Transcript Ch10-Diseases of Infancy & Childhood

Diseases of
Infancy
& Childhood
Diseases of Infancy
and Childhood
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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
INFANT MORTALITY
USA 1970: 20
 USA 2000: 7
 USA WHITE: X
 USA BLACK: 2X
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SWEDEN 3
 INDIA 82
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Major Time Spans
 Neonatal
 first
period
four weeks of life
 Infancy
 the
first year of life
1 – 4 years (preschool)
 Age 5 – 14 years (school age)
 Age
MORTALITY by TIME SPAN
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NEONATE (0-4 WEEKS): CONGENITAL,
PREMATURITY
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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
Causes1
Rate 2
Under 1 Year: All
727.4
Causes
1–4 Years: All
32.6
Causes
5–14 Years: All
18.5
Causes
15–24 Years: All
80.7
Causes
1Rates
are expressed per 100,000 population
congenital heart disease
2Excludes
Congenital Anomalies
Definitions
Causes
Pathogenesis
• 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 Survival of
Early Pregnancy
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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
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
Frequency
Cause
(%)
Genetic
Chromosomal aberrations
10–15
Mendelian inheritance
2–10
Environmental
Maternal/placental infections
Maternal disease states
Drugs and chemicals
Irradiations
Multifactorial (Multiple Genes ?
Environment)
Unknown
2–3
6–8
1
1
20–25
40–60
Adapted from Stevenson RE, et al (eds): Human Malformations and Related Anomalies.
New York, Oxford University Press, 1993, p. 115.
Embryonic Development
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Embryonic period
weeks 1- 8 of pregnancy
 organogenesis occurs in this period
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Fetal period
weeks 9 to 38
 marked by further growth and maturation
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Critical Periods Of Development
Genetic Causes
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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
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Single gene mutations
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covered 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 Chemicals
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Drugs
13 cis-retinoic acid (acne agent)
 warfarin
 angiotensin converting enzyme inhibitors
(ACEI)
 anticonvulsants
 oral diabetic agents
 thalidomide
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Alcohol
Tobacco
Teratogen Actions
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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
Diabetes Mellitus
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Fetal Macrosomy (>10 pounds)
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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
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Oral agents not approved in pregnancy
Diabetics attempting to conceive should be
placed on insulin
Birth Weight and Gestational Age
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Appropriate for gestational age (AGA)
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between 10 and 90th percentile for gestational
age
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Small for gestational age (SGA) , <10%
Large for gestational age (LGA) , >90%
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Preterm
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born before 37 weeks (<2500 grams)
Post-Term
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delivered after 42 weeks
Prematurity
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Defined as gestational age <
37 weeks
Second most common cause of neonatal
mortality (after congenital anomalies)
Risk factors for prematurity
Preterm Premature Rupture Of fetal
Membranes (PPROM)
 Intrauterine infection
 Uterine, cervical, and placental abnormalities
 Multiple gestation
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Fetal Growth Restriction
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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
Maternal
Fetal FGR
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Chromosomal abnormalities
17% of FGR overall
 up to 66% of fetuses with ultrasound
malformations
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Fetal Infection
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Infection: TORCH (Toxoplasmosis, Other,
Rubella, Cytomegalovirus, Herpes)
Characterized by symmetric growth
restriction – head and trunk proportionally
involved
Placental FGR
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Vascular
umbilical cord anomalies (single artery,
constrictions, etc)
 thrombosis and infarction
 multiple gestation
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Confined placental mosaicism
mutation in trophoblast
 trisomy is common
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Placental FGR tends to cause
asymmetric growth with relative
sparing of the head
Maternal FGR
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Most common cause of FGR by far
Vascular diseases
preeclampsia (toxemia of pregnancy)
 hypertension
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Toxins
ethanol
 narcotics and cocaine
 heavy smoking
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Organ Immaturity
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Lungs
alveoli differentiate in 7th month
 surfactant deficiency
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Kidneys
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glomerular differentiation is incomplete
Brain
impaired homeostasis of temperature
 vasomotor control unstable
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Liver
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inability to conjugate and excrete bilirubin
APGAR (Appearance, Pulse, Grimace, Activity, Respiration)
Evaluation Of The Newborn Infant
Sign
Heart rate
Respiratory
effort
Muscle tone
0
Absent
Absent
1
Below 100
Slow, irregular
Limp
Response to
catheter in
nostril (tested
after
oropharynx is
clear)
Color
No
response
Some flexion of Active motion
extremities
Grimace
Cough or
sneeze
Blue, pale
2
Over 100
Good, crying
Body pink,
Completely
extremities blue pink
Data from Apgar V: A proposal for a new method of evaluation of the
newborn infant. Anesth Analg 32:260, 1953.
Apgar Score and 28 Day Mortality
 Score
may be evaluated at 1 and
5 minutes
 5 minute scores
 0-1,
50% mortality
 4, 20% mortality
 ≥ 7, 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)
• 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 Factors
1)
Prematurity
by far the greatest risk factor
 affected infants are nearly always premature
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2) Maternal diabetes mellitus
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insulin suppresses surfactant secretion
3) Cesarean delivery
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normal delivery process stimulates surfactant
secretion
RDS Pathology
 Gross
solid and airless (no crepitance)
 sink in water
 appearance is similar to liver tissue*
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 Microscopic
atelectasis and dilation of alveoli
 hyaline membranes composed of fibrin and
cell debris line alveoli (HMD former name)
 minimal inflammation
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V/Q
Mismatch
RDS Prevention and Treatment
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Delay labor until fetal lung is mature
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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
Treatment Complications
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Oxygen toxicity
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Retrolental fibroplasia
 hypoxia causes ↑ Vascular Endothelial Growth Factor
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oxygen derived free radicals damage tissue
(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
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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
Necrotizing Enterocolitis
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Incidence is directly proportional to
prematurity, like RDS
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approaches 10% with severe prematurity
2000 cases yearly in USA
Pathogenesis
not fully understood
 intestinal ischemia
 inflammatory mediators
 breakdown of mucosal barrier
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Necrotizing Enterocolitis
Hydrops Fetalis
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Chromosomal abnormalities
Turner syndrome with cystic hygromas
 other
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Cardiovascular with heart failure
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anemia with high output failure
immune hemolytic anemia
 hereditary hemolytic anemia (α-thalassemia)
 parvovirus B19 infection
 twin to twin in utero transfusion
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congenital heart defects
Hydrops Fetalis
Immune Hydrops
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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
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mother is Rh Neg and fetus is Rh Pos
ABO and other antigens involved less often
Pathogenesis of Sensitization
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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)
Treatment of Immune Hydrops
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In utero
identification of at risk infants via blood typing
by amniocentesis, (Chorionic Villi Sampling)
CVS, or fetal blood sampling
 fetal transfusions via umbilical cord
 early delivery
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Live born infant
monitoring of hemoglobin and bilirubin
 exchange transfusions
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Kernicterus
Pathogenesis of Immune Hydrops
Inborn Errors of Metabolism
(Genetic)
PhenylKetonUria (PKU)
Galactosemia
Cystic
Fibrosis (CF)
(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 Fibrosis
 Normal
Gene
 Mutational Spectra
 Genetic/Environmental Modifiers
 Morphology
 Clinical Course
Cystic Fibrosis (Mucoviscidosis)
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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
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Widespread disorder in epithelial chloride
transport affecting fluid secretion in
 exocrine glands
 epithelial lining of the respiratory,
gastrointestinal, and reproductive tracts
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Abnormally viscid mucus secretions
Cellular Metabolism Of The Cystic Fibrosis
Transmembrane Regulator (CFTR)
Harrison’s Internal Med, 16th Ed
CFTR Gene: Normal
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Cystic Fibrosis Transmembrane Conductance
Regulator (CFTR)
CTFR → epithelial chloride channel protein
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Sweat gland
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agonist induced regulation of the chloride channel
interacts with epithelial sodium channels (ENaC)
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
CFTR Gene: Cystic Fibrosis
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Sweat gland
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CTFR absence decreases luminal Cl− resorption
ENaC decreases Na+ resorption
sweat is hypertonic
Respiratory and Intestinal epithelium
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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
CFTR Gene: Mutational Spectra
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More than 800 mutations are known
These are grouped into six classes
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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
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Other genes and environment further
modify expression of CFTR
Clinical Manifestations Of Mutations In The Cystic
Fibrosis Gene
Organ Pathology
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Plugging of ducts with viscous mucus and loss of
ciliary function of respiratory mucosa
Pancreas
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Liver
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plugging of bile canaliculi with portal inflamation
biliary cirrhosis may develop
Genitalia
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atrophy of exocrine pancreas with fibrosis
islets are not affected
Absence of vas deferens and azoospermia
Sweat glands
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normal 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 Diagnosis
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Clinical criteria
sinopulmonary
 gastrointestinal
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pancreatic
 intestinal
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salt loss
 male genital tract
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Sweat chloride analysis
Nasal transepithelial potential difference
DNA Analysis
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gene sequencing
Clinical Course and Treatment
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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

Sudden Infant Death
Syndrome (SIDS)
Epidemiology
Morphology
Pathogenesis
Sudden Infant Death Syndrome
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NIH Definition
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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
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another name based on the fact that most die
in their sleep
Epidemology of SIDS
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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
Morphology of SIDS
exclusion

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
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Subtle changes in brain stem neurons
Autopsy typically reveals no clear cause of
death
Pathogenesis of SIDS
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Generally accepted to be multifactorial
Triple risk model
Vulnerable infant
 Critical development period in homeostatic
control
 Exogenous stressors

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Brain stem abnormalities, associated
defective arousal, and cardio-respiratory
control
Prevention of SIDS

Maternal factors
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attention to risk factors previously mentioned
redress problems in medical care for underprivileged
Environmental
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avoid prone sleeping
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Avoid sleeping on soft surfaces
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back to sleep program: infant should sleep in supine position
no pillows, comforters, quilts, sheepskins, and stuffed toys
Sleeping clothing (such as a sleep sack) may be used in
place of blankets.
Avoid hyperthermia

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
no excessive blankets
set thermostat to appropriate temperature
avoid space heaters
Diagnosis of SIDS
exclusion

SIDS is a diagnosis of

Complete autopsy
Examination of the death scene
Review of the clinical history
Differential diagnosis

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child abuse
 intentional suffocation
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TUMORS
Benign
Malignant
BENIGN
Hemangiomas
Lymphatic
Tumors
Fibrous Tumors
Teratomas (also can be
malignant)
Hemangioma
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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
Teratomas


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

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Aproximately 12% are malignant
often composed of immature tissue
 occur in older children

Sacrococcygeal Teratoma
MALIGNANT
Neuroblastic
Tumors
Wilms Tumor
Incidence and Types
TABLE 10-9 -- Common Malignant Neoplasms of Infancy and Childhood
0 to 4 Years
5 to 9 Years
Leukemia
Leukemia
Retinoblastoma
Retinoblastoma
Neuroblastoma
Neuroblastoma
10 to 14 Years
Wilms tumor
Hepatoblastoma
Hepatocarcinoma
Soft tissue sarcoma (especially Soft tissue sarcoma
rhabdomyosarcoma)
Hepatocarcinoma
Soft tissue sarcoma
Teratomas
Central nervous system tumors Central nervous system
tumors
Ewing sarcoma
Lymphoma
Osteogenic sarcoma
Thyroid carcinoma
Hodgkin disease
Small

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Round Blue 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

Neuroblastomas
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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
Neuorblastoma Morphology

Small round blue cell tumor
neuorpil formation
 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
Neuorblastoma
**
*
*Neuropil
**Homer-Wright Rosettes
Clinical Course and Prognosis



Hematogenous and lymphatic metastases to liver,
lungs and bone
90% produce catecholamines, but hypertension is
uncommon
Age and stage are most important prognostically

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Amplification of N-myc oncogene



< 1 year age: good prognosis regardless of stage
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
Wilms Tumor




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

Clinical Features


Most children present with a large
abdominal mass
Treatment

nephrectomy and combination chemotherapy
two
year survival up to
90% even with spread
beyond the kidney
Pathogenesis of Wilms Tumor

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

Pathology of Wilms Tumor

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