Andersons pediatric cardiology 1564

examinationoftheascendingaortarevealsdegenerationoftheelasticfibers,socalledcysticmedialnecrosis,whichismostsevereinpatientswithaneurysms.
Theleafletsoftheaorticvalvescontainincreasedamountsofacid
mucopolysaccharide.Themitralvalvarannulusisdilatedandmaybecome
calcified.Pulmonaryarterialdilationandaneurysmformationhavealsobeen
reported.201TheECGmayshowsignsofleftventricularandleftatrial
enlargementwhenthereissignificantvalvarinsufficiency.Disturbancesof
rhythm—suchasfirst-degreeatrioventricularblock,atrialectopicbeats,atrial
flutter,fibrillation,andtachycardia—arecommon.Ventriculararrhythmiasare
presentinaboutone-thirdofthepatientsduringchildhood.Progressingwithage,
theyappeartobecloselyrelatedtomitralvalveprolapse.202Radiographic
examinationofthecardiacshadowisdifficultinthepresenceofthoracicskeletal
deformities.Cardiacenlargementmaybeseeninthepresenceofvalvar
insufficiencyanddilationoftheascendingaorta.Serialechocardiographic
evaluationisessential.Mitralvalveprolapseisaveryfrequentfinding.Dilation
oftheaorticroot,sometimeswithparadoxicalmotionoftheposterioraortic
wall,iscommon.Mitralandaorticincompetencewillleadtoleftatrialandleft
ventricularvolumeoverload.Dopplerechocardiographyshouldincreasethe
earlydiagnosisofthevalvarabnormalities.Cardiacmagneticresonancestudies
havealsobecomepartoftheregularassessmentofpatientswithaortopathyto
monitorthedegreeandextentofaorticdilationandassociatedvascular
abnormalities.Suchstudieshavealsodemonstrateddecreasedaortic
distensibilityandincreasedstiffnessinchildrenwithMarfansyndrome.203
Imagingisrecommended6monthsfollowingdiagnosis.Iftheaorticrootsizeis
stableandlessthan4.5cm,yearlyimagingisrecommended.Ifaorticroot
dimensionsaregreaterthan4.5orthereisrapidlyprogressivedilation(>0.5cm
peryear)morefrequentimagingislikelyneeded.
Thepathophysiologyofdilationoftheaorticrootislikelyduetoacomplex
interplaybetweenalteredvascularmuralcompositionandotherdestructive
processes.Thedefectivecollagenrendersthearterialwallslessdistensible,but
thisalonehasnotproventoleadtoarterialdilation.Thedilationitselfmaybe
relatedtoapoptosisofvascularsmoothmusclecells,whichhasbeenshownto

berelatedtoangiotensinIIreceptorsignalingpathways.204Additionally,
defectivemicrofibrilsresultinexcessiveactivityoftransforminggrowthfactor
(TGF)-β,whichisnormallyregulatedbylatentTGF-βbindingproteinsboundto
microfibrils.ThisexcessiveTGF-βsignalingleadstodisorderedformationof
thematrixandmaybeaprincipalcauseofthevasculardilationfoundinthese


patients.205PatientswithLoeys-Dietzsyndromeandotherdisorderssimilarto
Marfansyndromehavebeenfoundtohavedefectsinthegeneencodingthe
TGF-βreceptor.206Thecomplexinterplaybetweenfibrillin,microfibrils,latent
TGF-βbindingproteins,TGF-β,andtheTGF-βreceptorprobablyaccountsfor
thewideclinicalvariabilityinMarfansyndromeandotherrelateddisorders.
Lifeexpectancyisveryvariable.Deathusuallyoccursinthefourthdecade,
mainlyfromcardiovascularcauses.207Cardiacfailure,dissectionoraneurysms
oftheaorta,andsuddendeatharethemostfrequentcauses.Incompetenceof
bothmitralandaorticvalvescarriesapoorprognosis.Thereisnospecific
treatmentforthiscondition.Cardiacfailureisbesttreatedwithdiureticsand
vasodilators,sincethepositiveinotropiceffectsofdigoxinmayfurtherdamage
theaorticroot.
Surgicalreplacementofthediseasedvalvesandoftheascendingaortamaybe
necessary.Thetimingofsurgeryforrepairorreplacementofvalvesor
replacementoftheaorticrootmustbedecidedinlightoftheknownrisksof
surgeryaswelloftherisksofnotperformingsurgery.Electivereplacementof
theaorticrootcanbeaccomplishedwitharelativelylowriskofmortality.208On
theotherhand,replacingtheaorticrootemergentlyduetoacutedissection
carriesamuchhigherriskofshort-andlong-termmortality.209Early
recommendationssuggestedelectivereplacementwhentherootreachedan
absolutediameterof60mm.Manypatientssufferdissectionsatsizes
significantlysmallerthanthis,andanannualriskofmortalityofnearly5%has
beendescribedforpatientswithanaorticrootgreaterthan50mm.210Surgeryis

currentlyrecommendedforanexternalrootdiametergreaterthan5.0cm.If
thereisrapiddilation,familyhistoryofearlierdissection,orclinically
significantaorticregurgitation,prophylacticrepairmaybeconsideredearlier.
Duetotheincreasedriskofdissectioninpregnancy,prophylacticrepairin
womenmaybeconsideredatanaorticrootdimensiongreaterthan4.0cm.211In
addition,proceduresthatallowforreplacementwhilemaintainingthenative
aorticvalvehavebeenevaluatedandappeartobesatisfactory,potentially
eliminatingtheneedforchronicanticoagulation.212,213
Prophylacticβ-blockadehasbeenusedtoslowtheprogressionofaortic
dilationandisrecommendedinallguidelines.Morerecently,angiotensin
receptorblockersandangiotensinconvertingenzymeinhibitorshavealsobeen
usedaloneorincombinationwithaβ-blocker.However,inarecentrandomized
controlledstudycomparingatenololwithlosartantherewasnoclinically


significantdifferenceintheprogressionofaorticrootdilationovera3-year
period.Inbothgroupstheaorticrootz-scoredecreasedsignificantlyovertime,
andthiseffectwasmorepronouncedinyoungerpatients.214

InfantileMarfanSyndrome
AninfantilevariantofMarfansyndromeisseenonrareoccasions.Theskeletal
andocularmanifestationsaresimilartotheadultformsbutthecardiovascular
featuresaredistinct.215Thereismarkedmyxomatousthickeningandredundancy
oftheleafletsofthemitralandtricuspidvalves,withelongationofthetendinous
cordsleadingtoseverevalvarinsufficiency.Morbidityandmortalityare
primarilyrelatedtomitralandtricuspidvalvardiseaseasopposedtoaortic
dissectionandrupture,asseenintheadultform.216Additionally,patientswith
theinfantilesyndromefrequentlyexhibitpulmonaryemphysematouschanges.
NeonateswiththeinfantilesyndromepresentwithCHFthatrespondspoorlyto
conventionaltherapy.Deathoftenoccurswithinthefirst2yearsoflife,although

surgicalrepairofmitralvalvediseaseatthisageisfeasible.Afamilyhistoryof
Marfansyndromeismuchlesscommonininfantswhopresentwithsevere
cardiovascularsymptomsearlyinlife.217Mostmutationsresultinginthe
infantilesyndromeoccurbetweenexons24and32inthefibrillingene.

Loeys-DietzSyndrome
Loeys-Dietzsyndromewasfirstdescribedin2005inacohortof10families
causedbymutationsintheTGFBR1orTGFBR2gene.Itischaracterizedby
hypertelorism,bifiduvula,and/orcleftpalateaswellasandgeneralizedarterial
tortuosity(Fig.59.4)withascendingaorticaneurysmalformationand
dissection.218ThereissomephenotypicaloverlapwithMarfansyndrome,but
thehypertelorism,palatalinvolvement,andwidespreadarterialchangeshelpto
differentiatethisfromMarfansyndromeandsimilardisorders.Recognitionof
thisdiseaseiscritical,asearlyevaluationforaorticaneurysmformationmay
leadtooperationatayoungage.Becauseoftheaggressivenatureofroot
dilationandhighriskfordissectionatsmalleraorticdimensions,replacementis
recommendedatdiametersof4.0cminadultsandatevensmallerdiametersin
children.219PatientswithLoeys-Dietzshouldhaveimagingatdiagnosisand6
monthsafterdiagnosis.Duetoriskforaneurysmsinothervesselsnotseenby
echocardiography,theyshouldalsohaveyearlymagneticresonanceimaging