Andersons pediatric cardiology 2075

FIG.77.6 FacialappearanceofRASopathies.(A)Noonan,(B)
cardiofaciocutaneous,(C)Costello.

Table77.7
PrevalenceofClinicalFeaturesinPatientsWithRASopathies
ClinicalFeature

NoonanFrequency LEOPARD
(%)
Frequency(%)

CFCFrequency CostelloFrequency
(%)
(%)


Facialanomalies
Shortstature
Congenitalheartdefect
Pulmonaryvalve
stenosis
Hypertrophic
cardiomyopathy
Atrialseptaldefect
Atrioventricularcanal
defect
Arrhythmia
Cryptorchidism
Curlyhair
Thoraxanomalies
Developmentaldelay

Feedingdifficulties
Pterygiumcolli
Sensorineuraldeafness
Keratosispilaris
Lentigines

95
75
80
55

85
35
80
25

100
80
85
40

100
100
65
45

25

70

25

40

15
5

0
3

20
0

5
0

0
80
65
65
40
40
30
5
5
0

25
50
20

40
20
30
15
25
3
95

0
70
95
60
100
75
10
0
95
0

30
80
90
75
100
100
5
0
40
0

InmostcasesoftheclassicNoonansyndrome,cognitiveabilitiesfallwithin
thenormalrange,eventhoughattention-deficit/hyperactivitydisorder,mood
disturbances,andproblemswithsocialinteractionhavebeenreported.
PatientswithLEOPARDsyndromehaveclinicalfeaturessimilartothoseof
Noonansyndromesbutspecificsignsaremultiplelentigines,café-au-laitspots,
andhearingdeficit.68,69
CFCandCostellosyndromesareassociatedwithsignificantdevelopmental
delay,predispositiontoepilepsy,andspecificcutaneousinvolvementconsisting
ofdryhyperkeratoticskin,sparseorabsenteyebrows,andcurlyhair.70,71

CardiacDefects
CHDsoccurin60%to90%ofpatientsaffectedbyRASopathies,andmost
commonlyincludepulmonaryvalvestenosis,hypertrophiccardiomyopathy,
AVCD,andatrialseptaldefect(seeTable77.7).72–75MinorCHDs,suchas
mitraloraorticvalveanomalies,tetralogyofFallot,andaorticcoarctationhave
beenpreviouslydescribed.76,77
VascularanomaliesalsoareassociatedwithRASopathies,mainlyaortic
dissection,aorticrootdilation,aneurysmofthesinusesofValsalva,andcoronary
arteriesdilation.78–83
Pulmonaryvalvestenosishasaquitedistinctanatomicpattern,with
thickened,elongatedandredundantcusps.Insomecases,pulmonaryvalve


stenosisis“supraannular,”consistingoffusionofthevalvarcuspswiththewall
ofthepulmonaryartery.84Thiscomplexanatomicconditionmayexplainthe
frequentunsuccessfulpercutaneouspulmonaryvalvetreatmentbyballoon
angioplasty.75
Hypertrophiccardiomyopathymaybemildorsevereandmaypresentfrom
theprenatalperiodtolatechildhoodbutgenerallyappearsearlyinlife,with
morethanhalfofcasesbeingdiagnosedby6monthsofage.Hypertrophy

involvestheleftventricle,consistingofasymmetricseptalthickeningand
frequentsystolicanteriormotionofthemitralvalve.85,86Theassociationwith
structuralmitralanomalies,likeprolapsing,myxomatous,redundant,orthick
valveleafletsarecommon.Anomalousinsertionofthemitralvalvecausing
subaorticstenosisisreported.87
AVCDisusuallyofthepartialtypeandmaybeassociatedwithsubaortic
stenosis,manifestingasleftventricularoutflowobstructionduetoanomalous
insertionofthemitralvalve.73,88Vascularmalformationsandaorticvalve
enlargementwithcoronaryanomaliesarereportedinaminorpercentage.
InpatientswithCostellosyndrome,cardiacrhythmdisturbancessuchasatrial
tachycardialikesupraventricular,chaotic,ormultifocalarecommon.89
Specificoutcomesforcardiacdefectsinthesepatientsintermsofmortalityor
freedomfromreinterventioncouldbeconsidered.RASopathieshavealowrisk
ofdeathfromcardiacmorbidity,butinthemeantime,itisassociatedwitha
higherriskforcardiacreintervention,particularlyinthesubgroupofpatients
withAVCDorhypertrophiccardiomyopathy.75

GeneticDefect
DifferentgenesareinvolvedintheetiologyofRASopathies.90,91Mutationsin
PTPN11aredetectableinapproximatelyhalfofpatientswithNoonansyndrome.
Heterozygousmutationsin15additionaldiseasegeneshavebeenidentifiedin
Noonansyndromeandrelatedconditions.CFCsyndromeislinkedtomutations
inBRAF,MEK1,andMEK2.92HRASmutationsareetiologicallyrelatedto
Costellosyndrome.93
Themajorityofthesegenesencodeforproteinsthataredirectlyinvolvedin
theRAS-mitogenactivatedproteinkinase(MAPK)signalingpathway,amajor
signaltransductioncascade.66
Clinicallyrelevantgenotype-phenotypecorrelationshavebeenestablished.In