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Diseases of Infancy

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Title: Diseases of Infancy


1
CHAPTER 10
  • Diseases of Infancy
  • And Childhood

2
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

3
Major Time Spans
  • Neonatal period
  • first four weeks of life
  • Infancy
  • the first year of life
  • Age 1 4 years
  • Age 5 14 years

4
1Rates are expressed per 100,000 population
2Excludes congenital heart disease
5
Congenital Anomalies
  • Causes
  • Definitions
  • Pathogenesis

6
  • 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

7
Malformations
Polydactyly syndactyly
Cleft Lip
Severe Lethal Malformation
8
Disruption by an amniotic band
9
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

10
The Oligohydramnios Sequence
11
Infant with oligohydramnios sequence
12
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.

13
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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15
CAUSES OF ANOMALIES
  • Genetic
  • karyotypic aberrations
  • single gene mutations
  • Environmental
  • infection
  • maternal disease
  • drugs and chemicals
  • irradiation
  • Multifactorial
  • Unknown

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17
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

18
Critical Periods Of Development
19
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

20
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

21
Drugs and Chemicals
  • Drugs
  • 13 cis-retinoic acid (acne agent)
  • warfarin
  • angiotensin converting enzyme inhibitors (ACEI)
  • anticonvulsants
  • oral diabetic agents
  • thalidomide
  • Alcohol
  • Tobacco

22
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

23
Multifactorial Causes
  • More than half of anomalies have no known cause
    and may be multifactorial
  • Folic acid deficiency is associated with neural
    tube defects

24
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

25
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

26
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

27
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

28
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

29
Constitutional Chromosomal Mosaicism
30
Maternal FGR
  • Most common by far
  • Vascular diseases
  • preeclampsia (toxemia of pregnancy)
  • hypertension
  • Toxins
  • ethanol
  • narcotics and cocaine
  • heavy smoking

31
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

32
Fetal Lung Maturation
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34
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

35
Birth Injuries(listed in order of frequency)
  • Clavicular fracture
  • Facial nerve injury
  • Brachial plexus injury
  • Intracranial injury
  • Humeral fracture
  • Lacerations

36
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

37
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

38
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

39
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

40
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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44
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

45
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

46
Necrotizing Enterocolitis
47
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

48
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

49
Hydrops Fetalis
50
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

51
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)

52
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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54
Kernicterus
55
Pathogenesis of Immune Hydrops
56
Inborn Errors of Metabolism(Genetic)
  • PhenylKetonUria (PKU)
  • Galactsemia
  • Cystic Fibrosis (CF) (Mucoviscidosis)

57
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

58
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

59
Cystic Fibrosis
  • Normal Gene
  • Mutational Spectra
  • Genetic/Environmental Modifiers
  • Morphology
  • Clinical Course

60
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

61
CFTR Structure And Activation
62
Cellular Metabolism Of The Cystic Fibrosis
Transmembrane Regulator (CFTR)
Harrisons Internal Med, 16th Ed
63
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

64
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

65
Chloride Channel Defect and Effects
66
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

67
Clinical Manifestations Of Mutations In The
Cystic Fibrosis Gene
68
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
73
CF Diagnosis
  • Clinical criteria
  • Sweat chloride analysis
  • Nasal transepithelial potential difference
  • DNA Analysis
  • gene sequencing

74
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

75
Sudden Infant Death Syndrome (SIDS)
  • Epidemiology
  • Morphology
  • Pathogenesis

76
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

77
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)

78
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

79
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

80
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

81
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

82
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

83
TUMORS
  • Benign
  • Malignant

84
BENIGN
  • Hemangiomas
  • Lymphatic Tumors
  • Fibrous Tumors
  • Teratomas (also can be malignant)

85
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

86
Congenital Capillary Hemangioma
At 2 years After spontaneous regression
At birth
87
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

88
Sacrococcygeal Teratoma
89
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

92
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

93
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

94
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

99
FISH for N-myc in Neuroblastoma
100
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

101
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

102
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

103
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
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