Ocularcoloboma
Congenitalheartdefect
Conotruncalheartdefect
Atrioventricularcanal
Septaldefects
Other
Growthdeficiency
Choanalatresiaorstenosis
Genitalhypoplasia
Cranialnervedysfunction
Cleftlipand/orpalate
Tracheoesophagealfistula
Renalanomalies
80–90
75–85
50
25
15
10
70–80
50–60
50–60
40
15–20
15–20
10
CardiacDefects
CHDsarepresentin75%to85%ofindividualswithCHARGEsyndromeand
areoftencomplex.Manytypesofheartdefectsoccur,includingconotruncal
anomalies(tetralogyofFallot,interruptedaorticarch,perimembranous
ventricularseptaldefect,double-outletrightventricle,andtruncusarteriosus),
aorticarchanomalies(vascularring,aberrantsubclavianartery),AVCDs(alone
orassociatedwithtetralogyofFallot),andseptaldefects(seeTable77.13).130,131
TheassociationbetweenAVCDandtetralogyofFallotrepresentsacardiac
phenotypewithstronggeneticcharacteristics,andCHARGEsyndromeisthe
secondgeneticconditionwiththiscardiacphenotypeafterDownsyndrome.132
GeneticDefect
CHD7,encodingthechromodomainhelicaseDNAbindingprotein,istheonly
geneknowntobeassociatedwithCHARGEsyndrome.133Pathogeneticvariants
orintragenicrearrangementsinCHD7aredetectedin65%to70%ofpatients
withCHARGEsyndrome.
VACTERLAssociation
ClinicalFeatures
VACTERLassociationischaracterizedbythepresenceofatleastthreeofthe
followingcongenitalmalformations:vertebraldefects(Fig.77.10),analatresia,
cardiacdefects,tracheoesophagealfistula,renalanomalies,andlimb
abnormalities(Table77.14).134,135Inaddition,patientsmayalsohaveother
congenitalanomalies.Significantmorbidityisassociatedwiththe
malformations,butneurocognitivefunctionisusuallynormal.
FIG.77.10 VertebralanomaliesinVACTERLassociation.
Table77.14
PrevalenceofClinicalFeaturesinPatientsWithVACTERLSyndrome
ClinicalFeature
Genitourinarymalformation
Vertebraldefect
Anorectalmalformation
Esophagealatresia
Congenitalheartdefect
Conotruncalheartdefect
Septaldefect
Heterotaxia
Frequency(%)
80–90
60–80
55–90
50–60
40–80
30
30
20
Left-sidedobstruction
Anomalouspulmonaryvenousreturn
Other
Radialdefect
Cognitivedeficit
Facialanomalies
10
5
5
40–50
15–20
15
CardiacDefects
Cardiacmalformationshavebeenreportedinapproximately40%to80%of
patientswithVACTERLassociation.136–138CHDsmayrangefromsevere
structuraldefectsincompatiblewithlifeornecessitatingseveralstagesof
surgery,tosubtleanatomicdefects.Severalcategoriesarediagnosed,including
conotruncaldefects,heterotaxia,AVCD,andseptaldefects(seeTable77.14).
(Thestudyofriskfactorsformortalityafterrepairofconotruncalanomaliesare
showingthatVACTERLsyndromeisaffectingadverselythesurgicaloutcome
forpredominantnoncardiacanomalies.)Thestudyonriskfactorsaffecting
mortalityafterrepairofconotruncalanomaliesbyMichielonetal.revealedthat
VACTERLsyndromenegativelyimpactedthesurgicaloutcomes.139
GeneticDefect
ThereisevidenceforstronggeneticheterogeneityofVACTERLassociation.
Althoughfamilialclusteringhasbeenreported,itisinfactrare.Themajorityof
casesarereportedasisolatedindividualsinthefamilies.
TheSonicHedgehogpathwaygeneshavebeensuspectedtobeimplicatedin
theetiologyofthediseasebecauseanimalswithmutationshavefeaturesof
VACTERLassociation.140Inaddition,mutationsordeletionsinFOXF1,agene
linkedtotheSonicHedgehog,resultinaVACTERL-likephenotype.141
Furthermore,disruptionofpathwaysinvolvingHoxandretinoicacidsignaling
havebeensuspectedtobeinvolved.142,143Amongenvironmentalinfluences,
maternaldiabetescanbecited.134,135
GoldenharSyndrome
ClinicalFeatures
TheGoldenharsyndrome(oroculo-auriculo-vertebralspectrum)ischaracterized
byunilateralmicrotia,hemifacialmicrosomiawithmandibularhypoplasia,