Dr. Domingo - Diseas of Infancy
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Transcript of Dr. Domingo - Diseas of Infancy
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DISEASESOFINFANCYANDCHILDHOOD
ALEJANDROL.DOMINGOJR.,MD.,FPSP,APCP
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Childrenarenotmerelylileadults,andtheir
diseasesarenotmerelyvariantsofadultdiseases.
Manychildhoodcondionsareuniqueto,oratleasttakedisncveformsin,thisstageof
life.
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InfantmortalityrateintheUShasshownadecline
fromalevelof20deaths/1000livebirthsin1970
toabout6.8deathsin2004.Althoughthedeathratehasconnuedtodecline
forallinfants,AfricanAmericansconnuetohave
arateofmorethantwice(13.6deaths/1000livebirths).
Infantmortalityratesvarywidely,worldwide,from
aslowas2.3deaths/1000livebirthsinSingaporetoashighas180deathsintheAfrican
subconnent.
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Eachstageofdevelopmentofinfantandchildis
preytoasomewhatdifferentgroupofdisorders:
1. Neonatalperiod(1st4wksoflife)2. Infancy(1styearoflife)3. Age1-4years4. Age5-14years
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TABLE10-1CAUSEOFDEATHRELATED
WITHAGE(2004)
UNDER1YEAR 685.2
-Congenitalmalformaons,deformaons,andchromosomalabnormalies
-Disordersrelatedtoshortgestaon&lowbirth
weight-Suddeninfantdeathsyndrome(SIDS)
-Newbornaffectedbymaternalcomplicaonsof
pregnancy
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-Newbornaffectedbycomplicaonsofplacenta,
cord,andmembranes
-Respiratorydistressofnewborn
-Accidents(unintenonalinjuries)
-BacterialSepsisofnewborn
-Intrauterinehypoxiaandbirthasphyxia
-Diseasesofthecirculatorysystem
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1-4YEARS 29.9
-Accidents&adverseeffects
-Congenitalmalformaons,deformaons,and
chromosomalabnormalies
-Malignantneoplasms
-Homicide&legalintervenon
-Diseasesoftheheart-Influenza&pneumonia
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5-14YEARS 16.8
-Accidents&adverseeffects
-Malignantneoplasms
-Homicide&legalintervenon-Congenitalmalformaons,deformaons,and
chromosomalabnormalies
-Suicide-Diseasesoftheheart
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15-24years 80.1
-Accidents&adverseeffects
-Homicide-Suicide
-Malignantneoplasms
-Diseasesoftheheart
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CONGENITALANOMALLIES
-aremorphologicdefectsthatarepresentatbirth,butsome,suchascardiacdefects&renalanomalies,maynotbecomeclinicallyapparentunlyearslater.
-congenitalmeansbornwith,butdoesnotimplyorexcludeagenecbasisforbirthdefect.
-120,000(1in33)babiesintheUShavecongenital
defectseachyear-mostcommoncauseofmorbidityinthe1styearof
&contributesignificantlytomorbidity&mortalitythroughouttheearlyyearsoflife.
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Defini>onsoftermsusedforvariouskindsof
errorsinmorphogenesis
MALFORMATIONSrepresentsprimaryerrorsof
morphogenesis,inw/cthereisanintrinsically
abnormaldevelopmentalprocess.-usuallyassociatedwithmulplegenecloci
(mulfactorial)¬theresultofasinglegeneor
chromosomaldefect.-ex:polydactyly,syndactyly,clelipwithorw/o
clepalate
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DISRUPTIONSresultfromsecondarydes-trucon
ofanorganorbodyregionthatwaspreviously
normalindevelopment;thus,incontrastto
malformaons,disruponsarisefromanextrinsic
disturbanceinmorphogenesis
-notheritable&hencenotassociatedwithriskof
recurrenceinsubsequentpregnancies
-ex:Amniocbands
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DEFORMATIONS-alsorepresentanextrinsic
disturbanceofdevelopmentratherthanan
intrinsicerrorofmorphogenesis.
-affectsabout2%ofNBtovaryingdegrees
-fundamentaltothepathogenesisofdeformaon
islocalizedorgeneralizedcompressionofthe
growingfetusbyabnormalbiomechanicalforces,
leadingeventuallytoavarietyofstructural
abnormalies.-mostcommonunderlyingfactorresponsiblefor
deformaonisuterineconstraint.
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-Betweenthe35th&38thweeksofgestaon,rapidincreaseinthesizeofthefetusoutpaces
thegrowthoftheuterus,&therelaveamountofamniocfluid(w/cnormallyactsasacushion)alsodecreases.
-factorsthatincreasethelikelihoodofexcessivecompressionofthefetus:maternalfactorsinclude1stpregnancy,smalluterus,malformed(bicornuate)uterus,&leiomyomas.Fetalor
Placentalfactorsincludeoligohydramnios,mulplefetuses,&abnormalfetalpresentaon.
-ex:Clubfeet
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SEQUENCEisacascadeofanomaliestriggeredby
oneiniangaberraon.
-abouthalftheme,congenitalanomaliesoccur
singly;intheremainingcases,mulplecongenital
anomaliesmaybeexplainedbyasingle,localized
aberraoninorganogenesis(malformaon,
disrupon,ordeformaon)thatsetsintomoon
secondaryeffectsinotherorgans.
-Ex:oligohydramnios(orPoer)sequence
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-Oligohydramnios(decreasedamniocfluid)
maybecausedbyavarietyofunrelated
maternal(utero-placentalinsufficiency),
placental(amniocleak),fetal(renalagenesis)
abnormaliesproducingfetalcompression
resulnginflaenedfacies,posionalabnormaliesofthehands&feet,hip
dislocaon,compromisedgrowthofthechest
wall&thusproducinghypoplasclungsw/cmaybethecauseoffetaldemise.
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SYNDROMEisaconstellaonofcongenital
anomalies,believedtobepathologicallyrelated,
that,incontrasttoasequence,cannotbeexplainedonthebasisofasingle,localized,
iniangdefect.
-mostoencausedbyasingleeologicagent,suchasaviralinfeconorspecificchromosomal
abnormality,w/csimultaneouslyaffectsseveral
ssues.
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AGENESISreferstothecompleteabsenceofan
organanditsassociatedprimordium.
APLASIAreferstotheabsenceofanorganbutone
duetofailureofdevelopmentoftheprimordium.
ATRESIAdescribestheabsenceofanopening,
usuallyofhollowvisceralorgan,suchasthetrachea&intesne
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HYPOPLASIAreferstoincompletedevelop-ment
ordecreasedsizeofanorganw/decreasednumbersofcells.
HYPERPLASIAreferstotheenlargementofanorganduetoincreasednumbersofcells.
HYPERTROPHYanabnormalityinanorganorassueasaresultofanincreaseinthesizeof
individualcells.
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HYPOTROPHYanabnormalityinanorganor
ssueasaresultofadecreaseinthesizeof
individualcells.
DYSPLASIAinthecontextofmalformaonsdescribesanabnormalorganizaonofcells.
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CAUSESOFANOMALIES
A. GenecB. EnvironmentalC.
Mulfactorial
D. Unknown(40-60%)
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GENETIC
A. Chromosomalaberra>ons10-15%-Trisomy21(Downsyndrome)hasprevalenceof12.8/10,000livebirths,followedbytrisomies18(2.3)&13(1.3)
-majorityoftheseaberraonsarisesasdefectsingametogenesis&soarenotfamilial.
-80-90%offetuseswithaneuploidy&other
abnormaliesofchromosomenumberdieinutero,themajorityintheearlieststagesofgestaon.
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B. MendelianInheritance 2-10%-arisingfromsingle-genemutaons
-90%areinheritedinanautosomaldominantorrecessivepaern,theremainderinX-linkedpaern.
-manyofthemutaonsthatgiverisetobirthdefectsinvolvelossoffunconofgenesinvolvedinnormalorganogenesis&devt.
-loss-of-funconmutaons(holoprosen-
cephaly)orgain-of-funconmutaons(dwarfism-thereisacvaonoffibroblastgrowthfactorreceptor3(FGFR3)w/cisa
negaveregulatorofbonegrowth).
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ENVIRONMENTALA. Maternal/placentalinfecons2-3%
-Rubella-at-riskperiodisthe1sttrimester;1st8wks>2nd8wks;congenitalrubellasyndrome-
cataract,heartdefect,deafness,mental
retardaon
-Toxoplasmosis-mostcommonfetalviral infxn;
at-riskperiodis2ndtrimester;mentalretardaon,
microcephaly,deafness,hepatosplenomegaly
-Syphilis-Cytomegalovirus
-Humanimmunodeficiencyvirus
-Enterovirusinfecons
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B.Maternaldiseasestates 6-8%
-Diabetes
-Phenylketonuria
-Endocrinopathies
C.Drugs&Chemicals 1%
-Alcohol -Folicacidantagonists-Androgens -Phenytoin
-Thalidomide -Warfarin
-13-cis-renoicacid -others
D.Irradiaons 1%
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MATERNALDIABETES
-maternalhyperglycemia-inducedfetalhyper-
insulinemiaresultsinincreasedbodyfat,muscle
mass,andorganomegaly>Fetalmacrosomia
-Diabe>cembryopathy-includecardiac
anomalies,neuraltubedefects,&othercns
malformaons
DRUGS & OTHER CHEMICALS
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DRUGS&OTHERCHEMICALS
ThalidomideatranquilizerformerlyusedinEuropecauseanextremelyhighfrequency
(50-80%)oflimbabnormaliesinexposedfetuses.
-mechanismofteratogenicityinvolvesdown-
regulaonofthedevelopmentallyimpor-tantwingless(WNT)signalingpathwaythroughupregulaonofendogenousWNTrepressors.
-nowusedasanneoplascagent,w/potentimmunomodulatory&an-angiogenicproperes.
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Alcoholprobablythemostwidelyusedteratogen,is
responsibleforseveralstructuralanomalies,as
wellasmoresubtlecognive&behavioraldefects
inthefetus,collecvelytermedFetalalcohol
spectrumdisorders(FASDs).
-mostseverelyaffectedinfantshavegrowth
retardaon,microcephaly,ASD,shortpalpebralfissures,&maxillaryhypoplasia labeledas
fetalalcoholsyndrome.
-experimentsinanimalssuggestprenatal exposure
disruptsatleast2seminal developmentalsignalingpathways:(1)renoicacid&(2)Hedgehog
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CigareVesmoke-derivednico>ne
-notyetconvincinglydemonstratedtobeateratogen,thereishighincidenceofspontaneousaborons,prematurelabor,andplacentalabnormaliesinpregnant
smokers -babiesborntosmokingmothersoen
havealowbirthweight&maybeproneto
SIDS -therefore,itisbesttoavoidnicone
exposureduringpregnancy
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RADIATION
-Inaddiontobeingmutagenic&
carcinogenic,radiaonisteratogenic.
-exposuretoheavydosesofradiaonduring
theperiodoforganogenesisleadto
malformaons,suchasmicrocephaly,
blindness,skulldefect,spinabifida,&other
deformies.
-usetooccurincasesofpregnantwomen
withcervicalcancertreatedwithradiaon
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MUTLIFACTORIAL
-20-25%
-ariseasaresultofinheritanceofmulplegenec
polymorphismsthatconferasuscepbilityphenotype.
Theinteraconofthisunderlyingphenotypewiththe
environmentisthenrequiredbeforethedisorderbecomesmanifest.
-ex:congenitalhipdislocaon-thereisashallowacetabular
socket&laxsupporngligamentsthataregenecally
determined,whereasfrankbreechposioninutero,w/
hipsflexed&kneesextendedisakeyenvironmental
factor.
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PATHOGENESISOFCONGENITAL
ANOMALIES
2GENERALPRINCIPLESOFDEVELOPMENTAL
PATHOLOGY
1. Themingoftheprenatalteratogenicinsulthasanimportantimpactontheoccurrence&the
typeofanomalyproduced(Fig.10-5)
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Theintrauterinedevelopmentofhumanscanbedividedintotwophases:
a.Embryonicperiodthe1st3wksaerferlizaon(earlyembryonicperiod),aninjuriousagentdamageseitherenoughcellstocausedeath&aboronoronlya
fewcells,presumablyallowingtheembryo torecoverw/odevelopingdefects.Between the3rd&9thwks,theembryoisextremel
suscepbletoteratogenesis,&thepeak
sensivityduringthisperiodoccurs betweenthe4th&5thwks.Duringthisme organsarebeingcraedoutofthegerm celllayers.
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b.Fetalperiodmarkedchieflybythe further
growthof&maturaonoftheorgans,withgreatlyreducedsuscepbility toteratogenic
agents.Instead,thefetusis suscepbleto
growthretardaonorinjury toalreadyformedorgans.
Itisthereforepossibleforagivenagenttoproducedifferentanomaliesifexposureoccursat
differentmesofgestaon.
2 The complex interplay between environmental
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2.Thecomplexinterplaybetweenenvironmentalteratogens&intrinsicgenecdefectsisunderscoredbythefactthatfeaturesof
dysmorphogenesiscausedbyenvironmentalinsultscanoenberecapitulatedbygenecdefectsinthepathwaystargetedbytheseteratogens.
-Ex:Cyclopamine-teratogenderivedfromtherootsofplantVeratumcalifonicum(Californialily)wheneatenbypregnantewesgivebirthto
lambsthathaveseverecranio-facialabnormaliesincludingholopro-sencephaly&cyclopia(singlefusedeye)duetomutaonofHedgehoggenes.
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DISORDERSOFPREMATURITY
Infantsbornbeforecompleonofhenormalgestaon
periodorwhohavefailedtogrownormallyduring
gestaonhavehighermorbidity&mortalityratesthan
full-terminfants.-aninfantweighing2300gm&bornat34wksAOGis
likelytobephysiologicallyimmature&thereforeat
greaterriskforsufferingtheconsequencesoforgan
systemimmaturitythanfullterminfantsalsoweighing2300gmbutwithcorrespondingfunconalmaturityof
mostorgansystems.
CLASSIFICATION OF INFANTS
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CLASSIFICATIONOFINFANTS
ACCORDINGTOBIRTHWEIGHT
-AppropriateforGestaonalAge(AGA)
-SmallforGestaonalAge(SGA)
-LargeforGestaonalAge(LGA)
*Infantswhosebirthweightsfallbetweenthe10th&
90thpercenlesforagivengestaonalageareconsideredAGA,thosewhofallaboveorbeloware
classifedasLGAorSGA,respecvely.
CLASSIFICATION OF INFANTS BASED
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CLASSIFICATIONOFINFANTSBASED
ONGESTATIONALAGE
-Preterm-bornbefore37weeks
-FullTermbornwithin37-42weeks
-Post-termbornaerthe42
nd
week
Suchclassificaonisusefulinriskstraficaon.
CAUSES OF PREMATURITY & FETAL
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CAUSESOFPREMATURITY&FETAL
GROWTHRESTRICTION
Prematurityisthe2ndmostcommoncauseof
neonatalmortality,behindcongenitalanomalies
-Majorriskfactors:
a.Pretermprematureruptureofplacental
membranes(PPROM)
-3%ofpregnancies
-30%ofpretermdeliveries
-spontaneousorinduced
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-pathophysiologyincludesinflammaonof placentalmembranes&enhanced
collagen degradaonbymatrix
metalloproteinases -fetal&maternaloutcomedependsonthe
gestaonageofthefetus,&effecve
prophylaxisofinfeconsinthe exposedamnioccavity.
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b.IntrauterineInfec>on
-majorcauseofpretermlaborwithorw/o
intactmembranes -presentinapproximately24%ofpreterm
births,&theearlierthegestaonalage thehigherthefrequencyofintra- amniocinfxn.
-chorioamnios/funisis
-microorganisms:Ureaplasmaurealycum,
Mycoplasmahominis,Gardnerella vaginalis(seeninbacterialvaginosis),Trichomonas,gonorrhea,&Chlamydia
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-Indevelopingcountries,malaria&HIV
aresignificantcausesofpreterm labor&prematurity
-itispostulatedthatsignalsproducedby
TLR-4(toll-likereceptors)deregulateprostaglandinexpression,w/cinturn
inducesuterinesmoothmuscle
contracons.
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c.Uterine,cervical,&placentalstructural
anomalies
-uterinedistoron(e.g.uterinefibroids)
-compromisedstructuralsupportofthe
cervix(cervicalincompetence)
-placentaprevia
-abrupoplacentae
d.Mulplegestaon(twinpregnancy)
H d f i f h N b
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HazardsofprematurityfortheNewborn
-Hyalinemembranedisease(Neonatalrespiratorydistresssyndrome)
-Necrozingenterocolis
-Sepsis-Intraventricularhemorrhage
-Long-termcomplicaons,includingdevelopmental
delay
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FetalGrowthRestric>on
-commonlyunderliesSGA
-alsocalledintrauterinegrowthretardaon
-canbedetectedbeforedeliverybyultraso-
graphicmeasurementofvariousfetal
dimensions,suchasbiparietaldiameter,
headcircumference,abdominal
circumference,femurlength,head-to-
abdominalcircumferencerao,femur
length-to-abdominalcircumferencerao, &
totalintrauterinevolume.
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3GroupsofInfluencesresul>ngtoFGR
1. Fetalinfluencesthatintrinsicallyreducegrowthpotenalofthefetusdespiteade-
quatesupplyofnutrientsfromthemother
-Chromosomaldisorders-triploidy(7%),
trisomy18(6%),trisomy21(1%),trisomy
13(1%),deleons/translocaon(2%)
-Congenitalanomalies
-Congenitalinfecons-Toxoplasmosis,
rubella,CMV,herpesvirus(TORCH)
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-InfantswhoareSGAbecauseoffetalfactorsare
usuallycharacterizedbysymmetricgrowth
restricon(alsoreferredtoaspropor>onate
FGR),meaningthatallorgansystemsaresimilarlyaffected.
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2.Placentaluteroplacentalsufficiencyorinsufficiencybecomesanextremelyimportant
influenceduringthethirdtrimesterduetothevigorousfetalgrowth
-insufficiencymayresultfrom:
-umbilical-placentalvascularanomalies suchassingleumbilicalartery, abnormal cordinseron,placental hemangioma
-placentalabrupon,placentaprevia, placentalthrombosis&infarcon, placental infecon,ormulple gestaons
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-PlacentalcausesofFGRtendtoresultinasymmetric(ordisproporonate)growth
retardaonofthefetuswithrelavesparingofthebrain.
-Physiologically,thistypeofFGRisviewedasadown-regulaonofgrowthinthelaerhalfofgestaonbecauseoflimitedavailabilityofnutrientsoroxygen.
-GenecmosaicismconfinedtotheplacentaisamorerecentlydiscoveredcauseofFGR(15%ofcasesofFGR)
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3.MaternalthemostcommonfactorsassociatedwithSGA
infantsarematernalcondionsthatresultindecreased
placentalbloodflow.-Vasculardiseases:preeclampsia(toxemiaof
pregnancy)&chronichypertension
-Inheritedthrombophilias:factorVLeidenmutaon
-Inheriteddiseaseofhypercoagulability
-Avoidablefactors:narcocabuse,alcoholintake,
heavycigareesmoking
-Maternalmalnutrion(prolongedhypoglycemia)
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TheSGAinfantfacesadifficultcourse,notonly
duringthestruggleforsurvivalintheperinatal
period,butalsoinchildhoodandadultlife.
DependingontheunderlyingcauseextentofFGR&,toalesserextent,thedegreeofprematurity,
thereisasignificantriskofmorbidityintheform
ofamajorhandicap,cerebraldysfuncon,
learningdisability,orhearingandvisual
impairment.
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NEONATALRESPIRATORYDISTRESSSYNDROME
(RDS)
CausesofRespiratoryDistressintheNB-excessivesedaonofthemother
-fetalheadinjuryduringdelivery
-aspiraonofbloodoramniocfluid-intrauterinehypoxiaduetocoilingofthe
umbilicalcordabouttheneck
-RDSorhyalinemembranediseaseisthemostcommon-thereisdeposionofa layerofhyalineproteinaceousmaterialin theperipheralairspaces
Cli i l P >
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ClinicalPresenta>on:
-infantalmostalwaysispreterm&AGA
-usuallyaffectthemalegender,thereis maternaldiabetes,anddeliveredbyCS
-resuscitaonmaybeneededatbirth,but
usuallyw/inafewminrhythmicbreathing&normalcolorarereestablished.Soon
aerward,oenw/in30min,breasthing
becomesmoredifficult,&w/inafewhourscyanosisbecomesevident.Fineralescan now
beheardonbothlungfields.
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-Chestx-rayfilmrevealsuniformminutereculogranulardensies,producingaso-
calledground-glasspicture.-Infull-blowncondiontherespiratory distresspersists,cyanosisincreases,&eventheadministraonof80%O2byavarietyofvenlatorymethodsfailsto improvethesituaon.
-Iftherapystavesoffdeathforthe1st3or4
days,however,theinfanthasanexcellentchanceofrecovery.
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E>ologyandPathogenesis:
-Immaturityofthelungsisthemostimportant substrate
onw/cRDSdevelops-incidenceofRDSisinverselyproporonal to
gestaonalage:occursabout60%ofinfants bornat
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Pulmonarysurfactant
-consistspredominantlyofdipalmitoyl
phosphadylcholine(lecithin),smalleramountsofphosphadylglycerol,&2groupsofsurfactant-associatedproteins.The1stgroupiscomposedofhydrophilicglyco-proteinsSP-A&SP-D,w/cplaya
roleinpulmonaryhostdefense(innateimmunity).The2ndgroupconsistsofhydrophobicsurfactantproteinsSP-B&SP-C,w/c,inconcertw/thesurfactantlipids,areinvolvedinthereduconofsurfacetensionattheair-liquidbarrierinthealveoliofthelung.
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-withreducedsurfacetensioninthealveoli, lesspressureisrequiredtokeepthempatent&hence
aerated-producedbytypeIIalveolarcells
-produconisnormallyacceleratedaerthe 35thwkofgestaoninthefetus
-deficiencyofsurfactant,thelungcollapsew/ eachsuccessivebreath,&soinfantsmust workashardw/eachsuccessivebreathas theydidw/the1st.
-progressiveatelectasis&reducedlungcomplianceleadtoatrainofeventsresulnginaprotein-rich,fibrin-richexudaonintothealveolarspacesw/formaonofhyalinemembranes
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-thehyalinemembranesconstutebarriers togas
exchange,leadingtoCO2 retenon&hypoxemia
-hypoxemiaitselffurtherimpairssurfactant synthesis&aviciouscycleensues
-synthesisismodulatedbyseveralhormones:
-glucocor>coidslowertheriskofdevRDS
-insulin-suppressessynthesisofsurfactant
-laborincreasesynthesisofsurfactant,hence, cesarean
seconbeforetheonsetoflabor mayincreasetherisk
ofRDS
Morphology
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Morphology
-lungsareofnormalsize,solid,airless,&reddishpurple,&usuallysinkinwater
-microscopically,alveoliarepoorlydeveloped,&thosethatarepresentarecollapsed.Whentheinfantdiesearlyinthecourseofthedisease,
necroccellulardebriscanbeseenintheterminalbronchioles&alveolarducts.Thenecrocmaterialsbecomeincorporatedw/ineosinophilichyalinemembranesliningthe
respiratorybronchioles,alveolarducts,&randomalveoli
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ClinicalCourse:
-clinicalcourse&prognosisvary,dependentonthe
maturity&birthweightoftheinfant&thepromptnessofinstuonoftherapy
-focusisonprevenon:
-bydelayinglaborunlfetallungreaches maturity
-inducingmaturaonofthelunginthefetus atrisk
-amniocfluidanalysistodeterminelungmaturaon
-prophylaccadministraonofsurfactanttoprematureinfants
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-cornerstoneoftreatmentisthedeliveryofsurfactant
replacementtherapy&oxygen.Ifuncomplicated
recoveryisw/in3-4days.
-Complicaonoftherapy-oxygentoxicitycausedby
oxygen-derivedfreeradicals
a.retrolentalfibroplasia(renopathyof
prematurity)
b.bronchopulmonarydysplasia
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InfantswhorecoverfromRDSareatincreasedrisk
fordevelopingothercomplicaonswithpreterm
birth;
-patentductusarteriosus
-intraventricularhemorrhage
-necrozingenterocolis
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NECROTIZINGENTEROCOLITIS
-Mostcommoninprematureinfants,w/incidence
beinginverselyproporonaltothegestaonalage
-occursinabout1of10verylowbirthweightinfants
(
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-nosinglebacterialinkedtodisease
-inflammatorymediatorsincludeplateletacvangfactor
(PAF),saidtoincreasemucosalpermeabilityby
promongenterocyteapoptosis&compromising
intercellularghtjuncons
-Clinicalcourse:
-onsetofbloodystools,abdominaldistenon,&developmentofcirculatorycollapse.
-abdominalx-rayshowgaswithinthe intesnalwall
(pneumatosisintesnalis) -ifdxearlycanbemanagedconservavely,butmany
cases(20-60%)requireresecon
Morphology:
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Morphology:
-typicallyinvolvestheterminalileum,cecum,
colon-segmentisdistended,friable,&congested,
orfranklygangrenous;perforaonswith
peritonismaybeseen-microscopically,theremaybemucosalor
transmuralcoagulavenecrosis,ulceraon,
bacterialcolonizaon,&submucosalgas
bubbles.Reparave changesmaybegin
shortlysuchas formaonofgranulaon
ssue&fibrosis.
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PERINATALINFECTIONS
Perinatalinfeconsareusuallyacquiredthrough
2primaryroutes:
1.transcervically(ascending)
2.transplacentally(hematologic)
TRANSCERICAL INFECTION
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TRANSCERICALINFECTION
-mostbacterial&fewviralinfecons
-maybeacquiredinuterooraroundthemeof
birth
-fetusingeneralareinfectedeitherbyinhaling
infectedamniocfluidintothelungsorby
passingthroughaninfectedbirthcanalduring
delivery
TRANSPLACENTAL INFECTION
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TRANSPLACENTALINFECTION
-mostparasic(toxoplasma,malaria)&viral
infecons&fewbacterialinfecons(Listeria,
Treponema)
-mayatanymeduringgestaon,occasionallyas
inhepB&HIV,atthemeofdeliveryvia
maternal-to-fetaltransfusion
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SEPSIS
Groupedclinicallybasedon:
1. Earlyonset(w/inthe1st7daysoflife)-mostlyacquiredatorshortlybeforebirth&
tendtoresultinclinicalsigns&symptoms ofpneumonia,sepsis,&occasionallymeningisw/in4or5daysoflife
-GroupBstreptococcusisthemostcommonorganismisolated&isthemostcommoncauseofbacterialmeningis
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FETAL HYDROPS
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FETALHYDROPS
-referstotheaccumulaonofedemafluidinthefetusduringintrauterinegrowth
-maybeImmunehydrops(asinHDN)orNonimmune
-intrauterinefluidaccumulaoncanbevariable,fromprogressivegeneralizededemaofthefetus(hydropsfetalis),ausuallylethalcondion,to
morelocalizeddegreesofedema,suchaspleural&peritonealeffusions,orcyschygroma,compablewithlife
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E>ology & Pathogenesis:
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E>ology&Pathogenesis:
-underlyingbasisisimmunizaonofthemotherby
bloodgroupangensonfetalredcells&thefreepassageofanbodiesfromthemotherthrough
theplacentatothefetus
-fetalredcellsmayreachthematernalcircula-onduringthelasttrimesterofpregnancy,whenthe
cytotrophoblastisnolongerpresentasabarrier,
orduringchildbirthitself
-onlytheDangenisamajorcauseofRh
incompabilityoftheRhsystem
FactorsthatinfluenceimmuneresponsetoRh+fetalred
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p
cellsthatreachthematernalcircula>on
-ConcurrentABOincompabilityprotectsthe mothervs
Rhimmunizaon,becausefetalred cellsare
promptlycoated&removedfromthe maternal
circulaonbyan-Aoran-BAbsthat donotcrossthe
placenta
-AbresponsedependsonthedoseofimmunizingAg;
hence,hemolycdiseasedevelopsonlywhenthe
motherhasexperiencedasignificanttransplacentalbleed(>1mlofRh+fetalredcells)
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-TheinialexposuretoRhAgevokesthe
formaonofIgMAbs,soRhdiseaseisuncommonw/the1stpregnancy.
Exposureduringasubsequent pregnancy
generallyleadstoabriskIgGAbresponse&theriskofimmune hydrops
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Pathogenesisofmaternal-fetalABOincom-pabilityisslightlydifferentfromthatofRhAg
-occursinapproximately20-25%ofpregnancies,butlaboratoryevidenceof HDoccursinonly1in10ofsuchinfants,& theHDissevereenoughtorequire treatmentinonly1in200cases
-factorsaccounngfortheabove:
1.mostan-A&an-BAbsareoftheIgm type&hencedonotcrossthe
placenta
2.neonatalredcellsexpressbloodgroup angens A and B poorl
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angensAandBpoorly
3.manycellsotherthanredcellsexpress
AandBangens&thusabsorb someofthetransferredanbody
-ABOHDoccursalmostexclusivelyininfantsofgroupAorBwhoarebornofgroupOmothers.Forunknownreasons,certaingroupOwomenpossessIgGAbsdirestedvsGroupAorBAgs(or
both)evenw/opriorsensizaon.Therefore,the1stbornmaybeaffected
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2 Consequences of Hemolysis in the neonate
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2ConsequencesofHemolysisintheneonate
1. ANEMIAdirectresultofredcellloss-ifmild-extramedullaryhematopoeisisinthespleen&
livermaysuffice
-ifsevereprogressiveanemiadevelops,&may
resultinhypoxicinjurytotheheart&liver.
-liverinjurywillleadtodecreaseinplasmaprotein
synthesissothatproteinsmaydroptolowlevelsof
2-2.5mg/dl.-cardiachypoxialeadtocardiacdecompensaon&
failure
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2.JAUNDICEdevelopsbecauseofhemolysis
producesunconjugatedbilirubin.Bilirubinalso
passesthroughtheinfantspoorlydeveloped
blood-brainbarrier.Beingwaterinsoluble,itbindstothelipidsinthebrain,resulngindamageto
theCNS,termedkernicterus.
NONIMMUNE HYDROPS
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NONIMMUNEHYDROPS
Table10-4SelectedCausesofNon-immune
FetalHydrops
-CARDIOVASCULARDEFECTS Malformaons;
Tachyarrhythmia;High outputfailure
-CHROMOSOMALANOMALIES
Turnersyndrome-duetoabnormaliesof
lymphacdrainage Trisomy21,Trisomy18(duetocardiac
structuralanomalies)
-FETALANEMIA
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Homozygousalpha-thalassemiamaybe themostcommoncauseof
nonimmunehydrops-THORACICCAUSES
CyscAdenoidmalformaon
Diaphragmachernia
-TWINGESTATION Twin-to-twintransfusion
-INFECTION
CMV,Syphilis,Toxoplasmosis
-TUMORS-GENETIC/METABOLICDISORDERS
-IDIOPATHIC(20%)
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Table 10 5 Abnormali>es Sugges>ng Inborn Errors
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Table10-5Abnormali>esSugges>ngInbornErrors
ofMetabolism
General-Dysmorphicfeatures;Deafness;Self-
mulaon;Abnormalhair;Abnormalbodyorurine
odor(sweatyfeet;mousyormusty;maplesyrup);Hepatosplenomegaly;Cardio-megaly;
Hydrops
NeurologicHypotoniaorhypertonia;coma;
persistentlethargy;seizures
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PHENYLKETONURIA (PKU)
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PHENYLKETONURIA(PKU)
-characterizedbyabnormaliesofphenlalanine
metabolism,resulnginhyperphenylalani-nemia
-autosomalrecessivecondion
-majorityiscausedbybi-allelicmutaonsofthegeneencodingtheenzymephenylalanine
hydroxylase(PAH)
-thedegreeofhyperphenylalaninemia&clinical
phenotypeisinverselyrelatedtotheamountof
residualenzymeacvity
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bi h i l b lit i i bilit t t
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-biochemicalabnormalityisaninabilitytoconvert
phenylalanineintotyrosineintheliverbythe
hepacPAHsystem,withtwoothercomponents:cofactortetrahydrobiopterin(BH4)&theenzyme
dihydropteridinereductase,w/cregeneratesBH4
-neonatalhyperphenylalaninemiacanbecausedbydeficiencesinanyofthesecomponents,but98%of
casesareduetoabnormaliesinPAH&therestto
abnormaliesinsynthesisorrecyclingofBH4
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b h f lif l d
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-by6monthsoflifeseveremental retardaon
becomesevident
-fewerthan4%ofuntreatedPKUchildren
haveIQvaluesgreaterthan50or60
-about1/3areneverabletowalk
-2/3cannottalk
-othersigns&symptomsincludeseizures,
otherneurologicabnormalies, decreased
pigmentaonofhair&skin,&eczema
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GALACTOSEMIA
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GALACTOSEMIA
-Autosomalrecessivedisorderofgalactosemetabolism
-normally,lactosefrommilkissplitintoglucoseand
galactoseintheintesnalmicrovillibylactase.Galactoseisthenconvertedtoglucoseinthree
steps:
Rxn1Galactose+ATP----Galactosekinase
Galactose-1-phosphate+ADP
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2variantsofGalactosemia:
1. Themorecommonvariantwithtotallackof
galactose-1-phosphateuridyltransferase(also
knownasGALT)involvedinreacon22. Therarevariantwithdeficiencyof
galactokinase,involvedinreacon1
lt f th t f l k l t 1
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-asaresultofthetransferaselack,galactose-1-
phosphateaccumulatesinmanylocaons,
includingtheliver,spleen,lensoftheeye,kidneys,heartmuscle,cerebralcortex,&
erythrocytes
-alternavemetabolicpathwaysareacvated,leadingtotheproduconofgalac>tol(apolyol
metaboliteofgalactose)andgalactonate,an
oxidizedby-productofexcessgalactose,bothofw/caccumulateinthessues.
Clinical picture is variable, the liver, eyes, and brain
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Clinicalpictureisvariable,theliver,eyes,andbrainbearthebruntofthedamage.
-early-to-develophepatomegalyisdue largelytofaychange,butlaterscarringsimilartocirrhosisofalcoholsupervenes
-opacificaonofthelens(cataract)develops,probablyduetowaterabsorponofthelensandswellsasgalactolaccumulates &
increasesitstonicity
-lossofnervecells,gliosis,&edemaare seeninthebrain,parcularlyinthe dentatenucleiofthecerebellum&the olivarynucleiofthemedulla
-infantsfailtothrivealmostfrombirth
i & di h /i f d f ild
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-voming&diarrheaappearw/inafewdaysofmildingeson
-jaundice&hepatomegalyevidentduringthe1stwkoflife
-cataractsdevelopw/inafewwks
-w/inthe1st6-12monthsoflifementalretardaonmaybedetected,butnotassevereasthatofseeninPKU
-aminoaciduria-increasedfrequencyoffulminantE.colisepcemia
-hemolysis&coagulopathycanoccur
DxofGalactosemia
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-canbesuspectedbydemonstraonofareducingsugarotherthanglucoseintheurine
-idenficaonofthedeficiencyoftransferaseinleukocytes&erythrocytes,morereliable
-assayofGALTacvityinculturedamniocfluid
cellsforantenataldiagnosis
-over140mutaonshavebeendocumented,glutamine-to-argininesubstuonatcodon188
(Gln188Arg)isthemostprevalentinnon-Hispanicwhites,whileaserine-to-leucinesubstuonatcodon135(Ser135Leu)ismostcommoninAfricanAmericans
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Tx:
-canbepreventedoramelioratedbyearlyremovalofgalactosefromthedietforatleastthe1st2yearsoflife
-controlinstutedsoonaerbirthprevents
cataracts&liverdamage&permitsalmostnormaldevelopment
-olderpaentsarefrequentlyaffectedbyspeech
disorder&gonadalfailure(prematureovarianfailure)&lesscommonly,byanataxiccondionevenwithdietaryrestricons
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-incidence of 1 in 2500 live births in Caucasian
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-incidenceof1in2500livebirthsinCaucasian
populaon,isthemostcommonlethalgenec
disease-carrierfrequencyinUSis1in20amongCaucasians
butlowerinAfricanAmericans,Asians,&
Hispanics-autosomalrecessivetransmission,but
heterozygotecarriershavehigherincidenceof
respiratory&pancreacdiseasesascomparedtothegeneralpopulaon
Cys>cFibrosis-AssociatedGene:NormalStructureand Func>on
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andFunc>on
-Theprimarydefectresultsfromabnormal
funconofanepithelialchloridechannelproteinencodedbythecyscfibrosistransmembraneconductanceregulator
(CFTR)geneonchromosome7q31.2-The1480-aminoacidpolypepdeencoded
byCFTRhas:2transmembranedomains(eachcontaining6alpha-helices)-these
formachannelthroughw/cchloridepasses;
:2 cytoplasmic nucleode binding domains
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:2cytoplasmicnucleode-bindingdomains
(NBDs)whereATPbinding&
hydrolysisoccurs&isessenalfortheopening&closingofthechannelpore in
responsetocAMP-mediated signaling
:aregulatorydomain(Rdomain)that containsproteinkinaseA&C
phosphorylaonsites
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AcvaonoftheCFTRchannelismediatedby
agonist-inducedincreasesincAMP,followedbyacvaonofaproteinkinaseAthat
phosphorylatestheRdomain.
SeveralimportantfacetsofCFTRfunconhave
emergedinrecentyears:
1. CFTRregulatesmulpleaddionalionchannels& ll l i il th h
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&cellularprocessprimarilythrough
interaconsinvolvingitsNBD.Theseinclude:
-outwardlyrecfiedchloridechannels
-inwardlyrecfiedK+channels
-epithelialNa+channel(ENaC)
-gapjunconchannels
-cellularprocessinvolvedinATPtransport&
mucussecreon
ENaC has possibly the most patho
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-ENaChaspossiblythemostpatho-
physiologicrelevanceincyscfibrosis
-situatedontheapicalsurfaceof
exocrineepithelialcells&is
responsibleforNa+uptakefromthe
luminalfluid,renderingithypotonic
-inhibitedbynormallyfunconingCFTR;
hence,incyscfibrosis,ENaCacvity
increases,markedlyaugmenngNa+ uptakeacrosstheapicalmembrane
(pulmonary&gastrointesnal)
-in human sweat ducts however ENaC
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-inhumansweatductshowever,ENaC
acvitydecreasesasaresultof
CFTRmutaons,therefore,a hypertonicluminalfluidcontaining
bothhigh sweatCl-&highNa+
contentisformedbasisforthe saltysweatthatmotherscanoen
detectintheiraffectedinfants.
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Class V: Reduced abundance these mutaons
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ClassV:Reducedabundance.thesemutaons
typicallyaffectintronicsplicesitesortheCFTR
promoter,suchthatthereisreducedamountof
normalprotein.Assow/milderphenotype
ClassVI:Alteredregula>onofseparateion
channels.MutaonsinthisclassaffecttheregulatoryroleofCFTRinregulaonofmulple
disnctcellularionchannels.
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Morphology:
-Pancreac abnormalies-85-90% present
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Pancreacabnormalies 85 90%present
-dilaonofsmallductstoatrophy&
progressivefibrosis-Smallbowelobstrucon-knownasmeconiumfetus
-Liver-pluggedcanaliculi,ductularproliferaon,
portalinflammaon,steatosis,focal biliarycirrhosis
-Salivaryglandschangessimilartothatofthe pancreas
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Clinical Features:
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ClinicalFeatures:
Table10-6ClinicalFeatures&DiagnoscCriteriafor
CyscFibrosis
1. Chronicsinopulmonarydiseasemanifestedbya.persistentcolonizaon/infeconw/typical
cyscfibrosispathogens,includingS. aureus,
nontypeableH.influenzae,mucoid &
nonmucoidP.aeruginosa,Burkholderia
b.chroniccough&sputumproducon
c persistent chest radiograph
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c.persistentchestradiograph
abnormalies(e.g.bronchiectasis,
atelectasis,infiltrates,hyperinflaon)
d.airwayobstruconmanifestedbywheezing&
airtrapping
e.nasalpolyps;radiographicorcomputed
tomographicabnormaliesofparanasal
sinuses
f.digitalclubbing
2 Gastrointesnal and nutrional
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2.Gastrointesnalandnutrionalabnormalies,including
a.Intesnal:meconiumileus,distalintesnalobstruconsyndrome,rectalprolapse
b.Pancreac:pancreacinsufficiency,
recurrentacutepancreas,chronicpancreas
c.Hepac:chronichepacdisease manifestedbyclinicalorhistologic evidenceoffocalbiliary
cirrhosis,or mullobularcirrhosis,prolongedneonatal jaundice
d Nutrional: failure to thrive (protein-calorie
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d.Nutrional:failuretothrive(protein-calorie
malnutrion),hypoproteinemia,edema,
complicaons2ndtofat-solublevitamin
deficiency
3.Salt-losssyndromes:acutesaltdepleon,chronic
metabolicalkalosis
4.Maleurogenitalabnormaliesresulngin
obstrucveazoospermia(congenitalbilateral
absenceofvasdeferens)
CRITERIAFORDIAGNOSISOFCF
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Oneormorecharacteriscphenotypicfeatures ORahistoryofcyscfibrosisinasibling
ORaposivenewbornscreeningtest result
ANDAnincreasedsweatchlorideconcentraonontwoormore
occasions
ORidenficaonof2CFmutaons
ORdemonstraonofabnormalepithelialnasal iontransport
SUDDENINFANTDEATHSYNDROME(SIDS)
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TheNaonalInstuteofChildHealth&HumanDevelopmentdefinesSIDSasthesuddendeath
ofaninfantunder1yearofagewhichremains
unexplainedaerthoroughcaseinvesgaon,includingperformanceofacompleteautopsy,
examinaonofthedeathscene,andreviewofthe
clinicalhistory.
Thus,SIDSisadiseaseofunknowncause.
Unclassifiedsuddeninfantdeathsuddendeath
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duringinfancywhereinevidenceofexcluding
alternavedxisequivocal,orapostermdxcannotbeperformed.
Infantsusuallydieswhileasleep,mostlyintheproneorsideposion,hencethepseudonymsofcrib
deathorcotdeath.
Epidemiology:
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Epidemiology:
-leadingcauseofdeathbetweenage1month &1yrinUS
-3rdleadingcauseofdeathoverallininfancy
-approx90%occurduringthe1st
6monthsoflife,mostbetweenages2&4months
-mostinfantsdieathome,usuallyduringthe
nightaeraperiodofsleep
Morphology:
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-nonspecificfindingssuchasmulplepetechiae,
pulmonaryvascularengorgementw/orw/opulmonaryedema;inthecns,astrogliosisofbrain
stem&cerebellum,andhypoplasiaofthearcuate
nucleus;extramedullaryhematopoiesis&periadrenalbrownfat
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Table10-7RiskFactors&PostmortemFindingsAssociatedwith SIDS
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withSIDS
PARENTAL
-Youngmaternalage(
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-Brainstemabnormalies,assow/delayed
developmentofarousal&cardio-respiratorycontrol
-Prematurity&/orlowbirthweight
-Malesex-productofamulplebirth
-SIDSinapriorsibling
-Antecedentrespiratoryinfecons-Germlinepolymorphismsinautonomic
nervoussystemgenes
ENVIRONMENT
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-Proneorsidesleepposion
-Sleepingonasosurface
-Hyperthermia
-Co-sleepingin1st3monthsoflife
POSTMORTEMABNORMALITIESDETECTEDINCASES
OF SUDDEN UNEXPECTED INFANT DEATH
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OFSUDDENUNEXPECTEDINFANTDEATH
-Infeconsviralmyocardis -bronchopneumonia
-Unsuspectedcongenitalanomaly
-congenitalaorcstenosis -anomalousoriginofthe(L)coronaryartery
fromthepulmonaryartery
-Traumacchildabuseintenonalsuffocaon (filicide)
-Genec&metabolicdefects
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-LongQTsyndrome(SCN5A&KCNQ1
mutaons)
-Fayacidoxidaondisorders(MCAD,
LCHAD,SCHADmutaons)
-Hisocytoidcardiomyopathy(MTCYB
mutaons)
-Abnormalinflammatoryresponsiveness
(paraldeleonsinC4a&C4b)
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SIDSisnottheonlycuaseofsuddenunexpected
deathininfancybutratherisadiagnosisof
exclusion.Therefore,performanceofan
autopsymayoenrevealfindingsthatwould
explainthecauseofsuddenunexpecteddeath.
TUMORS&TUMOR-LIKELESIONSOFINFANCY&CHILDHOOD
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-2%ofallmalignanttumorsoccurininfancy&childhood
-canceraccountsfor9%ofdeathsintheUS,
accidentscausemoredeaths-benigntumorsmorecommon,butcancause
seriouscomplicaonsbecauseoftheirlocaon
orrapidincreaseinsize
2specialcategoriesoftumor-likelesions
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1. Heterotopia(orchoristoma)isappliedtomicroscopicallynormalcellsorssuesthatarepresentinabnormallocaons
Ex:pancreacrestinthewallofstomachor
smallintesneorsmallmassof adrenalfoundinthekidney,lungs,or ovaries
-usuallyoflilesignificance,butcanbe confusedclinicallyw/neoplasmsor rarelymaybethesitesoforiginoftrueneoplasmse.g.adrenalCAinovary
2.Hamartomareferstoanexcessive,focalover-
th f ll & t th
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growthofcells&ssuesnavetotheorgan
inw/citoccurs.-althoughthecellularelementsaremature&
idencaltothosefoundintheremainderof
theorgan,theydonotreproducethenormalarchitectureofthesurroundingssue.
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LYMPHATICTUMORS
Lymphangiomas are hamartomatous or neo-plasc
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Lymphangiomas arehamartomatousorneo plasc
-characterizedbycysc&cavernousspaces
-occurinskinbutaremoreoenencounteredinthedeeperregionsoftheneck,axilla, mediasnum,retroperitonealssue
-tendtoincreaseinsizeaerbirth,duetoaccumulaonoffluid&buddingofpreexisngspaces,thereforemayencroachonvitalstructuressuchasthoseinthemediasnumornervetrunksin
theaxilla,&giverisetoclinicalproblems
Lymphangiectasisrepresentabnormaldilaonof
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preexisnglymphchannels.
-usuallypresentsasadiffuseswellingofpartorallofanextremityproducing considerable
distoron&deformaon
-lesionisnotprogressive,however,&doesnotextendbeyonditsoriginallocaon butcreates
cosmecproblems&difficult tocorrect
surgically
FIBROUSTUMORS
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-Rangefromsparselycellularproliferaonof
spindle-shapedcells(designatedasfibromatosis)torichlycellularlesionsindis-nguishablefromfibrosarcomaoccurringinadults(designatedascongenital-infan>lefibrosarcomas)
-Biologicbehaviorcannotbepredictedonhistologyalone;haveexcellentprognosiscomparedtoadultfibrosarcoma
-ETV6-NTRK3fusiontranscriptisausefuldiagnoscmarker
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2PeaksinIncidence:
1 At approximately 2 years of age are congenital
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1. Atapproximately2yearsofagearecongenitalneoplasms
2. Lateadolescenceorearlyadulthoodmayalsobeofprenataloriginbutaremoreslowlygrowing
SacrococcygealTeratomasmostcommonteratomasofchildhood(40%ormore)witha
frequencyof1in20,000-40,000livebirths,&fourmesmorecommoningirlsthanboys.
-about75%arematureteratomas
-12% unequivocally malignant & lethal
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-12%unequivocallymalignant&lethal
-about13%immatureteratomastheirmalig-nantpotenalcorrelateswiththeamountofimmature
ssue,usuallyneuroepithelialelements,present
-mostbenignteratomasareencounteredinyoungerinfants(
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Cancersofinfancy&childhooddifferbiologically&
histologicallyfromtheircounterpartsoccurringlaterinlife.Themaindifferencesare:
-Incidence&typeoftumor
-Relavelyfrequentdemonstraonofaclose
relaonshipbetweenabnormaldevelopment
(teratogenesis)&tumorinducon(oncogenesis)
-Prevalenceofunderlyingfamilialorgenec
aberraons
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-Tendencyoffetal&neonatalmalignanciesto
regressspontaneouslyorcytodifferenate
-Improvedsurvivalorcureofmanychildhood
tumors,sothatmoreaenonisnowbeing
devotedtominimizingtheadverse delayed
effectsofchemotherapy& radiaontherapy
insurvivors,includingthe developmentof
secondmalignancies.
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Themostcommonneoplasmsinchildren
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1. Leukemia(principallyALL)2. Neuroblastoma3. Wilmstumor4. Hepatoblastoma5. Renoblastoma6. Rhabdomyosarcoma7. Teratoma8. Ewingsarcoma
posterior fossa neoplasms
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-posteriorfossaneoplasms
9.Juvenileastrocytoma10.Medulloblastoma
11.Ependymoma
*Leukemiaaloneaccountsformoredeathsin
childrenyoungerthan15yrsthanallofthe
othertumorscombined.
Histologically,malignantnon-hematopoiec
pediatric neoplasms tend to have more primive
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pediatricneoplasmstendtohavemoreprimive
(embryonal)ratherthanpleomorphic-anaplascmicroscopicappearance,areoencharacterized
bysheetsofcellsw/small,roundnuclei,&
frequentlyshowfeaturesoforganogenesisspecific
tothesiteoftumororigin.
-becauseofthis,theyaredesignatedbythe
suffixblastoma,ex.Nephroblastoma,
hepatoblastoma,neuroblastoma
Because of their primive histologic
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Becauseoftheirprimivehistologic
appearance,manychildhoodtumorsarecollecvelyreferredtoassmallroundcelltumors.
Thedifferenaldiagnosisincludeneuroblastoma,
Wilmstumor,lymphoma,rhab-domyosarcoma,
Ewingsarcoma/primiveneuroectodermaltumor,
medulloblastoma,andrenoblastoma.
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Iftheanatomicsiteoforiginisknown,diagnosisis
usuallypossibleonhistologicgroundsalone.Occasionally,acombinaonofchromosomeanalysis,
immunoperoxidasestains,orelectronmicroscopyis
requiredfordefinivediagnosis.
THENEUROBLASTICTUMORS
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-thisincludestumorsofthesympathecganglia&adrenalmedullathatarederivedfromprimordialneuralcrestcellspopulangthesesites.
-asafamily,demonstratescertaincharacterisc
featuresincludingspontaneousortherapy-induceddifferenaonofprimiveneuroblastsintomatureelements,spontaneoustumorregression,&awiderangeofclinicalbehavior&
prognosis.
Neuroblastomamostimportantmemberofthefamily
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-mostcommonextracranialsolidtumorof
childhood,&mostfrequentlydiagnosedtumorofinfancy
-prevalenceisabout1in7000livebirths
-medianageatdxis18months-about40%ofcasesdiagnosedininfancy
-mostoccursporadically,but1-2%arefamilial
-germlinemutaonintheanaplas>clymphomakinase(ALK)genehasbeenidenfiedasamajorcauseoffamilialpredisposiontoneuroblastoma
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-neuropilw/careneuricprocesses appearaseosinophilicfibrillary materials
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materials
-Homer-WrightpseudoroseVescanbe foundinw/cthetumorcellsare concentricallyarrangedabouta centralspacefilledw/neuropil
-largercellshavingmoreabundant cytoplasm,largervesicularnuclei,&prominentnucleolus,represenng
ganglioncellsinvariousstagesof maturaon,maybefoundw/primiveneuroblasts(ganglioneuro-blastoma)
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-blueberrymuffinbabymulplecutaneous
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y y pmetastasesthatcausedeepbluediscoloraonof
theskin
-90%ofneuroblastomas,regardlessoflocaonproducecatecholaminesw/careanimportant
diagnoscfeature(i.e.,elevatedbloodlevelsofcatecholamines&elevatedurinelevelsofthemetabolitesvanillylmandelicacid(VMA)&homovanillicacid(HVA)buthypertensionis
muchlessfrequentthanw/pheochromocytomas
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Pathogenesis&Gene>cs:
TheriskofWilmstumorisincreasedinassow/atleast4
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recognizablegroupsofcongenitalmalformaonsassow/
disnctchromosomalloci:
I.WAGRsyndrome,characterizedbyaniridia,genital
anomalies,&mentalretardaon&a33%chanceof
developingWilmstumor.-ptw/thissyndromecarryconstuonal(germline)
deleonsof11p13.
-Wilmstumor-assogeneWT1&aconguously deleted
autosomalgeneforaniridia,PAX6located on
chromosome11p13
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-WT1encodesaDNA-bindingtranscriponf
actor that is expressed w/in several
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actorthatisexpressedw/inseveral
ssues,includingthekidney&gonads,duringembryogenesis
-WT1proteiniscricalfornormalrenal&
gonadaldevevlopment
III.Beckwith-Wiedemansyndrome(BWS),
characterizedbyenlargementofbodyorgans
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y g y g
(organomegaly),macroglosia,hemihyper-trophy,omphalocele,&abnormallargecellsinthe
adrenalcortex.
-chromosomalregionhasbeenlocalizedtoband
11p15.5(WT2),distaltotheWT1locus
-imprinngabnormaliesofIGF2havethe
strongestrelaonshiptotumorpredisposion
-alsoatincreasedriskfordeveloping
hepatoblastoma,pancreatoblastoma,adreno-
corcaltumors,&rhabdomyosarcomas.
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-itisimportanttodocumentthepresenceof
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p p
nephrogenicrestsintheresectedspecimen,sincethepaentsareatanincreasedriskof
developingWilmstumorofthecontralateral
kidney&requirefrequent®ularsurveillance
formanyyears.
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Anaplasia,inapprox5%,definedaspresenceof
cells w/ large hyperchromac pleomorphic
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cellsw/large,hyperchromac,pleomorphic
nuclei&abnormalmitoses-correlatesw/thepresnceofp53mutaons&
theemergenceofresistancetochemotherapy
(p53elicitspro-apoptocsignalsinresponsetoDNAdamage)
ClinicalFeatures:
-most children present w/ a large abdominal mass
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mostchildrenpresentw/alargeabdominalmass
thatmaybeunilateralor,whenverylarge,mayextendacrossthemidline&downintothepelvis
-hematuria,painintheabdomen,intesnalobstrucon,&appearanceofhypertension
-pulmonarymetastasesmaybepresentatthemeofprimarydiagnosis
-mostpaentscanexpecttobecured
-anaplaschistologyremainsacricaldeterminantofadverseprognosis
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