Andersons pediatric cardiology 2077

FIG.77.8 FacialappearanceofKabukisyndrome.

CardiacDefects
TheprevalenceofCHDinKabukisyndromeisapproximately70%.Anatomic
typesincludeaorticcoarctationandotherleft-sidedobstructivelesions(bicuspid
aorticvalve,hypoplasticleftheart),septaldefects,andconotruncalanomalies
(seeTable77.9).104–106
Patientswithaorticmalformationcanhaveadditionalanomaliesofthemitral
valve,consistinginmitralstenosiswithsupramitralring,dysplasticmitralvalve,
andbicuspidaorticvalve.Thesemultipleleft-sidedobstructionsaresimilarto
thoseobservedinthespectrumoftheso-calledShonecomplex,107identifiedas
theassociationofaorticcoarctation,membranoussubaorticstenosis,bicuspid
aorticvalve,mitralstenosiswith“parachute”mitralvalvewithsinglepapillary
muscle,andsupramitralring.
Aorticdilatationhasalsobeenseeninassociationwithcongenitalaortic
lesionsinpatientswithKabukisyndrome,sothesepatientsareatincreasedrisk
ofaorticaneurysm.106Forthisreason,annualmonitoringforaorticdilatationis
suggested.Inaddition,apredispositiontovascularhypertensionshouldalsobe


consideredinpatientswithKabukisyndrome.
SeptaldefectsarealsofrequentinKabukisyndromeandincludeatrialseptal
defectofostiumsecundumtypeandperimembranoussubaorticventricular
septaldefect,andconotruncaldefectsalsooccurinaminorityofthepatients.

GeneticDefect
Kabukisyndromeisgeneticallyheterogeneousbecausefivecausativegenesare
knownatpresent.Thefirstidentifiedandmorefrequentlyinvolvedgeneis
KMT2D(MLL2),mappingto12q13.12,108andisimplicatedin60%to80%of
thecases.TheKDM6Agene,mappingtoXp11.3,isthesecondgeneassociated
withKabukisyndrome.109Morerecently,threeadditionalgenesinvolvedina

minorityofpatientshavebeenidentified.110–112

AlagilleSyndrome
ClinicalFeatures
Alagillesyndrome(ALGS)isanautosomaldominantdisorderinvolvingthe
liver,heart,eyes,face,andskeleton.Themajorclinicalfeaturesarecholestasis,
characterizedbybileductpaucityonliverbiopsy,posteriorembryotoxoninthe
eye,mildfacialfeatures,andbutterflyvertebrae.Jaundicepresentsasconjugated
hyperbilirubinemiaintheneonatalperiod(Table77.10).113Inapproximately
15%ofaffectedindividuals,theliverdiseaseprogressestocirrhosisandliver
failure,necessitatinglivertransplantation.Cognitivedevelopmentisusually
normal.
Table77.10
PrevalenceofClinicalFeaturesinPatientsWithAlagilleSyndrome
ClinicalFeature
Chroniccholestasis
Congenitalheartdefect
Peripheralpulmonarystenosis
TetralogyofFallot
Septaldefects
Aorticcoarctation
Other
Bileductpaucity
Facialanomalies

Frequency(%)
95
95
65
15

5
5
10
75–85
70–90


Eyeembryotoxon
Vertebralanomalies
Renalanomalies
Developmentaldelay/intellectualdisability

60–80
40–50
25–40
15

CardiacDefects
Cardiacdefectsoccurin90%ofthepatients.Thepulmonaryvasculature
(pulmonaryvalve,pulmonaryartery,anditsbranches)ismostcommonly
involved.Pulmonicstenosis(peripheralandbranch)isthemostcommoncardiac
finding,buttetralogyofFallot(withandwithoutpulmonaryatresia),ventricular
septaldefect,atrialseptaldefect,aorticstenosis,andcoarctationoftheaortaalso
hasbeenreported(seeTable77.10).113,114InchildrenwithtetralogyofFallot
(withandwithoutpulmonaryatresia)andALGS,themultipleandsevere
peripheralpulmonaryarterystenosismayrepresentanimportantriskfactorat
correctiveoperation.

GeneticDefect
TwogenesareknowntocauseALGS:JAG1andNOTCH2.115–117Mutationsin

JAG1aredetectedin90%ofthepatients,whereaspathogenicvariantsin
NOTCH2arediagnosedin1%to2%ofpatientswithALGS.Thephenotypeof
ALGScausedbymutationofJAG1isindistinguishablefromthephenotype
causedbymutationofNOTCH2.

Holt-OramSyndrome
ClinicalFeatures
Holt-Oramsyndromeisanautosomaldominantdiseasecharacterizedbyupper
extremitymalformationsinvolvingradial,thenar,orcarpalbones,CHD,or
cardiacconductiondisease(Table77.11).118Upperlimbmalformationscan
rangefromtriphalangealorabsentthumbtophocomelia(Fig.77.9).
Intermediatepresentationsmayalsobeobserved.Slopingshouldersand
restrictionofshoulderjointmovementcanalsobepresent.
Table77.11
PrevalenceofClinicalFeaturesinPatientsWithHolt-OramSyndrome