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Diseases of Diseases of
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Diseases of InfancyDiseases of Infancyand Childhoodand Childhood
Congenital AnomaliesCongenital Anomalies Birth Weight and Gestational AgeBirth Weight and Gestational Age Birth InjuriesBirth Injuries Perinatal InfectionsPerinatal Infections Respiratory Distress Syndrome (RDS)Respiratory Distress Syndrome (RDS) Necrotizing EnterocolitisNecrotizing Enterocolitis Intraventricular HemorrhageIntraventricular Hemorrhage HydropsHydrops Inborn Metabolic/Genetic ErrorsInborn Metabolic/Genetic Errors Sudden Infant Death Syndrome (SIDS)Sudden Infant Death Syndrome (SIDS) TumorsTumors
INFANT MORTALITYINFANT MORTALITY
USA 1970: 20USA 1970: 20 USA 2000: 7USA 2000: 7 USA WHITE: XUSA WHITE: X USA BLACK: 2XUSA BLACK: 2X
SWEDEN 3SWEDEN 3 INDIA 82INDIA 82
Major Time SpansMajor Time Spans NeonatalNeonatal period period
first four weeks of lifefirst four weeks of life InfancyInfancy
the first year of lifethe first year of life Age 1 – 4 years (preschool)Age 1 – 4 years (preschool) Age 5 – 14 years (school age)Age 5 – 14 years (school age)
MORTALITY by TIME MORTALITY by TIME SPANSPAN
NEONATE (0-4 WEEKS): NEONATE (0-4 WEEKS): CONGENITAL, CONGENITAL, PREMATURITYPREMATURITY
UNDER ONE YEAR:UNDER ONE YEAR: CONGENITAL, CONGENITAL, PREMATURITY/WEIGHT, SIDSPREMATURITY/WEIGHT, SIDS
1-4 YEARS:1-4 YEARS: ACCIDENTS, CONGENITAL, ACCIDENTS, CONGENITAL, TUMORSTUMORS
5-14 YEARS:5-14 YEARS: ACCIDENTS, TUMORS, ACCIDENTS, TUMORS, HOMICIDESHOMICIDES
15-24 YEARS: ACCIDENTS, HOMICIDE, ACCIDENTS, HOMICIDE, SUICIDE (SUICIDE (NONE ARE “NATURAL” CAUSESNONE ARE “NATURAL” CAUSES))
Cause of Death Related with Age
Causes1 Rate 2 Under 1 Year: All Causes
727.4
1–4 Years: All Causes
32.6
5–14 Years: All Causes
18.5
15–24 Years: All Causes
80.7
1Rates are expressed per 100,000 population 2Excludes congenital heart disease
Congenital Congenital AnomaliesAnomalies
DefinitionsDefinitionsCausesCausesPathogenesisPathogenesis
• Malformations– primary errors of morphogenesis, usually multifactorial– e.g. congenital heart defect
• Disruptions– secondary disruptions of previously normal organ or body region– e.g. amniotic bands
• Deformations– extrinsic disturbance of development by biomechanical forces– e.g. uterine constraint
• Sequence– a pattern of cascade anomalies explained by a single localized
initiating event with secondary defects in other organs– e.g. Oligohydramnios (Or Potter) Sequence
• Syndrome– a constellation of developmental abnormalities believed to be
pathologically related– e.g Turner syndrome
Malformations
Polydactyly & syndactyly
Cleft Lip Severe Lethal Malformation
Disruption by an amniotic band
Oligohydramnios (Or Potter) Sequence • Oligohydramnios (decreased amniotic
fluid) – Renal agenesis– Amniotic leak
• Fetal Compression– flattened facies– club foot (talipes equinovarus)
• Pulmonary hypoplasia– fetal respiratory motions important for lung
development
• Breech Presentation
The Oligohydramnios “Sequence”
Infant with oligohydramnios sequence
Organ Specific Anomalies• Agenesis: complete absence of an organ • Atresia: absence of an opening • Hypoplasia: incomplete development or
under- development of an organ with decreased numbers of cells
• Hyperplasia: overdevelopment of an organ associated with increased numbers of cells
• Hypertrophy: increase in size with no change in number of cells
• Dysplasia: in the context of malformations (versus neoplasia) describes an abnormal organization of cells
Implantation and the Implantation and the Survival of Early Pregnancy Survival of Early Pregnancy Only 50-60% of all conceptions advance Only 50-60% of all conceptions advance
beyond 20 weeksbeyond 20 weeks Implantation occurs at day 6-7Implantation occurs at day 6-7 75% of loses are implantation failures and 75% of loses are implantation failures and
are not recognizedare not recognized Pregnancy loss after implantation is 25-40%Pregnancy loss after implantation is 25-40%
NEJM 2001; 345:1400-1408
Approximate Frequency of the More Common Congenital “Malformations” in the United States
Malformation
Frequency per 10,000 Total
Births
Clubfoot without central nervous system anomalies 25.7
Patent ductus arteriosus 16.9
Ventricular septal defect 10.9
Cleft lip with or without cleft palate 9.1
Spina bifida without anencephalus 5.5
Congenital hydrocephalus without anencephalus 4.8
Anencephalus 3.9
Reduction deformity (musculoskeletal) 3.5
Rectal and intestinal atresia 3.4
Adapted from James LM: Maps of birth defects occurrence in the U.S., birth defects monitoring program (BDMP)/CPHA, 1970–1987. Teratology 48:551, 1993.
#1
#2
#3
CAUSES OF ANOMALIES• Genetic
• karyotypic aberrations• single gene mutations
• Environmental• infection• maternal disease• drugs and chemicals• irradiation
• Multifactorial
•Unknown
Causes of Congenital Anomalies in Humans
Cause Frequency
(%)
Genetic
Chromosomal aberrations 10–15
Mendelian inheritance 2–10
Environmental
Maternal/placental infections 2–3
Maternal disease states 6–8
Drugs and chemicals 1
Irradiations 1
Multifactorial (Multiple Genes ? Environment)
20–25
Unknown 40–60 Adapted from Stevenson RE, et al (eds): Human Malformations and Related Anomalies. New York, Oxford University Press, 1993, p. 115.
Embryonic DevelopmentEmbryonic Development
EmbryonicEmbryonic period period weeks 1- 8 of pregnancyweeks 1- 8 of pregnancy organogenesis occurs in this period organogenesis occurs in this period
FetalFetal period period weeks 9 to 38weeks 9 to 38 marked by further growth and maturationmarked by further growth and maturation
Critical Periods Of Development
Genetic CausesGenetic Causes Karyotypic abnormalitiesKaryotypic abnormalities
80-90% of fetuses with aneuploidy die in utero80-90% of fetuses with aneuploidy die in utero trisomy 21 (Down syndrome) most common trisomy 21 (Down syndrome) most common
karyotypic abnormality (21,18,13)karyotypic abnormality (21,18,13) sex chromosome abnormalities next most sex chromosome abnormalities next most
common (Turner and Klinefelter)common (Turner and Klinefelter) autosomal chromosomal deletion usually lethalautosomal chromosomal deletion usually lethal karyotyping frequently done with aborted karyotyping frequently done with aborted
fetuses with repeated abortionsfetuses with repeated abortions Single gene mutationsSingle gene mutations
covered in separate chapterscovered in separate chapters
Maternal Viral Infection• Rubella (German measles)
– at risk period first 16 weeks gestation– defects in lens (cataracts), heart, and CNS
(deafness and mental retardation)– rubella immune status important part of
prenatal workup
• Cytomegalovirus– most common fetal infection– highest at risk period is second trimester– central nervous system infection
predominates
Drugs and ChemicalsDrugs and ChemicalsDrugsDrugs
13 cis-retinoic acid (acne agent)13 cis-retinoic acid (acne agent) warfarinwarfarin angiotensin converting enzyme inhibitors angiotensin converting enzyme inhibitors
(ACEI)(ACEI) anticonvulsantsanticonvulsants oral diabetic agentsoral diabetic agents thalidomidethalidomide
AlcoholAlcoholTobaccoTobacco
Teratogen Teratogen ActionsActions
• • Proper Proper cell migrationcell migration to predetermined locations that to predetermined locations that influence the development of other structures influence the development of other structures
• • Cell proliferationCell proliferation, which determines the size and form of , which determines the size and form of embryonic organs embryonic organs
• • Cellular interactionsCellular interactions among tissues derived from among tissues derived from different structures (e.g., ectoderm, mesoderm), which different structures (e.g., ectoderm, mesoderm), which affect the differentiation of one or both of these tissues affect the differentiation of one or both of these tissues
• • Cell-matrix associationsCell-matrix associations, which affect growth and , which affect growth and differentiation differentiation
• • Programmed cell death (Programmed cell death (apoptosisapoptosis)), which, as we have , which, as we have seen, allows orderly organization of tissues and organs seen, allows orderly organization of tissues and organs during embryogenesis during embryogenesis
• • Hormonal influencesHormonal influences and and mechanical forcesmechanical forces, which , which affect morphogenesis at many levelsaffect morphogenesis at many levels
Diabetes MellitusDiabetes Mellitus Fetal Macrosomy (>10 pounds)Fetal Macrosomy (>10 pounds)
maternal hyperglycemia increases insulin maternal hyperglycemia increases insulin secretion by fetal pancreas, insulin acts with secretion by fetal pancreas, insulin acts with growth hormone effectsgrowth hormone effects
Diabetic EmbryopathyDiabetic Embryopathy most crucial period is immediately post most crucial period is immediately post
fertilizationfertilization malformations increased 4-10 fold with malformations increased 4-10 fold with
uncontrolled diabetes, involving heart and CNSuncontrolled diabetes, involving heart and CNS Oral agents not approved in pregnancyOral agents not approved in pregnancy Diabetics attempting to conceive should be Diabetics attempting to conceive should be
placed on insulinplaced on insulin
Birth Weight and Birth Weight and Gestational AgeGestational Age
Appropriate for gestational age (AGA)Appropriate for gestational age (AGA) between 10 and 90between 10 and 90thth percentile for gestational percentile for gestational
age age Small for gestational age (Small for gestational age (SGASGA) , <10%) , <10% Large for gestational age (Large for gestational age (LGALGA) , >90%) , >90%
PretermPreterm born before born before 3737 weeks (<2500 grams) weeks (<2500 grams)
Post-TermPost-Term delivered after delivered after 4242 weeks weeks
PrematurityPrematurity
Defined as gestational age Defined as gestational age < 37 < 37 weeksweeks Second most common cause of neonatal Second most common cause of neonatal
mortality (after congenital anomalies)mortality (after congenital anomalies) Risk factors for prematurityRisk factors for prematurity
Preterm Preterm PPremature remature RRupture upture OOf fetal f fetal MMembranes (PPROM)embranes (PPROM)
Intrauterine infectionIntrauterine infection Uterine, cervical, and placental abnormalitiesUterine, cervical, and placental abnormalities Multiple gestationMultiple gestation
Fetal Growth Fetal Growth RestrictionRestriction At least 1/3 of infants born at term are < 2.5kgAt least 1/3 of infants born at term are < 2.5kg
Undergrown rather than immatureUndergrown rather than immature Commonly underlies Commonly underlies SGASGA (small for gestational (small for gestational
age)age) Prenatal diagnosis: ultrasound measurementsPrenatal diagnosis: ultrasound measurements ClassificationClassification
FetalFetal PlacentalPlacental
MaternalMaternal
Fetal FGRFetal FGR Chromosomal abnormalitiesChromosomal abnormalities
17% of FGR overall17% of FGR overall up to 66% of fetuses with ultrasound up to 66% of fetuses with ultrasound
malformationsmalformations Fetal InfectionFetal Infection
Infection: TORCH (Infection: TORCH (TToxoplasmosis, oxoplasmosis, OOther, ther,
RRubella, ubella, CCytomegalovirus, ytomegalovirus, HHerpes)erpes) Characterized by symmetric growth Characterized by symmetric growth
restriction – restriction – head and trunk head and trunk proportionally involvedproportionally involved
Placental FGRPlacental FGR VascularVascular
umbilical cord anomalies (single artery, umbilical cord anomalies (single artery, constrictions, etc)constrictions, etc)
thrombosis and infarctionthrombosis and infarction multiple gestationmultiple gestation
Confined placental mosaicismConfined placental mosaicism mutation in trophoblastmutation in trophoblast trisomy is commontrisomy is common
Placental FGR tends to cause Placental FGR tends to cause asymmetric growth with asymmetric growth with relative relative sparing of the head sparing of the head
Maternal FGRMaternal FGR Most common cause of FGR by farMost common cause of FGR by far Vascular diseasesVascular diseases
preeclampsia (toxemia of pregnancy)preeclampsia (toxemia of pregnancy) hypertensionhypertension
ToxinsToxins ethanolethanol narcotics and cocainenarcotics and cocaine heavy smokingheavy smoking
Organ ImmaturityOrgan Immaturity LungsLungs
alveoli differentiate in 7alveoli differentiate in 7 thth month month surfactant deficiencysurfactant deficiency
KidneysKidneys glomerular differentiation is incompleteglomerular differentiation is incomplete
BrainBrain impaired homeostasis of temperatureimpaired homeostasis of temperature vasomotor control unstablevasomotor control unstable
LiverLiver inability to conjugate and excrete bilirubininability to conjugate and excrete bilirubin
Evaluation Of The Newborn Infant Sign 0 1 2 Heart rate Absent Below 100 Over 100 Respiratory effort
Absent Slow, irregular Good, crying
Muscle tone Limp Some flexion of extremities
Active motion
Response to catheter in nostril (tested after oropharynx is clear)
No response
Grimace Cough or sneeze
Color Blue, pale Body pink, extremities blue
Completely pink
Data from Apgar V: A proposal for a new method of evaluation of the newborn infant. Anesth Analg 32:260, 1953.
APGAR (Appearance, Pulse, Grimace,
Activity, Respiration)
Apgar Score and 28 Day Apgar Score and 28 Day MortalityMortality
Score may be evaluated at 1 and Score may be evaluated at 1 and 5 minutes5 minutes
5 minute scores5 minute scores 0-1, 50% mortality0-1, 50% mortality 4, 20% mortality4, 20% mortality ≥ ≥ 7, nearly 0% mortality7, nearly 0% mortality
Perinatal Infection• Transcervical (ascending)
– inhalation of infected amniotic fluid• pneumonia, sepsis, meningitis• commonly occurs with PROM
– passage through infected birth canal• herpes virus– caesarian section for active herpes
• Transplacental (hematogenous)– mostly viral and parasitic
• HIV—at delivery with maternal to fetal transfusion• TORCH• parvovirus B19 (Fifth), erythema infectiosum
– bacterial• Listeria monocytogenes
Fetal Lung Maturation
Neonatal Respiratory Distress Syndrome (RDS) (HMD)
• 60,000 cases / year in USA with 5000 deaths• Incidence is inversely proportional to
gestational age• The cause is lung immaturity with decreased
alveolar surfactant– surfactant decreases surface tension– first breath is the hardest since lungs must be
expanded– without surfactant, lungs collapse with each
breath
RDS Risk FactorsRDS Risk Factors
1)1) Prematurity Prematurity by far the greatest risk factorby far the greatest risk factor affected infants are nearly always prematureaffected infants are nearly always premature
2)2) Maternal diabetes mellitus Maternal diabetes mellitus insulin suppresses surfactant secretioninsulin suppresses surfactant secretion
3)3) Cesarean delivery Cesarean delivery normal delivery process stimulates surfactant normal delivery process stimulates surfactant
secretionsecretion
RDS PathologyRDS Pathology
GrossGross solid and airless (no crepitance)solid and airless (no crepitance) sink in watersink in water appearance is similar to liver tissue*appearance is similar to liver tissue*
MicroscopicMicroscopic atelectasis and dilation of alveoliatelectasis and dilation of alveoli hyaline membranes composed of fibrin and hyaline membranes composed of fibrin and
cell debris line alveoli (HMD former name)cell debris line alveoli (HMD former name) minimal inflammationminimal inflammation
V/QMismatc
h
RDS Prevention and RDS Prevention and TreatmentTreatment
Delay labor until fetal lung is matureDelay labor until fetal lung is mature amniotic fluid phospholipid levels are useful in amniotic fluid phospholipid levels are useful in
assessing fetal lung maturityassessing fetal lung maturity Induce fetal lung maturation with antenatal Induce fetal lung maturation with antenatal
corticosteriodscorticosteriods Postnatal surfactant replacement therapy Postnatal surfactant replacement therapy
with oxygen and ventilator supportwith oxygen and ventilator support
Treatment ComplicationsTreatment Complications Oxygen toxicityOxygen toxicity
oxygen derived free radicals damage tissueoxygen derived free radicals damage tissue Retrolental fibroplasiaRetrolental fibroplasia
hypoxia causes ↑ hypoxia causes ↑ VVascular ascular EEndothelial ndothelial GGrowth rowth FFactor actor ((VEGFVEGF) and angiogenesis) and angiogenesis
Oxygen Rx suppresses VEGF and causes endothelial Oxygen Rx suppresses VEGF and causes endothelial apoptosisapoptosis
Bronchopulmonary “dysplasia”Bronchopulmonary “dysplasia” oxygen suppresses lung septation at the saccular stageoxygen suppresses lung septation at the saccular stage mechanical ventilationmechanical ventilation
epithelial hyperplasia, squamous metaplasia, and peribronchial epithelial hyperplasia, squamous metaplasia, and peribronchial and interstitial fibrosis were seen with old regimens of ventilator and interstitial fibrosis were seen with old regimens of ventilator usage and no surfactant use, but are now uncommonusage and no surfactant use, but are now uncommon
lung septation is still impairedlung septation is still impaired
Necrotizing EnterocolitisNecrotizing Enterocolitis Incidence is directly proportional to Incidence is directly proportional to
prematurity, like RDSprematurity, like RDS approaches 10% with severe prematurityapproaches 10% with severe prematurity
2000 cases yearly in USA2000 cases yearly in USA PathogenesisPathogenesis
not fully understoodnot fully understood intestinal ischemiaintestinal ischemia inflammatory mediatorsinflammatory mediators breakdown of mucosal barrierbreakdown of mucosal barrier
Necrotizing Enterocolitis
Hydrops FetalisHydrops Fetalis Chromosomal abnormalitiesChromosomal abnormalities
Turner syndrome with cystic hygromasTurner syndrome with cystic hygromas otherother
Cardiovascular with heart failureCardiovascular with heart failure anemia with high output failureanemia with high output failure
immune hemolytic anemiaimmune hemolytic anemia hereditary hemolytic anemia (α-thalassemia)hereditary hemolytic anemia (α-thalassemia) parvovirus B19 infectionparvovirus B19 infection twin to twin in utero transfusiontwin to twin in utero transfusion
congenital heart defectscongenital heart defects
Hydrops Fetalis
Immune HydropsImmune Hydrops Fetus inherits red cell antigens from the Fetus inherits red cell antigens from the
father that are foreign to the motherfather that are foreign to the mother Mother forms IgG antibodies which cross Mother forms IgG antibodies which cross
the placenta and destroy fetal RBCsthe placenta and destroy fetal RBCs Fetus develops severe anemia with CHF Fetus develops severe anemia with CHF
and compensatory ↑ hematopoiesis and compensatory ↑ hematopoiesis (frequently extramedullary)(frequently extramedullary)
Most cases involve Rh D antigenMost cases involve Rh D antigen mother is Rhmother is Rh Neg and fetus is Rh PosNeg and fetus is Rh Pos
ABO and other antigens involved less oftenABO and other antigens involved less often
Pathogenesis of Pathogenesis of SensitizationSensitization
Fetal RBCs gain access to maternal Fetal RBCs gain access to maternal circulation largely at delivery or upon circulation largely at delivery or upon abortionabortion
Since IgM antibodies are involved in Since IgM antibodies are involved in primary response and prior sensitization is primary response and prior sensitization is necessary, the first pregnancy is not necessary, the first pregnancy is not usually affectedusually affected
Maternal sensitization can be prevented in Maternal sensitization can be prevented in most cases with Rh immune globulin most cases with Rh immune globulin (Rhogam) given at time of delivery or (Rhogam) given at time of delivery or abortion (spontaneous or induced)abortion (spontaneous or induced)
Treatment of Immune Treatment of Immune HydropsHydrops
In uteroIn utero identification of at risk infants via blood typing identification of at risk infants via blood typing
by amniocentesis, (by amniocentesis, (CChorionic horionic VVilli illi SSampling) ampling) CVS, or fetal blood samplingCVS, or fetal blood sampling
fetal transfusions via umbilical cordfetal transfusions via umbilical cord early deliveryearly delivery
Live born infantLive born infant monitoring of hemoglobin and bilirubinmonitoring of hemoglobin and bilirubin exchange transfusionsexchange transfusions
Kernicterus
Pathogenesis of Immune Hydrops
Inborn Errors of Inborn Errors of MetabolismMetabolism
(Genetic)(Genetic)PPhenylhenylKKetonetonUUria (ria (PKUPKU))GalactosemiaGalactosemiaCCystic ystic FFibrosis (ibrosis (CFCF) ) (Mucoviscidosis)(Mucoviscidosis)
PHENYLKETONURIA (PKU)• Ethnic distribution
– common in persons of Scandinavian descent – uncommon in persons of African-American and
Jewish descent
• Autosomal recessive• Phenylalanine hydroxylase deficiency leads
to hyperphenylalaninemia, brain damage, and mental retardation
• Phenylananine metabolites are excreted in the urine
• Treatment is phenylalanine restriction• Variant forms exist
GALACTOSEMIA• Autosomal recessive • Lactose → glucose + galactose• Galactose-1-phosphate uridyl transferase (GALT)
– GALT is involved in the first step in the transformation of galactose to glucose
– absence of GALT activity → galactosemia
• Symptoms appear with milk ingestion– liver (fatty change and fibrosis), lens of eye (cataracts),
and brain damage involved (mechanism unknown)
• Diagnosis suggested by reducing sugar in urine and confirmed by GALT assay in tissue
• Treatment is removal of galactose from diet for at least the two first years of life
Cystic Cystic FibrosisFibrosis Normal GeneNormal Gene
Mutational SpectraMutational Spectra Genetic/Environmental ModifiersGenetic/Environmental Modifiers MorphologyMorphology Clinical CourseClinical Course
Cystic Fibrosis Cystic Fibrosis (Mucoviscidosis) (Mucoviscidosis) Autosomal recessiveAutosomal recessive
Most common lethal genetic disease Most common lethal genetic disease affecting Caucasians (1 in 3,200 live births affecting Caucasians (1 in 3,200 live births in the USA)in the USA) 2-4% of population are carriers2-4% of population are carriers Uncommon in Asians and African-Americans Uncommon in Asians and African-Americans
Widespread disorder in epithelial chloride Widespread disorder in epithelial chloride transport affecting fluid secretion in transport affecting fluid secretion in exocrineexocrine glands glands epithelial lining of the respiratory, epithelial lining of the respiratory,
gastrointestinal, and reproductive tractsgastrointestinal, and reproductive tracts Abnormally viscid mucus secretionsAbnormally viscid mucus secretions
Cellular Metabolism Of The Cystic Fibrosis
Transmembrane Regulator (CFTR)
Harrison’s Internal Med, 16th Ed
CFTR Gene: NormalCFTR Gene: Normal CCystic ystic FFibrosis ibrosis TTransmembrane Conductance ransmembrane Conductance
RRegulator (egulator (CFTRCFTR)) CTFR → epithelial chloride channel proteinCTFR → epithelial chloride channel protein
agonist induced regulation of the chloride channelagonist induced regulation of the chloride channel interacts with epithelial sodium channels (ENaC)interacts with epithelial sodium channels (ENaC)
Sweat glandSweat gland CTFR activation increases luminal ClCTFR activation increases luminal Cl− − resorptionresorption ENaC increases NaENaC increases Na++ resorption resorption sweat is hypotonicsweat is hypotonic
Respiratory and Intestinal epitheliumRespiratory and Intestinal epithelium CTFR activation increases active luminal secretion of CTFR activation increases active luminal secretion of
chloridechloride ENaC is inhibitedENaC is inhibited
CFTR Gene: Cystic CFTR Gene: Cystic FibrosisFibrosis
Sweat glandSweat gland CTFR absence decreases luminal ClCTFR absence decreases luminal Cl− − resorptionresorption ENaC decreases NaENaC decreases Na++ resorption resorption sweat is hypertonicsweat is hypertonic
Respiratory and Intestinal epitheliumRespiratory and Intestinal epithelium CTFR absence decreases active luminal secretion of CTFR absence decreases active luminal secretion of
chloridechloride lack of inhibition of ENaC is opens sodium channel with lack of inhibition of ENaC is opens sodium channel with
active resorption of luminal sodiumactive resorption of luminal sodium secretions are decreased but isotonicsecretions are decreased but isotonic
Chloride Channel Defect and Effects
CFTR Gene: Mutational CFTR Gene: Mutational SpectraSpectra
More than 800 mutations are knownMore than 800 mutations are known These are grouped into six classesThese are grouped into six classes
mild to severemild to severe Phenotype is correlated with the Phenotype is correlated with the
combination of these allelescombination of these alleles correlation is best for pancreatic diseasecorrelation is best for pancreatic disease genotype-phenotype correlations are less genotype-phenotype correlations are less
consistent with pulmonary diseaseconsistent with pulmonary disease Other genes and environment further Other genes and environment further
modify expression of CFTRmodify expression of CFTR
Clinical Manifestations Of Mutations In The Cystic Fibrosis Gene
Organ PathologyOrgan Pathology Plugging of ducts with viscous mucus and loss of Plugging of ducts with viscous mucus and loss of
ciliary function of respiratory mucosaciliary function of respiratory mucosa PancreasPancreas
atrophy of exocrine pancreas with fibrosisatrophy of exocrine pancreas with fibrosis islets are not affectedislets are not affected
LiverLiver plugging of bile canaliculi with portal inflamationplugging of bile canaliculi with portal inflamation biliary cirrhosis may developbiliary cirrhosis may develop
GenitaliaGenitalia Absence of vas deferens and azoospermiaAbsence of vas deferens and azoospermia
Sweat glandsSweat glands normal histologynormal histology
Lung Pathology in CF• More than 95% of CF patients die of
complications resulting from lung infection• Viscous bronchial mucus with obstruction
and secondary infection– S. aureus– Pseudomonas– Hemophilus
• Bronchiectasis– dilatation of bronchial lumina– scarring of bronchial wall
Cystic Fibrosis
Clinical Manifestations
CF DiagnosisCF Diagnosis Clinical criteriaClinical criteria
sinopulmonarysinopulmonary gastrointestinalgastrointestinal
pancreaticpancreatic intestinalintestinal
salt losssalt loss male genital tractmale genital tract
Sweat chloride analysisSweat chloride analysis Nasal transepithelial potential differenceNasal transepithelial potential difference DNA AnalysisDNA Analysis
gene sequencing gene sequencing
Clinical Course and Clinical Course and TreatmentTreatment
Highly variable – median life expectance is Highly variable – median life expectance is 30 years30 years
7% of patients in the United States are 7% of patients in the United States are diagnosed as adults diagnosed as adults
Clearing of pulmonary secretions and Clearing of pulmonary secretions and treatment of pulmonary infectiontreatment of pulmonary infection
TransplantationTransplantation lunglung liver-pancreasliver-pancreas
SSudden udden IInfant nfant DDeath eath SSyndrome (yndrome (SIDSSIDS))
EpidemiologyEpidemiologyMorphologyMorphologyPathogenesisPathogenesis
Sudden Infant Death Sudden Infant Death SyndromeSyndrome
NIH DefinitionNIH Definition sudden death of an infant under 1 year of age sudden death of an infant under 1 year of age
which remains unexplained after a thorough which remains unexplained after a thorough case investigation, including performance of a case investigation, including performance of a complete autopsy, examination of the death complete autopsy, examination of the death scene, and review of the clinical historyscene, and review of the clinical history
Crib deathCrib death another name based on the fact that most die another name based on the fact that most die
in their sleepin their sleep
Epidemology of SIDSEpidemology of SIDS
Leading cause of death in USA of infants Leading cause of death in USA of infants between 1 month and 1 year of agebetween 1 month and 1 year of age
90% of deaths occur ≤ 6 months age, 90% of deaths occur ≤ 6 months age, mostly between 2 and 4 monthsmostly between 2 and 4 months
In USA 2,600 deaths in 1999 (down from In USA 2,600 deaths in 1999 (down from 5,000 in 1990)5,000 in 1990)
Risk Factors for SIDS• Parental
– Young maternal age (age <20 years)– Maternal smoking during pregnancy– Drug abuse in either parent, specifically paternal marijuana and
maternal opiate, cocaine use– Short intergestational intervals– Late or no prenatal care– Low socioeconomic group– African American and American Indian ethnicity (? socioeconomic
factors)• Infant
– Brain stem abnormalities, associated defective arousal, and cardiorespiratory control
– Prematurity and/or low birth weight– Male sex– Product of a multiple birth– SIDS in a prior sibling– Antecedent respiratory infections
• Environment– Prone sleep position– Sleeping on a soft surface– Hyperthermia– Postnatal passive smoking
Morphology of SIDSMorphology of SIDS
SIDS is a diagnosis of SIDS is a diagnosis of exclusionexclusion
Non-specific autopsy findingsNon-specific autopsy findings Multiple petechiae Multiple petechiae Pulmonary congestion ± pulmonary edemaPulmonary congestion ± pulmonary edema These may simply be agonal changes as they These may simply be agonal changes as they
are found in non-SIDS deaths alsoare found in non-SIDS deaths also Subtle changes in brain stem neuronsSubtle changes in brain stem neurons Autopsy typically reveals no clear cause of Autopsy typically reveals no clear cause of
deathdeath
Pathogenesis of SIDSPathogenesis of SIDS Generally accepted to be multifactorialGenerally accepted to be multifactorial Triple risk modelTriple risk model
Vulnerable infantVulnerable infant Critical development period in homeostatic Critical development period in homeostatic
controlcontrol Exogenous stressorsExogenous stressors
Brain stem abnormalities, associated Brain stem abnormalities, associated defective arousal, and cardio-respiratory defective arousal, and cardio-respiratory controlcontrol
Prevention of SIDSPrevention of SIDS Maternal factorsMaternal factors
attention to risk factors previously mentionedattention to risk factors previously mentioned redress problems in medical care for underprivilegedredress problems in medical care for underprivileged
EnvironmentalEnvironmental avoid prone sleepingavoid prone sleeping
back to sleep program: infant should sleep in supine positionback to sleep program: infant should sleep in supine position Avoid sleeping on soft surfacesAvoid sleeping on soft surfaces
no pillows, comforters, quilts, sheepskins, and stuffed toys no pillows, comforters, quilts, sheepskins, and stuffed toys Sleeping clothing (such as a sleep sack) may be used in Sleeping clothing (such as a sleep sack) may be used in
place of blankets. place of blankets. Avoid hyperthermiaAvoid hyperthermia
no excessive blanketsno excessive blankets set thermostat to appropriate temperatureset thermostat to appropriate temperature avoid space heatersavoid space heaters
Diagnosis of SIDSDiagnosis of SIDS
SIDS is a diagnosis of SIDS is a diagnosis of exclusionexclusion
Complete autopsyComplete autopsy Examination of the death sceneExamination of the death scene Review of the clinical historyReview of the clinical history Differential diagnosisDifferential diagnosis
child abusechild abuse intentional suffocationintentional suffocation
TUMORSTUMORSBenignBenign
MalignantMalignant
BENIGNBENIGNHemangiomasHemangiomasLymphatic TumorsLymphatic TumorsFibrous TumorsFibrous TumorsTeratomas (also can be Teratomas (also can be malignant)malignant)
HemangiomaHemangioma Benign tumor of blood vesselsBenign tumor of blood vessels Are the most common tumor of infancyAre the most common tumor of infancy Usually on skin, especially face and scalpUsually on skin, especially face and scalp Regress spontaneously in many casesRegress spontaneously in many cases
Congenital Capillary Hemangioma
At birth At 2 yearsAfter spontaneous regression
TeratomasTeratomas Composed of cells derived from more than Composed of cells derived from more than
one germ layer, usually all threeone germ layer, usually all three Sacrococcygeal teratomasSacrococcygeal teratomas
most common childhood teratomamost common childhood teratoma frequency 1:20,000 to 1:40,000 live birthsfrequency 1:20,000 to 1:40,000 live births 4 times more common in boys than girls4 times more common in boys than girls
Aproximately 12% are malignantAproximately 12% are malignant often composed of immature tissueoften composed of immature tissue occur in older childrenoccur in older children
Sacrococcygeal Teratoma
MALIGNANTMALIGNANT
Neuroblastic TumorsNeuroblastic TumorsWilms TumorWilms TumorIncidence and TypesIncidence and Types
TABLE 10-9 -- Common Malignant Neoplasms of Infancy and Childhood
0 to 4 Years 5 to 9 Years 10 to 14 Years
Leukemia Leukemia
Retinoblastoma Retinoblastoma
Neuroblastoma Neuroblastoma
Wilms tumor
Hepatoblastoma Hepatocarcinoma Hepatocarcinoma
Soft tissue sarcoma (especially rhabdomyosarcoma)
Soft tissue sarcoma Soft tissue sarcoma
Teratomas
Central nervous system tumors Central nervous system tumors
Ewing sarcoma
Lymphoma Osteogenic sarcoma
Thyroid carcinoma
Hodgkin disease
SmallSmall Round Blue Round Blue Cell Cell TumorsTumors
Frequent in pediatric tumorsFrequent in pediatric tumors Differential diagnosisDifferential diagnosis
LymphomaLymphoma NeuroblastomaNeuroblastoma Wilms tumorWilms tumor RhabdomyosarcomaRhabdomyosarcoma Ewings tumorEwings tumor
Diagnostic proceduresDiagnostic procedures immunoperoxidase stainsimmunoperoxidase stains electron microscopyelectron microscopy chromosomal analysis and molecular markerschromosomal analysis and molecular markers
NeuroblastomasNeuroblastomas Second most common malignancy of Second most common malignancy of
childhood (650 cases / year in USA)childhood (650 cases / year in USA) Neural crest originNeural crest origin
adrenal gland – 40 %adrenal gland – 40 % sympathetic ganglia – 60%sympathetic ganglia – 60%
In contrast to retinoblastoma, most are In contrast to retinoblastoma, most are sporadic but familiar forms do occursporadic but familiar forms do occur
Median age at diagnosis is 22 monthsMedian age at diagnosis is 22 months
Neuorblastoma Neuorblastoma MorphologyMorphology
Small round blue cell tumorSmall round blue cell tumor neuorpil formationneuorpil formation rosette formationrosette formation immunochemistry – neuron specific enolaseimmunochemistry – neuron specific enolase EM – secretory granules (catecholamine)EM – secretory granules (catecholamine)
Usual features of anaplasiaUsual features of anaplasia high mitotic rate is unfavorablehigh mitotic rate is unfavorable evidence of Schwann cell or ganglion evidence of Schwann cell or ganglion
differentiation favorabledifferentiation favorable Other prognostic predictors are used by Other prognostic predictors are used by
pathologists and oncologistspathologists and oncologists
Neuorblastoma
*Neuropil **Homer-Wright Rosettes
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Clinical Course and Clinical Course and PrognosisPrognosis
Hematogenous and lymphatic metastases to liver, Hematogenous and lymphatic metastases to liver, lungs and bonelungs and bone
90% produce catecholamines, but hypertension is 90% produce catecholamines, but hypertension is uncommonuncommon
Age and stage are most important prognosticallyAge and stage are most important prognostically < 1 year age: good prognosis regardless of stage< 1 year age: good prognosis regardless of stage
Amplification of N-myc oncogeneAmplification of N-myc oncogene present in 25-30% of cases and is unfavorablepresent in 25-30% of cases and is unfavorable up to 300 copies on N-myc has been observedup to 300 copies on N-myc has been observed
Risk StratificationRisk Stratification low risk: 90% cure ratelow risk: 90% cure rate high risk 20% cure ratehigh risk 20% cure rate
Wilms TumorWilms Tumor Most common primary renal tumor of Most common primary renal tumor of
childhoodchildhood Incidence 10 per million children < 15 yearsIncidence 10 per million children < 15 years Usually diagnosed between age 2-5Usually diagnosed between age 2-5 5 – 10 % are multi-focal, i.e., bilateral5 – 10 % are multi-focal, i.e., bilateral
synchronoussynchronous metachronousmetachronous
Clinical FeaturesClinical Features Most children present with a large Most children present with a large
abdominal massabdominal mass TreatmentTreatment
nephrectomy and combination chemotherapynephrectomy and combination chemotherapy
two year survival up to two year survival up to 90% even with spread 90% even with spread beyond the kidneybeyond the kidney
Pathogenesis of Wilms Pathogenesis of Wilms TumorTumor
10% of Wilms tumors arise in one of three 10% of Wilms tumors arise in one of three congenital malformation syndromes with congenital malformation syndromes with distinct chromosomal locidistinct chromosomal loci Familial disposition for Wilms is rare, and most Familial disposition for Wilms is rare, and most
of these patients have of these patients have de novode novo mutations mutations Nephrogenic rests of adjacent parenchymaNephrogenic rests of adjacent parenchyma
present in 40% of unilateral tumors, 100% of present in 40% of unilateral tumors, 100% of bilateral tumorsbilateral tumors
if found in one kidney, these rests predict an if found in one kidney, these rests predict an increased risk for tumor in the contralateral increased risk for tumor in the contralateral kidneykidney
Pathology of Wilms Pathology of Wilms TumorTumor
GrossGross well circumscribed fleshy tan tumorwell circumscribed fleshy tan tumor areas of hemorrhage and necrosisareas of hemorrhage and necrosis
Microscopic: triphasic appearanceMicroscopic: triphasic appearance BlastemaBlastema: small blue cells: small blue cells Epithelial elementsEpithelial elements: tubules & glomeruli: tubules & glomeruli Stromal elementsStromal elements
AnaplasiaAnaplasia correlates with p53 mutation and poor correlates with p53 mutation and poor
prognosis and resistance to chemotherapyprognosis and resistance to chemotherapy
Wilms Tumor