dr. domingo - diseas of infancy

7/29/2019 Dr. Domingo - Diseas of Infancy

1/178

DISEASESOFINFANCYANDCHILDHOOD

ALEJANDROL.DOMINGOJR.,MD.,FPSP,APCP


2/178

Childrenarenotmerelylileadults,andtheir

diseasesarenotmerelyvariantsofadultdiseases.

Manychildhoodcondionsareuniqueto,oratleasttakedisncveformsin,thisstageof

life.


3/178

InfantmortalityrateintheUShasshownadecline

fromalevelof20deaths/1000livebirthsin1970

toabout6.8deathsin2004.Althoughthedeathratehasconnuedtodecline

forallinfants,AfricanAmericansconnuetohave

arateofmorethantwice(13.6deaths/1000livebirths).

Infantmortalityratesvarywidely,worldwide,from

aslowas2.3deaths/1000livebirthsinSingaporetoashighas180deathsintheAfrican

subconnent.


4/178

Eachstageofdevelopmentofinfantandchildis

preytoasomewhatdifferentgroupofdisorders:

1. Neonatalperiod(1st4wksoflife)2. Infancy(1styearoflife)3. Age1-4years4. Age5-14years


5/178

TABLE10-1CAUSEOFDEATHRELATED

WITHAGE(2004)

UNDER1YEAR 685.2

-Congenitalmalformaons,deformaons,andchromosomalabnormalies

-Disordersrelatedtoshortgestaon&lowbirth

weight-Suddeninfantdeathsyndrome(SIDS)

-Newbornaffectedbymaternalcomplicaonsof

pregnancy


6/178

-Newbornaffectedbycomplicaonsofplacenta,

cord,andmembranes

-Respiratorydistressofnewborn

-Accidents(unintenonalinjuries)

-BacterialSepsisofnewborn

-Intrauterinehypoxiaandbirthasphyxia

-Diseasesofthecirculatorysystem


7/178

1-4YEARS 29.9

-Accidents&adverseeffects

-Congenitalmalformaons,deformaons,and

chromosomalabnormalies

-Malignantneoplasms

-Homicide&legalintervenon

-Diseasesoftheheart-Influenza&pneumonia


8/178

5-14YEARS 16.8


-Malignantneoplasms

-Homicide&legalintervenon-Congenitalmalformaons,deformaons,and

chromosomalabnormalies

-Suicide-Diseasesoftheheart


9/178

15-24years 80.1


-Homicide-Suicide

-Malignantneoplasms

-Diseasesoftheheart


10/178

CONGENITALANOMALLIES

-aremorphologicdefectsthatarepresentatbirth,butsome,suchascardiacdefects&renalanomalies,maynotbecomeclinicallyapparentunlyearslater.

-congenitalmeansbornwith,butdoesnotimplyorexcludeagenecbasisforbirthdefect.

-120,000(1in33)babiesintheUShavecongenital

defectseachyear-mostcommoncauseofmorbidityinthe1styearof

&contributesignificantlytomorbidity&mortalitythroughouttheearlyyearsoflife.


11/178

Defini>onsoftermsusedforvariouskindsof

errorsinmorphogenesis

MALFORMATIONSrepresentsprimaryerrorsof

morphogenesis,inw/cthereisanintrinsically

abnormaldevelopmentalprocess.-usuallyassociatedwithmulplegenecloci

(mulfactorial)&nottheresultofasinglegeneor

chromosomaldefect.-ex:polydactyly,syndactyly,clelipwithorw/o

clepalate


12/178

DISRUPTIONSresultfromsecondarydes-trucon

ofanorganorbodyregionthatwaspreviously

normalindevelopment;thus,incontrastto

malformaons,disruponsarisefromanextrinsic

disturbanceinmorphogenesis

-notheritable&hencenotassociatedwithriskof

recurrenceinsubsequentpregnancies

-ex:Amniocbands


13/178

DEFORMATIONS-alsorepresentanextrinsic

disturbanceofdevelopmentratherthanan

intrinsicerrorofmorphogenesis.

-affectsabout2%ofNBtovaryingdegrees

-fundamentaltothepathogenesisofdeformaon

islocalizedorgeneralizedcompressionofthe

growingfetusbyabnormalbiomechanicalforces,

leadingeventuallytoavarietyofstructural

abnormalies.-mostcommonunderlyingfactorresponsiblefor

deformaonisuterineconstraint.


14/178

-Betweenthe35th&38thweeksofgestaon,rapidincreaseinthesizeofthefetusoutpaces

thegrowthoftheuterus,&therelaveamountofamniocfluid(w/cnormallyactsasacushion)alsodecreases.

-factorsthatincreasethelikelihoodofexcessivecompressionofthefetus:maternalfactorsinclude1stpregnancy,smalluterus,malformed(bicornuate)uterus,&leiomyomas.Fetalor

Placentalfactorsincludeoligohydramnios,mulplefetuses,&abnormalfetalpresentaon.

-ex:Clubfeet


15/178

SEQUENCEisacascadeofanomaliestriggeredby

oneiniangaberraon.

-abouthalftheme,congenitalanomaliesoccur

singly;intheremainingcases,mulplecongenital

anomaliesmaybeexplainedbyasingle,localized

aberraoninorganogenesis(malformaon,

disrupon,ordeformaon)thatsetsintomoon

secondaryeffectsinotherorgans.

-Ex:oligohydramnios(orPoer)sequence


16/178

-Oligohydramnios(decreasedamniocfluid)

maybecausedbyavarietyofunrelated

maternal(utero-placentalinsufficiency),

placental(amniocleak),fetal(renalagenesis)

abnormaliesproducingfetalcompression

resulnginflaenedfacies,posionalabnormaliesofthehands&feet,hip

dislocaon,compromisedgrowthofthechest

wall&thusproducinghypoplasclungsw/cmaybethecauseoffetaldemise.


17/178

SYNDROMEisaconstellaonofcongenital

anomalies,believedtobepathologicallyrelated,

that,incontrasttoasequence,cannotbeexplainedonthebasisofasingle,localized,

iniangdefect.

-mostoencausedbyasingleeologicagent,suchasaviralinfeconorspecificchromosomal

abnormality,w/csimultaneouslyaffectsseveral

ssues.


18/178

AGENESISreferstothecompleteabsenceofan

organanditsassociatedprimordium.

APLASIAreferstotheabsenceofanorganbutone

duetofailureofdevelopmentoftheprimordium.

ATRESIAdescribestheabsenceofanopening,

usuallyofhollowvisceralorgan,suchasthetrachea&intesne


19/178

HYPOPLASIAreferstoincompletedevelop-ment

ordecreasedsizeofanorganw/decreasednumbersofcells.

HYPERPLASIAreferstotheenlargementofanorganduetoincreasednumbersofcells.

HYPERTROPHYanabnormalityinanorganorassueasaresultofanincreaseinthesizeof

individualcells.


20/178

HYPOTROPHYanabnormalityinanorganor

ssueasaresultofadecreaseinthesizeof

individualcells.

DYSPLASIAinthecontextofmalformaonsdescribesanabnormalorganizaonofcells.


21/178

CAUSESOFANOMALIES

A. GenecB. EnvironmentalC.

Mulfactorial

D. Unknown(40-60%)


22/178

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.


23/178

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).


24/178

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


25/178

B.Maternaldiseasestates 6-8%

-Diabetes

-Phenylketonuria

-Endocrinopathies

C.Drugs&Chemicals 1%

-Alcohol -Folicacidantagonists-Androgens -Phenytoin

-Thalidomide -Warfarin

-13-cis-renoicacid -others

D.Irradiaons 1%


26/178

MATERNALDIABETES

-maternalhyperglycemia-inducedfetalhyper-

insulinemiaresultsinincreasedbodyfat,muscle

mass,andorganomegaly>Fetalmacrosomia

-Diabe>cembryopathy-includecardiac

anomalies,neuraltubedefects,&othercns

malformaons

DRUGS & OTHER CHEMICALS


27/178

DRUGS&OTHERCHEMICALS

ThalidomideatranquilizerformerlyusedinEuropecauseanextremelyhighfrequency

(50-80%)oflimbabnormaliesinexposedfetuses.

-mechanismofteratogenicityinvolvesdown-

regulaonofthedevelopmentallyimpor-tantwingless(WNT)signalingpathwaythroughupregulaonofendogenousWNTrepressors.

-nowusedasanneoplascagent,w/potentimmunomodulatory&an-angiogenicproperes.


28/178

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


29/178

CigareVesmoke-derivednico>ne

-notyetconvincinglydemonstratedtobeateratogen,thereishighincidenceofspontaneousaborons,prematurelabor,andplacentalabnormaliesinpregnant

smokers -babiesborntosmokingmothersoen

havealowbirthweight&maybeproneto

SIDS -therefore,itisbesttoavoidnicone

exposureduringpregnancy


30/178

RADIATION

-Inaddiontobeingmutagenic&

carcinogenic,radiaonisteratogenic.

-exposuretoheavydosesofradiaonduring

theperiodoforganogenesisleadto

malformaons,suchasmicrocephaly,

blindness,skulldefect,spinabifida,&other

deformies.

-usetooccurincasesofpregnantwomen

withcervicalcancertreatedwithradiaon


31/178

MUTLIFACTORIAL

-20-25%

-ariseasaresultofinheritanceofmulplegenec

polymorphismsthatconferasuscepbilityphenotype.

Theinteraconofthisunderlyingphenotypewiththe

environmentisthenrequiredbeforethedisorderbecomesmanifest.

-ex:congenitalhipdislocaon-thereisashallowacetabular

socket&laxsupporngligamentsthataregenecally

determined,whereasfrankbreechposioninutero,w/

hipsflexed&kneesextendedisakeyenvironmental

factor.


32/178

PATHOGENESISOFCONGENITAL

ANOMALIES

2GENERALPRINCIPLESOFDEVELOPMENTAL

PATHOLOGY

1. Themingoftheprenatalteratogenicinsulthasanimportantimpactontheoccurrence&the

typeofanomalyproduced(Fig.10-5)


33/178

Theintrauterinedevelopmentofhumanscanbedividedintotwophases:

a.Embryonicperiodthe1st3wksaerferlizaon(earlyembryonicperiod),aninjuriousagentdamageseitherenoughcellstocausedeath&aboronoronlya

fewcells,presumablyallowingtheembryo torecoverw/odevelopingdefects.Between the3rd&9thwks,theembryoisextremel

suscepbletoteratogenesis,&thepeak

sensivityduringthisperiodoccurs betweenthe4th&5thwks.Duringthisme organsarebeingcraedoutofthegerm celllayers.


34/178

b.Fetalperiodmarkedchieflybythe further

growthof&maturaonoftheorgans,withgreatlyreducedsuscepbility toteratogenic

agents.Instead,thefetusis suscepbleto

growthretardaonorinjury toalreadyformedorgans.

Itisthereforepossibleforagivenagenttoproducedifferentanomaliesifexposureoccursat

differentmesofgestaon.

2 The complex interplay between environmental


35/178

2.Thecomplexinterplaybetweenenvironmentalteratogens&intrinsicgenecdefectsisunderscoredbythefactthatfeaturesof

dysmorphogenesiscausedbyenvironmentalinsultscanoenberecapitulatedbygenecdefectsinthepathwaystargetedbytheseteratogens.

-Ex:Cyclopamine-teratogenderivedfromtherootsofplantVeratumcalifonicum(Californialily)wheneatenbypregnantewesgivebirthto

lambsthathaveseverecranio-facialabnormaliesincludingholopro-sencephaly&cyclopia(singlefusedeye)duetomutaonofHedgehoggenes.


36/178

DISORDERSOFPREMATURITY

Infantsbornbeforecompleonofhenormalgestaon

periodorwhohavefailedtogrownormallyduring

gestaonhavehighermorbidity&mortalityratesthan

full-terminfants.-aninfantweighing2300gm&bornat34wksAOGis

likelytobephysiologicallyimmature&thereforeat

greaterriskforsufferingtheconsequencesoforgan

systemimmaturitythanfullterminfantsalsoweighing2300gmbutwithcorrespondingfunconalmaturityof

mostorgansystems.

CLASSIFICATION OF INFANTS


37/178

CLASSIFICATIONOFINFANTS

ACCORDINGTOBIRTHWEIGHT

-AppropriateforGestaonalAge(AGA)

-SmallforGestaonalAge(SGA)

-LargeforGestaonalAge(LGA)

*Infantswhosebirthweightsfallbetweenthe10th&

90thpercenlesforagivengestaonalageareconsideredAGA,thosewhofallaboveorbeloware

classifedasLGAorSGA,respecvely.

CLASSIFICATION OF INFANTS BASED


38/178

CLASSIFICATIONOFINFANTSBASED

ONGESTATIONALAGE

-Preterm-bornbefore37weeks

-FullTermbornwithin37-42weeks

-Post-termbornaerthe42

nd

week

Suchclassificaonisusefulinriskstraficaon.

CAUSES OF PREMATURITY & FETAL


39/178

CAUSESOFPREMATURITY&FETAL

GROWTHRESTRICTION

Prematurityisthe2ndmostcommoncauseof

neonatalmortality,behindcongenitalanomalies

-Majorriskfactors:

a.Pretermprematureruptureofplacental

membranes(PPROM)

-3%ofpregnancies

-30%ofpretermdeliveries

-spontaneousorinduced


40/178

-pathophysiologyincludesinflammaonof placentalmembranes&enhanced

collagen degradaonbymatrix

metalloproteinases -fetal&maternaloutcomedependsonthe

gestaonageofthefetus,&effecve

prophylaxisofinfeconsinthe exposedamnioccavity.


41/178

b.IntrauterineInfec>on

-majorcauseofpretermlaborwithorw/o

intactmembranes -presentinapproximately24%ofpreterm

births,&theearlierthegestaonalage thehigherthefrequencyofintra- amniocinfxn.

-chorioamnios/funisis

-microorganisms:Ureaplasmaurealycum,

Mycoplasmahominis,Gardnerella vaginalis(seeninbacterialvaginosis),Trichomonas,gonorrhea,&Chlamydia


42/178

-Indevelopingcountries,malaria&HIV

aresignificantcausesofpreterm labor&prematurity

-itispostulatedthatsignalsproducedby

TLR-4(toll-likereceptors)deregulateprostaglandinexpression,w/cinturn

inducesuterinesmoothmuscle

contracons.


43/178

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


44/178

HazardsofprematurityfortheNewborn

-Hyalinemembranedisease(Neonatalrespiratorydistresssyndrome)

-Necrozingenterocolis

-Sepsis-Intraventricularhemorrhage

-Long-termcomplicaons,includingdevelopmental

delay


45/178

FetalGrowthRestric>on

-commonlyunderliesSGA

-alsocalledintrauterinegrowthretardaon

-canbedetectedbeforedeliverybyultraso-

graphicmeasurementofvariousfetal

dimensions,suchasbiparietaldiameter,

headcircumference,abdominal

circumference,femurlength,head-to-

abdominalcircumferencerao,femur

length-to-abdominalcircumferencerao, &

totalintrauterinevolume.


46/178

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)


47/178

-InfantswhoareSGAbecauseoffetalfactorsare

usuallycharacterizedbysymmetricgrowth

restricon(alsoreferredtoaspropor>onate

FGR),meaningthatallorgansystemsaresimilarlyaffected.


48/178

2.Placentaluteroplacentalsufficiencyorinsufficiencybecomesanextremelyimportant

influenceduringthethirdtrimesterduetothevigorousfetalgrowth

-insufficiencymayresultfrom:

-umbilical-placentalvascularanomalies suchassingleumbilicalartery, abnormal cordinseron,placental hemangioma

-placentalabrupon,placentaprevia, placentalthrombosis&infarcon, placental infecon,ormulple gestaons


49/178

-PlacentalcausesofFGRtendtoresultinasymmetric(ordisproporonate)growth

retardaonofthefetuswithrelavesparingofthebrain.

-Physiologically,thistypeofFGRisviewedasadown-regulaonofgrowthinthelaerhalfofgestaonbecauseoflimitedavailabilityofnutrientsoroxygen.

-GenecmosaicismconfinedtotheplacentaisamorerecentlydiscoveredcauseofFGR(15%ofcasesofFGR)


50/178

3.MaternalthemostcommonfactorsassociatedwithSGA

infantsarematernalcondionsthatresultindecreased

placentalbloodflow.-Vasculardiseases:preeclampsia(toxemiaof

pregnancy)&chronichypertension

-Inheritedthrombophilias:factorVLeidenmutaon

-Inheriteddiseaseofhypercoagulability

-Avoidablefactors:narcocabuse,alcoholintake,

heavycigareesmoking

-Maternalmalnutrion(prolongedhypoglycemia)


51/178

TheSGAinfantfacesadifficultcourse,notonly

duringthestruggleforsurvivalintheperinatal

period,butalsoinchildhoodandadultlife.

DependingontheunderlyingcauseextentofFGR&,toalesserextent,thedegreeofprematurity,

thereisasignificantriskofmorbidityintheform

ofamajorhandicap,cerebraldysfuncon,

learningdisability,orhearingandvisual

impairment.


52/178

NEONATALRESPIRATORYDISTRESSSYNDROME

(RDS)

CausesofRespiratoryDistressintheNB-excessivesedaonofthemother

-fetalheadinjuryduringdelivery

-aspiraonofbloodoramniocfluid-intrauterinehypoxiaduetocoilingofthe

umbilicalcordabouttheneck

-RDSorhyalinemembranediseaseisthemostcommon-thereisdeposionofa layerofhyalineproteinaceousmaterialin theperipheralairspaces

Cli i l P >


53/178

ClinicalPresenta>on:

-infantalmostalwaysispreterm&AGA

-usuallyaffectthemalegender,thereis maternaldiabetes,anddeliveredbyCS

-resuscitaonmaybeneededatbirth,but

usuallyw/inafewminrhythmicbreathing&normalcolorarereestablished.Soon

aerward,oenw/in30min,breasthing

becomesmoredifficult,&w/inafewhourscyanosisbecomesevident.Fineralescan now

beheardonbothlungfields.


54/178

-Chestx-rayfilmrevealsuniformminutereculogranulardensies,producingaso-

calledground-glasspicture.-Infull-blowncondiontherespiratory distresspersists,cyanosisincreases,&eventheadministraonof80%O2byavarietyofvenlatorymethodsfailsto improvethesituaon.

-Iftherapystavesoffdeathforthe1st3or4

days,however,theinfanthasanexcellentchanceofrecovery.


55/178

E>ologyandPathogenesis:

-Immaturityofthelungsisthemostimportant substrate

onw/cRDSdevelops-incidenceofRDSisinverselyproporonal to

gestaonalage:occursabout60%ofinfants bornat


56/178

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.


57/178

-withreducedsurfacetensioninthealveoli, lesspressureisrequiredtokeepthempatent&hence

aerated-producedbytypeIIalveolarcells

-produconisnormallyacceleratedaerthe 35thwkofgestaoninthefetus

-deficiencyofsurfactant,thelungcollapsew/ eachsuccessivebreath,&soinfantsmust workashardw/eachsuccessivebreathas theydidw/the1st.

-progressiveatelectasis&reducedlungcomplianceleadtoatrainofeventsresulnginaprotein-rich,fibrin-richexudaonintothealveolarspacesw/formaonofhyalinemembranes


58/178

-thehyalinemembranesconstutebarriers togas

exchange,leadingtoCO2 retenon&hypoxemia

-hypoxemiaitselffurtherimpairssurfactant synthesis&aviciouscycleensues

-synthesisismodulatedbyseveralhormones:

-glucocor>coidslowertheriskofdevRDS

-insulin-suppressessynthesisofsurfactant

-laborincreasesynthesisofsurfactant,hence, cesarean

seconbeforetheonsetoflabor mayincreasetherisk

ofRDS

Morphology


59/178

Morphology

-lungsareofnormalsize,solid,airless,&reddishpurple,&usuallysinkinwater

-microscopically,alveoliarepoorlydeveloped,&thosethatarepresentarecollapsed.Whentheinfantdiesearlyinthecourseofthedisease,

necroccellulardebriscanbeseenintheterminalbronchioles&alveolarducts.Thenecrocmaterialsbecomeincorporatedw/ineosinophilichyalinemembranesliningthe

respiratorybronchioles,alveolarducts,&randomalveoli


60/178

ClinicalCourse:

-clinicalcourse&prognosisvary,dependentonthe

maturity&birthweightoftheinfant&thepromptnessofinstuonoftherapy

-focusisonprevenon:

-bydelayinglaborunlfetallungreaches maturity

-inducingmaturaonofthelunginthefetus atrisk

-amniocfluidanalysistodeterminelungmaturaon

-prophylaccadministraonofsurfactanttoprematureinfants


61/178

-cornerstoneoftreatmentisthedeliveryofsurfactant

replacementtherapy&oxygen.Ifuncomplicated

recoveryisw/in3-4days.

-Complicaonoftherapy-oxygentoxicitycausedby

oxygen-derivedfreeradicals

a.retrolentalfibroplasia(renopathyof

prematurity)

b.bronchopulmonarydysplasia


62/178

InfantswhorecoverfromRDSareatincreasedrisk

fordevelopingothercomplicaonswithpreterm

birth;

-patentductusarteriosus

-intraventricularhemorrhage

-necrozingenterocolis


63/178

NECROTIZINGENTEROCOLITIS

-Mostcommoninprematureinfants,w/incidence

beinginverselyproporonaltothegestaonalage

-occursinabout1of10verylowbirthweightinfants

(


64/178

-nosinglebacterialinkedtodisease

-inflammatorymediatorsincludeplateletacvangfactor

(PAF),saidtoincreasemucosalpermeabilityby

promongenterocyteapoptosis&compromising

intercellularghtjuncons

-Clinicalcourse:

-onsetofbloodystools,abdominaldistenon,&developmentofcirculatorycollapse.

-abdominalx-rayshowgaswithinthe intesnalwall

(pneumatosisintesnalis) -ifdxearlycanbemanagedconservavely,butmany

cases(20-60%)requireresecon

Morphology:


65/178

Morphology:

-typicallyinvolvestheterminalileum,cecum,

colon-segmentisdistended,friable,&congested,

orfranklygangrenous;perforaonswith

peritonismaybeseen-microscopically,theremaybemucosalor

transmuralcoagulavenecrosis,ulceraon,

bacterialcolonizaon,&submucosalgas

bubbles.Reparave changesmaybegin

shortlysuchas formaonofgranulaon

ssue&fibrosis.


66/178

PERINATALINFECTIONS

Perinatalinfeconsareusuallyacquiredthrough

2primaryroutes:

1.transcervically(ascending)

2.transplacentally(hematologic)

TRANSCERICAL INFECTION


67/178

TRANSCERICALINFECTION

-mostbacterial&fewviralinfecons

-maybeacquiredinuterooraroundthemeof

birth

-fetusingeneralareinfectedeitherbyinhaling

infectedamniocfluidintothelungsorby

passingthroughaninfectedbirthcanalduring

delivery

TRANSPLACENTAL INFECTION


68/178

TRANSPLACENTALINFECTION

-mostparasic(toxoplasma,malaria)&viral

infecons&fewbacterialinfecons(Listeria,

Treponema)

-mayatanymeduringgestaon,occasionallyas

inhepB&HIV,atthemeofdeliveryvia

maternal-to-fetaltransfusion


69/178

SEPSIS

Groupedclinicallybasedon:

1. Earlyonset(w/inthe1st7daysoflife)-mostlyacquiredatorshortlybeforebirth&

tendtoresultinclinicalsigns&symptoms ofpneumonia,sepsis,&occasionallymeningisw/in4or5daysoflife

-GroupBstreptococcusisthemostcommonorganismisolated&isthemostcommoncauseofbacterialmeningis


70/178

FETAL HYDROPS


71/178

FETALHYDROPS

-referstotheaccumulaonofedemafluidinthefetusduringintrauterinegrowth

-maybeImmunehydrops(asinHDN)orNonimmune

-intrauterinefluidaccumulaoncanbevariable,fromprogressivegeneralizededemaofthefetus(hydropsfetalis),ausuallylethalcondion,to

morelocalizeddegreesofedema,suchaspleural&peritonealeffusions,orcyschygroma,compablewithlife


72/178

E>ology & Pathogenesis:


73/178

E>ology&Pathogenesis:

-underlyingbasisisimmunizaonofthemotherby

bloodgroupangensonfetalredcells&thefreepassageofanbodiesfromthemotherthrough

theplacentatothefetus

-fetalredcellsmayreachthematernalcircula-onduringthelasttrimesterofpregnancy,whenthe

cytotrophoblastisnolongerpresentasabarrier,

orduringchildbirthitself

-onlytheDangenisamajorcauseofRh

incompabilityoftheRhsystem

FactorsthatinfluenceimmuneresponsetoRh+fetalred


74/178

p

cellsthatreachthematernalcircula>on

-ConcurrentABOincompabilityprotectsthe mothervs

Rhimmunizaon,becausefetalred cellsare

promptlycoated&removedfromthe maternal

circulaonbyan-Aoran-BAbsthat donotcrossthe

placenta

-AbresponsedependsonthedoseofimmunizingAg;

hence,hemolycdiseasedevelopsonlywhenthe

motherhasexperiencedasignificanttransplacentalbleed(>1mlofRh+fetalredcells)


75/178

-TheinialexposuretoRhAgevokesthe

formaonofIgMAbs,soRhdiseaseisuncommonw/the1stpregnancy.

Exposureduringasubsequent pregnancy

generallyleadstoabriskIgGAbresponse&theriskofimmune hydrops


76/178


77/178

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


78/178

angensAandBpoorly

3.manycellsotherthanredcellsexpress

AandBangens&thusabsorb someofthetransferredanbody

-ABOHDoccursalmostexclusivelyininfantsofgroupAorBwhoarebornofgroupOmothers.Forunknownreasons,certaingroupOwomenpossessIgGAbsdirestedvsGroupAorBAgs(or

both)evenw/opriorsensizaon.Therefore,the1stbornmaybeaffected


79/178

2 Consequences of Hemolysis in the neonate


80/178

2ConsequencesofHemolysisintheneonate

1. ANEMIAdirectresultofredcellloss-ifmild-extramedullaryhematopoeisisinthespleen&

livermaysuffice

-ifsevereprogressiveanemiadevelops,&may

resultinhypoxicinjurytotheheart&liver.

-liverinjurywillleadtodecreaseinplasmaprotein

synthesissothatproteinsmaydroptolowlevelsof

2-2.5mg/dl.-cardiachypoxialeadtocardiacdecompensaon&

failure


81/178


82/178

2.JAUNDICEdevelopsbecauseofhemolysis

producesunconjugatedbilirubin.Bilirubinalso

passesthroughtheinfantspoorlydeveloped

blood-brainbarrier.Beingwaterinsoluble,itbindstothelipidsinthebrain,resulngindamageto

theCNS,termedkernicterus.

NONIMMUNE HYDROPS


83/178

NONIMMUNEHYDROPS

Table10-4SelectedCausesofNon-immune

FetalHydrops

-CARDIOVASCULARDEFECTS Malformaons;

Tachyarrhythmia;High outputfailure

-CHROMOSOMALANOMALIES

Turnersyndrome-duetoabnormaliesof

lymphacdrainage Trisomy21,Trisomy18(duetocardiac

structuralanomalies)

-FETALANEMIA


84/178

Homozygousalpha-thalassemiamaybe themostcommoncauseof

nonimmunehydrops-THORACICCAUSES

CyscAdenoidmalformaon

Diaphragmachernia

-TWINGESTATION Twin-to-twintransfusion

-INFECTION

CMV,Syphilis,Toxoplasmosis

-TUMORS-GENETIC/METABOLICDISORDERS

-IDIOPATHIC(20%)


85/178


86/178

Table 10 5 Abnormali>es Sugges>ng Inborn Errors


87/178

Table10-5Abnormali>esSugges>ngInbornErrors

ofMetabolism

General-Dysmorphicfeatures;Deafness;Self-

mulaon;Abnormalhair;Abnormalbodyorurine

odor(sweatyfeet;mousyormusty;maplesyrup);Hepatosplenomegaly;Cardio-megaly;

Hydrops

NeurologicHypotoniaorhypertonia;coma;

persistentlethargy;seizures


88/178


89/178

PHENYLKETONURIA (PKU)


90/178

PHENYLKETONURIA(PKU)

-characterizedbyabnormaliesofphenlalanine

metabolism,resulnginhyperphenylalani-nemia

-autosomalrecessivecondion

-majorityiscausedbybi-allelicmutaonsofthegeneencodingtheenzymephenylalanine

hydroxylase(PAH)

-thedegreeofhyperphenylalaninemia&clinical

phenotypeisinverselyrelatedtotheamountof

residualenzymeacvity


91/178

bi h i l b lit i i bilit t t


92/178

-biochemicalabnormalityisaninabilitytoconvert

phenylalanineintotyrosineintheliverbythe

hepacPAHsystem,withtwoothercomponents:cofactortetrahydrobiopterin(BH4)&theenzyme

dihydropteridinereductase,w/cregeneratesBH4

-neonatalhyperphenylalaninemiacanbecausedbydeficiencesinanyofthesecomponents,but98%of

casesareduetoabnormaliesinPAH&therestto

abnormaliesinsynthesisorrecyclingofBH4


93/178


94/178

b h f lif l d


95/178

-by6monthsoflifeseveremental retardaon

becomesevident

-fewerthan4%ofuntreatedPKUchildren

haveIQvaluesgreaterthan50or60

-about1/3areneverabletowalk

-2/3cannottalk

-othersigns&symptomsincludeseizures,

otherneurologicabnormalies, decreased

pigmentaonofhair&skin,&eczema


96/178

GALACTOSEMIA


97/178

GALACTOSEMIA

-Autosomalrecessivedisorderofgalactosemetabolism

-normally,lactosefrommilkissplitintoglucoseand

galactoseintheintesnalmicrovillibylactase.Galactoseisthenconvertedtoglucoseinthree

steps:

Rxn1Galactose+ATP----Galactosekinase

Galactose-1-phosphate+ADP


98/178


99/178

2variantsofGalactosemia:

1. Themorecommonvariantwithtotallackof

galactose-1-phosphateuridyltransferase(also

knownasGALT)involvedinreacon22. Therarevariantwithdeficiencyof

galactokinase,involvedinreacon1

lt f th t f l k l t 1


100/178

-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


101/178

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


102/178

-voming&diarrheaappearw/inafewdaysofmildingeson

-jaundice&hepatomegalyevidentduringthe1stwkoflife

-cataractsdevelopw/inafewwks

-w/inthe1st6-12monthsoflifementalretardaonmaybedetected,butnotassevereasthatofseeninPKU

-aminoaciduria-increasedfrequencyoffulminantE.colisepcemia

-hemolysis&coagulopathycanoccur

DxofGalactosemia


103/178

-canbesuspectedbydemonstraonofareducingsugarotherthanglucoseintheurine

-idenficaonofthedeficiencyoftransferaseinleukocytes&erythrocytes,morereliable

-assayofGALTacvityinculturedamniocfluid

cellsforantenataldiagnosis

-over140mutaonshavebeendocumented,glutamine-to-argininesubstuonatcodon188

(Gln188Arg)isthemostprevalentinnon-Hispanicwhites,whileaserine-to-leucinesubstuonatcodon135(Ser135Leu)ismostcommoninAfricanAmericans


104/178

Tx:

-canbepreventedoramelioratedbyearlyremovalofgalactosefromthedietforatleastthe1st2yearsoflife

-controlinstutedsoonaerbirthprevents

cataracts&liverdamage&permitsalmostnormaldevelopment

-olderpaentsarefrequentlyaffectedbyspeech

disorder&gonadalfailure(prematureovarianfailure)&lesscommonly,byanataxiccondionevenwithdietaryrestricons


105/178

-incidence of 1 in 2500 live births in Caucasian


106/178

-incidenceof1in2500livebirthsinCaucasian

populaon,isthemostcommonlethalgenec

disease-carrierfrequencyinUSis1in20amongCaucasians

butlowerinAfricanAmericans,Asians,&

Hispanics-autosomalrecessivetransmission,but

heterozygotecarriershavehigherincidenceof

respiratory&pancreacdiseasesascomparedtothegeneralpopulaon

Cys>cFibrosis-AssociatedGene:NormalStructureand Func>on


107/178

andFunc>on

-Theprimarydefectresultsfromabnormal

funconofanepithelialchloridechannelproteinencodedbythecyscfibrosistransmembraneconductanceregulator

(CFTR)geneonchromosome7q31.2-The1480-aminoacidpolypepdeencoded

byCFTRhas:2transmembranedomains(eachcontaining6alpha-helices)-these

formachannelthroughw/cchloridepasses;

:2 cytoplasmic nucleode binding domains


108/178

:2cytoplasmicnucleode-bindingdomains

(NBDs)whereATPbinding&

hydrolysisoccurs&isessenalfortheopening&closingofthechannelpore in

responsetocAMP-mediated signaling

:aregulatorydomain(Rdomain)that containsproteinkinaseA&C

phosphorylaonsites


109/178

AcvaonoftheCFTRchannelismediatedby

agonist-inducedincreasesincAMP,followedbyacvaonofaproteinkinaseAthat

phosphorylatestheRdomain.

SeveralimportantfacetsofCFTRfunconhave

emergedinrecentyears:

1. CFTRregulatesmulpleaddionalionchannels& ll l i il th h


110/178

&cellularprocessprimarilythrough

interaconsinvolvingitsNBD.Theseinclude:

-outwardlyrecfiedchloridechannels

-inwardlyrecfiedK+channels

-epithelialNa+channel(ENaC)

-gapjunconchannels

-cellularprocessinvolvedinATPtransport&

mucussecreon

ENaC has possibly the most patho


111/178

-ENaChaspossiblythemostpatho-

physiologicrelevanceincyscfibrosis

-situatedontheapicalsurfaceof

exocrineepithelialcells&is

responsibleforNa+uptakefromthe

luminalfluid,renderingithypotonic

-inhibitedbynormallyfunconingCFTR;

hence,incyscfibrosis,ENaCacvity

increases,markedlyaugmenngNa+ uptakeacrosstheapicalmembrane

(pulmonary&gastrointesnal)

-in human sweat ducts however ENaC


112/178

-inhumansweatductshowever,ENaC

acvitydecreasesasaresultof

CFTRmutaons,therefore,a hypertonicluminalfluidcontaining

bothhigh sweatCl-&highNa+

contentisformedbasisforthe saltysweatthatmotherscanoen

detectintheiraffectedinfants.


113/178


114/178


115/178

Class V: Reduced abundance these mutaons


116/178

ClassV:Reducedabundance.thesemutaons

typicallyaffectintronicsplicesitesortheCFTR

promoter,suchthatthereisreducedamountof

normalprotein.Assow/milderphenotype

ClassVI:Alteredregula>onofseparateion

channels.MutaonsinthisclassaffecttheregulatoryroleofCFTRinregulaonofmulple

disnctcellularionchannels.


117/178

Morphology:

-Pancreac abnormalies-85-90% present


118/178

Pancreacabnormalies 85 90%present

-dilaonofsmallductstoatrophy&

progressivefibrosis-Smallbowelobstrucon-knownasmeconiumfetus

-Liver-pluggedcanaliculi,ductularproliferaon,

portalinflammaon,steatosis,focal biliarycirrhosis

-Salivaryglandschangessimilartothatofthe pancreas


119/178

Clinical Features:


120/178

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


121/178

c.persistentchestradiograph

abnormalies(e.g.bronchiectasis,

atelectasis,infiltrates,hyperinflaon)

d.airwayobstruconmanifestedbywheezing&

airtrapping

e.nasalpolyps;radiographicorcomputed

tomographicabnormaliesofparanasal

sinuses

f.digitalclubbing

2 Gastrointesnal and nutrional


122/178

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


123/178

d.Nutrional:failuretothrive(protein-calorie

malnutrion),hypoproteinemia,edema,

complicaons2ndtofat-solublevitamin

deficiency

3.Salt-losssyndromes:acutesaltdepleon,chronic

metabolicalkalosis

4.Maleurogenitalabnormaliesresulngin

obstrucveazoospermia(congenitalbilateral

absenceofvasdeferens)

CRITERIAFORDIAGNOSISOFCF


124/178

Oneormorecharacteriscphenotypicfeatures ORahistoryofcyscfibrosisinasibling

ORaposivenewbornscreeningtest result

ANDAnincreasedsweatchlorideconcentraonontwoormore

occasions

ORidenficaonof2CFmutaons

ORdemonstraonofabnormalepithelialnasal iontransport

SUDDENINFANTDEATHSYNDROME(SIDS)


125/178

TheNaonalInstuteofChildHealth&HumanDevelopmentdefinesSIDSasthesuddendeath

ofaninfantunder1yearofagewhichremains

unexplainedaerthoroughcaseinvesgaon,includingperformanceofacompleteautopsy,

examinaonofthedeathscene,andreviewofthe

clinicalhistory.

Thus,SIDSisadiseaseofunknowncause.

Unclassifiedsuddeninfantdeathsuddendeath


126/178

duringinfancywhereinevidenceofexcluding

alternavedxisequivocal,orapostermdxcannotbeperformed.

Infantsusuallydieswhileasleep,mostlyintheproneorsideposion,hencethepseudonymsofcrib

deathorcotdeath.

Epidemiology:


127/178

Epidemiology:

-leadingcauseofdeathbetweenage1month &1yrinUS

-3rdleadingcauseofdeathoverallininfancy

-approx90%occurduringthe1st

6monthsoflife,mostbetweenages2&4months

-mostinfantsdieathome,usuallyduringthe

nightaeraperiodofsleep

Morphology:


128/178

-nonspecificfindingssuchasmulplepetechiae,

pulmonaryvascularengorgementw/orw/opulmonaryedema;inthecns,astrogliosisofbrain

stem&cerebellum,andhypoplasiaofthearcuate

nucleus;extramedullaryhematopoiesis&periadrenalbrownfat


129/178

Table10-7RiskFactors&PostmortemFindingsAssociatedwith SIDS


130/178

withSIDS

PARENTAL

-Youngmaternalage(


131/178

-Brainstemabnormalies,assow/delayed

developmentofarousal&cardio-respiratorycontrol

-Prematurity&/orlowbirthweight

-Malesex-productofamulplebirth

-SIDSinapriorsibling

-Antecedentrespiratoryinfecons-Germlinepolymorphismsinautonomic

nervoussystemgenes

ENVIRONMENT


132/178

-Proneorsidesleepposion

-Sleepingonasosurface

-Hyperthermia

-Co-sleepingin1st3monthsoflife

POSTMORTEMABNORMALITIESDETECTEDINCASES

OF SUDDEN UNEXPECTED INFANT DEATH


133/178

OFSUDDENUNEXPECTEDINFANTDEATH

-Infeconsviralmyocardis -bronchopneumonia

-Unsuspectedcongenitalanomaly

-congenitalaorcstenosis -anomalousoriginofthe(L)coronaryartery

fromthepulmonaryartery

-Traumacchildabuseintenonalsuffocaon (filicide)

-Genec&metabolicdefects


134/178

-LongQTsyndrome(SCN5A&KCNQ1

mutaons)

-Fayacidoxidaondisorders(MCAD,

LCHAD,SCHADmutaons)

-Hisocytoidcardiomyopathy(MTCYB

mutaons)

-Abnormalinflammatoryresponsiveness

(paraldeleonsinC4a&C4b)


135/178

SIDSisnottheonlycuaseofsuddenunexpected

deathininfancybutratherisadiagnosisof

exclusion.Therefore,performanceofan

autopsymayoenrevealfindingsthatwould

explainthecauseofsuddenunexpecteddeath.

TUMORS&TUMOR-LIKELESIONSOFINFANCY&CHILDHOOD


136/178

-2%ofallmalignanttumorsoccurininfancy&childhood

-canceraccountsfor9%ofdeathsintheUS,

accidentscausemoredeaths-benigntumorsmorecommon,butcancause

seriouscomplicaonsbecauseoftheirlocaon

orrapidincreaseinsize

2specialcategoriesoftumor-likelesions


137/178

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


138/178

growthofcells&ssuesnavetotheorgan

inw/citoccurs.-althoughthecellularelementsaremature&

idencaltothosefoundintheremainderof

theorgan,theydonotreproducethenormalarchitectureofthesurroundingssue.


139/178


140/178

LYMPHATICTUMORS

Lymphangiomas are hamartomatous or neo-plasc


141/178

Lymphangiomas arehamartomatousorneo plasc

-characterizedbycysc&cavernousspaces

-occurinskinbutaremoreoenencounteredinthedeeperregionsoftheneck,axilla, mediasnum,retroperitonealssue

-tendtoincreaseinsizeaerbirth,duetoaccumulaonoffluid&buddingofpreexisngspaces,thereforemayencroachonvitalstructuressuchasthoseinthemediasnumornervetrunksin

theaxilla,&giverisetoclinicalproblems

Lymphangiectasisrepresentabnormaldilaonof


142/178

preexisnglymphchannels.

-usuallypresentsasadiffuseswellingofpartorallofanextremityproducing considerable

distoron&deformaon

-lesionisnotprogressive,however,&doesnotextendbeyonditsoriginallocaon butcreates

cosmecproblems&difficult tocorrect

surgically

FIBROUSTUMORS


143/178

-Rangefromsparselycellularproliferaonof

spindle-shapedcells(designatedasfibromatosis)torichlycellularlesionsindis-nguishablefromfibrosarcomaoccurringinadults(designatedascongenital-infan>lefibrosarcomas)

-Biologicbehaviorcannotbepredictedonhistologyalone;haveexcellentprognosiscomparedtoadultfibrosarcoma

-ETV6-NTRK3fusiontranscriptisausefuldiagnoscmarker


144/178

2PeaksinIncidence:

1 At approximately 2 years of age are congenital


145/178

1. Atapproximately2yearsofagearecongenitalneoplasms

2. Lateadolescenceorearlyadulthoodmayalsobeofprenataloriginbutaremoreslowlygrowing

SacrococcygealTeratomasmostcommonteratomasofchildhood(40%ormore)witha

frequencyof1in20,000-40,000livebirths,&fourmesmorecommoningirlsthanboys.

-about75%arematureteratomas

-12% unequivocally malignant & lethal


146/178

-12%unequivocallymalignant&lethal

-about13%immatureteratomastheirmalig-nantpotenalcorrelateswiththeamountofimmature

ssue,usuallyneuroepithelialelements,present

-mostbenignteratomasareencounteredinyoungerinfants(


147/178

Cancersofinfancy&childhooddifferbiologically&

histologicallyfromtheircounterpartsoccurringlaterinlife.Themaindifferencesare:

-Incidence&typeoftumor

-Relavelyfrequentdemonstraonofaclose

relaonshipbetweenabnormaldevelopment

(teratogenesis)&tumorinducon(oncogenesis)

-Prevalenceofunderlyingfamilialorgenec

aberraons


148/178

-Tendencyoffetal&neonatalmalignanciesto

regressspontaneouslyorcytodifferenate

-Improvedsurvivalorcureofmanychildhood

tumors,sothatmoreaenonisnowbeing

devotedtominimizingtheadverse delayed

effectsofchemotherapy& radiaontherapy

insurvivors,includingthe developmentof

secondmalignancies.


149/178

Themostcommonneoplasmsinchildren


150/178

1. Leukemia(principallyALL)2. Neuroblastoma3. Wilmstumor4. Hepatoblastoma5. Renoblastoma6. Rhabdomyosarcoma7. Teratoma8. Ewingsarcoma

posterior fossa neoplasms


151/178

-posteriorfossaneoplasms

9.Juvenileastrocytoma10.Medulloblastoma

11.Ependymoma

*Leukemiaaloneaccountsformoredeathsin

childrenyoungerthan15yrsthanallofthe

othertumorscombined.

Histologically,malignantnon-hematopoiec

pediatric neoplasms tend to have more primive


152/178

pediatricneoplasmstendtohavemoreprimive

(embryonal)ratherthanpleomorphic-anaplascmicroscopicappearance,areoencharacterized

bysheetsofcellsw/small,roundnuclei,&

frequentlyshowfeaturesoforganogenesisspecific

tothesiteoftumororigin.

-becauseofthis,theyaredesignatedbythe

suffixblastoma,ex.Nephroblastoma,

hepatoblastoma,neuroblastoma

Because of their primive histologic


153/178

Becauseoftheirprimivehistologic

appearance,manychildhoodtumorsarecollecvelyreferredtoassmallroundcelltumors.

Thedifferenaldiagnosisincludeneuroblastoma,

Wilmstumor,lymphoma,rhab-domyosarcoma,

Ewingsarcoma/primiveneuroectodermaltumor,

medulloblastoma,andrenoblastoma.


154/178

Iftheanatomicsiteoforiginisknown,diagnosisis

usuallypossibleonhistologicgroundsalone.Occasionally,acombinaonofchromosomeanalysis,

immunoperoxidasestains,orelectronmicroscopyis

requiredfordefinivediagnosis.

THENEUROBLASTICTUMORS


155/178

-thisincludestumorsofthesympathecganglia&adrenalmedullathatarederivedfromprimordialneuralcrestcellspopulangthesesites.

-asafamily,demonstratescertaincharacterisc

featuresincludingspontaneousortherapy-induceddifferenaonofprimiveneuroblastsintomatureelements,spontaneoustumorregression,&awiderangeofclinicalbehavior&

prognosis.

Neuroblastomamostimportantmemberofthefamily


156/178

-mostcommonextracranialsolidtumorof

childhood,&mostfrequentlydiagnosedtumorofinfancy

-prevalenceisabout1in7000livebirths

-medianageatdxis18months-about40%ofcasesdiagnosedininfancy

-mostoccursporadically,but1-2%arefamilial

-germlinemutaonintheanaplas>clymphomakinase(ALK)genehasbeenidenfiedasamajorcauseoffamilialpredisposiontoneuroblastoma


157/178


158/178

-neuropilw/careneuricprocesses appearaseosinophilicfibrillary materials


159/178

materials

-Homer-WrightpseudoroseVescanbe foundinw/cthetumorcellsare concentricallyarrangedabouta centralspacefilledw/neuropil

-largercellshavingmoreabundant cytoplasm,largervesicularnuclei,&prominentnucleolus,represenng

ganglioncellsinvariousstagesof maturaon,maybefoundw/primiveneuroblasts(ganglioneuro-blastoma)


160/178


161/178

-blueberrymuffinbabymulplecutaneous


162/178

y y pmetastasesthatcausedeepbluediscoloraonof

theskin

-90%ofneuroblastomas,regardlessoflocaonproducecatecholaminesw/careanimportant

diagnoscfeature(i.e.,elevatedbloodlevelsofcatecholamines&elevatedurinelevelsofthemetabolitesvanillylmandelicacid(VMA)&homovanillicacid(HVA)buthypertensionis

muchlessfrequentthanw/pheochromocytomas


163/178


164/178


165/178

Pathogenesis&Gene>cs:

TheriskofWilmstumorisincreasedinassow/atleast4


166/178

recognizablegroupsofcongenitalmalformaonsassow/

disnctchromosomalloci:

I.WAGRsyndrome,characterizedbyaniridia,genital

anomalies,&mentalretardaon&a33%chanceof

developingWilmstumor.-ptw/thissyndromecarryconstuonal(germline)

deleonsof11p13.

-Wilmstumor-assogeneWT1&aconguously deleted

autosomalgeneforaniridia,PAX6located on

chromosome11p13


167/178

-WT1encodesaDNA-bindingtranscriponf

actor that is expressed w/in several


168/178

actorthatisexpressedw/inseveral

ssues,includingthekidney&gonads,duringembryogenesis

-WT1proteiniscricalfornormalrenal&

gonadaldevevlopment

III.Beckwith-Wiedemansyndrome(BWS),

characterizedbyenlargementofbodyorgans


169/178

y g y g

(organomegaly),macroglosia,hemihyper-trophy,omphalocele,&abnormallargecellsinthe

adrenalcortex.

-chromosomalregionhasbeenlocalizedtoband

11p15.5(WT2),distaltotheWT1locus

-imprinngabnormaliesofIGF2havethe

strongestrelaonshiptotumorpredisposion

-alsoatincreasedriskfordeveloping

hepatoblastoma,pancreatoblastoma,adreno-

corcaltumors,&rhabdomyosarcomas.


170/178


171/178

-itisimportanttodocumentthepresenceof


172/178

p p

nephrogenicrestsintheresectedspecimen,sincethepaentsareatanincreasedriskof

developingWilmstumorofthecontralateral

kidney&requirefrequent&regularsurveillance

formanyyears.


173/178


174/178

Anaplasia,inapprox5%,definedaspresenceof

cells w/ large hyperchromac pleomorphic


175/178

cellsw/large,hyperchromac,pleomorphic

nuclei&abnormalmitoses-correlatesw/thepresnceofp53mutaons&

theemergenceofresistancetochemotherapy

(p53elicitspro-apoptocsignalsinresponsetoDNAdamage)

ClinicalFeatures:

-most children present w/ a large abdominal mass


176/178

mostchildrenpresentw/alargeabdominalmass

thatmaybeunilateralor,whenverylarge,mayextendacrossthemidline&downintothepelvis

-hematuria,painintheabdomen,intesnalobstrucon,&appearanceofhypertension

-pulmonarymetastasesmaybepresentatthemeofprimarydiagnosis

-mostpaentscanexpecttobecured

-anaplaschistologyremainsacricaldeterminantofadverseprognosis


177/178


178/178

HAVEANICEDAY!

dr. domingo - diseas of infancy

Documents