DISEASES

OF
INFANCY
AND
CHILDHOOD
CONGENITAL ANOMALIES
structural defects - present at birth,
some, may not become clinically apparent until
years later.
does not imply or exclude a genetic basis for birth
defects.
important cause of infant mortality.
continue to be a significant cause of illness,
disability, and death throughout the early
years of life.
Malformations
primary errors of morphogenesis.
intrinsically abnormal developmental
process.
usually multifactorial rather than the result
of a single
gene or chromosomal defect.
 Disruptions
secondary destruction of an organ or body
region that
was previously normal in development;

arise from an extrinsic disturbance in

morphogenesis.
not heritable and hence are not associated
with risk of
recurrence in subsequent pregnancies.
Amniotic bands
resultant formation of "bands" that
encircle,compress,
or attach to parts of the developing fetus,
Deformations
an extrinsic disturbance of development
rather than an
intrinsic error of morphogenesis.
growing fetus
by abnormal biomechanical forces, leading
eventually to
a variety of structural abnormalities.
most common underlying factor - uterine
constraint.
Between 35th and 38th weeks of gestation,
rapid increase in the size of the fetus
outpaces the growth of the uterus,
and the relative decreases in the
amount of
amniotic fluid (normally acts as a
cushion)
However,
several factors increase the likelihood of
excessive
compression of the fetus
1. maternal conditions
first pregnancy,
 2. Factors relating to the fetus
multiple fetuses,
oligohydramnios,
abnormal fetal presentation.

Sequence
multiple congenital anomalies that result from
secondary
effects of a single localized aberration in
organogenesis.
initiating event may be a
malformation,
deformation, or
disruption.
Oligohydramnios (or Potter) sequence
decreased amniotic fluid, (unrelated maternal,
placental,
or fetal abnormalities. )
 2. Uteroplacental insufficiency
maternal hypertension or severe toxemia
3. Renal agenesis in the fetus

The fetal compression associated with significant

oligohydramnios in turn results in a classic
phenotype in the
newborn infant,
flattened facies
positional abnormalities of the hands and feet .
hips may be dislocated.
growth of the chest wall and the contained
lungs is also compromised
If the embryologic connection between these
defects and the initiating event is not recognized, a
sequence may be mistaken for a malformation
syndrome.
 Malformation syndrome
presence of several defects that cannot be
explained on the
basis of a single localizing initiating error in
morphogenesis.
most often caused by a single causative factor
(viral infection or a specific chromosomal
abnormality) that simultaneously affects several
tissues.
Organ-specific malformation
Agenesis - complete absence of an organ or
its anlage
Aplasia - incomplete development
Hypoplasia underdevelopment of an organ.
Atresia - absence of an opening
Stenosis - narrow opening
Etiology Of Malformation.
almost half have no recognized cause.
known causes of errors - two major categories:

1. Genetic
Mendelian disorders - single – gene defects
Autosomal dominant disorders
Autosomal recessive disorders
X-linked disorders
Disorders of multifactorial inheritance
Cytogenetic disorders involving autosomes
Cytogenetic disorders involving sex
chromosomes
Single-gene disorders with atypical pattern
of
inheritance
diseases caused by triplet repeat
mutations
Multifactorial inheritance
interaction - environmental factors with two
or more
genes of small
effect

conditioned by
nongenetic influences governed
additive
effect

most common genetic cause of congenital

malformation
pathology are relevant regardless of the etiologic
agent:
1• timing of the prenatal insult has an important
impact on both the occurrence and the type of
malformation produced.
Embryonic period,
occupying the first 9 weeks of pregnancy,
Fetal period,
which terminates at birth.

Early embryonic period (first 3 weeks after

fertilization),
injurious agent damages either enough cells to
cause
death and abortion,
or
only a few cells, presumably allowing the
embryo to
recover without developing defects.
Between 3rd and 9th weeks,
embryo is extremely susceptible to -
teratogenesis;
peak sensitivity - between the 4th and 5th weeks.
(organogenesis)
fetal period that follows organogenesis is marked
chiefly by
further growth and maturation of the organs,
with greatly
reduced susceptibility to teratogenic agents.
Instead,
fetus is susceptible to growth retardation or
injury to
already-formed organs.

It is therefore possible for the same teratogenic

agent to
produce different effects if exposure occurs at
 PERINATAL INFECTIONS
Infections of the fetus and neonate may be acquired
1.Transcervically (ascending infections)
cervicovaginal canal - acquired in utero or
during birth.
most bacterial infections
few viral infections
In general,
the fetus acquires the infection by "inhaling"
infected amniotic fluid into the lungs or by
passing through an infected birth canal during
delivery.
is usually associated with inflammation of the
placental membranes (chorioamnionitis) and
inflammation of the umbilical cord (funisitis).
usually gives rise to pneumonia and, in severe
cases, to sepsis and meningitis.
 2. Transplacentally (hematologic infections).
usually caused by viruses, parasites and
some
bacteria
infecting microbes gain access to the fetal
bloodstream through chorionic villi.
effects are more widespread than those of
ascending infections.
most important transplacental infections
TORCH.
Toxoplasma (T),
Rubella virus (R),
Cytomegalovirus (C),
Herpesvirus (H)
and
any of a number of other (O)
microbes such as T. pallidum.
These agents are grouped together because they
may evoke similar clinical and pathologic
manifestations, including
fever,
encephalitis,
chorioretinitis,
hepatosplenomegaly,
pneumonia,
myocarditis, and
hemolytic anemia.
 PREMATURITY AND INTRAUTERINE GROWTH
RETARDATION
Prematurity
most common cause of neonatal mortality and
morbidity
gestational age less than 37 weeks also weigh
less than
normal (<2500 g).
major risk factors
premature rupture of membranes (PROM),
chorioamnionitis,
placental abnormalities
twin pregnancy

Children born before completion of the full period of

gestation have higher morbidity and mortality
rates than do full-term infants.
 Immaturity of organ systems in preterm infants
makes them especially vulnerable to several
complications, including
• Hyaline membrane disease
(respiratory distress syndrome)
• Necrotizing enterocolitis
• Intraventricular and germinal matrix hemorrhage
Although preterm infants have low birth weights,
it is usually appropriate once adjusted for their
gestational age.
In contrast,
small for-gestational-age (SGA) infants suffer from
intrauterine growth retardation (IUGR). infants who
weigh less than 2500 g are born at term and are
therefore undergrown rather than immature.
IUGR
result from fetal, maternal, or
placental abnormalities,
although in many cases the specific cause-
Among fetal causes - those that impair growth
despite an
adequate uteroplacental axis.
chromosomal disorders,
congenital malformations,
congenital infections.
Caused by factors intrinsic to the fetus
Growth retardation - symmetric
(affects all organ systems
equally).

Placental causes - any factor that compromises the

uteroplacental supply line.
placenta previa
placental abruption
placental infarction.

Placental/Maternal causes
Maternal factors
most common cause of the growth deficit in SGA
infants.
vascular diseases
preeclampsia ("toxemia of pregnancy")
chronic hypertension.
In addition,
maternal narcotic abuse,
alcoholism, and
heavy cigarette smoking

SGA infant
handicapped not only in the perinatal period but
also in
childhood and adult life.
increased risk for
cerebral dysfunction,
learning disabilities,
 RESPIRATORY DISTRESS
causes in the NEWBORN
excessive sedation of the mother,
fetal head injury during delivery,
aspiration of blood or amniotic fluid,
intrauterine hypoxia brought about by coiling
of the umbilical cord about the neck.
However,
most common cause– RDS (hyaline membrane
disease)
because of the formation of "membranes" in
the peripheral airspaces
Pathogenesis.
basically a disease of premature infants.
affects 15% to 20% of those born between
32 and 36 weeks' gestation,
prevalence increases to 60% for infants
delivered before
28 weeks.
Other contributing influences
maternal diabetes,
cesarean section before the onset of labor,
twin gestation.
Males - at greater risk
fundamental defect
inability of the immature lung to synthesize
sufficient
surfactant - dipalmitoylphosphatidylcholine
(lecithin)
Surfactant synthesis is regulated by hormones.
Corticosteroids
stimulate the formation of surfactant lipids and
associated
apoproteins
conditions associated with intrauterine stress
and fetal
growth restriction that increase corticosteroid
release
Thyroxine
acts synergistically with corticosteroids, but
insulin
antagonizes this effect.
Uncontrolled diabetes in a pregnant woman
compensatory hyperinsulinism in the fetus -
suppress
surfactant
synthesis.
In a lung deficient in surfactant,
Alveoli tend to collaps - relatively greater
inspiratory effort is
required

infant rapidly tires from

breathing, and
generalized atelectasis sets in.

resulting hypoxia sets into motion

a
sequence of events that lead to

epithelial and endothelial damage

and eventually to the
formation of hyaline membranes.
Clinical Features.
Although with other causes of respiratory distress
the newborn may be apneic or hypoxic from the
moment of birth,
infants with RDS usually appear normal at birth
but within minutes to a few hours develop a labored,
grunting respiration that progressively worsens and,
unless controlled by therapy, causes death.
Major cause of death in the neonatal period.

death and morbidity may result not only from

hypoxemia
other complications of a premature birth
intraventricular hemorrhage,
necrotizing enterocolitis.
A minority of infants who survive RDS suffer long­term
sequelae related to
Neurodevelopmental defects
result from the effects of hypoxia on neurons
or
from intracerebral hemorrhage
Chronic lung disease.
Bronchopulmonary dysplasia,
multifactorial etiology.
primary anoxic injury,
exposure to the high concentrations of
oxygen
positive-pressure ventilation

Pathologic findings
hyperplasia and squamous metaplasia of
bronchial
epithelium,
Several months after the acute injury,
extensive interstitial fibrosis and
"honeycombing," analogous to the changes
following diffuse alveolar damage in adults

Estimates of fetal pulmonary maturity

measuring the concentration of surfactant
phospholipids
(e.g., lecithin) in amniotic fluid obtained by
amniocentesis.
NECROTIZING ENTEROCOLITIS
is predominantly a complication of premature
infants and is associated with a high perinatal
morbidity and mortality.
it is multifactorial.
Intestinal ischemia is a prerequisite and may
result from either generalized hypoperfusion or
selective reduction of blood flow to the
intestines in order to divert oxygen to vital
organs such as the brain.
Other predisposing conditions include
bacterial colonization of the gut and
administration of formula feeds,
both of which aggravate mucosal injury in
the immature bowel.
Typically involves the terminal ileum, cecum, and
right colon, although any part of the small or
large intestine may be involved.
Morphology
Gross
involved
segment is
distended,
friable, and
congested
or it can be
frankly
gangrenous;
intestinal
perforation
with
accompanyi
ng
peritonitis
may be
seen.
Microscopically,
mucosal or transmural coagulative necrosis,
ulceration,
bacterial colonization, and
submucosal gas bubbles

Reparative changes,
such as granulation tissue and fibrosis,
may be seen shortly after the acute episode.
The clinical course is fairly typical,
with the onset of bloody stools,
abdominal distention, and
development of circulatory collapse.
Abdominal radiographs often demonstrate
gas within the intestinal wall
(pneumatosis intestinalis).

When detected early on, NEC can often be managed

conservatively, but many cases require operative
intervention and resection of the necrotic segments
of bowel.
is associated with high perinatal mortality;
infants who survive often develop post-NEC
strictures from fibrosis caused by the healing
process.-
SUDDEN INFANT DEATH SYNDROME
"the sudden and unexpected death of an
infant less than 1 year of age whose death
remains unexplained after the performance of a
complete autopsy, examination of the scene of
death, and review of the case history."
Leading cause of death during the first year of life
in developed countries.
In 90% of cases, the infant is younger than 6
months; most are between the ages of 2 and
4months.
Diagnosis of SIDS in children younger than 1 month
or older than 6 months should be made with
caution.
Usually, death occurs during sleep and without
any apparent struggle; "crib death" and "cot
death:“
Cause is unknown,
 several factors related to both the mother and
the infant are associated with an increased risk
of SIDS
there is an increased risk of SIDS in infants who
sleep in a prone position.
Anatomic studies of victims have yielded
inconsistent histologic findings, such as the
presence of thymic petechiae or
congestion of pulmonary vessels.
These features are usually subtle, of uncertain
significance, and not present in all cases.
The importance of a postmortem examination rests
in identifying other causes of sudden death in
infancy, such as unsuspected myocarditis,
congenital heart disease, or bronchopneumonia (the
presence of any of which would exclude a diagnosis
of SIDS), and in ruling out the possibility of child
abuse.
A variety of microscopic alterations have been found
in certain regions of the brain, most importantly the
brain stem.
In this locale are structures that control
respiratory and cardiac rhythm or coordinate the
body's response to hypoxemia and hypercarbia (e.g.,
the arcuate nucleus).
It should be noted,
however, could either lead to or result from chronic
hypoxia, so the possibility exists that they are not of
themselves the basic defects.
but it could be a disorder with multiple origins –
metabolic, neural or infection
but suffice it to say that none of these theories,
alone or in combination, can at present
explain these tragic deaths.
HYDROPS FETALIS
Generalized edema of the fetus, a severe
manifestation of progressive fluid accumulation
during intrauterine growth that is frequently
lethal.
Causes are manifold;
do not always result in hydrops fetalis,
which represents the most severe
manifestation in the spectrum of intrauterine
fluid accumulation;
It is not uncommon to have more localized
degrees of edema, such as
isolated pleural and peritoneal effusions,
postnuchal fluid accumulation
(cystic hygroma ).
Immune Hydrops
Immune hydrops fetalis
results from an antibody-induced hemolytic
disease in the newborn that is caused by blood
group incompatibility between mother and fetus.
occurs only when the fetus inherits red cell
antigenic determinants from the father that are
foreign to the mother.
most common antigens to result in clinically
significant hemolysis are the Rh and ABO
Rh system
only the D antigen - major cause
Fetal red cells may reach the maternal circulation
during the
last trimester of pregnancy, when the
cytotrophoblast is no longer present as a
barrier, or
during childbirth itself ( fetomaternal bleed).
Mother - sensitized to antigen - develops antibodies
freely traverse the placenta to the fetus - red cell
destruction.
Once immune hemolysis is initiated
progressive anemia in the fetus, with resultant
tissue ischemia, intrauterine cardiac failure, and
peripheral pooling of fluid (edema),
cardiac failure may be the final pathway by
which edema occurs in many cases of
nonimmune HF as well.
Several factors influence the immune response to
Rh­positive fetal red cells that reach the
maternal circulation.
1. Concurrent ABO incompatibility protects the
mother against Rh immunization because the
fetal red cells are promptly coated by
isohemagglutinins and removed from the
maternal circulation.
 2. The antibody response depends on the dose of
immunizing antigen; hence, hemolytic disease
develops only when the mother has experienced
a significant transplacental bleed
(more than 1 mL of Rh-positive red cells).
3. The isotype of the antibody is important
because IgG but not IgM antibodies can cross
the placenta.
Initial exposure to Rh antigen evokes the formation
of IgM antibodies, so Rh disease is very
uncommon with the first pregnancy.
Subsequent exposure during the second or third
pregnancy generally leads to a brisk IgG antibody
response.
Currently,
Rh-negative mothers are administered anti-D
globulin soon after the delivery of an Rh-
positive baby
anti-D antibodies mask the antigenic sites
on the fetal red cells that may have leaked
into the maternal circulation during
childbirth, thus preventing long-lasting
sensitization to Rh antigens.
ABO incompatibility
occurs in approximately 20% to 25% of
pregnancies, only a small fraction of infants
subsequently born develop hemolysis, and in
general the disease is much milder than is Rh
incompatibility.
Hemolytic disease occurs almost exclusively in
infants of group A or B who are born to group
O mothers.
Normal anti-A and anti-B isohemagglutinins
in group O mothers are usually of the IgM
type and so do not cross the placenta.
 However,
for reasons not well understood, certain group O
women possess IgG antibodies directed against
group A or B antigens (or both) even without prior
sensitization.
Therefore,
the firstborn may be affected.
Fortunately,
even with transplacentally acquired antibodies,
lysis of the infant's red cells is minimal.

There is no effective method of preventing

hemolytic disease resulting from ABO
incompatibility.
Nonimmune Hydrops
The major causes include those associated with
cardiovascular defects,
chromosomal anomalies, and
fetal anemia.
Both structural and functional (i.e., arrhythmias)
cardiovascular defects may result in
intrauterine cardiac failure and hydrops.
Among the chromosomal anomalies,
45,X karyotype (Turner syndrome) and
trisomies 21 and 18
are associated with fetal hydrops; most often,
the basis for this is the presence of
underlying structural cardiac anomalies,
although in Turner syndrome, there may be
an abnormality of lymphatic drainage from
the neck leading to postnuchal fluid
accumulation (cystic hygromas).
Fetal anemias
due to causes other than Rh or ABO
incompatibility also result in hydrops fetalis
(HF).
Transplacental infection
by parvovirus B19
is increasingly recognized as an important
cause of HF .
The virus gains entry into erythroid precursors
(normoblasts), where it replicates. This leads to
erythrocyte maturation arrest and aplastic
anemia.
Parvoviral intranuclear inclusions can be seen
within circulating and marrow erythroid
precursors
Parvoviral
intranuclear
inclusion

Extramedullary
Hematopoeisis,
lung
Basis for HF in fetal anemia of both immune and
nonimmune cause is
Tissue ischemia with secondary myocardial
dysfunction and circulatory failure.
Additionally,
secondary liver failure may ensue,
with loss of synthetic function
contributing to hypoalbuminemia,
reduced oncotic pressure, and edema.
 MORPHOLOGY
The anatomic findings vary with both the severity of
the disease and the underlying etiology
HF represents the most severe and generalized
manifestation and
Lesser degrees of edema such as
isolated pleural, peritoneal, or
postnuchal fluid collections can occur.
Accordingly,
infants may be stillborn, die within
the first few days, or recover completely.
The presence of dysmorphic features suggests
underlying constitutional chromosomal
abnormalities;
Post­mortem examination may reveal a
cardiac anomaly.
In HF associated with fetal anemia,
both fetus and placenta are characteristically
pale; in most cases,
the liver and spleen are enlarged from cardiac
failure and congestion.
Additionally, the bone marrow shows
compensatory hyperplasia of erythroid
precursors (parvovirus-associated aplastic
anemia being a notable exception), and
extramedullary hematopoiesis is present in the
liver,
spleen,
other tissues such as the kidneys, the
lungs, and even the heart.
The increased hematopoietic activity accounts for
the presence in the peripheral circulation of large
numbers of immature red cells,
including
reticulocytes,
normoblasts/erythroblasts

Presence of hemolysis in Rh or ABO incompatibility

Is associated with the added complication of
increased circulating bilirubin from the red cell
breakdown.
Unconjugated hyperbilirubinemia is marked
(usually above 20 mg/dL in full-term infants,
often less in premature infants), the central
nervous system may be damaged (kernicterus).
The basal ganglia and brain stem are
particularly prone to deposition of bilirubin
pigment, which imparts a characteristic yellow
hue to the parenchyma.
Adults are protected from this effect of
hyperbilirubinemia by the blood-brain barrier.
Clinical Course.
Early recognition of HF is imperative,
HF that results from Rh incompatibility may be
more or less accurately predicted, because it
correlates well with rapidly rising Rh antibody
titers in the mother during pregnancy.
Amniotic fluid obtained by amniocentesis may
show high levels of bilirubin.
Human antiglobulin test (Coombs test)
is positive on fetal cord blood if the red
cells have been coated by maternal
antibody.
Antenatal exchange transfusion is an effective
form of therapy.
Postnatally, phototherapy is helpful because
visible light converts bilirubin to readily excreted
dipyrroles.
Administration of anti-D globulins to the mother can
prevent the occurrence of Rh erythroblastosis.

Group ABO hemolytic disease is more difficult to

predict but is readily anticipated by awareness
of the blood incompatibility between mother
and father and by hemoglobin and bilirubin
determinations in the vulnerable newborn
infant.
In fatal instances of HF,
a thorough postmortem examination is
imperative to determine the cause of hydrops
and to exclude a potentially recurring cause
such as a chromosomal abnormality.
CYSTIC FIBROSIS
most common lethal autosomal recessive
disorder that affects whites.
distinctly uncommon among Asians and blacks.
associated with a widespread defect in the
secretory process of all exocrine glands.
abnormally viscid mucus secretions that block
the airways and the pancreatic ducts are
responsible for the two most important clinical
manifestations:
recurrent and chronic pulmonary infections and
pancreatic insufficiency.
In addition, although the exocrine sweat glands
are structurally normal (and remain so
throughout the course of this disease),
a high level of sodium chloride in the sweat
is a consistent and characteristic
biochemical abnormality.
Pathogenesis.
the primary defect is in the transport of chloride
(Cl) ions across epithelia.
The changes in mucus are considered secondary
to the disturbance in transport of Cl ions.
In normal epithelia,
the transport of Cl- ions across the cell membrane
occurs through transmembrane proteins that form
chloride channels.
are like gates through which C1- ions enter or
leave the cell.
two types
1. those that are opened by a cyclic adenosine
monophosphate (cAMP) –dependent
pathway, and others that are regulated by
Ca" also called
cystic fibrosis transmembrane conductance
regulators(CFTRs), are defective.
Mutations in the CFTR gene render the epithelial
membranes relatively impermeable to Cl- ion.
However,
the impact of this defect on transport function is
tissue-specific.
In Sweat Glands,
the concentrations of Na+ and CI- secreted
into the gland lumen are normal, but the epithelium
that lines the sweat ducts is impermeable to Cl-
Hence, as the sweat moves toward the surface, the
normal reabsorption of Cl- through CFTR, and the
accompanying cation Na+, fails to occur.
This is responsible for the high concentration of NaCI
in the sweat of CF patients.
 In the Respiratory Tract, - Mucoviscidosis
the flow of Cl- ions and the consequences of
CFTR mutation are quite different.
In the normal airway epithelium, Cl- is secreted
into the airways through cAMP-dependent
chloride channels.
The impaired transport of Cl- from the
epithelium into the lumen of the airways
causes a series of secondary effects, which
lead ultimately to increased absorption of Na+
and water from the airspace to the blood.
This lowers the water content of the mucus
blanket coating the respiratory epithelium.

In the GIT – meconium ileus

CTFR –secretions of chloride
The resulting dehydration of the mucus layer leads to
defective mucociliary action and the accumulation of
viscid secretions that obstruct the air passages and
predispose to recurrent pulmonary infections
However,
obstruction alone seems insufficient to explain the
pathogenesis of pulmonary disease, and it is believed
that many other factors contribute.
The lung in cystic fibrosis
is characterized by an exaggerated yet
ineffective inflammatory response.
The excessive neutrophilic inflammatory
reaction seems to occur independently of
infection;
high levels of interleukin 8 (IL-8),
antimicrobial peptide defensin is reduced in
lung fluids
 Recent studies indicate that due to the C1- channel
defect, the epithelium in CF consumes more oxygen
than normal epithelium, thus creating an anaerobic
environment.
The normally aerobic Pseudormonas aeruginosa
responds to this change by asssuming a mucoid
phenotype that is resistant to phagocytosis by
neutrophils. Thus, the exuberant neutrophil response
damages tissues while the bacteria seem to go home
free.
The pathogenesis of pancreatic dysfunction
is even less clear.
obstruction of pancreatic ducts may cause total
loss of exocrine pancreatic function.
isolated chronic pancreatitis has been
related to mutations in the CF gene (CFTR).
The CFTR gene is located on chromosome 7 (7q31-
32), and to date more than 300 mutations have been
identified in this gene.
70% of patients have a common mutation
characterized by a three-base pair deletion leading to
the deletion of phenylalanine at amino acid position
508 (▲F508).
30% of cases are due to a variety of other
genetic lesions, including frameshifts, missense, and
nonsense mutations.
 The severity of clinical manifestations and the
organ systems involved are related to the
nature of the mutation.
The homozygous for delta F508 mutation, the most
common form, leads
to a virtual absence of CFTR in the cell
membrane and hence extreme impermeability
to Cl- ions.
patients have severe disease with early
pancreatic insufficiency and variable
degrees of respiratory disease.
By contrast, some of the other, much less common
mutations give rise to Cl- channels that allow
relatively normal chloride transport; in patients with
such mutations, sweat chloride is normal, and male
infertility may be the only manifestation of the
disease.
MORPHOLOGY
The anatomic changes in CF are highly variable and
depend on the type of mutation and hence the
severity of expression of this genetic disorder.
Pancreatic abnormalities are present in
approximately 85% of patients.
may consist only of accumulations of
characteristic hypereosinophilic secretions,
representing viscid mucin, within dilated
ducts.
In more advanced cases,
The ducts become totally plugged, causing
atrophy of the exocrine glands;
the islets of Langerhans are usually, but
not always, spared.
The ducts may be converted into cysts
separated only by islets of Langerhans and an
abundant fibrous stroma,
Loss of pancreatic secretion may lead to severe
malabsorption, particularly of fats.
A resultant lack of vitamin A, a fat-soluble vitamin,
may then contribute to squamous metaplasia of
the linings of the ducts.
Hypereosinophilic secretions similar to those in the
pancreas may be present within ileal, colonic,
appendiceal, and salivary glands.

Obstruction of the small bowel

secondary to impacted viscid mucin
(meconium ileus) is not an uncommon
complication in newborns with CF; intestinal
obstruction may be severe enough to cause
rupture in utero, resulting in meconium
peritonitis.
In approximately 25% of patients,
inspissation of mucus within the bile ducts
impairs excretion of bile, adding to the
malabsorption problems; over time, biliary
cirrhosis may develop in a proportion of these
patients.

The ducts and glands of the male reproductive tract

are commonly affected; obstruction of vas deferens,
epididymis, and seminal vesicles results in
azoospermia and infertility in more than 95% of CF
males.
Bilateral absence of the vas deferens is a rare
manifestation of CF, but in some males, it may be the
only feature suggesting an underlying CFTR
mutation.
Pulmonary lesions are seen in almost every case and,
with adequate treatment of the pancreatic
problems, are the most serious aspect of this
disease.
Retention of abnormally viscid mucin within the
small airways leads to dilation of bronchioles and
bronchi with secondary infection, so that severe
chronic bronchitis, bronchiectasis, and lung
abscesses are frequent sequelae.
two pathogens most commonly isolated in CF
patients.
Staphylococcus aureus
P. aeruginosa, the mucoid form rarely found in
persons who do not have CF, is found in more
than 50% of those who have the disease.
Burkholderia cepacia, an opportunistic bacterium
that is particularly difficult to eradicate.
The subtended pulmonary parenchyma may undergo
Clinical Features.
The clinical manifestations
extremely varied and
range from mild to severe and
from onset at birth to onset years later.
Meconium ileus - 5% to 10% of cases come
to clinical attention at
birth or soon after
Malabsorption - More commonly,
manifestations of (e.g., large,
foul-smelling stools; abdominal
distention; and poor weight
gain) appear during the first
year of life.
Avitaminosis A, D, E, or K – due to faulty fat
absorption

If the child survives these hazards,

 pulmonary problems
chronic cough,
persistent lung infections,
obstructive pulmonary disease, and
cor pulmonale
may make their appearance.
upper respiratory tract manifestations –
some patients
chronic sinusitis,
recurrent nasal polyps).
Persistent pulmonary infections
are responsible for 80% to 90% of the deaths.
The diagnosis of CF is based on clinical findings and
the biochemical abnormalities in sweat.
sweat chloride test
An increase in sweat electrolytes is common
(often the mother makes the diagnosis because her
infant "tastes salty").
Genetic analysis
in patients with atypical symptoms, or
in cases in which the sweat test is difficult to
administer (or, rarely, normal).
Direct mutation analysis in the antenatal period
In couples with a
previously affected offspring, or
who have been identified as CF carriers,
Provides reliable results with regard to CFTR
status in the unborn child.
TUMORS AND TUMOR-LIKE LESIONS OF INFANCY
AND CHILDHOOD
Malignant neoplasms
are the second most common cause of death in
children between the ages of 4 and 14 years;
Benign tumors are even more common than are
cancers.
It is difficult to segregate, on morphologic
grounds, true tumors from tumor-like lesions in
the infant and child.
Two special categories of tumor-like lesions should
be recognized.
• Heterotopia or choristoma
refers to microscopically normal cells or tissues
that are present in abnormal locations.
are usually of little significance, but they can be
confused clinically with neoplasms.
 Examples
a rest of pancreatic tissue found in the wall of
the stomach or small intestine, or
a small mass of adrenal cells found in the
kidney, lungs, ovaries, or elsewhere.

• Hamartoma
refers to an excessive but focal overgrowth of
cells and tissues native to the organ in which it
occurs.
Although the cellular elements are mature and
identical to those found in the remainder of
the organ, they do not reproduce the normal
architecture of the surrounding tissue.
can be thought of as the linkage between
malformations and neoplasms.
The line of demarcation between a hamartoma and a
benign neoplasm is frequently tenuous and is
variously interpreted.
Hemangiomas,
lymphangiomas,
rhabdomyomas of the heart, and
adenomas of the liver
are considered by some to be hamartomas and by
others to be true neoplasms.

Benign Tumors
Virtually any tumor may be encountered in the
pediatric age group, but three – occur commonly in
childhood.
hemangiomas,
lymphangiomas,
sacrococcygeal teratomas
Hemangiomas
most common tumors of infancy.
Both cavernous and capillary hemangiomas
located in the skin, particularly on the face and
scalp - produce flat to elevated, irregular, red-
blue masses;
port wine stains - flat, larger lesions
may enlarge as the child gets older, but in many
instances they spontaneously regress.
The vast majority of superficial hemangiomas
have no more than a cosmetic significance;
rarely, they may be the manifestation of a
hereditary disorder associated with disease
within internal organs, such as the
Von Hippel-Lindau and
Sturge-Weber syndromes.
Lymphangiomas
the lymphatic counterpart of hemangiomas.
characterized by cystic and cavernous spaces
lined by endothelial cells and surrounded by
lymphoid aggregates; the spaces usually
contain pale fluid.
occur on the skin but, more importantly, are also
encountered in the deeper regions of the neck,
axilla, mediastinum, and retroperitoneum.
Although histologically benign,
they tend to increase in size after birth and
may encroach on mediastinal structures or
nerve trunks in axilla.
Cystic hygromas
postnuchal collections of lymphatic fluid that
are commonly seen in aborted fetuses with a
45,X karyotype (Turner syndrome); unlike
lymphangiomas, dilated endothelium-lined
Sacrococcygeal teratomas
most common germ cell tumors of childhood,
accounting for 40% or more of cases.
approximately 10% are associated with
congenital anomalies,
primarily defects of the hindgut and
cloacal region and
other midline defects
(e.g., meningocele, spina bifida)
not believed to result from local effects of
the tumor.
approximately 75% of these tumors are
histologically mature with a benign course,
and about 12% are unmistakably malignant
and lethal.
the remainder are designated immature
teratomas, and their malignant potential
correlates with the amount of immature tissue
Most of the
benign
teratomas are
encountered in
younger infants
(<4 months),
whereas
children with
malignant
lesions tend to
be somewhat
older.
Malignant Tumors
The organ systems involved most commonly
hematopoietic system,
neural tissue,
soft tissues.
This is in sharp contrast to adults, in whom tumors
of the lung, heart, prostate, and colon are the
most common forms.
Differ biologically and histologically from those in
adults.
The main differences are
1• Relatively frequent demonstration of a
close relationship between abnormal
development (teratogenesis) and tumor
induction (oncogenesis)
2• Prevalence of constitutional genetic
abnormalities or syndromes that
predispose to cancer
 3• Tendency of fetal and neonatal
malignancies to spontaneously regress or
undergo "differentiation" into mature
elements
4• Improved survival or cure of many
childhood tumors.
Histologically,
In general,
they tend to have a primitive (embryonal) rather
than pleomorphic-anaplastic microscopic
appearance,
frequently they exhibit features of
organogenesis specific to the site of tumor
origin.
Because of their primitive histologic
appearance, many childhood tumors have
been collectively referred to as
small, round, blue cell tumors.
 Characterized by sheets of cells with small, round
nuclei.
include neuroblastoma,
lymphoma,
rhabdomyosarcoma,
Ewing sarcoma
(peripheral neuroectodermal tumor),
Wilms tumor.

There are usually sufficient distinctive features to

render a definitive diagnosis on the basis of
histologic examination alone, but when necessary,
clinical and radiographic findings, combined with
ancillary studies (e.g., chromosome analysis,
immunoperoxidase stains, and electron microscopy)
are used.
NEUROBLASTOMA
Most common solid tumor of childhood other than
central nervous system neoplasms,
about 15% of all childhood cancer deaths.
Most (80% to 90%) are found in children younger
than 5 years, many in the first year of life.
Demonstrate several unique features in their
natural history, including
spontaneous regression and
spontaneous- or
therapy­induced maturation.
Neural crest origin,
may arise any­where in the sympathetic
nervous system from the head to the pelvis.
75% arise within the abdomen:
half in the adrenal glands
half in the abdominal paravertebral
autonomic ganglia.
 Most occur sporadically, but a few are familial
with autosomal dominant transmission, and in
such cases the neoplasms may involve both of
the adrenals or multiple primary autonomic
sites.

MORPHOLOGY
Range from
microscopic nodules (usually in infants)
appear to be circumscribed or even
encapsulated,
to larger masses that virtually fill the
abdomen.
often grow into nearby organs (kidney,
liver, pancreas).
Advanced disease frequently invades the renal
vein, often extending into the inferior vena cava.
On cross-section
gray-white, soft, and friable, and larger tumors
often have areas of hemorrhage, necrosis, cystic
degeneration, and calcification.
Histologically,
the cells, which grow in solid sheets, are round to
ovoid and primitive-looking with large,
hyperchromatic nuclei surrounded by scant
cytoplasm.
characteristic features can often be identified in
Rosettes (Homer-Wright pseudorosettes), in
which the tumor cells are arranged about
the periphery of a central space filled with
fibrillar extensions of the cells.
Immunochemical detection of neuron-specific
enolase and ultrastructural demonstration
of small, membrane-bound, cytoplasmic
catecholamine-containing secretory
Some neoplasms show signs of maturation, either
spontaneous or therapy-induced.
Ganglion cells - larger cells having more
abundant cytoplasm with large
vesicular nuclei and a prominent
nucleolus –
in various stages of maturation, may be
found in tumors admixed with primitive
neuroblasts (ganglioneuroblastoma).
Even better-differentiated lesions contain many
more large cells resembling mature ganglion cells in
the absence of residual neuroblasts - ganglioneuroma
Maturation of neuroblasts into ganglion cells is
usually accompanied by the appearance of spindle-
shaped
Schwann cells - a reactive population recruited
from the surrounding non-
neoplastic tissues by the tumor cells.
Clinical Course.
Children younger than 2 years
generally present with protuberant abdomen
owing to an abdominal mass,
fever,
weight loss.
In older children,
may remain unnoticed until metastases
cause
hepatomegaly,
ascites, and
bone pain.
Metastasize widely through the hematogenous
and lymphatic systems, particularly to liver,
lungs, and bones, in addition to the bone
marrow.
About 90% regardless of location, produce
catecholamines.
which are an important diagnostic feature
elevated blood levels of catecholamines and
elevated urine levels of catecholamine
metabolites such as
vanillylmandelic acid [VMA] and
homovanillic acid [HVA]).
Despite the elaboration of catecholamines,
hypertension is much less frequent with these
neoplasms than with pheochromocytomas

Many factors influence prognosis, but the most

important are the stage of the tumor and the age of
the patient.
Staging assumes great importance in
establishing a prognosis.
Stage IV-S (S stands for special)
the outlook for these patients is excellent,
despite the spread of disease
the primary tumor would be classified as being
in stage I or II but for the presence of
metastases, which are limited to liver, skin,
and bone marrow, without bone involvement.
Such infants have an excellent prognosis with
minimal therapy, and it is not uncommon for
the primary or metastatic tumors to undergo
spontaneous regression.
Age is the other important determinant of outcome,
and children younger than 1 year have a much more
favorable outlook than do older children at a
comparable stage of disease.
Most neoplasms in the infant years are stage I or II,
or stage IV-S.
Molecular and genetic analysis
provides prognostic information.
Deletion of the short arm of chromosome 1
(1p36) is usually associated with aggressive
disease; presumably some of these
deletions involve the TP73 (formerly p73)
gene, belonging to the TP53 (formerly p53)
family of tumor suppressor genes.
Amplification of the MYCN (formerly N-myc)
oncogene is also a harbinger of poor
prognosis.
There is a high degree of concordance between
1p36 deletion and increase in MYCN copy
numbers, and tumors with this genetic
profile have an extremely aggressive
phenotype.
RETINOBLASTOMA
most common malignant eye tumor of childhood.
unusual in several aspects when compared with
most other solid tumors.
frequently occurs as a congenital tumor,
it can be multifocal and bilateral,
it undergoes spontaneous regression, and
patients have a high incidence of second
primary tumors.
The incidence decreases with age, most cases
being diagnosed before the age of 4 years.
occur in both familial and sporadic patterns.
Familial cases
typically develop multiple tumors that are
bilateral, although they may be unifocal
and unilateral.
also at increased risk for developing
osteosarcoma and other soft tissue tumors.
 Sporadic cases
nonheritable tumors are unilateral and
unifocal.
MORPHOLOGY
arise from a cell of neuroepithelial origin, usually
in the posterior retina
The tumors tend to be nodular masses, often with
satellite seedings.
Histologically
Undifferentiated areas of these tumors are found
to be composed of small, round cells with large

hyperchromatic nuclei and scant cytoplasm,

resembling undifferentiated retinoblasts.
Differentiated structures,
most characteristic of these being the rosettes
Flexner-Wintersteiner rosettes - clusters of
cuboidal or short columnar cells
 The nuclei are displaced away from the
lumen, which by light microscopy appears to
have a limiting membrane resembling the
external limiting membrane of the retina.

Tumor cells may disseminate beyond the eye through

optic nerve or
subarachnoid space.

The most common sites of distant metastases are

central nervous system,
skull,
distal bones, and
lymph nodes
Clinical Features.
The median age at presentation is 2 years, although
the tumor may be present at birth.
The presenting findings include
poor vision,
strabismus,
whitish hue to the pupil ("cat's eye reflex"), and
pain and tenderness in the eye.
Approximately 60% to 70% of the tumors are
associated with a germ-line mutation in the RBI
gene and are hence heritable. (familial)
The remaining 30% to 40% of the tumors develop
sporadically, and these have somatic RBI gene
mutations.
Untreated,
the tumors are usually fatal, but after early
treatment with enucleation, chemotherapy, and
radiotherapy, survival is the rule.

Some tumors spontaneously regress, and patients

with familial retinoblastoma are at increased risk
for developing osteosarcoma and other soft tissue
tumors.
WILMS TUMOR
Nephroblastoma,
Most common primary tumor of the kidney in
children.
Most cases occur in children between 2 and 5
years of age..
Three groups of congenital malformations are
associated with an increased risk of developing
Wilms tumor. Patients with the
1.WAGR syndrome - 33% chance
characterized by
aniridia,
genital abnormalities, and
mental retardation,
2.Denys-Drash syndrome
characterized by
gonadal dysgenesis and
renal abnormalities.
Both of these conditions are associated with loss of
genetic material on
chromosome 11p13 - tumor suppressor gene
Wilms tumor 1 (WTI ) has
been mapped.
3.Beckwith­Wiedemann syndrome
These patients have enlargement of individual
body organs (e.g., tongue, kidneys, or liver), or
entire body segments (hemihypertrophy);
enlargement of adrenal cortical cells (adrenal
cytomegaly) is a characteristic microscopic
feature
chromosome 11p15.5. - WT2
but the precise
identity of the gene
implicated in
tumorigenesis remains
unknown.
 Disorder of genomic imprinting, and aberrant
expression of normally repressed
growth-promoting genes such as
insulin-like growth factor 2
("loss of imprinting") is postulated to result in
both organ enlargement and tumorigenesis.
Thus, these associations suggest that in some cases
congenital malformations and tumors represent
related manifestations of genetic damage affecting a
single gene or closely linked genes.
MORPHOLOGY
Grossly,
large, solitary, well-circumscribed mass,
10% are either bilateral or multicentric at the
time of diagnosis.
On cut section,
soft, homogeneous, and tan to gray, with
occasional foci of hemorrhage, cystic
degeneration, and necrosis.
Microscopically,
characterized by recognizable attempts to
recapitulate different '' stages of nephrogenesis.
The classic triphasic combination of
blastemal - sheets of small blue cells, with
few distinctive ' features,
epithelial cell - form of abortive tubules or
glomeruli.
stromal - usually fibrocytic or myxoid in nature,
although skeletal muscle "differentiation“
is not uncommon.
rarely, other heterologous elements
squamous or mucinous epithelium,
smooth muscle, adipose tissue, cartilage,
and osteoid and neurogenic tissue.
Is observed in most lesions, although the percentage
of each component is variable.

Approximately 5% of tumors contain foci of

anaplasia
(cells with large, hyperchromatic, pleomorphic
nuclei and abnormal mitoses).
The pattern of distribution of anaplastic cells within
the primary tumor (focal vs. diffuse) has important
implications in therapy and prognosis.
Nephrogenic rests
are putative precursor lesions and are
sometimes present in the renal parenchyma
adjacent to the tumor.
have a spectrum of histologic appearances,
expansile masses that resemble Wilms
tumors (hyperplastic rests) to
sclerotic nests consisting predominantly of
fibrous tissue with occasional admixed
immature tubules or glomeruli.
It is important to document the presence of
nephrogenic rests in the resected specimen, since
these patients are at an increased risk of
developing Wilms tumors in the contralateral
kidney.
Clinical Course.
Patients' complaints are usually referable to the
tumor's enormous size.
Commonly,
there is a readily palpable abdominal
mass, which may extend across
the midline and down into the pelvis
Less often,
the patient presents with
fever and
abdominal pain,
with hematuria, or,
occasionally,
with intestinal obstruction
as a result of pressure from the tumor.
The prognosis
is generally very good, and excellent results are
obtained with a combination of nephrectomy and
chemotherapy.

Two-year survival rates are as high as 90%, even for

tumors that have spread beyond the kidney, and
survival for 2 years usually implies a cure.

Tumors with diffuse anaplasia, especially those with

extrarenal spread, have the least favorable outcome,
underscoring the need for correctly identifying this
histologic pattern.