Andersons pediatric cardiology 1562

DisordersofCollagenSynthesisor
ExtracellularMatrix
Thegroupofdisordersofcollagensynthesisincludesseveraldiseaseswith
cardiacinvolvement.IncludedinthisdiscussionareEhlers-Danlossyndrome,
cutislaxa,osteogenesisimperfecta,andMarfansyndrome.Alcaptonuriaalso
comesintothisgeneralgroupbut,asyet,cardiacdiseasehasnotbecome
manifestinchildhood.Directcardiacinvolvementdoesnotoccurin
epidermolysisbullosa,buttheheartmaybeaffectedwhentheconditionis
complicatedbyamyloidosis.

Ehlers-DanlosSyndrome
Phenotypicalfeaturesunitethebiochemicallyandgeneticallyheterogeneous
groupofdisordersincludedinEhlers-Danlossyndrome.Thestigmasare
hyperextensibleskinandjoints,easybruising,andpoorhealingofwounds.A
distinctivefacialappearanceincludesepicanthicfolds,aflatbridgeofthenose,
andprominentdownwardpointingears.Apartfromthepalmsandsoles,theskin
issmoothandrubbery.Inlaterlifeitmayhanginfoldsfromtheelbows.
Prematuredeathiscommoninthemostsevereform,andthebabieshavepoor
musculartone.Inadditiontotheepicanthicfolds,ocularsignsincludeeasy
eversionoftheuppereyelid,knownastheMeteniersign,bluescleras,anda
dislocatedlens.Avarietyofcongenitalcardiacmalformationshavebeen
reported,176–178beingfoundinapproximatelyone-eighthofpatientsinone
study.Prolapseofthemitralvalvehadpreviouslybeenreportedtobecommon
inthesepatients,butamorerecentstudyshowsanincidencesimilartothatof
thegeneralpopulation.148
Morethan10subtypesofEhlers-Danlossyndromehavebeendescribed,but
sixmajorsubtypesarerecognized,comprisingnine-tenthsofindividuals
affected.Patientstypicallyfallintothehypermobility,classical,orvasculartype.
ClassicEhlers-Danlossyndrome,incorporatingtypesIandII,demonstratesthe
typicalcutaneousfindings.Itmostoftenresultsfromdefectsinoneormoreof
thecollagenorprocollagengenes.Thehypermobilitytypeissimilar,withjoint

hypermobilitythepredominantclinicalfeature.Bothofthesetypes,thoughnot
characteristicallydemonstratingvascularchanges,havebeenshowntobe


associatedwithdilationoftheaorticrootandvalvardysfunction.179thevascular
type,alsoknownasEhlers-DanlossyndrometypeIV,resultsfrommutationsin
theCOL3A1geneencodingtypeIIIcollagenandaccountsfor5%to10%ofall
Ehlers-Danloscases.180Thesepatientsareatriskforarterialrupture,which
typicallyoccursaftertheonsetofthethirddecadeoflife.181Themediansurvival
forpatientswithEhlers-DanlossyndrometypeIVisupto48yearsofage
primarilyduetoarterialruptureandoftenwithoutprecedinganeurysms.Surgery
maybeneededforlife-threateningcomplications,butaconservativeapproachis
usuallypreferredowingtotissuecharacteristics,poorwoundhealing,and
hemorrhagerisk.182Amoresevererecessiveformhasbeenreported,including
boththecutaneousfindingsoftheclassicformcoupledwithcardiacvalvar
involvement.183

CutisLaxa
Cutislaxais,again,ageneticallyheterogeneousgroupofconditions
characterizedinthephenotypebytheskinbeingsoloosethatitappearstoolarge
forthebody.UnlikethecaseinEhlers-Danlossyndrome,thelaxskinisslowto
recoilafterbeingstretched.Cutislaxahassomefeaturesincommonwiththe
Ehlers-Danlossyndrome,suchasfragilityoftheskin,hypermobilejoints,and
easybruising.Therearecharacteristicfacies,includingalongupperlip,a
hookednose,andashortcolumella.Thedefectofconnectivetissuealsoresults
inadeepvoice,owingtolaxvocalcords.Herniasandrectalorvaginalprolapse
canalsobeseen.Thediseasecanbeinheritedinbothautosomaldominantand
autosomalrecessiveforms.Fromthecardiacstandpoint,peripheralpulmonary
stenosis184andaorticdilationhavebeenreported.185Thesefindings,coupled
withreportsofsupravalvaraorticstenosis,186havehelpedleadtothediscovery

thatdefectsintheelastingeneareonecauseofthisdisorder.187Defectsinother
genes,includingfibulin-4andfibulin-5,havealsobeenimplicatedinsome
forms.188,189Anothermajorcomplicationiscorpulmonale,sincetheassociated
emphysemaisfrequentlyprogressiveandsevere.190Patientswiththeneonatal
variantofcutislaxacanhaveseveremitralregurgitationwithdysplasticvalvar
leaflets.191

OsteogenesisImperfecta


OsteogenesisimperfectiscausedbymutationsingenesforcollagentypeI.Bone
fragilityisthemainclinicalfeatureofthiscondition.Althoughthefracturesare
subperiosteal,withlittledisplacement,themultiplicityoffracturesleadsto
bowingofthelongbones.Additionally,thevertebraearebiconcave,withthe
discsometimesperforatingthevertebralbodytogivetheappearanceknownas
Schmorlnodes.Theskullisfrequentlymadeuplargelyofwormianbonesand
showsfrontalandparietalbossing.Theskeletaldeformitiesleadtoshortstature.
Theskinisthinbutnotlax.Thescleraeareblueinmosttypes.Intheso-called
typeIIIvariantofthedisease,theymaybecomelessbluewithage.Despite
collagentypeIbeinganimportantcardiacproteinclinically,significantcardiac
diseaseisrareinchildrenandyoungadultswithosteogenesisimperfecta.192The
cardiovascularmanifestationsincludeaorticandmitralregurgitationowingto
dilationofthevalvarhingesor,inthelatter,toprolapsefromrupturedcords.It
hasbeensuggestedthataorticrootdilationmaybepresentinacertainsubsetof
patientswithosteogenesisimperfectaandthatitappearstobenonprogressive.193
Insomepatients,aorticormitralvalvardiseaseissevereandmayrequire
replacementsurgery.Thiscarriesahigherthannormalriskduetobleeding
complicationsrelatedtotissuefriability.Administrationofrecombinantfactor
VIIamaybehelpfulincontrollingbleedinginthesepatients.194Aorticstenosis,
defectsoftheovalfossa,andtetralogyofFallothavealsobeenreported.195

MarfanSyndrome
Marfansyndromeistransmittedasanautosomaldominantdiseasewithvariable
clinicalexpression.Theprevalenceisestimatedat2to3per10,000.Thedisease
isduetodefectsintheFBN1geneonchromosome15q21,whichencodes
fibrillin-1,animportantcomponentofconnectivetissues.Morethan600
mutationsinthegenehavebeenidentified,andapproximatelyone-quarterto
three-tenthsofcasesrepresentnewmutations.Althoughexpressionofthe
diseaseishighlyvariable,evenamongfamilymemberswiththesamegenetic
defect,somecorrelationsbetweengenotypeandphenotypehavebeen
clarified.196Morethanseven-tenthsofthoseaffectedarediagnosedbeforethe
ageof10years.Physicalfeaturesofthesyndromemaybepresentatbirth.197
Affectedpersonsareusuallyverytall,withanincreaseinthelengthofthelimbs
comparedwiththetrunk.Theirarmspanexceedstheirheight(Fig.59.3A).They
havelongthinfingers(seeFig.59.3B–C),hypermobilejoints,kyphoscoliosis,
andchestdeformities.Higharchingofthepalate,withdentalcrowding,is