PEDIATRIC DISEASE

Oleh : Rizki Widya Nur

Pembimbing :
dr. Ika Pawitra Miranti, M.Kes, Sp.PA
Neonatal period (the first 4 weeks of life)
• The most hazardous time
Infancy (the first year of life)

• Pose the highest risk of death

1 year and 14 years of age

• Injuries resulting from accidents are the

leading cause of death
 CONGENITAL ANOMALIES
• Structural defects that are present at
birth, although some, may not become
clinically apparent until years later (such
as cardiac defects and renal anomalies).
• In US +/- 120,000 babies are born with a
birth defect each year (1 : 33).
• Congenital anomalies are an important
cause of infant mortality.
Malformation
• Primary errors of morphogenesis
• Intrinsically abnormal developmental
• Usually are multifactorial, manifest in any of several
patterns
Disruptions
• Result from secondary
destruction of an organ
or body region that was
previously normal in
development
• Arise from an extrinsic
disturbance in
morphogenesis
• Associated with risk of
recurrence in
subsequent pregnancies
Deformations
• Represent an extrinsic disturbance of development
• Caused by localized or generalized compression of
the growing fetus by abnormal biomechanical
forces
• Maternal condition  first pregnancy, small
uterus, malformed (bicornuate) uterus, and
leiomyomas.
• Relating to the fetus  presence of multiple
fetuses, oligohydramnios, and abnormal fetal
presentation
Sequence
•Multiple congenital anomalies that
result from secondary effects of a single
localized aberration in organogenesis.

Infant with oligohydramnios (Potter)

sequence. Note flattened facial
features and deformed foot
Malformation
syndrome
The presence of several
defects that cannot be
explained on the basis of a
single localizing initiating
error in morphogenesis. Ex ;
Viral infection or
chromosomal abnormality
Organ-specific
malformations
Agenesis : complete
absence of an organ
Atresia : the absence of
an opening, usually of a
hollow visceral organ or
duct such as intestines
and bile ducts.
 Genetic

ETIOLOGY Environtmental

Multifactorial
 PATHOGENESIS
1. The timing

• Early ( 0-3 weeks)  injurious

agent damages either enough cells
Embryoic period to cause death and abortion
• 3- 9 weeks  extremely susceptible
to teratogenesis

• fetus is susceptible to growth

Fetal period retardation or injury to already
formed organs
2. The complex interplay between environmental
teratogens and intrinsic genetic defects
- Cyclopamine = plant teratogen, present in
subsets of fetuses with holoprosencephaly.
- Valproic acid = an anti-epileptic. Induce critical
transcription factors to homeobox (HOX)
proteins. HOX proteins have been implicated in
the patterning of limbs, vertebrae, and
craniofacial structures (valproic acid
embryopathy)
- The vitamin A (retinol) = Excessive exposure
to retinoic acid also is teratogenic, retinoic
acid embryopathy including CNS, cardiac, and
craniofacial defects, such as cleft lip and cleft
palate.
 PERINATAL INFECTION

TRANSCERVICAL TRANSPLACENTAL
(ASCENDING INFECTIONS) INFECTION

• Caused by spread of microbes from • Access to the fetal bloodstream by

the cervicovaginal canal and may be crossing the placenta via the
acquired in utero or during birth. chorionic villi.
• Bacterial infections (e.g., α- • TOxoplasma
hemolytic streptococcal infection) • Rubella virus
• Viral infections (e.g., herpes simplex) • Cytomegalo virus
• Herpes virus
• and others.
 PREMATURITY
AND
FETAL GROWTH RESTRICTION
 PREMATURITY
• A gestational age less than 37 weeks
• Weigh less than normal (<2500 gm)
• Risk factors :
Preterm premature rupture of membranes;
Intrauterine infection leading to inflammation of
the placental membranes (chorioamnionitis);
Structural abnormalities of the uterus, cervix, and
placenta;
 multiple gestation (twin pregnancy)
The immaturity of organ systems in preterm
infants makes them especially vulnerable to
several important complications:
Respiratory distress syndrome, also called
hyaline membrane disease

Necrotizing enterocolitis

Sepsis

Intraventricular and germinal matrix

hemorrhage

Long-term sequelae, including

developmental delay
 Fetal Growth Restriction
Fetal abnormalities
• Chromosomal disorders
• Congenital anomalies
• Congenital infections.
Placental abnormalities
• Placenta previa (low implantation of the placenta),
• Placental abruption (separation of placenta from the decidua by a retroplacental
clot),
• Placental infarction.

Maternal factors
• Preeclampsia and chronic hypertension
• Maternal narcotic abuse alcohol intake, and heavy cigarette smoking
• Maternal malnutrition (in particular, prolonged hypoglycemia)
RESPIRATORY DISTRESS SYNDROME

Also know as hyaline membrane disease

Common causes :
1. Excessive sedation of the mother
2. Fetal head injury during delivery
3. Aspiration of blood or amniotic fluid
4. Intrauterine hypoxia secondary to compression
from coiling of the umbilical cord about the neck.
 PATHOGENESIS
• About 60% born at less than 28 weeks’
gestation, 30% born between 28 to 34 weeks’
gestation, and less than 5% of those born after
34 weeks’ gestation.
• Fundamental defect in RDS is the inability of
the immature lung to synthesize sufficient
surfactant.
• Corticosteroids stimulate the
formation of surfactant lipids.
• Intrauterine stress and fetal
growth restriction, which
increase corticosteroid release,
lower the risk of developing
RDS.
• The compensatory high blood
levels of insulin in infants of
diabetic mothers can suppress
surfactant synthesis (why
infants of diabetic mothers are
at higher risk for developing
RDS)
• Labor is known to increase
surfactant synthesis;
accordingly, cesarean section
performed before the onset of
labor also may be associated
with increased risk for RDS.
MORPHOLOGY
• If the infant dies within the first several hours
of life, only necrotic cellular debris will be
present in the terminal bronchioles and
alveolar ducts.
• If the infant with RDS dies after several days,
evidence of reparative changes, including
proliferation of type II pneumocytes and
interstitial fibrosis, is seen.
NECROTIZING ENTEROCOLITIS
• Occurs in premature infants
• occurs in approximately 1 of 10 very-low-
birth-weight infants (<1500 gm)
Manifestasion :
 Bloody stools,
 Abdominal distention,
 Development of circulatory collapse,
 Abdominal radiographs demonstrate gas
within the intestinal wall (pneumatosis
intestinalis)
The involved segment typically is distended, friable,
and congested, or it can be frankly gangrenous;
intestinal perforation with accompanying peritonitis
may be seen.
• Microscopic examination : mucosal or
transmural coagulative necrosis, ulceration,
bacterial colonization, and submucosal gas
bubbles .
• Granulation tissue and fibrosis, may be seen
shortly after resolution of the acute episode.
 SUDDEN INFANT DEATH
SYNDROME (SIDS)

The sudden death of an infant under 1 year of

age which remains unexplained after a
thorough case investigation ( a complete
autopsy, examination of the death scene, and
review of the clinical history )
Factors Associated With Sudden
Infant Death Syndrome (SIDS)
 MORPHOLOGY
• Multiple petechiae are the most common
finding in the typical SIDS autopsy (in
approximately 80% of cases); these usually are
present on the thymus, visceral and parietal
pleura, and epicardium.
• The lungs usually are congested, and vascular
engorgement with or without pulmonary
edema is present in a majority of cases.
• Hypoplasia of the arcuate nucleus
 FETAL HYDROPS

The accumulation of edema fluid in the fetus

during intrauterine growth.
The fluid accumulation : generalized edema of the
fetus (hydrops fetalis), a usually lethal condition.
Isolated pleural and peritoneal effusions or
postnuchal fluid collections (cystic hygroma), that
often are compatible with life.
 Immune hydrops
• Results from an antibody-induced hemolytic
disease in the newborn that is caused by
blood group incompatibility between mother
and fetus.

1. Rh-Incompability
2. ABO-Incompability
 RH- Incompability
When the cytotrophoblast is no longer present as a barrier (the last
trimester of pregnancy or during child birth itself (fetomaternal bleed)

Mother becomes sensitized to the foreign antigen and produces

antibodies

Freely traverse the placenta to the fetus

Red cell destruction

Progressive anemia in the fetus

Tissue ischemia, intrauterine cardiac failure, and peripheral pooling of

fluid (edema)
• Prophylaxis : Rh-negative mothers are given
Rh immune globulin (RhIg) at 28 weeks and
within 72 hours after delivery of an Rh-
positive baby. The RhIg masks 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-Incompability
• ABO hemolytic disease occurs almost exclusively in
infants of blood group A or B who are born to
mothers of blood group O.
• Group O women possess IgG antibodies directed
against group A or B antigens (or both) even
without previous sensitization.
• There is no effective method of preventing
hemolytic disease resulting from ABO
incompatibility
 Nonimmune Hydrops

Major
cause

Structural cardiovascular Transplacental

defects Fetal anemias
infection
 MORPHOLOGY
 Dysmorphic features
 Cardiac anomaly
 Pale
 Liver and spleen are enlarged
 Extramedullary hematopoiesis is present in the liver, the
spleen, and possibly in other tissues such as the kidneys, the
lungs, the lymph nodes, and even the heart
 Large numbers of normoblasts, and even more immature
erythroblasts (erythroblastosis fetalis)
 The basal ganglia and brain stem are particularly prone to
deposition of bilirubin pigment, which imparts a characteristic
yellow hue to the parenchyma (kernicterus)
TUMORS AND TUMOR-LIKE LESIONS
OF INFANCY AND CHILDHOOD
 TUMOR-LIKE LESIONS
Heterotopia Hamartoma

Microscopically Excessive but

normal cells or focal overgrowth
tissues that are of cells and
present in tissues native to
abnormal the organ in
locations. which it occurs
 Tumors/
Neoplasm

Malignant Benign
neoplasms neoplasms

Neuroblas Retinoblas Wilms Hemangio Lympangi

toma toma Teratoma
Tumor ma oma
 Benign Neoplasm

Haemangioma
• The most common neoplasms of infancy.
• Most hemangiomas are located in the skin,
particularly on the face and scalp.
• Hemangiomas may enlarge as the child ages,
but in many instances they spontaneously
regress.
 Benign Neoplasm
Lymphangioma

• Represent the lymphatic counterpart of hemangiomas.

• Microscopic examination shows cystic and cavernous
spaces lined by endothelial cells and surrounded by
lymphoid aggregates; the spaces usually contain pale fluid.
• They may occur on the skin, neck, axilla, mediastinum,
andn retroperitoneum.
• Although histologically benign, they tend to increase in
size after birth and may encroach on mediastinal
structures or nerve trunks in axilla.
 Benign Neoplasm
Teratoma
• Sacrococcygeal teratomas are the most common
teratomas of childhood, accounting for 40% or
more of cases.
• 75% of these tumors are mature teratomas with
a benign course, and about 12% are unmistakably
malignant and lethal.
• Most of the benign teratomas are encountered in
younger infants (4 months of age or younger),
whereas children with malignant lesions tend to
be somewhat older.
Malignant Neoplasm
 Exhibit features
of organogenesis
specific to the
site of tumor
origin
Exhibit a
Referred to as
primitive
small, round,
(embryonal)
blue-cell tumors.
appearance

Malignant
Pediatric
Neoplasms
NEUROBLASTOMA
• Neuroblastomas arise from neural crest–
derived cells in the sympathetic ganglia and
adrenal medulla.
• 7% to 10% of all pediatric neoplasms, and as
many as 50% of malignancies diagnosed in
infancy.
• 1% to 2% are familial, with autosomal
dominant transmission, mutations in the
anaplastic lymphoma kinase (ALK).
 MORPHOLOGY
• 40% of neuroblastomas arise in the adrenal
medulla.
• Most common locations : paravertebral region of
the abdomen (25%) and posterior mediastinum
(15%)
• Macroscopically : range in size from clinically
silent minute nodules (in situ lesions) to large
masses weighing more than 1 kg.
• On transection : soft, gray-tan, brainlike tissue.
Larger tumors have areas of necrosis, cystic
softening, and hemorrhage.
• Histologically, classic neuroblastomas are
composed of small, primitive-appearing cells with
dark nuclei, scant cytoplasm, and poorly defined
cell borders growing in solid sheets.

• Mitotic activity, nuclear breakdown

(“karyorrhexis”), and pleomorphism

• Maturation of neuroblasts into ganglion cells

usually is accompanied by the appearance of
Schwann cells.
Neuroblastoma
This tumor is composed of small cells embedded in a finely
fibrillar matrix (neuropil). A Homer-Wright pseudorosette (tumor
cells arranged concentrically around a central core of neuropil) is
seen in the upper right corner.
Ganglioneuromas
clusters of large ganglion cells with vesicular nuclei and
abundant eosinophilic cytoplasm (arrow). Spindle-shaped
Schwann cells are present in the background.
 Age

Amplification
Staging of the MYCN

PROGNOSIS

Histology
DNA
Ploidy

Others
STAGING
• 4S tumors have
an excellent
prognosis with
minimal
therapy.
• Most (60% to
80%) children
present with
stage 3 or 4
tumors, and
only 20% to 40%
present with
stage 1, 2A, 2B,
or 4S
neuroblastomas.
Age
• The outlook for children younger than 18 months is much more
favorable than for older children at a comparable stage of
disease.

Histology
• Evidence of schwannian stroma and gangliocytic differentiation
is indicative of a favorable prognosis.

Amplification of the MYCN

• The greater the number of copies, the worse the prognosis
DNA ploidy

• Tumors that are hyperdiploid (with whole

chromosome gains) having more favorable
prognosis than near-diploid.

Others

• Expression of TrkA, a high-affinity receptor for nerve

growth factor that is indicative of differentiation
toward sympathetic ganglia lineage, is associated
with favorable prognosis.
 Clinical Course
• < 2 years : protuberant abdomen resulting from an
abdominal mass, fever, and weight loss.
• > 2 years : unnoticed until metastases cause hepatomegaly,
ascites, and bone pain.
• Metastasize particularly to liver, lungs, bones, and the
bone marrow.
• Multiple cutaneous metastases associated with deep blue
discoloration to the skin (earning the rather unfortunate
moniker of “blueberry muffin baby”)
• Elevated blood levels of catecholamines and elevated urine
levels of catecholamine metabolites such as
vanillylmandelic acid [VMA] and homovanillic acid [HVA]
RETINOBLASTOMA

• The most common primary intraocular

malignancy of children.
• 40% associated with germline mutation in the
RB1 gene and heritable.
• Patients with familial retinoblastoma are at
increased risk for the development of
osteosarcoma and other soft tissue tumors.
 MORPHOLOGY
• Retinoblastomas tend to be nodular masses,
usually in the posterior retina, often with
satellite seedings
• On microscopic examination, undifferentiated areas
of these tumors are found to be composed of small,
round cells with large hyperchromatic nuclei and
scant cytoplasm, resembling undifferentiated
retinoblasts.
• Flexner- Wintersteiner rosettes  clusters of
cuboidal or short columnar cells arranged around a
central lumen (in contrast with the pseudorosettes
of neuroblastoma, which lack a central lumen).
• 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.
Higher-power view showing Flexner-Wintersteiner
rosettes (arrow) and numerous mitotic figures.
 Clinical Features
• Poor vision, strabismus, a whitish hue to the
pupil (“cat’s eye reflex”), and pain and
tenderness in the eye.
• The median age at presentation is 2 years,
although the tumor may be present at birth.
• Untreated, the tumors usually are fatal, but
when treated with chemotherapy,
radiotherapy, and (in locally advanced tumors)
enucleation, survival is the rule.
 WILMS TUMOR
(Nephroblastoma)
• Is the most common primary tumor of the
kidney in children
• Most cases occurring in children between 2
and 5 years of age.
• The relationship between congenital
malformation and increased risk of tumors
• Three groups of congenital malformations are
associated with an increased risk for Wilms
tumor.

WAGR syndrome

Denys-Drash syndrome (DDS)

Beckwith-wiedemann syndrome
(BWS)
 • Wilms tumor, Aniridia, Genital
abnormalities and mental
WAGR Retardation
syndrome
• Loss of genetic material (i.e.,
deletions) of WT1

• Gonadal dysgenesis and early

onset nephropathy leading to
DD renal failure
syndrome
• A dominant negative
inactivating mutation in WT1
 Beckwith- Wiedemann syndrome
(BWS)
• Exhibit enlargement of individual body organs
(e.g., tongue, kidneys, or liver) or entire body
segments (hemihypertrophy); enlargement of
adrenal cortical cells (adrenal cytomegaly)
• The genetic locus that is involved in these
patients is in band p15.5 of chromosome 11
distal to the WT1 locus (“WT2”)
• Increased risk for the development of
hepatoblastoma, adrenocortical tumors,
rhabdomyosarcomas, and pancreatic tumors.
 MORPHOLOGY
• Large, solitary, well-circumscribed mass, 10%
are either bilateral or multicentric
• On cut section, the tumor is soft,
homogeneous, and tan to gray, with
occasional foci of hemorrhage, cystic
degeneration, and necrosis.
microscopic examination

The classic triphasic combination

- Blastemal : Sheets of small blue

cells, with few distinctive features
- Epithelial: bortive tubules or
glomeruli
- Stromal : fibrocytic or myxoid in
nature, although skeletal muscle
“differentiation” is not uncommon
 Clinical Course
• Palpable abdominal mass (extend across the
midline and down into the pelvis.)
• fever
• abdominal pain
• hematuria
• Intestinal obstruction as a result of pressure
from the tumor.
MOLECULAR DIAGNOSIS OF
MENDELIAN AND COMPLEX
DISORDERS
 Prenatal

Inherited
Postnatal
Indications for
genetic analysis

Acquired
 Prenatal Genetic Analysis
• Offered to all patients who are at risk of having
cytogenetically abnormal progeny.

• Some important indications are the following:

 Advanced maternal age (beyond 34 years), which is
associated with greater risk of trisomies
 Confirmed carrier status (the progeny would be at risk
for chromosomal disorders)
 Fetal abnormalities observed on ultrasound, or an
abnormal result on routine maternal blood screening
 A chromosomal abnormality or mendelian disorder
affecting a previous child
 Determination of fetal sex when the patient or partner is
a confirmed carrier of an X-linked genetic disorder
 Postnatal genetic
Genetic analysis
Analysis
• Usually is performed on peripheral blood
lymphocytes.
• Indications are as follows:
 Multiple congenital anomalies
 Suspicion of a metabolic syndrome
 Unexplained mental retardation and/or
developmental delay
 Suspected aneuploidy (e.g., features of Down
syndrome) or other syndromic chromosomal
abnormality (e.g., deletions, inversions)
 Suspected monogenic disease, whether
previouslydescribed or unknown
 Molecular
Diagnosis of
Number
Abnormalities

Flourescence In Arrays Based

Situ Hybridization Genomic
(FISH) Hybrization (CGH)
 FISH
 For identifying chromosomal changes
 Can be performed on prenatal samples (e.g.,
cells obtained by amniocentesis, chorionic villus
biopsy, or umbilical cord blood), peripheral blood
lymphocytes, and even archival tissue sections.
 FISH is used for the detection of numeric
abnormalities of chromosomes (aneuploidy),
subtle microdeletions and complex translocations
not indentifiable by routine karyotyping, and
gene amplification (e.g., MYCN amplification in
neuroblastomas).
Arrays Based Genomic Hybrization
(CGH)

 To determine copy number variations

 DNA are labeled with two different
fluorescent dyes that fluoresce red and
green, respectively.
 Can identify uniparental disomy, in which
loss of heterozygosity is seen within an
affected region having diploid DNA
content.
An 18-year-old woman gives birth to a term infant after
an uncomplicated pregnancy and delivery. Over the first 2
days of life, the infant becomes mildly icteric. On physical
xamination, there are no morphologic abnormalities.
Laboratory studies show a neonatal bilirubin
concentration of 4.9 mg/dL. The direct Coombs test of
the infant’s RBCs yields a positive result. The infant’s
blood type is A negative, and the mother’s blood type is O
positive. Based on these findings, which of the following
events is most likely to occur?

A Complete recovery
B Failure to thrive
C Hemolytic anemia throughout infancy
D Kernicterus
E Respiratory distress syndrome
A
This mild hemolytic anemia is most likely due to an ABO
incompatibility with maternal blood type O, which results
in anti-A antibody coating fetal cells. Most anti-A and
anti-B antibodies are IgM. In about 20% to 25% of
pregnancies, there are also IgG antibodies, which cross
the placenta in sufficient titer to produce mild hemolytic
disease in most cases. The bilirubin concentration in the
term infant in this case is not high enough to produce
kernicterus. ABO incompatibilities are not likely to have
such serious consequences for subsequent pregnancies as
does Rh incompatibility. As the infant matures, the level
of maternal antibody diminishes, hemolysis abates, and
the infant develops normally. Respiratory distress is
unlikely at term because of appropriate fetal lung
maturity.
The parents of a 2-year-old boy are concerned because their son
seems to have no vision in his right eye. On examination there is
strabismus and a whitish appearance to the pupil on the right,
with tenderness to orbital palpation. Vision on the left appears
to be intact. An enucleation of the right eye is performed,
followed by radiation and chemotherapy. There is no recurrence
on the right, but at age 5 years, a similar lesion develops in the
left eye. At age 12 years, the boy develops an osteosarcoma of
the left distal femur. Which of the following genetic mechanisms
is most likely to produce these findings?

A Aneuploidy
B Chromosomal translocation
C Trinucleotide repeat mutation
D Germline mutation
E Multifactorial inheritance
F Uniparental disomy
G X-linked gene defect
D
This child has inherited an abnormal RB1 gene, and
early in life the other allele is lost, leading to loss of tumor
suppression and development of a retinoblastoma. About 60%
to 70% of retinoblastomas are associated with germline
mutations. Aneuploidy usually results in fetal loss, although
monosomy X and trisomies 13, 18, and 21 occasionally may lead
to live births. Chromosomal translocations may be seen with
other tumors, such as chronic myelogenous leukemia, acute
promyelocytic leukemia, and Burkitt lymphoma. Trinucleotide
repeats are typically not associated with neoplasms.
Multifactorial inheritance may be associated with complex
diseases, such as diabetes mellitus, hypertension, and bipolar
disorder. Uniparental disomy is a mechanism for chromosomal
imbalance, and neoplasia is unlikely. X-linked single-gene
defects are unlikely to lead to neoplasia.