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1.

Discuss the pathogenesis of deformations, and give examples of underlying factors, which may lead to
deformations via such pathogenetic mechanisms.
a. Deformations: Definition localized or generalized compression of the growing fetus by
abnormal biomechanical forces Will hit after 8 weeks.
i. Arises later in development than malformations. This is because the fetus already has
developed various of the body (arms, legs, ect) that become influenced by
biomechanical forces.
ii. The MOST COMMON DEFORMATION = UTERINE CONSTRAINT
1. Factors that affect the propensity for a fetus to be affects by uterine constraint

Maternal factors
Fetal factors
First pregnancy
Multiple fetuses
Small uterus
Oligohydramnios
Leiomyoma
Abnormal presentation
iii. Sequence: Potter Sequence
1. Sequence that describes the pathogenesis of multiple congenital abnormalities
that result from secondary effects of a single localized aberration in
organogenesis.
2. The INITIATING event may be malformation, deformation, or disruption.
b. One of the risk factors for deformation is oligohydramnios, and a well studied sequence called
the potter sequence describes factors that result in oligohydramnios and the affect it can
have on a fetus.
c. oligohydramnios --> compression of fetus --> limb deformities --> facial anomalies/
deformities and pulmonary hypoplasia which is the cause of death - this is all due to the lack of
the childs ability to urinate during in-utero --> Lack of Pee results in Potter sequence. The
oligohydramnios causes
i. Fetal compression
1. Altered facies
2. Defects of limbs
3. Breech
presentation
ii. Pulmonary hypoplasia









2. List the most common birth injuries (cranial injuries, fractures, peripheral nerve injuries, and liver
rupture)
a. Mechanical to anoxic (low 02) damage
b. Occur in 5/1000 live births
c. Predisposing factors: cephalopelvic disproportion (disproportionate child head is larger than
mothers pelvis http://www.youtube.com/watch?v=Pr216HObUIA), difficult labor (breech
presentation child exits womb feet first rather than head first.), Prematurity (neonate is not
able to handle the stressors of the new environment. Depending on how the child responds to
this new environment he/she will be assigned a number = THE APGAR SCORE (will be covered
later in objectives but a quick look = its a number that determines the chances of survival are
by assessing childs physiological condition and responsiveness



3. Discuss intrauterine and perinatal infections in terms of:
a. Routes of spread
i. Ascending from the vagina and cervix
ii. Hematogenous dissemination from the placenta, then from placenta into amniotic
fluid (transplacental infection Consider all of the TORCHEs)
iii. Direct contact at birth
iv. From environment post partum
v. Accidental introduction at the time a procedure ie amniocentesis.


*First two are most common routes
b. Common causative organisms
i. Ascending infection Mostly d/t bacteria, some by virus passage through birth

canal.
1. Clinical pathologies: Chlorioamnionitis, Funisitis, Pneumonia, Menigitis, Sepsis
ii. Hematogenous spread = TORCH and SLAVE
iii. Toxoplasmosis
iv. Other infections slave
v. Rubella
vi. CMV
vii. HSV, HIV
1. SLAVE
2. Syphilis
3. Listeria monocytogenes
4. Adenovirus
5. Varicella
6. Enterovirus

4. State the most common cause of death in children, as well as the most common non-traumatic cause
of death in children:
a. under one year of age
i. congenital abnormalities, deformations and chromosomal anomalies
ii. traumatic maternal complications of pregnancy
b. between one and four years of age
i. traumatic injuries
ii. non traumatic congenital anomalies
c. between five and fourteen years of age
i. traumatic injuries
ii. non traumatic malignant neoplasms





5. List the common abnormalities in morphogenesis and discuss their etiopathogenesis. (Malformation,
Disruption, Deformation, sequence)
a. Malformation (primary structural abnormality)
i. Intrinsic abnormal developmental process. Primary structural abnormality with

poor formation of tissue due to localized error that occurs DURING development.
ii. Examples of malformation: Polydactyly and syndactyly, cleft lip, cleft palate, congenital
heart disease
iii. Malformation syndromes The presence of >1 developmental anomalie of >2 systems
due to a common etiology
1. Examples: Down Syndrome and Klinefelter interestingly klinefelters is more
common than downs in males (1:600 compared to 1:500)
b. Disruption (secondary cause of structural abnormality)
i. Structural defect caused by SECONDARY DESTRUCTION or interface with a
previously normally formed part. A disruption arises from an EXTRINSIC
disturbance in morphogenesis.
1. extrinsic disturbance in the morphogenesis
ii. Example: Amniotic band entanglement followed by amputation or disfigurement of a
formed body part. (infarction, necrosis)
1. Amniotic band disruption sequence
c. Deformation (occurs later in fetal life due to compression)
i. (localized compression of the growing fetus by abnormal biomechanical forces)
ii. Explained in first objective
iii. Example: Uterine constraint
1. POTTER SEQUENCE
2. Sequence Sequence refers to multiple congenital anomalies that result
from secondary effects of a single localized aberration in organogenesis. The
initiating event may be a malformation, deformation, or disruption. An excellent
example is the oligohydramnios (or Potter) sequence.

6. Define Prematurity and intrauterine growth retardation (IUGR) discuss common complications of
Prematurity
a. Prematurity and intrauterine growth retardation is the second cause of death in the fetus.
b. Prematurity birth preterm, which
is less than 37 weeks or a weight
below 2500g. Normal term infant is
37-43 weeks. Below 2500g can be
characterized as either premature
or IUGR for their gestational age
thus would be classified as Small
Gestational Age (SGA = Below 10th
percentile for age).
c. Define IUGR: this classification
defines a set of causes that result in
abnormal or hindered development
of the child. Further subclasses are
symmetrical IUGR and
asymmetrical IUGR. Symmetrical
and asymmetrical refer to the
developmental affects on the child,
for instance symmetrical IUGR
means that both the head and body are equally affected by the development growth
abnormality, whereas in asymmetric, the brain gets precedence and will not be as severely
affected by the developmental abnormality as compared to the rest of the body.


Major Risk Factors of Prematurity:

1. Premature rupture of membranes

2. Intrauterine infections

3. Structural abnormalities of the uterus, cervix, or placenta

4. Multiple gestations

Describe the complications prematurity:
d. Hyaline membrane disease (respiratory distress syndrome of the newborn)
i. The most common cause of infant death in the united states
ii. Formation of hyaline membranes in peripheral alveoli. Differ from ARDS in ARDS the
onset is due to some infection or drug intake which results in hyaline membrane
containing PMNs, fibrin, platelets, whereas in RDS - the hyaline membrane will only
contain fibrin and platelets
iii. Immaturity of type II pneumocytes results in decrease surfactant production,
decreased compliance
iv. Causes of RDS:
1. Prematurity - #1 cause
2. Perinatal asphyxia
3. Maternal diabetes - excess insulin has been shown to decrease surfactant
production
4. C-Section - normal birth through canal is going to stimulate adrenaline release
which is going to stimulate type II pneumocytes to secrete surfactant - thus with
a C-section - there is no vaginal birth and less adrenaline will be present within
the child.
5. Twin gestation
6. Male Sex


CXR -> Ground glass opacities

Timing
Less than 12 hours
12-24 hours

If infant dies SEVERAL days after

Microscopy
NECROTIC CELLULAR DEBRIS IN TERMINAL
BRONCHIOLES and ALVEOLAR DUCTS
HYALINE MEMBRANES, Membranes are
composed of necrotic alveolar type II
pneumocytes and fibrin, remember NO PMNs
(thats in ARDSs Hyaline membranes)
Evidence of reparative changes, including
proliferation of type II pneumocytes and
interstitial fibrosis


e. Necrotizing enterocolitis
i. Disease or premature infants along with infants of low birth weight results in
mortality of 20-50%
ii. In clinical vignette look out for following formula feeds and preterm infant
iii. Bacterial colonization of the gut
iv. Clinical features Abdominal distention, bloody stools, DIC, progressing to death
v. Diagnosis Abdominal radiographs will show: DILATED LOOPS OF BOWEL - WILL SEE
GAS IN LOOPS OF BOWEL = PNEUMATOSIS INTESTINALIS --> NEC will affect the
terminal ileum to ascending colon.
vi. MORPHOLOGY: coagulative necrosis extending into muscularis mucosa
1. Coagulative necrosis of mucosa breaching through submucosa and muscularis
mucosa. Also characteristic air filled spaces beneath the mucosa - pneumatosis
intestinalis.
vii. Complications
Early
Sepsis, shock, DIC, acute tubular necrosis leading
to acute renal failure and intestinal perforation
Late
Short gut syndrome, malabsorption, and stricture
formation

f. Intraventricular and germinal matrix hemorrhage
i. Bleeding into the germinal matrix with extension into the ventricles and beyond. N/B

germinal matrix is a source of nerve cells in embryo and fetuses (up to 33 wks of
gestation) thus following 33wks this will not present. Germinal area is a rich vascular
network thats sensitive to anoxia. 4 grades.
ii. Rapid death can ensue massive hemorrhage, falx cerebri herniation, however if child
survives will see cavitations or pseudocysts SURROUNDED BY HEMOSIDERIN LADEN
MACROPHAGES and GLIOSIS

7. Describe the following disorders:
a. congenital rubella syndrome
b. bronchopulmonary dysplasia (BPD)
c. cystic fibrosis (CF, mucoviscidosis)
d. Dubin-Johnson syndrome
e. phenylketonuria
f. galactosemia
g. sudden infant death syndrome (SIDS)

Disorder
Incidence Etiology and
Morphology
and Epi
Path
Congenita Frequency Maternal rubella Inclusion bodies, lymphocytic
l Rubella 2-3% for all infection in FIRST infiltrate check with dani and
Syndrome congenital trimester
harris not in notes not in robbins
abnormaliti Vertical
es
transmission
hematogenous
thru placenta
TORCH
Bronchop
Long term
-peribronchial fibrosis
ulmonary
sequelae of
-fibrotic obliteration of bronchioles
dysplasia
neonatal RDS
-OVER DISTENDED ALVEOLI
(BPD)
-Caused by
-squamous metaplasia of bronchial
arrested
epithelium
development of
-increase levels of TNF, macrophage
alveolar septation inflammatory protein 1, IL-8
at SACCULAR

stage of
development
Cystic
Discovered -AR
Phosphorylation of CFTR by PKA
Fibrosis
at 2 -12
-F508 ch7, CFTR using cAMP chloride channel in
months
-Most common in apical membrane of exocrine gland

whites
resulting in thick mucous secretions.

-TWO CLINICAL
Complications:
CUES in children
-Atelectasis
-NASAL POLYPS
-Emphysema
-RECTAL
-Bronchiectasis (Cystic fibrosis that
PROLAPSE
leads to bronchiectasis will be present
in upper lobe whereas other forms of
bronchiectasis due to infection will be
present in lower lobes of lung)
-Pancreas: Secondary dilation and
cystic changes of distal ducts and
atrophy of secretory cells, FIBROSIS,
and destruction of EXOCRINE

Clinical course
PDA, Cataracts,
deafness = classic
triad.

Alveolar hypoplasia
(decrease in
number of mature
alveoli)

-chronic pulm
disease with
repeated infections
-def. pancreatic
function
-inspissated
mucous in SI, liver,
and reproductive
tract
-Lung
obstruction of
bronchioles with
mucous. Marked
hyperplasia and
hypertrophy of
Goblet / alveolar

parenchyma.
-Liver: FOCAL BILIARY CIRRHOSIS
(late) d/t obstruction and bile duct
hyperplasia. AZOOSPERMIA AND
INFERTILITY, may see meconium in
SI.
Dubin-
Johnson

-AR
-Defective
transport of
conjugated
bilirubin from
hepatocytes to
canicular lumen

Phenylket
onuria

Maternal disease
-AR
-Pt mutation on
ch.12q (long arm)
-def. in
phenyalanine
hydroxylase

Galactose
mia

-BLACK LIVER
-Accumulation of coarse, iron free,
DARK BROWN granules in
hepatocytes and Kuppfer cells, then
on EM pigment is located in
lysosomes and composed of
EPINEPHRINE metabolites NOT
BILIRUBIN PIGMENT
-hyperphenylalaninemia causes
irreversible brain damage
-formation of phenylketones

cells.

Presentation
-foul smelling
steatorrhea
-malnutrition
-edema
-failure to thrive
Asymptomatic
except for mild
jaundice

-INFANT WILL BE
NORMAL AT BIRTH,
then will develop
mental problems
after few months.
-microcephaly
-mental
retardation
-growth retardation
-congenital heart
defects
-MOUSY ODOR TO
URINE
-FAIR SKIN, BLUE
EYES, BLONDE
HAIR lack of
melanin.
AR
Extensive and uniform fat
Infants fed milk
-def of galactose- accumulation in the liver and marked rapidly develop
1 phosphate
bile duct proliferation, cholestasis,
hepatosplenomegaly
uridyl transferase and fibrosis
, jaundice and
-Cirrhosis may develop in few
hypoglycemia
months
-Cataracts and
mental retardation






Sudden infant death syndrome
-Sudden death of an infant under one year of age
-To make diagnosis investigation includes:
-Complete autopsy, exam scene where death occurred, and review of clinical history.
-Pathogenesis: popular hypothesis prolonged spell of apnea followed by cardiac arrhythmia
-Gross: petechia on surface of lung, pleura, heart and thymus. Gliosis of brain stem,
-Morph: MEDIAL hypertrophy of small pulmonary arteries and extramedullary hematopoiesis.



Childhood cirrhosis:
-A1At def
-Biliary atresia
-Galactosemia
-Wilson's disease
-Cystic Fibrosis

8. Discuss various causes of neonatal jaundice
a. Hemolytic disease of the newborn
b. Crigler-Najjar syndrome
c. Rotor syndrome
d. Biliary atresia
e. Idiopathic neonatal hepatitis

Causes of
Etiology and Path
Morphology
Neonatal
Jaundice
Hemolytic
Pathological jaundice 2 -Ab induced hemolytic disease
disease of the
types: unconjugated and
that is caused between the
newborn
conjugated HDoN =
mother and fetus due to
unconjugated
incompatibility of blood types.
hyperbilirubinemia
-Most common antigens Rh and
-Erythroblastosis Fetalis ABO.
Crigler Najjar
Syndrome

Pathological Jaundice
Normal liver morphology
unconjugated
hyperbilirubinemia
-AR
-Type I COMPLETE
absence of UDP-
glucoronyltransferase
unconjugated
hyperbilirubinemia leading
to bilirubin encephalopathy
-Type II Less sever 50%
active UDP gtf enzyme

Clinical Course
-Death in utero
most extreme form
-hydrops fetalis
most severe form in
live born infants
-kernicterus
bilirubin
encephalopathy
Type I most
patients die within
the first year of life.
-Jaundice,
kernicterus,
increase in
unconjugated bili
-Type II is
treatable with
Phenobarbital
whereas type I is
not.

Rotor
Syndrome a
milder form of
Dubin- Johnson

Biliary Atresia

Idiopathic
Neonatal
hepatitis

Familial conjugated
hyperbilirubinemia
-Idiopathic
-Defect in the excretion of
conjugated bilirubin into
the biliary canaliculi with
the bilirubin being
absorbed into the blood
Conjugated
Hyperbilirubinemia
-complete obstruction of
the lumen of the
extrahepatic biliary
WITHIN FIRST THREE
MONTHS OF LIFE
-Most frequent cause of
GALL STONES in infants
-Most common
INDICATION for liver
transplant in infants

-idiopathic
-50-60% of neonatal
hepatitis
-More MALES than females

-Low pigment deposition,


dissociation of liver cells,
occasional necrotic foci, and
fibrin deposition.

-Jaundice,
epigastric
discomfort,
episodic pain, fever

-Inflammation and fibrosing


stricture of the hepatic and
common bile ducts
-INTRAhepatic or
EXTRAhepatic

-Intrahepatic: PERIDUCTULAR
inflammation of intrahepatic bile
duct leading to progressive
destruction of the intrahepatic
biliary tree
-Extrahepatic: biliary obstruct,
portal tract edema and fibrosis,
marked ductal proliferation,
parenchymal choliesthasis
-Giant cell transformation
synctial cells
-Ballooning Swollen hepatocyte
-Acidophilic degeneration
Councilman bodies
-Cholestasis BILE LAKES

2 forms fetal type


(20%) and
Perinatal type
(80%)
-refer to slide
below

-Jaundice
-Dark Urine
-Hepatomegaly

9. Discuss the following pediatric neoplasms:


a. Neuroblastoma
b. Retinoblastoma
c. Wilms tumor (nephroblastoma)

Pediatric Frequency Age of


Neoplas
Onset
ms
Neurobla 7-10% of -<5yrs
stoma
childhood
malignanc
y
-Second
most
common
tumor in
children

Role of genetics Morphology


/Environment

Clinical
Prognosis
Behavior

small, round, blue


cell
-small size, lack of
cytoplasm and dark
round nuclei that stain
dark blue on H&E
-Tumor arising from
primitive neural crest
cells

-Mets to
bones,
lymph,
liver,
BM, subq
tissues

Retinobl
astoma
Wilms

tumor
(nephrob
lastoma)

2-5yrs
-#1
renal
tumor

Sporadic
WT1 (WAGR
syndrome and
Denys-Dash
syndrome)
WT2 =
Beckwith-
Weildman

small, round, blue


cell
-Triphasic pattern
-Blastema
-Stroma
-Epithelium
-ANAPLASTIC subtype


Neuroblastoma

-Staging
-TrkA =
increased
expression
indicates good
prognosis.
-Deletion of
1p or gain of
17q = poor
prognosis

3Ls - tumor
spreads to
lungs, liver,
lymph nodes
- if met occurs
to other
organs than
the 3Ls then
its not likely
to be wilms


Retinoblastoma:

Nephroblastoma:


DOWN SYNDROME

EDWARD SYNDROME

-trisomy 18, 21, 13


-all have mental retardation and cardiovascular abnormalities.
-21, 13 = umbilical hernia
-18,13 = renal anomalies, rocker bottom feet
-21 = epicanthal fold, simian crease in hands, predilection for leukemia.

PATAU SYNDROME