Andersons pediatric cardiology 1554

progress.39
ScheieSyndrome.
PatientswithScheiesyndromearelessseverelyaffectedandhavenormalstature
andintellect.Theyalsohaveanearnormallifespan.Themoststrikingfeatures
arecornealcloudingandstiffjoints.Typicalcardiacmanifestationsareaortic
stenosisandregurgitationormitralregurgitation.40,41Theseshouldbemanaged
inasimilarfashiontothatemployedinotherwisenormalsubjects.Scheie
syndromeisinheritedinautosomalrecessivefashion.
Hurler-ScheieSyndrome.
Hurler-Scheiesyndromefallsinseveritybetweenthetwoextremesofα-Liduronidasedeficiency.Thepatientshaveshortstaturewithmentalretardation
andmultiplebonydefects.Thereiscloudingofthecorneaandstiffjoints,clawhandbeingparticularlycommon.Aorticandmitralvalveinvolvementisthe
primarymanifestation,butasymmetricseptalhypertrophyhasalsobeen
reported.42TheclinicalcourseisintermediatebetweenHurlerandScheie
syndromes,patientslivingintoadolescenceoreventothethirddecade.

MucopolysaccharidosisTypeII(Hunter
Syndrome,IduronateSulfataseDeficiency)
Deficiencyofiduronatesulfateresultsinblockeddegradationofdermatan
sulfate.ThedifferenceinclinicalprofilebetweenthisandHurlerandScheie
syndromes(e.g.,theabsenceofcornealcloudinginHuntersyndrome)may
resultfromspecificvariabilityinthedegreeofblockageofdegradationofthe
mucopolysaccharide.Furthermore,itmaybethattheblocktodegradation
causedbytheaccumulationofiduronatesulfatemaybebypassedby
hyaluronidase.ThesevereandmildformsofHuntersyndromebothhavetotal
(orneartotal)deficiencyofiduronatesulfatase.However,aswith
mucopolysaccharidosistypeI,theclinicalphenotypemayberepresentativeof
thedegreeofresidualenzymeactivityspecifictocertaingenemutations,of
whichmorethan300havebeenfoundforHuntersyndrome.43
Theconditioncanoccurwithawidevariationinseverity,whichtendstorun
trueinanygivenfamily.Apartfromtheextremerarityofcornealcloudingin
Huntersyndromeandthepresenceofhearingloss,theclinicalfeaturesarethose

ofHurlersyndrome,althoughusuallylesssevere.Apositivedistinguishing
physicalsignpointedoutbyHunterhimself(1916)istheoccurrenceofpebblelikeivory-coloredskinlesions.Theseareseenoverthescapulaeand
occasionallyonthepectoralregions.
Cardiacinvolvementproducesallthemanifestationssofarmentioned,namely
aorticandmitralregurgitationorstenosis,ischemicchanges,andevidenceof
myocardialdepositionanddysfunction.Echocardiographyisausefulmethodfor
evaluatingcardiacinvolvementinHuntersyndrome.Theclinicalcourseis
extremelyvariable.Severelyaffectedindividualsmaydieinadolescence.Atthe
oppositeendofthespectrum,however,survivalbeyondthesixthdecadehas
beenreported.Deathinyoungerpatientsisusuallyassociatedwithprogressive
neurologicdeterioration.ThediseaseisinheritedasanX-linkedrecessivetrait,
althoughcasesinfemaleshavebeenreported.44Sincethereproductivefitnessof
theHuntergeneislow,alargeproportionofcasesresultfromnewmutations.
RecentlyanewtreatmentforHuntersyndromehasemergedwiththe
developmentofrecombinanthumaniduronate-2-sulfatase.Thisiswelltolerated
andassociatedwithimprovementinseveraloutcomeparameters,including
forcedvitalcapacity,urinaryexcretionofglycosaminoglycans,liverandspleen
volume,and6-minutewalkdistance.45,46However,theeffectofenzymetherapy
onthecardiaclesionsremainstobedetermined.47

MucopolysaccharidosisTypeIII(Sanfilippo
Syndrome)
ThedegradationofheparansulfateandN-sulfatedorN-acetylatedα-linked
glucosaminerequiresfiveenzymes:N-sulfoglucosaminesulfohydrolase
(sulfamidase),α-2-acetamido-2-deoxy-D-glucoside
acetamidodeoxyglucohydrolase(α-N-acetylglucosaminidase),heparanacetyl
CoA:α-glucosaminideN-acetyltransferase,N-acetylglucosamine-6-sulfatase,and
N-glucosamine-3-O-sulfatase.Deficiencyofoneofthefiveenzymesrequired

forthisdegradationresultsintheSanfilipposyndrome,whichisanautosomal
recessivedisorder.Consequentlytherearefivebiochemicallydistincttypesof
thedisease(designatedatoe),althoughtheyallpresentthesameclinical
features.Incidentally,typeehasyettobeuncoveredinhumans,althoughit
existsinanimalmodels.48
Theonsetisusuallyevidentinthefirstfewyearsoflifewith“behavioral”


problems.Mentalandneurologicdeteriorationaresevereandleadtodeathinthe
firsttwodecades.Bone,joint,andcardiacinvolvementisgenerallylesssevere
thaninHurlersyndrome.Cornealcloudingisneverseen.
Thereiswidevariationintheseverityandageatdeathinallfourforms,but
typeaislikelytobethemostsevere.Inheritanceisinautosomalrecessive
fashion.Cardiacinvolvementissimilartothatofothermucopolysaccharidoses,
withanumberofpatientsreportedtohavemitralvalveinvolvement.49,50
Althoughtreatmentisprimarilysupportive,animalstudieshavebeenundertaken
toassessenzymereplacementtherapyinamousemodelwith
mucopolysaccharidosistypeIII-b.51

MucopolysaccharidosisTypeIV(Morquio
Syndrome)
Morquiosyndromeresultsfromdefectivedegradationofkeratansulfate.It
occursintwobiochemicallydistinctforms.So-calledtypeaisduetoa
deficiencyofn-acetylgalactosamine-6-sulfatesulfatase,whereastypebresults
fromdeficiencyofβ-galactosidase.Thetwotypeshavesimilarclinicalfeatures,
buttypebislesssevere,sometimesbeingcalledthe“long-legged”variant.
Despitethegenerallyincreasedseverityoffeatureswithtypea,moremildforms
oftypeacanoccur.Keratansulfateisexcretedintheurineintypea,butthisis
lessevidentintypeb.
Keratansulfateisfoundincartilage,intervertebraldiscs,andthecornea.Thus

skeletalinvolvementwithdwarfism,pectusexcavatum,andbowedlegsarethe
mostobviousmanifestations.Cornealcloudingiscommon.Incontrasttothe
mucopolysaccharidosesdescribedearlier,thejointsinpatientswithMorquio
syndromearehyperextensible.Absenceorseverehypoplasiaoftheodontoid
process,togetherwithlaxityofitsassociatedligaments,leadstoatlanto-occipital
subluxationandconsequentcervicalmyelopathy.Sinustachycardiaisacommon
featureofthisdisease,butthemechanismisunclear.Valvesoftheheartare
ofteninvolved,withthickeningofmitralandaorticleaflets,althoughsignificant
valvedysfunctionislesscommon.Aorticrootdilation,concentricleft
ventricularhypertrophyand,rarely,asymmetricseptalhypertrophyhaveallbeen
described.52,53Survivalbeyondthethirdorfourthdecadeisnotunusual.The
effectsofthecervicalmyelopathyandrespiratoryproblemsaretheusualcause
ofdeath.Experimentationwithenzymereplacementtherapyinanimalshasbeen