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ImagingConsiderations
Becauseofthevastnumberofanatomicanomaliesthatmaybepresentinthe
settingofisomerism,imagingbecomesofgreatimportance.Thoseinvolvedwith
imagingpatientswithisomerismmustbeawareofthevariousmanifestationsof
isomerismandshouldbethoroughintheirinterpretationofanyacquiredimages.
Terminologymustbeselectedcarefully,andtermssuchas“situsambiguous”
shouldbeavoided,withfindingsexplicitlydescribed.48,85,114–116Fetalmagnetic
resonanceimagingisabletodemonstratemanyoftheseanomalies.Whilethisis
notroutinelyindicated,thosewhoundergofetalimagingshouldhavethese
imagesreviewedwithattentionpaidtoallorgansystemstofindassociated
anomalies.85,117,118Cardiacimagingisofobviousimportance.Echocardiography
isthecornerstoneofsuchimaging,butmaybelimitedinsomeregard,
particularlyinimagingtheatrialappendages.Therestofthecardiacanatomyis
welldemonstratedbyechocardiography.Computedtomographyandmagnetic
resonanceimagingmayalsobeusedandcanbehelpfulindelineatingthe
morphologyoftheatrialappendages,particularlythevenousanatomy.119Inthe
eventthattheatrialappendagescannotbeimagedwell,anaggregateofanatomic
anomaliescanhelpsegregateisomerismintoitssubsets.Thepresenceofan
interruptedaorticarch,biventricularcirculation,andthepresenceofacoronary
sinusaremorefrequentinleftisomerism,whereassupracardiacorinfracardiac
totalanomalouspulmonaryvenousconnection,functionallyuniventricular
circulation,andpulmonaryoutflowtractobstructionaremorefrequentinright
isomerism.120


CiliaryDysfunction
Ciliaarehair-likeorganelles,sensoryormotile,thatarepresentonnearlyevery
cellinthehumanbody,withatleastasinglesensoryciliumbeingpresentedon
eachcell.Thesesensoryciliaareimportantincell-cellsignaling.Motileciliaare
foundintheepithelialcellliningoftherespiratorytractandthereproductive
system.Motileciliaareresponsibleformovingfluidsandparticlesinthebody.

Ciliahavebeenfoundtobeinvolvedinlateralizationoforgans,vision,hearing,
taste,productionandclearanceofcerebrospinalfluid,movementofparticles,
andimmuneresponse.
Abnormalitiesincilia,orciliarydysfunction,canthushaveavarietyof
consequences.Ciliarydysfunctionhasbeennotedinupto40%ofthosewith
isomerism,withthosewithciliarydysfunctionhavingincreasedsinopulmonary
disease.Thosewithmutationsinknownciliarygenesseemtohaveworse
clinicalphenotypes.121–123Investigationsintociliaryfunctioninthosewith
isomerismarestillintheirinfancy,butitappearsthatciliarydysfunctionmaybe
amechanismofincreasedmorbidityandmortalityinthosewithisomerism.
Studiesinanimalmodelsofciliarydysfunctionwithnormalciliaryultrastructure
havedemonstratedthatfunctioncanberestoredtosomeextentinthesepatients.
Ciliarydysfunctioninthosewithisomerism,nonetheless,isnotsynonymous
withwhatisseeninthosewithprimaryciliarydyskinesia.Theultrastructureof
thecilia,asdemonstratedbyelectronmicroscopy,isoftennormalinthosewith
isomerism.Rather,thedensityofcilia,thebeatfrequencyofthecilia,andthe
beatsynchronizationareabnormal.Thussimpleelectronmicroscopydoesnot
ruleoutciliarydysfunctioninthosewithisomerism.Videomicroscopyonnasal
epitheliumobtainedvianasalswabcanallowforquantificationofciliary
function.Exhalednitricoxidemayalsobeasurrogatemarkerofciliaryfunction,
withthosewhohaveciliarydysfunctionhavinglowerexhalednitricoxide
levels.121
Theimportanceofciliainthosewithisomerismgoesbeyondjustpostnatal
life.Ciliarydysfunctionlikelyhasmechanisticimplicationsinisomerism.Cilia
areresponsibleforproducingaleftwardflowofextraembryonicfluidthat
impactsorganlateralizationbydistributionofgrowthfactorsandproteins.In
addition,sensoryaberration,particularlysecondarytoabnormalcalcium
signaling,mayalsoprovideanothermechanismtohownodalciliaunderpin

isomerism.124–127Muchhasnowbeenlearnedconcerningthegeneticpathways
producingthesechanges,withexperimentsconfirmingtherealityofisomerism
oftheatrialappendages.Thusitisknownthatciliaintheprimitivenodecreatea
wavethatdrivesmoleculesinonespecificdirectionacrossthecellsofthe
developingembryo,withexpressionofthegeneNodalmostlyconfinedtothe
leftside.Thewaveofmolecularmaterialproducedfromthenode,which
influencesdevelopmentoflateralizedfeatures,isstoppedfromcrossingthe
midlineoftheembryobyaprocessknowntobeundertheinfluenceofthegene
Sonichedgehog.Becauseofthismidlinebarrier,othergenes,suchasLefty,and
Pitx2,alongwiththegeneCited2,alsoknowntobepartofthegeneticcascade,
havetheirexpressionconfinedtotheleftsideofthebody,thusproducingthe
morphologicallyleftcharacteristic.ThisiswhyknockingoutgenessuchasPitx2
orCited2inmiceproducesanimalswithunequivocalrightisomerism(Fig.
26.19,top),whileknockingoutLefty-1permitstheleft-forminggenestooccupy
therightsideofthebody,thusproducingleftisomerism(seeFig.26.19B,
right).9,128