Andersons pediatric cardiology 1575

infiltrate,andacutenecrotizingvasculitis.351Uponrecovery,therecanbe
multiplefocalscarswithresidualmyocardialdysfunction.
Drug-inducedcardiomyopathiesaremostcommonlyattributedtoalcohol,
cobalt,andtheanthracyclines.Theyproduceadilatedcardiomyopathywithpoor
contractility,leadingtoCHF.Ofthesedrugs,theanthracyclinesarethemost
important,astheyarewidelyusedinthetreatmentofchildhoodcancer.


MiscellaneousSystemicDisorders
Hutchinson-GilfordProgeria
Progeriaisadiseaseofprematureagingfrequentlyduetoamutationinthe
laminAgene.Thedefectivegeneproduct,progerin,undergoesabnormal
posttranslationalprocessingandleadstoabnormalmorphologyofthenuclear
envelope,withthickeningofthenuclearlamina,lossofperipheral
heterochromatin,blebbingofthenuclearenvelope,andclusteringofnuclear
pores.352Thepathogenesisofplaqueformationisdifferentfromtypicaladult
atherosclerosis.ChildrenwithHutchinson-Gilfordprogeriahavesignificant
thickeningoftheadventitia,whichmaybeduetotheaccumulationof
progerin.353Affectedchildrenarenormalduringthefirstmonthsoflife,
exhibitingevidenceofthediseaseinthesecondyearwithfailuretothrive,loss
ofsubcutaneousfat,scleroderma,alopecia,andthedevelopmentofatypical
facies.Thisconsistsofadisproportionatelylargeheadfortheface,abeaked
nose,micrognathia,thinlips,andprominenteyes.Skeletalabnormalitiesinclude
dystrophicclavicles,thoracicdeformities,knock-knees,persistentpatencyofthe
fontanelle,andosteoarthritis.Intellectualdevelopmentisnormal.354The
cardiovascularsystemisaffectedbyprematureatherosclerosisofthecoronary
arteriesandaorta.Mostpatientshaveischemicheartdiseaseandsufferfrom
myocardialinfarctionsorstroke,withdeathatameanageof13years.Some
presentwithadilatedcardiomyopathyandcardiacfailurewithnormalcoronary
arteries.Calcificationofthemitralandaorticvalvesiscommon.355Functionof
theadrenal,thyroid,parathyroid,andpituitaryglandsisnormal.Thereis,

however,resistancetoinsulin,andthereareabnormallevelsoflipidsinthe
serum,withanincreaseintotallipidsaswellaspre-βandβlipoproteins.Dietary
treatmentwithreductionofthelipidstowithinthenormalrangedoesnotseem
toalterthecourseofthedisease.

ArteriohepaticDysplasia(AlagilleSyndrome)
Arteriohepaticdysplasiaischaracterizedbychroniccholestasis.Itusually
becomesapparentwithinthefirst3monthsoflifewithprolongedjaundice.
Involvedinfantsmaypresentlaterwithaheartmurmur.356Theotherfeatures
makingupthissyndromeareatypicalfacies,vertebralmalformations,


peripheralpulmonarystenosis,andocularinvolvement.Delayedphysical,
mental,andsexualdevelopmenthasnotbeenconsistentlyreported.357The
diseaseissometimesassociatedwithdefectsintheJAG1gene,whichencodesa
ligandforthenotchtransmembranereceptor.358Thissignalingmechanismis
importantforvasculardevelopment.359
Thecharacteristicfacialappearanceconsistsofaprominentforehead,deep-set
eyeswithmildhypertelorism,andasmallpointedchin.Ophthalmologic
examinationrevealschorioretinalatrophyandpigmentclumping,whichmaybe
pathognomonic.Peripheralpulmonarystenosisisthetypicalcardiovascular
anomaly.Onphysicalexamination,thereisaprominentleftparasternalimpulse
andanejectionsystolicmurmurattheupperleftsternalborderradiatingtothe
back,whereitmaybeheardextendingintodiastole.TheECGshowsright
ventricularhypertrophy.Cardiacsizemaybenormalorincreasedonthechest
radiograph,andthelungfieldsmayappearnormaloroligomeric.Structural
intracardiacdiseaseispresentinupto1in4patients,includingtetralogyof
Fallotwithorwithoutpulmonaryatresia,valvarpulmonarystenosis,isolated
atrialseptaldefectandventricularseptaldefect.360
Manypatientshaveanomaliesofthevertebralarches,usuallywithabutterfly

appearanceofthedorsalvertebrae.Xanthomasofthepalms,extensorsurfaces,
andskincreasesofthehandsareseenwhenhyperlipidemiaispresent.Elevated
lipidsandcholesterolintheserumarecontrolledbytheuseofcholestyramine
andtheadditionofcornoiltothediet.Arteriohepaticdysplasiaisconfirmedby
liverbiopsy,whichshowsthebileductstobeabsentfrommostportalareas.
Periportalfibrosisisabsentormild,andtheextrahepaticsystemispatent.
Additionallaboratoryfindingsincludeelevated5′-nucleotidase,alkaline
phosphatase,transaminases,andbilirubin.Theperipheralpulmonarystenosisis
notprogressiveanddoesnotinfluencethelong-termprognosisofthedisease.
Liverdysfunctionandcomplexcongenitalheartdiseasehavebeenamongthe
mostprominentcausesofmortality.361

SickleCellHemoglobinopathy
Sicklecellhemoglobinopathyisachronicanemiathatpredominantlyaffects
individualsofAfricandescent.Theunderlyingabnormalityisthesubstitutionof
glutamicacidbyvalineinthesixthpositionoftheβchainofhemoglobin.This
resultsintheformationofhemoglobinS.Whenthetensionofoxygenis
reduced,thehemoglobinSmoleculespolymerizeandproduceacrescent-or