaflatsupraorbitalrimandorbitthatappearshigherontheaffectedside,with a frontal bulge on the contralateral side (see Fig.100.4).Thenoseoftenappearstotwistawayfromthecoronalfusion.Geneticsyndromesaremorefrequentlyseeninindividualswithcoronalsynostosis,includingSaethre–Chotzensyndrome,Muenke syndrome, and craniofrontonasal dysplasia. Allfamiliesofchildrenwithcoronalsynostosisshouldbeofferedgeneticconsultationand/orgenetictestingtoincludeFGFR2,FGFR3,TWIST1,TCF12,andEFNB1onthebasisofclinicalexamination.

Metopic synostosis(15%–20%ofsinglesuturecraniosynostosis)hasaprevalenceof0.8per10,000livebirths(Bouletetal.,2008),althoughrecentreportssuggestthatmetopicsynostosismaybeascommonascoronalsynostosis(Leeetal.,2012).Riskfactorsincludemale sex, twin gestation, and in utero exposure to valproate.Syndromes,associatedanomalies,andchromosomalabnormalitiesoccur inapproximatelyone-quarterof individualswithmetopicsynostosis (Lajeunieetal.,1998;Azimietal.,2003).Prematurefusionofthemetopicsutureresultsinatriangularheadshape,ortrigonocephaly,whichfeaturesamidlineforeheadridge,fronto-temporalnarrowing,pterionconstriction,hypotelorism,andanincreasedbiparietaldiameter (seeFig.100.4). Isolatedmetopicridging iscommon in infancy,doesnotdistort foreheadshape,andisnotassociatedwithmetopicsynostosis.

Lambdoid synostosis (3%of single suturecraniosynostosis) istheleastcommonformofsinglesuturesynostosis.Itischaracterizedbyflatteningoftheipsilateralocciput,posterior–inferiordisplace-mentoftheear,bulgeofthemastoidprocessonthefusedside,andaskullbasetilteddownwardontheaffectedside.

Multiple Suture SynostosisMultiple suture (ormultisuture) synostosisdescribespatientswhohavetwoormorefusedsutures.Althoughchildrenwithmultisuturesynostosis aremore likely tohaveaknownsyndromic formof

• Fig. 100.4 Head shapes in single suture synostosis. From left to right: normal head shape, sagittal synostosis, coronal synostosis, and metopic synostosis.


degreesofproptosis,withoutsignificantmidfacehypoplasia(Fig.100.8).

Saethre–Chotzensyndrome(OMIM101400) iscausedbyamutationintheTWIST1geneonchromosome7.Theinheritanceisautosomaldominant,andmanychildrenwithSaethre–Chotzensyndromewillhaveanaffectedparent.Inadditiontocraniosyn-ostosis,affectedindividualscommonlyhavealowfrontalhairline,ptosis,2–3syndactylyofthefingers,cervicalspineanomalies,andduplicatedhalluces.Althoughlearningdifficultiesmaybenoted,cognitiveimpairmentisnottypicalofSaethre–Chotzensyndromecausedby intragenicmutations.Childrenwithdeletions ratherthanpointmutationsoftendemonstratesignificantdevelopmentaldelays.

partialsyndactylyofthehandsandfeet(Fig.100.7).MutationsinFGFR1 andFGFR2 causePfeiffer syndrome.Type1 (i.e.,classic)Pfeiffersyndromeinvolvesmildmanifestationsincludingbrachycephaly,midfacehypoplasia,anddigitalmalformations.Type2 consists of cloverleaf skull, extremeproptosis, digitalmalformations, elbow ankylosis, developmental delay, andneurologiccomplications.Type3issimilartotype2butwithoutacloverleafskull.

Muenkesyndrome(OMIM602849)isanautosomaldominantsyndromecausedbyasingleP250RmutationintheFGFR3gene.LikeApertsyndrome,Muenkesyndromeisassociatedwithadvancedpaternalage.IndividualswithMuenkesyndromemayhavecoronalcraniosynostosis(unilateralorbilateral)ormacrocephalyandvariable

A

B

C

• Fig. 100.5 (A) Infant with Apert syndrome, a high and full forehead, proptosis and exotropia, midface hypoplasia, and a trapezoid-shaped mouth. (B, C) Hands and feet in Apert syndrome. Note the syndactyly symmetrically affecting hands and feet. All five digits may be webbed, or a single toe, finger, or thumb may be free.

A B

• Fig. 100.6 (A) Infant with Crouzon syndrome with brachycephaly. (B) Proptosis is seen in the lateral view.


belowthesubglottis to thecarinaorbronchus; rarely, thecarti-laginous sleeve canbeginmoreproximally, at the level of thecricoidcartilage.Infantswithcongenitaltrachealanomaliesmayhavefixedstridor,apnea,cyanosis,orincreasedworkofbreathingbecauseofmultilevelairwayobstruction.

NeurologicabnormalitiessuchashydrocephalusandincreasedICPmayarise,especiallyinmultisuturecraniosynostosis.IncreasedICPdue toconstraintof thegrowingbrainwithina restrictedcalvariumisusuallyoflowgradeandchronic,causingsymptomaticintracranialhypertensionwhenbraingrowthisrapidduringthefirst2yearsoflife.ICPissuesintheneonatearenotusuallylifethreatening,giventheopenfontanelandcompensatorysplayingofnormal suturesorerosionof thecalvarium,butbrain injuryandcognitive impairmentmayresult if skull-expandingsurgeryisnotperformed.

Hydrocephalus,whichismorecommoninCrouzonandPfeiffersyndromescomparedwithothermultisuturesynostosissyndromes,canoccurasaresultofobstructionofcerebrospinalfluidatthebasalcistern,aqueductalstenosis,orimpededvenousfloworwhenthere is an associatedChiarimalformation.Hydrocephalus isextremelycommonincloverleafskull.Individualswithmultisuturecraniosynostosis (particularlyApert syndrome)morecommonlyhavenonprogressivedistortionventriculomegalyorcompensatedhydrocephalus,whichdoesnotrequireshunting(Collmannetal.,2005).Abnormalitiesofthecorpuscallosumandseptumpellucidumhavebeendescribed inApert syndrome,andneuroimagingandgeneticadvanceswill illustrate linksbetweenbrainarchitecture,phenotype,andgenotype(Fernandesetal.,2016).Seizurespresent-inginmultisuturecraniosynostosissyndromesareusuallyduetoencephalopathyratherthanincreasedICP.Epilepsyismorecommon

Cloverleafskullcanresultfromanyformofmultisuturecra-niosynostosis.The skull forms a trilobular appearance, as thecerebrumbulgesthroughthesagittalandsquamosalsutures,becauseofcraniosynostosisaffectingthecoronal,metopic,andlambdoidsutures.Cloverleafskullcanbeisolatedormorecommonlyassoci-atedwithasyndrome,anditisestimatedthatupto20%ofcasesrepresentPfeiffersyndrome.

ICU ConcernsThemostsignificantconcernsforthenewbornwithcraniosynostosisare airwaycompromise (specifically,upper airwayobstruction)andintracranialhypertension.

Midfacehypoplasiaandtrachealanomaliesthatmaybepresentin syndromic craniosynostosis can lead to significant airwaycompromise(seeTable100.2).Withmidfacehypoplasia,thereisdecreasedNP/oropharyngeal spacebecauseof a smallmaxilla,narrowing at the level of the posterior choanae andposteriordisplacementofbonyandsofttissuestructures,leadingtobreathingproblems,obstructivesleepapnea,asphyxia,andevendeath(Fig.100.9).ObstructivesleepapneaiscommoninApert,Pfeiffer,andCrouzonsyndromes.

Cartilaginoustrachealabnormalitiescanbepresentinmultisuturecraniosynostosissyndromes.Verticallyfusedtrachealcartilage(alsoreferredtoastrachealcartilaginoussleeve,solidcartilaginoustrachea,andstovepipe trachea) inCrouzonandPfeiffer syndromesmayproducearigidtrachearesultinginupperairwaystenosis,inabilitytoclearsecretions,andincreasedriskofinjurybecauseofdecreaseddistensibility.Characteristictrachealcartilaginousringsarefusedtoformacontinuoussleeveofcartilage,whichmayextendfrom

A B C

• Fig. 100.7 (A, B) Infant with Pfeiffer syndrome, brachycephaly, a high forehead, midface hypoplasia, proptosis, and ocular hypertelorism. (C) An older child with Pfeiffer syndrome and the typical broad thumbs with radial deviation.

A B C

• Fig. 100.8 (A, B) Infant with Muenke syndrome, acrobrachycephaly due to bicoronal synostosis, and absence of proptosis. (C) Sibling of the infant in (A, B) also with Muenke syndrome; note the downslanting palpebral fissures.


disease, and inutero constraint (oligohydramnios, twins, fetalmovement),andthebirthhistoryshouldbeascertained,specificallylookingforriskfactors.

Adetailedphysicalexaminationshouldbeperformedaspartof the initial evaluation, looking foranyotheranomalies,withspecificattentiontocleftpalate, limbdefects,heartdefects,andearanomalies.Theassessmentofcranialandfaceshape,mobilityof the sutures,presenceof sutural ridging, skullbase symmetry,andearpositionisimportant.Facialappearance,withparticularattention to thedegreeofmaxillaryhypoplasia, is important indetermining the risk of airway compromise due to midfacehypoplasia. Ifconcerningairwaysymptomsarepresent, suchassnoring,stridor,orapnea,consultationwithasleepspecialistandpolysomnographymayhelptoquantifythepresenceandseverityofobstructivesleepapnea.Consultationwithanotolaryngologistandairwayendoscopymayhelpidentifythetypesanddegreeofairwaynarrowing (Wengeretal.,2017).Particularattention tothepresenceof trachealmalformations, suchasvertically fusedtrachealcartilage,iscrucialinsomecraniosynostosissyndromes.

withincreasingnumberofsuturesinvolved,andseizuresoccurinapproximately10%ofindividualswithCrouzonsyndrome(Cohen,2000).

Conductiveandmixedhearing loss,mostcommonlydue tomiddleeardisease,ossicularabnormalities,andexternalauditorycanalstenosisoratresia,canbepresentinsyndromiccraniosyn-ostosis.ProfoundsensorineuralhearinglosshasbeendescribedinSaethre–Chotzensyndrome(Leeetal.,2002).

EvaluationTheevaluationofthepatientwithcraniosynostosisincludesrecogniz-ingandconfirmingthetypeofsuturefusion,clinical syndromeidentification,evaluationforassociatedanomalies,andpreparednessforsurgicalrepair.Acraniofacialteammadeupoftheappropriatespecialties allowsproperplanningandcoordination so that thepatientmayreceivethebestpossiblecare(McCarthyetal.,2012).

Thefamilyandprenatalhistory, includingdocumentationofaffected familymembers, teratogenexposure,maternal thyroid

A B

C D

• Fig. 100.9 (A, B) Three-dimensional reconstruction of a child with Apert syndrome with significant midface hypoplasia, leading to upper airway obstruction. Also notable is acrobrachycephaly due to bicoronal synostosis and the typical pattern of sagittal suture patency. (C) Computed tomography (CT) scan axial slice at the level of the skull base in a newborn with Apert syndrome. The arrow pointing to the airway illustrates significant airway obstruction. (D) CT scan of a newborn illustrating a normal airway (arrow).


feeding,anddentalmalocclusion.Thisisusuallyperformedlaterinchildhood.

For all individuals with craniosynostosis, we recommendinvolvementofacraniofacialteam,includingmembersspecializinginpediatrics,neurosurgery,ophthalmology,oralsurgery,ortho-dontics,otolaryngology,nursing,nutrition,plasticsurgery,andsocialwork.

Disorders of the First and Second Branchial Arches

Craniofacial MicrosomiaEpidemiology and GeneticsCFM(OMIM164210),acongenitalmalformationinwhichthereisasymmetricdeficiencyinskeletalandsofttissueononeorbothsidesoftheface,isthemostfrequentlyencounteredformoffacialasymmetry.CFMaffectsapproximately1in5600births(Grabb,1965).IndividualswithfeaturesofCFMhavebeenclassifiedunderavarietyofdifferentdiagnoses(hemifacialmicrosomia,oculoau-riculovertebral spectrum, facioauriculovertebral syndrome,firstandsecondbranchialarchsyndrome,otomandibulardysostosis,Goldenhar syndrome, lateral facial dysplasia) attesting to thephenotypicvariabilityofdisorders associatedwithmandibularhypoplasia.MostoftenCFMisasporadicconditionwitharecur-renceriskofapproximately2%forfuturepregnancies,unlessthereisaknownfamilyhistoryofmicrotiaorCFM(Beleza-Meirelesetal.,2014;Heikeetal.,2014).Variouscauses,bothenvironmentalandheritable,havebeenstudied,andformost,thecauseisthoughttobemultifactorial.

PhenotypeCFMisprimarily a syndromeof thefirstor secondbranchialarches, resulting inunderdevelopmentof theear, temporoman-dibularjoint,mandibularramusandbody,andmasticationmuscles.Theaffectedearmayhaveanexternal soft-tissuemalformationwithorwithoutpreauricular tagsandmaybe lower inpositioncomparedwiththeearonthecontralateralside.Hearinglossmayresultfrommaldevelopmentoftheossicularchainandastenoticoratreticexternalauditorycanal.Secondbranchialarchdefectscaninvolvethefacialnerveandmusclesoffacialexpression,whichcan exacerbate the appearanceof facial asymmetry.Evenwithbilateral facial involvement, there is usually asymmetry (Fig.100.10A).Thepresenceofmicrotiacanbeassociatedwithsignificantriskofhearinglossontheaffectedsideandincreasedriskofhearinglossinthecontralateralear(seeFig.100.10B).InfantswithCFMareoftenborn small for theirgestationalage,and theperinatalhistorymay include polyhydramnios due to fetal swallowingdysfunction.

AcommonclassificationsystemforCFMistheOMENSsystem,whichcharacterizesthedegreeofinvolvementoffacialstructures:orbital distortion, mandibular hypoplasia, ear anomaly, nerveinvolvement,softtissuedeficiency(Gougoutasetal.,2007;Birgfeldetal.,2011).Extracraniofacial anomalies associatedwithCFM,includingrenal,cardiac,andvertebralanomalies,arecommonandwillaffectrecommendationsforscreeningandsurveillance.

There canbe extreme variability of phenotypic expression,rangingfromisolatedmicrotiatosignificantmandibularhypoplasia,bilateralmicrotia,clefting,andextracranialinvolvement.IsolatedmicrotiamayrepresentaformefrusteofCFM.Othercraniofacialfeaturesincludeexternalauditorycanalstenosisoratresia,unilateral

Withtheincreasedawarenessofthiscondition,thediagnosisofthese tracheal malformationsis increasingly made on directlaryngoscopy/bronchoscopyorwithMRI.

Neurologicassessmentincludesascertainingthehistory,brainimaging,anaudiologicevaluation(earlyscreeningforhearinglossinconjunctionwithregularotologicexaminations),ophthalmologicevaluation,andongoingdevelopmentalassessments.Inmultisuturecraniosynostosis, it is important tomonitor thepatient foranysignsorsymptomsofincreasedICP.Evaluationofthepatientforhydrocephalus shouldbeapartof the initial assessmentof allchildren with multisuture craniosynostosis. CT with three-dimensionalreconstructionwillultimatelyconfirmthediagnosisofcraniosynostosis,delineate thedegreeof suture involvement,andhelpwithpreoperativeplanning.MRImaybehelpful indefininganyassociatedCNSanomalies.Ophthalmologyconsulta-tionisvaluableinmanagementofproptosis,strabismus,ornys-tagmusandindeterminingthepresenceofpapilledemaoropticatrophy.

In addition to the foregoing general recommendations,syndrome-specific recommendationsareoutlinedas follows. InApertsyndromeacardiacandgenitourinaryevaluationisrecom-mended.Ifproptosisispresent,ascanoccurinApert,Crouzon,andPfeiffersyndromes,ocularlubricantsmaybehelpfulinpreven-tionof exposurekeratopathy. InApert,Crouzon,Pfeiffer, andSaethre-Chotzen syndromes, associated vertebral anomalies,especiallyfusions,maybepresent,detectedonspineradiographs,andmore accurately visualizedwithCT imaging. If any limbabnormalitiesare seen,as inApert, Jackson–Weiss,Pfeiffer,andSaethre–Chotzensyndromes,radiographswithorthopedicconsulta-tionshouldbeobtained.

Allindividualswithsinglesuturesynostosisanddevelopmentaldelayorassociatedbirthdefectsshouldbeevaluatedbyageneticisttodetermineassociationwithaclinicalsyndromeandtheroleofgenetictesting.Thefamiliesofchildrenwithmultisuturesynostosiscausedbyknownclassic craniosynostosis syndromes shouldbeofferedappropriategenetic testingandgenetic counseling.Theremainingchildrenwithmultisuturesynostosisintheabsenceofaknownsyndromicformshouldbeofferedgeneticconsultationandpossiblemoleculargenetictesting.

ManagementAlthoughthespecifictimingofthesurgicaltreatmentmaydifferbetween teams, it is generally accepted that individuals withsynostosisshouldundergocranialsurgeryinthefirstyearoflife.Cranioplasty involves releaseof fused suturesandrepositioningandreconstructionofthecalvaria,soastopreventincreasedICPand progressive abnormal craniofacial development. Severaltechniques,includingendoscopicstripcraniectomy,calvariadistrac-tion,andtraditionalcranioplasty,arecurrentlyused.

Earlyrecognitionoftrachealmalformationscanbe lifesaving(Letsburapaetal.,2010).Awarenessofpotentialairwaycompromiseandproactiveairwaymanagementarecrucialinmanycraniosynos-tosissyndromes.Temporizingmeasurestobypassairwayobstructionincludeplacementofnasal stents, endotracheal intubation,andultimatelytracheostomy.Specificairwaymanagementinsyndromiccraniosynostosiswilldependonthelevelandseverityofobstruc-tion.Seriouscautionmustbeexercisedintheplacementandcareof tracheostomies inpatientswith tracheal cartilaginous sleevemalformationbecauseofabnormaltissuehealingandgranulationtissue formation.Midfacial surgerymaybenecessary in somechildrenwhohaveproblemswithairwayobstruction,swallowing,


Treacher Collins SyndromeTCS ismost commonly an autosomal dominant disorder ofcraniofacialdevelopmentthataffectsapproximately1 in50,000livebirths (Rovinetal.,1964).As inCFM,the tissuesaffectedinTCSarisefromthefirstandsecondbranchialarches.Themajorclinical featuresofTCS includehypoplasiaof facialbones (par-ticularly themandible andzygoma), external ear anomaliesormicrotia,externalauditorycanalatresia,bilateralconductivehearingloss,lateraldownwardslopingpalpebralfissures,andlowereyelidcolobomas(Fig.100.11A–B).Hearinglossispresentinupto50%ofindividualswithTCS(Dixonetal.,2007).InseverecasesthezygomaticarchmaybeabsentandCPmayoccur.ExtracraniofacialfeaturesarerareinTCS.MutationsinoneofthreegenesTCOF1,POLR1C,andPOLR1DarecausativeofTCS,andmutationsintheTCOF1geneaccount for71%–93%ofaffected individuals(OMIM154500).DiagnosisofTCS isusuallymadeclinicallyandcanbe confirmedwithgenetic testing (Katsanis and Jabs,2012).InnewbornswithTCS,airwaymanagementmayberequiredtoaddressnarrowingoftheairwayorextremeshorteningofthemandible(seeFig.100.11C).WhencomparedwiththatinCFM,themandibularhypoplasiainTCSisusuallybilateralandsymmetric,leading to increased riskofupperairwayobstruction, increasedneedfortracheostomy,andriskofdeathintheneonatalperiod.ChoanalatresiaorstenosisandseveremicrognathiawithglossoptosiscanleadtoairwayobstructionintheinfantwithTCS(KatsanisandJabs,2012).

Intensive Care Unit ConcernsMandibularhypoplasiainCFMcanleadtoupperairwayobstructionthatmaybeobviousonphysical examination,presentingwithstertororstridorandincreasedworkofbreathing,ormaybemoresubtle, aswith snoringobstructive sleepapnea.Bilateral severemandibularandmalarinvolvementinTCSleadstoairwayobstruc-tion at the level of nasopharynx and base of the tongue andsubstantialrespiratorycompromise.

InfantswithCFMmayhave feedingdifficulties thatmayberelated tomacrostomiaaffecting lip seal,palatedysfunction,ormorecommonlyswallowcoordinationissuesanddysphagiarelatedtohypoglossaldysfunctionandmuscularandbonyunderdevelop-ment. InfantswithMoebius syndromemayhavecranialnervepalsiesthataffectswallowandoralcoordination.Theseinfantsareathigher riskofaspirationand shouldbemonitoredclinically,

macrostomia(transversefacialcleftleadingtolateraldisplacementoftheoralcommissureandthemostcommonformoforofacialcleftinginCFM),cleftlipand/orpalate,temporomandibularjointankylosis,ankyloglossia,preauricularorfacialpits(mostcommonin thedistributionof the facialnerve),midfacehypoplasiaandmalocclusion,epibulbarlipodermoids(seeFig.100.10C),microph-thalmia, eyelidandocular colobomas, facialpalsy, and seventhnerveparesisandothercranialnervepalsies.Goldenharsyndromehashistoricallybeendescribed as a subgroupvariantofCFMcharacterizedbyvertebral anomalies andepibulbardermoids inadditiontotheearandjawfindings.InCFM,deficientgrowthofthehypoplasticmandibleandthecompensatorygrowthofthecontralateralmaxillaandzygomacontribute to significant facialasymmetry thatprogresseswithgrowth.Conversely, facial andskullasymmetrycausedbydeformation(intrauterineorpostnatallywithplagiocephalyand torticollis)willoften reducewith time,repositioning,andtreatmentoftorticollis.

Other Branchial Arch MalformationsMoebius SyndromeMoebiussyndrome(OMIM157900)isararecongenitalconditionaffectingapproximately2000peopleworldwide (BroussardandBorazjani,2008).Thesixthandseventhcranialnervesareuniversallyaffected.Sixthnervepalsy leads to inability toabduct theeyesbeyondthemidline.Thisisusuallybilateralbutmaybeunilateralorasymmetric.Paralysisoffacialmusclesresultsfromtheseventhnervepalsy.Whilenewbornsmayhavea “masklike facies,” thepresentationmaynotberecognizedinthenewbornperiod(McKayetal.,2016).Feedingdifficultiesmayresultfromswallowingandsuckingproblems,aspiration,andpalatalweaknessrelatedtomorewidespreadcranialnerveinvolvement.Therehavebeenassociationswithchestwallabnormalities,includingabsenceofthepectoralismuscle, suggesting a pathogenic relationshipwith thePolandanomaly(OMIM173800).Exposureconjunctivitisandkeratopathycanoccurinchildrenwithfacialparalysisandlagophthalmosandshouldbepreventedwithocular lubricants.LimbdefectsoccurinhalfofchildrenwithMoebiussyndrome,mostcommonlytalipesdeformity; however, transverse limb anomalies are also seen.Individualswithhypoglossia–hypodactyliaorHanhartsyndromecanhaveseverelimbdeformities,ankyloglossia,andtemporoman-dibular joint ankylosis, in addition toMoebius syndrome–likefeaturesandmicrognathia,andareatriskofsignificantswallowingdysfunctionandairwaycompromise(Yasudaetal.,2003).

A B C

• Fig. 100.10 (A, B) Infant with craniofacial microsomia, mandibular asymmetry, and left-sided microtia. (C) Child with an epibulbar lipodermoid and craniofacial microsomia.


malformations.Ophthalmologyconsultationshouldbesoughtforappropriatemanagementofepibulbar lipodermoids,colobomas(ifpresent),andriskofexposurekeratopathy.Malocclusionanddental issueswillneed tobe addressed as the childgetsolder.Childrenshouldundergocervicalspinescreeningradiographstoidentifyvertebraldefectsinsegmentation.Ifthenewbornhasnosymptomsofcervicalspineabnormality,screeningfour-viewcervicalspineradiographscanbedeferreduntil thechildis2to3yearsold,whencervicalvertebraearemoreeasilyimaged.Appropriatecervical spine imaging is recommended inchildrenundergoingsurgerybefore2yearsofageandchildrenwithheadtiltorsignsofvertebralanomalies.

MildairwayobstructioninCFMmaybereducedorminimizedwithpronepositioning.However, infantswith severebilateralmandibularhypoplasiamayhavesignificantairwaycompromiseandrequiretracheostomyplacement.Incaseswithsignificantairwaycompromise,referraltoacraniofacialcentertodetermineoptimalandsafeairwaymanagementshouldbepursued.Fortreatmentofmandibularunderdevelopment, surgery timing isdependenton

especiallyiftheyarefailingtothriveordevelopinganyconcernsforaspirationorlowerrespiratorytractdisease.

ManagementInnewbornswithsuspectedCFM,anevaluationforanyassociatedanomalies shouldbeundertaken.All childrenwithexternalearanomaliesoranyevidenceoffirstorsecondbranchialarchabnor-malities shouldundergoadiagnostichearingevaluation in thenewbornperiod,with follow-upaudiometry in thefirstyearoflife.Ifthereisanyhearingloss,ongoingmonitoringofhearingisroutine.Itisalsoimportanttomonitorearhealthandeustachiantubefunctioninthepatent/hearingear.CTtoassessmiddleandinnerearanatomy isnot recommended in theneonatalperiod.Consultationforearreconstructionandatresiarepairshouldoccurby4yearsofage,althoughhearingamplificationandauralhabilita-tioninhearinglosscanbeinitiatedearlier.

Renalultrasonographyandcardiacexamination(echocardiogram)shouldbeundertakenininfancytoidentifyanyseriousstructural

A

C

B

• Fig. 100.11 (A) Infant with Treacher Collins syndrome (TCS), microtia, severe mandibular and zygomatic hypoplasia, and airway obstruction requiring tracheostomy. (B) An older child with TCS, downslanting palpebral fissures, eyelid colobomas, and bilateral microtia wearing a hearing augmentation device. (C) Three-dimensional reconstruction of TCS. Note the severe mandibular and zygomatic hypoplasia, which may lead to significant airway compromise. Also notable are the orbital defects seen in TCS.


Intensive Care Unit ConcernsThemostimportantpostnatalemergencyinCHARGEsyndromeisbilateralposteriorchoanalatresia(Blakeetal.,2009).Neonatewithbilateral choanal atresiawillhavebreathingdifficulty andcyanosiswithin thefirsthourof life.Aswithall formsofnasalobstruction,cryingrelievesthecyanosisbecauseitallowstheobligatenosebreathertotakeinairthroughthemouth;feedingexacerbatesrespiratorydistress.Leftuntreated, thenewbornwithbilateralchoanal atresia can asphyxiate anddie. Symptomsofbilateralchoanal stenosisorunilateralatresiamaynotpresentuntilafterthenewbornperiodwithchronicrhinorrheaorbreathingproblemsassociatedwith respiratory infections.Respiratorydistress in anewbornwithCHARGEsyndromeisusuallyduetochoanalatresia,butotherfeatures,includingswallowingdysfunctionandreflux,cancontribute toaspirationand lower respiratory tractdisease.Theseinfantsmayalsohavemicrognathiaandglossoptosis,puttingthemat riskof airwayobstructionat the levelof thepharynx/hypopharynx. InfantswithCHARGE syndromemay requiremultiple surgicalproceduresduringthefirstyearof lifeandareatincreasedriskofpostoperativeairwayevents(Blakeetal.,2009;Bergmanetal.,2010).

CyanoticheartdiseasemaypresentintheimmediatenewbornperiodbecauseoftetralogyofFallot,outflowtractanomalies,andinterruptedaorticarch.AwarenessandrecognitionoftheassociationofCHARGEsyndromeandcongenitalheartdefectsarecrucial.

Asignificantcauseofmorbidityisfeedingdifficulty.Feedingandsecondarygrowthproblemsarecommoninearlyinfancyandmaybeattributedtoswallowingdysfunction,pharyngealincoordination,gastroesophagealreflux,andaspiration.Cranialnervepalsies(specificallycranialnervesV,IX,andX)maycontributetoswallowingdysfunction,andtracheoesophagealfistula(TEF)contributestoaspirationrisk.AlthoughitiswelldescribedthatinfantswithCHARGEsyndromewhosurvivethenewbornperiodaremorelikelytosurvivechildhood,theriskofdeathininfancyremains.Malesex,bilateralchoanalatresia,TEF, cyanoticheartdisease, atrioventricular septaldefects,CNSmalformations,andventriculomegalyhaveallbeenassociatedwithreducedlifeexpectancyinindividualswithCHARGEsyndrome(Tellieretal.,1998;Issekutzetal.,2005;Blakeetal.,2009).Astudyof77

thedegreeofmandibularhypoplasia,mandibulargrowth,occlusion,andairway involvement.Forchildrenwith severehypoplasiaofthemandible,bonegraftingmaybenecessaryforjawreconstructionbeforemandibledistraction.Oral feeding shouldbe introducedwhentheairwayisstable.Oralstimulationisimportanttopreventoralaversion.Giventheriskof feedingdifficultyandaspirationin infantswithmalformationsof thefirstandsecondbranchialarches, early consultationwithboth a dietitian and a feedingtherapistisrecommended.

CHARGE Syndrome

Epidemiology and GeneticsThe termCHARGE (coloboma,heart defect,atresia choanae,retardedgrowthanddevelopment,genitalhypoplasia,earanomalies/deafness)wasfirstcoinedbyPagon,giventheobservationthattheassociatedmalformationsoccurredmorefrequentlytogetherthanonewouldexpecton thebasisof chance (Pagonetal.,1981).Overtime,thefacialfeaturesandassociatedmalformationswerebettercharacterizedasasyndrome,withmutationsinatleastonemajorgenedescribed(OMIM214800).

Thismultiplemalformation condition has a prevalence ofapproximately 1 in 10,000 births (Blake and Prasad, 2006).AlthoughmultiplechromosomalaberrationshavebeenreportedinchildrenwiththephenotypeofCHARGEsyndrome,mutationsin theCHD7 geneaccount for65%–70%of cases.When thediagnosisofCHARGEsyndromeissuspected,moleculartestingformutations in theCHD7genecanbeperformedtoconfirmthediagnosisandprovidemoreinformationtoassistincounselingfortheparentsandthepatient.ForchildreninwhomCHD7genetestingresultsarenormal,evaluationforchromosomalabnormalitiesandcopynumbervariants ispossiblewithuseof comparativegenomichybridizationandsingle-nucleotidepolymorphismarraytechnology(Lalanietal.,2012).

PhenotypeThediagnosisofCHARGEsyndromeisbasedonacombinationofmajorandminorclinicalcriteria,butthediagnosisshouldbesuspected inanyneonatewithanyof themajorcharacteristics:ocularcoloboma(80%–90%),choanalatresiaorstenosis(50%–60%), cranial nerve dysfunction or facial palsy (40%–90%,dependingonwhichcranialnerve is involved),orcharacteristicCHARGEears (90%–100%) (Lalani etal.,2012).As inotherconditionswithsevereairwayobstructionorswallowingdysfunction,polyhydramnios is commonlypresentprenatallywhenbilateralchoanalatresiaispresent.

Distinctiveearanomalies (hypoplastic lobes, cuppedor lop,positionisoftenlowsetandposteriorlyrotated)ordeafnessoccursinmostindividualswithCHARGEsyndrome(Fig.100.12).Hearinglosscanbeacombinationofconductiveandsensorineuralhearingloss.Othercraniofacial features include square facewithmalarflattening,broadforehead,facialasymmetry,pinchednostrils,fullnasaltip, longphiltrum,andCP(40%).Ocularcolobomascanrangefromacolobomaoftheiristoanophthalmia.Cardiacdefectscanbeamajor sourceofmorbidity in infantswithCHARGEsyndromeandarefoundapproximately80%ofthetime.Conotrun-cal andaorticarchanomalies are themostcommoncongenitalheartdefects,butatrioseptaldefects,ventriculoseptaldefects,patentductusarteriosus,hypoplasticleft-sidedheart,andvascularringshavealsobeendescribed.

A

B

• Fig. 100.12 (A) Child with CHARGE syndrome with (B) classic ear malformation—hypoplastic lobes, cupped and low set.


walldefectssuggeststhediagnosisofBWS.AschildrenwithBWSareatriskofneoplasmsinearlychildhood,recognitionanddiagnosisofBWSareconsequential.Datasuggestapossiblelinkbetweenimprintingdisordersandassistedreproduction,andthusinfantsconceivedbyinvitrofertilizationmaybeathigherriskofBWS(Maheretal.,2003). If thereare featuresofBWSpresentorafamilyhistoryofBWS,geneticistsmayrecommend11p15methyla-tion studies and chromosomemicroarray analysis to identifyabnormalitiesofthe11p15region.Althoughgenetictestingcanprovideconfirmationofdiagnosisin80%ofindividuals,clinicalsuspicionof thediagnosis is sufficient for initiationofmedicalmanagementand tumor surveillance studies.Currently, the fre-quencyofscreeningstudyrecommendationsisindependentoftheunderlyingmolecularcause;however,thiswilllikelychangeinthefuture as childrenwithBWSdue to a gainofmethylation atimprintingcenter1andpaternal11p15uniparentaldisomyhaveahigherriskofdevelopingtumors(Mussaetal.,2016).Atthistime,initiationofscreeningstudiesandconsultationwithgeneticsarerecommended(Brioudeetal.,2013).

PhenotypeBWSisadisorderofovergrowthwithmultiplefeatures,includingmacrosomia,macroglossia,visceromegaly(involvingthekidneys,pancreas, liver, spleen,oradrenalglands),abdominalwalldefects(including rectusdiastasis,umbilicalhernia, andomphalocele),hemihypertrophy(asymmetricovergrowthofoneormoreregionsofthebody),renalanomalies(structuralanomaliesandnephrocal-cinosis),andadrenocorticalcytomegaly(Fig.100.13).MacroglossiaisthemostfrequentandmostobviousmanifestationofBWS(presentmorethan95%ofthetime)(Elliottetal.,1994).Othercraniofacialfeatures include capillarynevusflammeus,metopic ridge, largefontanel,mandibularprognathism,prominenteyes,anteriorearlobelinearcreases,andposteriorhelicalpits.LesscommonfindingsinBWS includeCP, cryptorchidism, and cardiacdefects (isolatedcardiomegalyismorecommonthancardiomyopathy).Theriskofembryonaltumors(Wilmstumor,hepatoblastoma,neuroblastoma,orrhabdomyosarcoma) inchildhoodisestimatedtobe7.5%,ofwhich95%present inthefirst8yearsof life, leadingtorecom-mendationsfortumorsurveillance(FirthandHurst,2005).

Some features suggestiveofBWSmaybepresentprenatally,includingpolyhydramnios (causedby swallowingdysfunction),preeclampsia,fetalmacrosomia,andalargeplacenta.Prematurityhasbeenreportedin50%ofbirths(Elliottetal.,1994),andinadditiontocomplicationsofprematurity,theneonatewithBWSmaydevelophypoglycemiaandpolycythemia.

Intensive Care Unit ConcernsHypoglycemiaduetohyperinsulinemiaandisletcellhyperplasiaoccursinupto50%ofneonateswithBWSandusuallydevelopsinthefirstfewdaysoflife(MunnsandBatch,2001).ItiscriticaltodetectandtreathypoglycemiainanyneonatewithfeaturesofBWStopreventseizuresandbraininjury.Polycythemiacanoccurandmayneedtobetreatedintheearlyneonatalperiod.

Obstructive airway symptomsmaypresent in thenewbornperiodifmacroglossiaissevere.However,airwayobstructionmorecommonlypresentslaterininfancy,outsidethenewbornperiod.Theenlarged tongue canocclude theupper airway, leading torespiratorydistress,apnea,andhypoxia.Alargetonguecanalsocontribute to feeding issues,dysphagia, andaspiration.Upperairway endoscopic evaluation by an otolaryngologist and an

individualswithCHARGEsyndromefoundmortalitytobe13%(Issekutzetal.,2005).

ManagementWhiletheclinicalneedswilldiffer,somechildrenwithCHARGEsyndromewillrequireintensivemedicalmanagementandundergomultiplesurgicalinterventionsininfancyandearlychildhood.Earlymanagement targetsairwaystabilizationandcirculatory support.With this inmind,neonateswithCHARGEsyndrome requireimmediateevaluationof their airwayandcardiac structureandfunction.Anoralairwayshouldbeplacedifbilateralchoanalatresiaissuspected.Thiscanstabilizetheairwaybybypassingthechoanalobstruction.Oncetheairwayhasbeensecured,aconfirmatoryCTscanofthenasalpassagescanbeobtained;aCTofthetemporalbonescanbeincludedinconjunctionwiththefacialCTandmayrevealthecharacteristicinnerearfindings(Mondinimalformationofthecochleaand/orabsentorhypoplasticsemicircularcanals)ofCHARGEsyndrome.Iftheoralairwaydoesnotallowadequateairentry,endotracheal intubationmaybe required. Inconsultationwithapediatricotolaryngologist, transnasal stentsmaybeplacedtokeepthenasalpassagespatentinchoanalstenosis(andpostop-erativelyafterchoanalatresiarepair).Giventhesignificantriskofcyanoticheartdefects,anechocardiogramandcardiologyconsultationshouldbeobtainedtoassistinmanagement.

Infants withCHARGE syndrome or suspectedCHARGEsyndromeshouldalsohaveaudiologicandophthalmologicevalu-ationsintheneonatalperiodandshouldbereferredtoBirthtoThree/earlyinterventionservices.Consultationwithanimmunolo-gistandimmuneevaluationshouldoccurfortheindividualwithCHARGEsyndromeandrecurrentinfections(Wongetal.,2015).Underdevelopmentof thegenitals andgenitourinaryanomaliesmay be present. If there is a concern for hypogonadism, thepituitary–gonadalaxiscanbeevaluatedininfancyandwillhelpdetermine the option for sex steroid therapy. Screening renalultrasonographyshouldalsobeperformed(BlakeandPrasad,2006).

Consultationswithbothafeedingspecialistandadietitianarerecommendedinthenewbornperiod.If thefindingsofanoralfeedingevaluationorvideofluoroscopicswallowstudyareconcerningforswallowingdysfunctionoraspiration,supplementaltubefeedingshouldbe initiated.Withprolonged feeding issues,gastrostomytubefeedingisoftennecessary.Infantswithseveregastroesophagealrefluxand/oraspirationriskmaybecandidatesforNissenfundo-plicationatthetimeofgastrostomytubeplacement.

Macroglossia/Beckwith– Wiedemann Syndrome

Epidemiology and GeneticsThetrueprevalenceofBeckwith–Wiedemannsyndrome(BWS;OMIM130650)isunknown,butithasbeenestimatedthatBWSaffects1in13,700births(Thorburnetal.,1970).Thisisprobablyanunderestimate,giventhattherearemildcasesofBWSthatgoundetected.ThegeneticsofBWSiscomplexandvariable.Mostcasesaresporadicandmayresultfromchromosomalrearrangement,mutations,orepigeneticeffects(DNAmethylationchanges)affectingimprintedgenesonchromosomeband11p15.5.Approximately80%of individualswith featuresofBWSare foundtohavean11p15.5abnormalitybyclinicallyavailabletesting(Shumanetal.,2016).AlthoughtherearenoconsensuscriteriafordiagnosisofBWS,thepresenceofmacroglossia,overgrowth,andabdominal


SurveillancefortumorsbeginsintheneonatewithBWSoratthe timeofdiagnosis.Abdominalultrasonography toassess thepatientfororganomegalyandbaselineCTorMRIoftheabdomenshouldbeperformed.Abdominalultrasonographyevery3monthsisrecommendedthrough8yearsofage.Inconjunction,staggeredserialserumalphafetoproteinmeasurements(every6to12weeks)arerecommendedthrough4yearsofagetoassistearlyidentificationofhepatoblastomasbeforedetectionbyscreeningultrasonography.

ReferraltoacraniofacialteammaybehelpfulinthemanagementoftheairwayobstructioninBWS,includingevaluationfortonguereductionand facialhemihypertrophy.Ageneticist andgeneticcounselormayrecommendgenetictestingforconfirmationofthediagnosisand/orrecurrenceriskcounseling.

Frontonasal Dysplasia, Hypertelorism, Encephalocele

EmbryologyFrontonasaldysplasia(FND;alsoknownasfrontonasal malformation,median cleft face syndrome,andfrontal nasal syndrome)isamalforma-tionresulting fromabnormalmorphogenesisof the frontonasalprocess.Thedevelopmentofthefacialmidlineisabnormal,leadingtoocularhypertelorismandassociatedcraniofacialfeatures.MostcasesofFNDaresporadic.

Phenotype and GeneticsFNDhasbeendefinedphenotypicallyascontainingtwoormoreofthefollowingcraniofacialfeatures:ocularhypertelorism;broaden-ingofthenasalroot;midlinefacialcleftaffectingthenose,lip,orpalate;unilateralorbilateralcleftingofthealaenasi;hypoplasticnasaltip;anteriorcraniumbifidum;andaV-shapedfrontalhairline

overnightsleepstudymayhelpunderstandtheseverityofairwaycompromiseandguideairwaytreatment.

MortalityamonginfantswithBWShasbeenreportedtobeashighas21%andisrelatedtocomplicationsofprematurityandmacroglossia(Shumanetal.,2010).

ManagementHypoglycemia in newborns should bemanaged according tostandardprotocols for treatingneonatalhypoglycemia. Ifhypo-glycemiapersistsorisrefractorytotherapy,additionalbiochemicaltestingandconsultationwithanendocrinologistshouldbecon-sidered(Roženkováetal.,2015).Neonateswithanomphalocelemayrequiresurgeryinthefirstfewdaysoflife.

Thereisnodefinitiveapproachtothemanagementofmacroglos-sia.Airwayobstructionmaybelessenedbytheplacingofthebabyonthesideorprone.Iftheinfantrequiresendotrachealintubation,itisimportanttoexercisecaution,becausemacroglossiacanaffectvisibilityofairwaystructures.Ifmacroglossiaresultsinsignificantairwayobstructionorprolonged intubation, tracheostomymaybeneededasa temporizingmeasure tobypass theobstruction.Tonguegrowthwillslowovertime,andasjawgrowthaccelerates,airwaycompromiseshoulddecrease.Somechildrenmaybenefitfromsurgicalreductionofthetongue,whichisusuallyperformedbetween2and4yearsofage,butmaybeofferedasearlyas3to6monthsatsomecenters.

Referralstoaninfantfeedingspecialistanddietitianarerecom-mendedintheinfantwithseveremacroglossiaoriftheinfantisnotgainingweight.Althoughsomeinfantsareabletofeedorally,otherswillbenefitfromsupplementaltubefeeding.

Althoughcardiacdefectsarerare,itisimportanttoperformathorough cardiac evaluation, including electrocardiogram andechocardiogramifanycardiacabnormalitiesaresuspected.

A B

• Fig. 100.13 (A) Premature newborn with Beckwith–Wiedemann syndrome, macroglossia, and rectus diastasis. (B) Same child at 6 months of age. Macroglossia has increased, and he now has a tracheostomy.


Intensive Care Unit Concerns

IntracranialabnormalitiesassociatedwithFNDmayputtheinfantatriskofCNSmanifestationssuchashydrocephalusorseizures.Ifthepituitaryglandisinvolvedordeficient,ascanbeseenwithHPEsequence,therecanbeseriousendocrineabnormalities(asdiscussedinOrofacialClefting).Also,frontonasalencephalocelemaycontribute toupperairwaycompromiseat the levelof thenasopharynx.

ManagementInanyinfantwithhypertelorismorfeaturesthatraisesuspicionforFND,awarenessofpotentialunderlyingmalformationsiscritical,andcranial imagingbyCTscanorMRIshouldbeconsidered.Instrumentationofthenoseandmouth,includingplacementofanasogastrictubeorsuctioncatheter,shouldbeavoidedorusedwithcautionuntiltheCNSanatomyhasbeendelineated.BecauseinfantswithFNDhaveahighincidenceoffrontonasalencephaloceleormeningocele,placementofthesecatheterscouldleadtobraininjury.IfaninfantwithFNDneedsurgentoremergentendotrachealintubation, intraoral structures shouldbeexaminedcarefully toprevent injury toherniatingCNSstructures if theyarepresent.ManagementofseizuresoranyelectrolytederangementsshouldbemanagedaspertheneonatalICUstandardprotocol.Consultationwithacraniofacialteam,includingspecialistsinophthalmology,canbehelpful inunderstanding thework-upandmanagement(including potential surgical interventions) for individualswithFND.

Prenatal Screening for Fetal Face AnomaliesTheexactroleoffetalfaceexaminationwithultrasonographyinalow-riskpregnancyisunderevaluation.Routineobstetricsurveillanceincludesamidtrimesteranatomicultrasoundexaminationat18to22weeks’gestation.Moststudies lookingat therecognitionrateand incidenceofultrasonographicdiagnosisoforofacialcleftingfocusonthisanatomicexamination.Adequateevaluationof thefacialstructureswithultrasonographycanbeachievedby16to17weeks’gestation.Thefollowingfacialfeaturescanbevisualizedwithtwo-dimensional routineultrasonographyat18weeks’gestationwithstandard facialviews (which includecoronal imagesof thenose, lips,andorbitsandsagittalprofileviews):orbital sizeandposition,eye size, includingmicrophthalmiaandanophthalmia,shapeofnose,nasalhypoplasia,lengthofthephiltrum,cleftsoftheupperlip,frontalbossing,retrognathia,micrognathia,macroglossia,andsofttissueabnormalities.CleftlipwithorwithoutCPcanbedetectedbyprenatalultrasonography,whereasisolatedCP,whichisnottypicallyassociatedwithacleftofthealveolus,maybeobscuredbythetongue,whichhasthesameechogenicityasthesecondarypalate, thusmakingprenataldiagnosisofCPOmoredifficult.Aretrospectivestudyinalow-riskpopulationdemonstratedthatroutineprenatalultrasonographywithstandardfacialviewsperformedat18weeks’estimatedgestationalagedetected93%ofcasesofcleftlipandpalate,67%ofcasesofisolatedcleftlip,and22%ofcasesofCPO(Cashetal.,2001).Newandincreasinglysensitivemethodsforidentifyingcraniofacialdifferencesprenatallyareemerging(Tonnietal.,2015;Rubioetal.,2016).Although thediagnosis isnotdefinitive,prenataldiagnosis isparticularlyvaluable inallowingappropriateprenatalcounseling(Maarseetal.,2015).Familieswhohavetheopportunitytomeetmembersofacraniofacialteambeforedeliveryoftenappreciatehavingsomeunderstandingofwhat to

(Wuetal.,2007).Gradingofhypertelorismisbestachievedbymeasurementof the interpupillarydistance. Ina termnewbornan interpupillary distance greater than 4.5cm is consideredhyperteloric(Jonesetal.,2013).FNDisaheterogeneousconditionwithgenetic forms (OMIM136760,OMIM613451,OMIM613456,associatedwithmutationsinthreeALXgenes),sporadicformswithoutassociatedanomalies, andFNDphenotypewithassociatedpatternofmalformations(subtypeofFND)orknowngeneticsyndromesuchascraniofrontonasalsyndrome(Wuetal.,2007;vandenElzenetal.,2014).

Inadditiontohypertelorism,eyeanomalies,includingepibulbardermoids,colobomas,ptosis,nystagmus,orcataracts,maybepresentinFNDandareassociatedwithamoreseverephenotypeandanincreased incidence ofCNS abnormalities (Wu etal., 2007).AssociatedCNSmanifestationsincludeencephalocele,agenesisofthecorpuscallosum,andabnormalneuronalmigration.Develop-mentaldelayisasignificantrisk,especiallywhenthereareCNSmalformations.When FND is associated with extracephalicanomaliesorwhenocularhypertelorism ismore severe, there isan increasedassociationwithcognitive impairment (Hennekametal.,2010d).Frontonasalencephaloceles(andmeningoceles)arethemostcommonencephalocelesinFND(Fig.100.14).

A subpopulationofpatientswith frontonasalmalformationalsohavecoronalcraniosynostosisandvariableskeletalandecto-dermaldefectsandhaveanX-linkedconditiontermedcraniofron-tonasal syndrome (CFNS,OMIM304110).Similarly toFND,facialfeaturesincludehypertelorism,frontalbossing,broadnasalbridge, andabifidnasal tip.ChildrenwithCFNSoftenhavesignificantfacialasymmetryduetounicoronalsynostosis.InthisX-linkedcondition,femalesareaffectedmoreseverelythanmales(andtypicallyhavehypertelorismandgroovednails),andmutationsaredetectedintheEFNB1gene.Affectedindividualsusuallyhavenormalintelligence.

• Fig. 100.14 Magnetic resonance imaging of an infant with frontonasal dysplasia and a midline cleft lip. The scan reveals a moderate-sized meningocele extending into the posterior nasopharynx. The white arrow points to midbrain meningocele coming through the cribriform plate; the black arrow points to the intraoral meningocele.


JohnstonDR,WattersK,FerrariLR,RahbarR.Laryngealcleft:evalua-tionandmanagement.Int J Pediatr Otorhinolaryngol.2014;78:905-911.

KatsanisSH,JabsEW.TreacherCollinssyndrome.GeneReviews(Internet).http://www.ncbi.nlm.nih.gov/books/NBK1532/.

McCarthy JG,WarrenSM,Bernstein J, etal.Parametersof care forcraniosynostosis.Cleft Palate Craniofac J.2012;49(S1):1S-24S.

McDonald-McGinnDM,SullivanKE,MarinoB,etal.22q11.2deletionsyndrome.Nat Rev Dis Primers.2015;1:15071.

RobinNH,MoranRT,Ala-KokkoL.Stickler syndrome.GeneReviews(Internet).http://www.ncbi.nlm.nih.gov/books/NBK1302.PostedJune9,2000.UpdatedMarch16,2017.

TheCenterforChildrenwithSpecialNeeds,WashingtonStateDepart-mentofHealthandSeattleChildren’sHospital,Seattle,WA.Cleft Lip and Palate: Critical Elements of Care. ed5,2010.http://www.doh.wa.gov/YouandYourFamily/InfantsandChildren/HealthandSafety/ChildrenwithSpecialHealthCareNeeds/Partners/MaxillofacialTeams.Thebookletcanbeaccessedhere:http://cshcn.org/wp-content/uploads/files/CriticalElementsofCare-CleftLipandPalate.pdf.

expect inthenewbornperiodandarearmedwithknowledgetohelptheirnewbabyreceivethebestcarepossible.

Suggested Readings

AgochukwuNB,SolomonBD,MuenkeM.Impactofgeneticsonthediagnosis andclinicalmanagementof syndromiccraniosynostoses.Childs Nerv Syst.2012;28(9):1447-1463.

BlakeKD,PrasadC.CHARGEsyndrome.Orphanet J Rare Dis.2006;1:34.

BreugemCC,EvansKN,PoetsCF,etal.Bestpracticesforthediagnosisandevaluationof infantswithRobinsequence:aclinicalconsensusreport.JAMA Pediatr.2016;170(9):894-902.

CieloCM,MontalvaFM,Taylor JA.Craniofacialdisorders associatedwithairwayobstruction in theneonate.Semin Fetal Neonatal Med.2016;21(4):254-262.

ElliottM,BaylyR,ColeT,etal.ClinicalfeaturesandnaturalhistoryofBeckwith-Wiedemannsyndrome:presentationof74newcases.Clin Genet.1994;46:168-174.

HeikeCL,LuquettiDV,HingAV.Craniofacialmicrosomiaoverview.GeneReviews(Internet).Availablefrom:http://www.ncbi.nlm.nih.gov/books/NBK5199/.PostedMarch19,2009.updatedOctober9,2014.

Complete references used in this text can be found online at www.expertconsult.com

http://www.expertconsult.com/

http://www.expertconsult.com/

http://www.ncbi.nlm.nih.gov/books/NBK5199/



http://www.ncbi.nlm.nih.gov/books/NBK1302

http://www.doh.wa.gov/YouandYourFamily/InfantsandChildren/HealthandSafety/ChildrenwithSpecialHealthCareNeeds/Partners/MaxillofacialTeams



http://cshcn.org/wp-content/uploads/files/CriticalElementsofCare-CleftLipandPalate.pdf


CHAPTER 100 Craniofacial Malformations 1437.e1

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PART XIXraniofacial and Orthopedic ConditionsC 100