Andersons pediatric cardiology 2076

fact,inNoonansubjectswithPTPN11mutations,ahigherprevalenceof
pulmonaryvalvestenosishasbeenrecognized.67Ontheotherhand,
hypertrophiccardiomyopathyisoverrepresentedinNoonanpatientswithRAF1
mutationsandinLEOPARDpatientswithspecificmutationsinPTPN11.68,75
AlsoinpatientswithRIT1mutatedgene,amoreseverecardiacphenotypehas
beendescribed.94

Ellis-VanCreveldSyndrome
ClinicalFeatures
TheEllis–vanCreveld(EVC)syndromeisanautosomalrecessive
chondroectodermaldysplasiabelongingtothegroupofshortribpolydactyly
syndromesandcharacterizedbyskeletalandcraniofacialabnormalities
associatedwithdysplasticteethandnails(Table77.8).95,96Theskeletal
anomaliesincludepostaxialpolydactylyofhandsandfeet(Fig.77.7),shortribs,
thoracicanomalies,shortlimbs,andfusionofcarpalbones.Craniofacialfeatures
arecharacterizedbymultiplelabiogingivalfrenum,prematureeruptionofteeth
orneonatalteeth,smallconicalteeth,andmissingprimaryorpermanentteeth.
Table77.8
PrevalenceofClinicalFeaturesinPatientsWithEllis–vanCreveldSyndrome
ClinicalFeature
Postaxialpolydactylyofhandsandfeet
Oralfrenula
Narrowthoraxwithshortribs
Dentalanomalies
Shortstature
Congenitalheartdefect
Atrioventricularcanaldefect,with/withoutcommonatrium,with/withoutleftsuperiorvena
cava
Heterotaxia
Atrialseptaldefect,ostiumsecundumtype
Aorticcoarctation

Other
Ectodermaldefects
Cleftlip

Frequency(%)
100
95
80
70
60
50–60
80
5
5
3
7
50
30


FIG.77.7 PolydactylyinEllis-vanCreveldsyndrome.

CardiacDefects
Approximately60%ofaffectedindividualshaveaCHD,morefrequentlyAVCD
associatedwithcommonatriumwithpersistentleftsuperiorvenacavaand
unroofedcoronarysinus(seeTable77.8).96,97TheassociationbetweenAVCD
andcommonatriumisrareinthenonsyndromicpatients,whereasitisrelatively
commoninEVCsyndrome96,97andinheterotaxysyndrome.98Leftward
displacementoftheatrialseptumwithconsequentdouble-outletrightatriumcan
bepresent,aswellasleft-sidedobstructivelesions.Inthesepatients,severe

thoracicanomaliesandleft-sidedobstructionscanrepresentriskfactorsfor
cardiacsurgery.DelayedsurgicalrepairofCHDsreducespostoperative
morbidityandimprovessurvival.99

GeneticDefect
EVCsyndromeisaciliopathyduetomutationlocalizedinchromosome4p16
encompassingEVC1andEVC2,twononhomologousgenescloselylocatedina
headtoheadconfiguration.95Inaddition,variantsinWDR35100and
DYNC2LI1101geneshavebeencausallyrelatedtoEVCsyndrome.Experimental
studiesinvestigatingmolecularpathwaysanddevelopmentalprocessesperturbed
inEVCsyndromehavedemonstratedthatEVCgenesareintracellular


componentsofthehedgehogsignaltransductionpathwaythatisrequiredfor
normaltranscriptionalactivationoftheIndianhedgehog(Ihh)targetgenes.95In
particular,EVCisapositivemediatoroftheIhh-regulatedbonegrowththat
localizesatthebaseofchondrocytecilia.

KabukiSyndrome
ClinicalFeatures
Kabukisyndromeisageneticallyheterogeneousdisordercharacterizedby
developmentaldelay,growthdefectwithfeedingdifficulties,skeletalanomalies,
CHD,renalmalformations,anorectalanomalies,persistenceoffetalfingertip
pads,anddistinctfacialanomalies(Table77.9),includingsparseeyebrows,long
palpebralfissures,eversionofthelateralthirdofthelowereyelids,pillowed
lowerlip,andlargeevertedears(Fig.77.8).102,103
Table77.9
PrevalenceofClinicalFeaturesinPatientsWithKabukiSyndrome
ClinicalFeature
Facialanomalies

Intellectualdisability
Hypodontia
Persistentfetalfingerpads
Hypotonia/motordevelopmentaldelay
Jointlaxity
Congenitalheartdefect
Aorticcoarctation
Bicuspidaorticvalve
Ventricularseptaldefect,perimembranoussubaortic
Atrialseptaldefect,ostiumsecundum
Conotruncalheartdefects
Other
Feedingdifficulties
Shortstature
Cleftlip/palate
Urogenitalanomalies

Frequency(%)
100
90
60–100
70–90
50–90
40–90
70
20
20
15
15
15

15
65–75
60
15–50
30–40