I n f a n c y
C h i l d h o o d

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Congenital Anomalies
Birth Weight and Gestational Age
Birth Injuries
Perinatal Infections
Respiratory Distress Syndrome (RDS)
Necrotizing Enterocolitis
Intraventricular Hemorrhage
Hydrops
Inborn Metabolic/Genetic Errors
Sudden Infant Death Syndrome (SIDS)
Tumors

 USA 1970: 20
 USA 2000: 7
 USA WHITE: X
 USA BLACK: 2X
 SWEDEN 3
 INDIA 82

 Neonatal period
 first four weeks of life
 Infancy
 the first year of life
 Age 1 – 4 years (preschool)
 Age 5 – 14 years (school age)

 NEONATE (0-4 WEEKS): CONGENITAL,
PREMATURITY
 UNDER ONE YEAR: CONGENITAL,
PREMATURITY/WEIGHT, SIDS
 1-4 YEARS: ACCIDENTS, CONGENITAL,
TUMORS
 5-14 YEARS: ACCIDENTS, TUMORS,
HOMICIDES
 15-24 YEARS: ACCIDENTS, HOMICIDE,
SUICIDE ( NONE ARE “NATURAL” CAUSES )

Cause of Death Related with Age
Causes
1
Rate
2
Under 1 Year: All
Causes
1 –4 Years: All
Causes
5 –14 Years: All
Causes
15 –24 Years: All
Causes
727.4
32.6
18.5
80.7
1 Rates are expressed per 100,000 population
2 Excludes congenital heart disease

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• 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

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

• 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 Survival of
Early Pregnancy
 Only 50-60% of all conceptions advance beyond 20 weeks
 Implantation occurs at day 6-7
 75% of loses are implantation failures and are not recognized
 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
Ventricular septal defect
Cleft lip with or without cleft palate
Spina bifida without anencephalus
16.9
10.9
9.1
5.5
Congenital hydrocephalus without anencephalus
Anencephalus
Reduction deformity (musculoskeletal)
4.8
3.9
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.

#2
#1
#3

• Genetic
• karyotypic aberrations
• single gene mutations
• Environmental
• infection
• maternal disease
• drugs and chemicals
• irradiation
• Multifactorial

Causes of Congenital Anomalies in Humans
Cause
Genetic
Chromosomal aberrations
Mendelian inheritance
Frequency
(%)
10–15
2–10
Environmental
Maternal/placental infections 2–3
Maternal disease states
Drugs and chemicals
Irradiations
6–8
1
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 period
 weeks 1- 8 of pregnancy
 organogenesis occurs in this period
 Fetal period
 weeks 9 to 38
 marked by further growth and maturation

Critical Periods Of Development

 Karyotypic abnormalities
 80-90% of fetuses with aneuploidy die in utero
 trisomy 21 (Down syndrome) most common karyotypic abnormality (21,18,13)
 sex chromosome abnormalities next most common (Turner and Klinefelter)
 autosomal chromosomal deletion usually lethal
 karyotyping frequently done with aborted fetuses with repeated abortions
 Single gene mutations
 covered in separate chapters

• 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

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 13 cis-retinoic acid (acne agent)
 warfarin
 angiotensin converting enzyme inhibitors
(ACEI)
 anticonvulsants
 oral diabetic agents
 thalidomide
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• Proper cell migration to predetermined locations that influence the development of other structures
• Cell proliferation , which determines the size and form of embryonic organs
• Cellular interactions among tissues derived from different structures (e.g., ectoderm, mesoderm), which affect the differentiation of one or both of these tissues
• Cell-matrix associations , which affect growth and differentiation
• Programmed cell death ( apoptosis ) , which, as we have seen, allows orderly organization of tissues and organs during embryogenesis
• Hormonal influences and mechanical forces , which affect morphogenesis at many levels

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Fetal Macrosomy (>10 pounds)
 maternal hyperglycemia increases insulin secretion by fetal pancreas, insulin acts with growth hormone effects
 Diabetic Embryopathy
 most crucial period is immediately post fertilization
 malformations increased 4-10 fold with uncontrolled diabetes, involving heart and CNS
 Oral agents not approved in pregnancy
 Diabetics attempting to conceive should be placed on insulin

 Appropriate for gestational age (AGA)
 between 10 and 90 th percentile for gestational age
 Small for gestational age ( SGA ) , <10%
 Large for gestational age ( LGA ) , >90%
 Preterm
 born before
37 weeks (<2500 grams)
 Post-Term
 delivered after
42 weeks

 Defined as gestational age
< 37 weeks
 Second most common cause of neonatal mortality (after congenital anomalies)
 Risk factors for prematurity
 Preterm P remature R upture O f fetal
M embranes (PPROM)
 Intrauterine infection
 Uterine, cervical, and placental abnormalities
 Multiple gestation

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At least 1/3 of infants born at term are < 2.5kg
 Undergrown rather than immature
 Commonly underlies SGA (small for gestational age)
 Prenatal diagnosis: ultrasound measurements
 Classification
 Fetal
 Placental
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 Chromosomal abnormalities
 17% of FGR overall
 up to 66% of fetuses with ultrasound malformations
 Fetal Infection
 Infection: TORCH (
T oxoplasmosis,
O ther,
R ubella, C ytomegalovirus, H erpes)
 Characterized by symmetric growth restriction – head and trunk proportionally involved

 Vascular
 umbilical cord anomalies (single artery, constrictions, etc)
 thrombosis and infarction
 multiple gestation
 Confined placental mosaicism
 mutation in trophoblast
 trisomy is common
 Placental FGR tends to cause asymmetric growth with relative sparing of the head

 Most common cause of FGR by far
 Vascular diseases
 preeclampsia (toxemia of pregnancy)
 hypertension
 Toxins
 ethanol
 narcotics and cocaine
 heavy smoking

 Lungs
 alveoli differentiate in 7 th month
 surfactant deficiency
 Kidneys
 glomerular differentiation is incomplete
 Brain
 impaired homeostasis of temperature
 vasomotor control unstable
 Liver
 inability to conjugate and excrete bilirubin

( A ppearance, P ulse, G rimace, A ctivity, R espiration)
Evaluation Of The Newborn Infant
Sign
Heart rate
Respiratory effort
Muscle tone Limp
0
Absent
Absent
1
Below 100
2
Over 100
Slow, irregular Good, crying
Some flexion of extremities
Grimace
Active motion
Response to catheter in nostril (tested after oropharynx is clear)
No response
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.

 Score may be evaluated at 1 and
5 minutes
 5 minute scores
 0-1, 50% mortality
 4, 20% mortality
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≥ 7, nearly 0% mortality

• 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

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

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 by far the greatest risk factor
 affected infants are nearly always premature
 2) Maternal diabetes mellitus
 insulin suppresses surfactant secretion
 3) Cesarean delivery
 normal delivery process stimulates surfactant secretion

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 solid and airless (no crepitance)
 sink in water
 appearance is similar to liver tissue*
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 atelectasis and dilation of alveoli
 hyaline membranes composed of fibrin and cell debris line alveoli (HMD former name)
 minimal inflammation

 Delay labor until fetal lung is mature
 amniotic fluid phospholipid levels are useful in assessing fetal lung maturity
 Induce fetal lung maturation with antenatal corticosteriods
 Postnatal surfactant replacement therapy with oxygen and ventilator support

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Oxygen toxicity
 oxygen derived free radicals damage tissue
Retrolental fibroplasia
 hypoxia causes ↑ V ascular E ndothelial G rowth F actor
( VEGF ) and angiogenesis
 Oxygen Rx suppresses VEGF and causes endothelial apoptosis
Bronchopulmonary “dysplasia”
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 oxygen suppresses lung septation at the saccular stage mechanical ventilation
 epithelial hyperplasia, squamous metaplasia, and peribronchial and interstitial fibrosis were seen with old regimens of ventilator usage and no surfactant use, but are now uncommon
 lung septation is still impaired

 Incidence is directly proportional to prematurity, like RDS
 approaches 10% with severe prematurity
 2000 cases yearly in USA
 Pathogenesis
 not fully understood
 intestinal ischemia
 inflammatory mediators
 breakdown of mucosal barrier

 Chromosomal abnormalities
 Turner syndrome with cystic hygromas
 other
 Cardiovascular with heart failure
 anemia with high output failure
 immune hemolytic anemia
 hereditary hemolytic anemia (α-thalassemia)
 parvovirus B19 infection
 twin to twin in utero transfusion
 congenital heart defects

Hydrops Fetalis

 Fetus inherits red cell antigens from the father that are foreign to the mother
 Mother forms IgG antibodies which cross the placenta and destroy fetal RBCs
 Fetus develops severe anemia with CHF and compensatory ↑ hematopoiesis
(frequently extramedullary)
 Most cases involve Rh D antigen
 mother is Rh Neg and fetus is Rh Pos
 ABO and other antigens involved less often

 Fetal RBCs gain access to maternal circulation largely at delivery or upon abortion
 Since IgM antibodies are involved in primary response and prior sensitization is necessary, the first pregnancy is not usually affected
 Maternal sensitization can be prevented in most cases with Rh immune globulin
(Rhogam) given at time of delivery or abortion (spontaneous or induced)

 In utero
 identification of at risk infants via blood typing by amniocentesis, ( C horionic V illi S ampling)
CVS, or fetal blood sampling
 fetal transfusions via umbilical cord
 early delivery
 Live born infant
 monitoring of hemoglobin and bilirubin
 exchange transfusions

Pathogenesis of Immune Hydrops

 P
K
U
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 C
F

• 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

• 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

 Normal Gene
 Mutational Spectra
 Genetic/Environmental Modifiers
 Morphology
 Clinical Course

 Autosomal recessive
 Most common lethal genetic disease affecting Caucasians (1 in 3,200 live births in the USA)
 2-4% of population are carriers
 Uncommon in Asians and African-Americans
 Widespread disorder in epithelial chloride transport affecting fluid secretion in
 exocrine glands
 epithelial lining of the respiratory, gastrointestinal, and reproductive tracts
 Abnormally viscid mucus secretions

Cellular Metabolism Of The Cystic Fibrosis
Transmembrane Regulator (CFTR)
Harrison’s Internal Med, 16 th Ed

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C ystic F ibrosis T ransmembrane Conductance
R egulator ( CFTR )
CTFR → epithelial chloride channel protein
 agonist induced regulation of the chloride channel
 interacts with epithelial sodium channels (ENaC)
Sweat gland
 CTFR activation increases luminal Cl
− resorption
 ENaC increases Na + resorption
 sweat is hypotonic
Respiratory and Intestinal epithelium
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CTFR activation increases active luminal secretion of chloride
ENaC is inhibited

 Sweat gland
 CTFR absence decreases luminal Cl
− resorption
 ENaC decreases Na + resorption
 sweat is hypertonic
 Respiratory and Intestinal epithelium
 CTFR absence decreases active luminal secretion of chloride
 lack of inhibition of ENaC is opens sodium channel with active resorption of luminal sodium
 secretions are decreased but isotonic

Chloride Channel Defect and Effects

 More than 800 mutations are known
 These are grouped into six classes
 mild to severe
 Phenotype is correlated with the combination of these alleles
 correlation is best for pancreatic disease
 genotype-phenotype correlations are less consistent with pulmonary disease
 Other genes and environment further modify expression of CFTR

Clinical Manifestations Of Mutations In The Cystic
Fibrosis Gene

 Plugging of ducts with viscous mucus and loss of ciliary function of respiratory mucosa
 Pancreas
 atrophy of exocrine pancreas with fibrosis
 islets are not affected
 Liver
 plugging of bile canaliculi with portal inflamation
 biliary cirrhosis may develop
 Genitalia
 Absence of vas deferens and azoospermia
 Sweat glands
 normal histology

• 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

 Clinical criteria
 sinopulmonary
 gastrointestinal
 pancreatic
 intestinal
 salt loss
 male genital tract
 Sweat chloride analysis
 Nasal transepithelial potential difference
 DNA Analysis
 gene sequencing

 Highly variable – median life expectance is
30 years
 7% of patients in the United States are diagnosed as adults
 Clearing of pulmonary secretions and treatment of pulmonary infection
 Transplantation
 lung
 liver-pancreas

S
I
D
S
SIDS
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 NIH Definition
 sudden death of an infant under 1 year of age which remains unexplained after a thorough case investigation, including performance of a complete autopsy, examination of the death scene, and review of the clinical history
 Crib death
 another name based on the fact that most die in their sleep

 Leading cause of death in USA of infants between 1 month and 1 year of age

90% of deaths occur ≤ 6 months age, mostly between 2 and 4 months
 In USA 2,600 deaths in 1999 (down from
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

 SIDS is a diagnosis of
 Non-specific autopsy findings
 Multiple petechiae
 Pulmonary congestion ± pulmonary edema
 These may simply be agonal changes as they are found in non-SIDS deaths also
 Subtle changes in brain stem neurons
 Autopsy typically reveals no clear cause of death

 Generally accepted to be multifactorial
 Triple risk model
 Vulnerable infant
 Critical development period in homeostatic control
 Exogenous stressors
 Brain stem abnormalities, associated defective arousal, and cardio-respiratory control

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Maternal factors
 attention to risk factors previously mentioned
 redress problems in medical care for underprivileged
Environmental
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 avoid prone sleeping
 back to sleep program: infant should sleep in supine position
Avoid sleeping on soft surfaces
 no pillows, comforters, quilts, sheepskins, and stuffed toys
 Sleeping clothing (such as a sleep sack) may be used in place of blankets.
Avoid hyperthermia
 no excessive blankets
 set thermostat to appropriate temperature
 avoid space heaters

 SIDS is a diagnosis of
 Complete autopsy
 Examination of the death scene
 Review of the clinical history
 Differential diagnosis
 child abuse
 intentional suffocation

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 Benign tumor of blood vessels
 Are the most common tumor of infancy
 Usually on skin, especially face and scalp
 Regress spontaneously in many cases

Congenital Capillary Hemangioma
At birth
At 2 years
After spontaneous regression

 Composed of cells derived from more than one germ layer, usually all three
 Sacrococcygeal teratomas
 most common childhood teratoma
 frequency 1:20,000 to 1:40,000 live births
 4 times more common in boys than girls
 Aproximately 12% are malignant
 often composed of immature tissue
 occur in older children

Sacrococcygeal Teratoma

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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
Neuroblastoma
Wilms tumor
Hepatoblastoma
Retinoblastoma
Neuroblastoma
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

Small
Cell Tumors
 Frequent in pediatric tumors
 Differential diagnosis
 Lymphoma
 Neuroblastoma
 Wilms tumor
 Rhabdomyosarcoma
 Ewings tumor
 Diagnostic procedures
 immunoperoxidase stains
 electron microscopy
 chromosomal analysis and molecular markers

 Second most common malignancy of childhood (650 cases / year in USA)
 Neural crest origin
 adrenal gland – 40 %
 sympathetic ganglia – 60%
 In contrast to retinoblastoma, most are sporadic but familiar forms do occur
 Median age at diagnosis is 22 months

 Small round blue cell tumor
 neuorpil formation
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 rosette formation immunochemistry – neuron specific enolase
EM – secretory granules (catecholamine)
 Usual features of anaplasia
 high mitotic rate is unfavorable
 evidence of Schwann cell or ganglion differentiation favorable
 Other prognostic predictors are used by pathologists and oncologists

*
*Neuropil
Neuorblastoma
**
**Homer-Wright Rosettes

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Hematogenous and lymphatic metastases to liver, lungs and bone
90% produce catecholamines, but hypertension is uncommon
Age and stage are most important prognostically
 < 1 year age: good prognosis regardless of stage
Amplification of N-myc oncogene
 present in 25-30% of cases and is unfavorable
 up to 300 copies on N-myc has been observed
Risk Stratification
 low risk: 90% cure rate
 high risk 20% cure rate

 Most common primary renal tumor of childhood
 Incidence 10 per million children < 15 years
 Usually diagnosed between age 2-5
 5 – 10 % are multi-focal, i.e., bilateral
 synchronous
 metachronous

 Most children present with a large abdominal mass
 Treatment
 nephrectomy and combination chemotherapy


 10% of Wilms tumors arise in one of three congenital malformation syndromes with distinct chromosomal loci
 Familial disposition for Wilms is rare, and most of these patients have de novo mutations
 Nephrogenic rests of adjacent parenchyma
 present in 40% of unilateral tumors, 100% of bilateral tumors
 if found in one kidney, these rests predict an increased risk for tumor in the contralateral kidney

 Gross
 well circumscribed fleshy tan tumor
 areas of hemorrhage and necrosis
 Microscopic: triphasic appearance
 Blastema : small blue cells
 Epithelial elements : tubules & glomeruli
 Stromal elements
 Anaplasia
 correlates with p53 mutation and poor prognosis and resistance to chemotherapy

Wilms Tumor