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