Diseases of Infancy

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CHAPTER 10

• Diseases of Infancy
• And Childhood

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Diseases of Infancyand Childhood

• 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

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Major Time Spans

• Neonatal period
• first four weeks of life
• Infancy
• the first year of life
• Age 1 4 years
• Age 5 14 years

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1Rates are expressed per 100,000 population
2Excludes congenital heart disease
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Congenital Anomalies

• Causes
• Definitions
• Pathogenesis

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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
• e.g. uterine constraint
• Sequence
• a pattern of cascade anomalies not explained by a
  single localized initiating event
• e.g. Oligohydramnios (Or Potter) Sequence
• Syndrome
• a constellation of developmental abnormalities
  believed to be palthologically related
• e.g Turner syndrome

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Malformations
Polydactyly syndactyly
Cleft Lip
Severe Lethal Malformation
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Disruption by an amniotic band
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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
  develolpment

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The Oligohydramnios Sequence
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Infant with oligohydramnios sequence
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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.

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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 3451400-1408
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CAUSES OF ANOMALIES

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

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Embryonic Development

• Embryonic period
• weeks 1- 8 of pregnancy
• organogenesis occurs in this period
• Fetal period
• weeks 9 to 38
• marked by further growth and maturation

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Critical Periods Of Development
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Genetic Causes

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

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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

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Drugs and Chemicals

• Drugs
• 13 cis-retinoic acid (acne agent)
• warfarin
• angiotensin converting enzyme inhibitors (ACEI)
• anticonvulsants
• oral diabetic agents
• thalidomide
• Alcohol
• Tobacco

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Diabetes Mellitus

• Fetal macrosomy (gt10 pounds)
• maternal hyperglycemia increases insulin
  secretion by fetal pancreas
• 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

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Multifactorial Causes

• More than half of anomalies have no known cause
  and may be multifactorial
• Folic acid deficiency is associated with neural
  tube defects

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Birth Weight and Gestational Age

• Appropriate for gestational age (AGA)
• between 10 and 90th percentile for gestational
  age
• Small for gestational age (SGA)
• Large for gestational age (LGA)
• Preterm
• born before 37 weeks
• Post-Term
• delivered after 42 weeks

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Prematurity

• Defined as gestational age lt 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

• At least 1/3 of infants born at term are lt 2500g
• Undergrown rather than immature
• Commonly underlies SGA (small for gestational
  age)
• Prenatal diagnosis ultrasound measurements
• Classification
• Fetal
• Placental
• Maternal

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Fetal FGR

• Chromosomal abnormalities
• 17 of FGR overall
• up to 66 of fetuses with ultrasound
  malformations
• Fetal Infection
• Infection TORCH (Toxoplasmosis, Other, Rubella,
  Cytomegalovirus, Herpes)
• Characterized by symmetric growth restriction

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Placental FGR

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

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Constitutional Chromosomal Mosaicism
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Maternal FGR

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

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Organ Immaturity

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

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Fetal Lung Maturation
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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

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Birth Injuries(listed in order of frequency)

• Clavicular fracture
• Facial nerve injury
• Brachial plexus injury
• Intracranial injury
• Humeral fracture
• Lacerations

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Head Injuries

• Intracranial hemorrhage
• most common important birth injury
• Caput succedaneum
• congestion and edema of vertex of head
• of little consequence
• Cephalhematmoa
• 25 are associated with skull fracture
• otherwise of little consequence

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Perinatal Infection

• Transcervical (ascending)
• inhalation of infected amniotic fluid
• pneumonia, sepsis, meningitis
• commonly occurs with PROM
• passage through infected birth canal
• herpes virus
• Transplacental (hematogenous)
• mostly viral and parasitic
• HIVat delivery with maternal to fetal
  transfusion
• TORCH
• parvovirus B19
• bacterial
• Listeria monocytogenes

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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

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RDS Prevention and Treatment

• 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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RDS Pathology

• Gross
• solid and airless (no crepitance)
• sink in water
• Microscopic
• atelectasis and dilation of alveoli
• hyaline membranes
• line alveoli
• composed of fibrin and cell debris
• little inflamation

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Treatment Complications

• Oxygen toxicity
• oxygen derived free radicals damage tissue
• Retrolental fibroplasia
• hypoxia causes ? Vascular Endothelial Growth
  Factor (VEGF) and angiogenesis
• Oxygen Rx suppresses VEGF and causes endothelial
  apoptosis
• Bronchopulmonary dysplasia
• oxygen suppresses lung septation at the saccular
  stage
• mechanical ventilation
• epithelial hyperplasia, squamous metaplasia, and
  peribronchial and interstitual fibrosis were seen
  with old regimens of ventilator usage and no
  surfactant use, but are now uncommon
• lung septation is still impaired

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Necrotizing Enterocolitis

• Incidence is inversely proportional to
  gestational age
• 2000 cases yearly in USA
• Pathogenesis
• not fully understood
• intestinal ischemia
• inflammatory mediators
• breakdown of mucosal barrier

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Necrotizing Enterocolitis
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Germinal Matrix Hemorrhage

• Ependyma lining of ventricles
• Subependymal (germinal matrix) tissue is
  sensitive to hypoxia and decreased perfusion
  pressure
• Apnea is a risk factor
• Subependymal hemorrhage occurs in up to 40-50 of
  infants lt 1500 grams

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Hydrops Fetalis

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

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Hydrops Fetalis
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Immune Hydrops

• 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

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Pathogenesis of Sensitization

• 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)

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Treatment of Immune Hydrops

• In utero
• identification of at risk infants via blood
  typing by amniocentesis, CVS, or fetal blood
  sampling
• fetal transfusions via umbilical cord
• early delivery
• Live born Infant
• monitoring of hemoglobin and bilirubin
• exchange transfusions

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Kernicterus
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Pathogenesis of Immune Hydrops
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Inborn Errors of Metabolism(Genetic)

• PhenylKetonUria (PKU)
• Galactsemia
• Cystic Fibrosis (CF) (Mucoviscidosis)

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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

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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

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Cystic Fibrosis

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

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Cystic Fibrosis (Mucoviscidosis)

• 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

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CFTR Structure And Activation
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Cellular Metabolism Of The Cystic Fibrosis
Transmembrane Regulator (CFTR)
Harrisons Internal Med, 16th Ed
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CFTR Gene Normal

• Cystic Fibrosis Transmembrane Conductance
  Regulator (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
• CTFR activation increases active luminal
  secretion of chloride
• ENaC is inhibited

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CFTR Gene Cystic Fibrosis

• 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

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Chloride Channel Defect and Effects
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CFTR Gene Mutational Spectra

• 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

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Clinical Manifestations Of Mutations In The
Cystic Fibrosis Gene
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Organ Pathology

• 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

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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

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Cystic Fibrosis Clinical Manifestations
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CF Diagnosis

• Clinical criteria
• Sweat chloride analysis
• Nasal transepithelial potential difference
• DNA Analysis
• gene sequencing

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Clinical Course and Treatment

• 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

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Sudden Infant Death Syndrome (SIDS)

• Epidemiology
• Morphology
• Pathogenesis

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Sudden Infant Death Syndrome

• 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

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Epidemology of SIDS

• 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)

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Risk Factors for SIDS

• Parental
• Young maternal age (age lt20 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

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Morphology of SIDS

• SIDS is a diagnosis of exclusion
• 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

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Pathogenesis of SIDS

• 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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Prevention of SIDS

• Maternal factors
• attention to risk factors previously mentioned
• redress problems in medical care for
  underprivileged
• Environmental
• 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

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Diagnosis of SIDS

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

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TUMORS

• Benign
• Malignant

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BENIGN

• Hemangiomas
• Lymphatic Tumors
• Fibrous Tumors
• Teratomas (also can be malignant)

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Hemangioma

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

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Congenital Capillary Hemangioma
At 2 years After spontaneous regression
At birth
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Teratomas

• Composed of cells derived from more than one germ
  layer, usually all three
• Sacrococcygeal teratomas
• most common childhood teratoma
• frequency 120,000 to 140,000 live births
• 4 times more common in boys than girls
• Aproximately 12 are malignant
• often composed of immature tissue
• occur in older children

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Sacrococcygeal Teratoma
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MALIGNANT

• Incidence and Types
• Neuroblastic Tumors
• Wilms Tumor

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Small 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

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Neuroblastomas

• 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

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Neuorblastoma Morphology

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

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Neuorblastoma


Neuropil Homer-Wright Rosettes
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Ganglioneuroblastoma Gross View
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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
• lt 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

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FISH for N-myc in Neuroblastoma
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Wilms Tumor

• Most common primary renal tumor of childhood
• Incidence 10 per million children lt 15 years
• Usually diagnosed between age 2-5
• 5 10 are multi-focal
• synchronous
• metachronous

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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

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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

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Wilms Tumor
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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