Diseases of

Infancy
&
Childhood
 Diseases of Infancy
and Childhood
 Congenital Anomalies
 Disorders of Prematurity
 Perinatal Infections
 Tumors
Congenital Anomalies
 Congenital anomalies
Congenital means “born with,”

Congenital anomalies are morphologic

defects that are present at birth, but some,
such as cardiac defects and renal
anomalies, may not become clinically
apparent until years later.
Epidemiology & importance of CD

It is estimated that about 120,000 (1 in 33)

babies are born with a birth defect each
year in the United States.

They are the most common cause of

mortality in the first year and contribute
significantly to morbidity and mortality
throughout the early years of life.
 Definitions
 Malformations
 primary errors of morphogenesis / development, 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 by biomechanical forces
e.g. uterine constraint
 Sequence
 a pattern of cascade anomalies explained by a single localized
initiating event with secondary defects in other organs
e.g. Oligohydramnios (Or Potter) Sequence
 Syndrome
 a constellation of developmental abnormalities believed to be
pathologically related
e.g. Turner syndrome
 Malformations
These are the errors of morphogenesis.

In which an intrinsic abnormal developmental process

present.

They are usually associated with multiple genetic loci

(multifactorial) and not the result of a single-gene or
chromosomal defect.

Malformations may present in several patterns.

Some, such as congenital heart defects and anencephaly
(absence of brain) involve single body systems, whereas in
other cases multiple malformations involving many organs
may coexist.
 Malformations

Polydactyly (one Cleft Lip Severe Lethal Malformation

or more extra digits) &
Syndactyly
(fusion of digits),
 Disruptions
These are the errors of morphogenesis.

These arise from an extrinsic disturbance in morphogenesis

These result from secondary destruction of an organ or

body region that was previously normal in development.
e.g. Amniotic bands, denoting rupture of amnion with
resultant formation of “bands” that encircle, compress,
or attach to parts of the developing fetus, are the example
of a disruption .

Disruptions are not heritable and hence are not associated

with risk of recurrence in subsequent pregnancies.
 Disruption by an amniotic band

Disruptions occur in a normally developing organ because

of an extrinsic abnormality that interferes with normal
morphogenesis. Amniotic bands are a frequent cause of
disruptions. In the illustrated example, note the placenta at
the right of the diagram and the band of amnion
extending from the top portion of the amniotic sac to
encircle the leg of the fetus.
 Deformations
These are the errors of morphogenesis.

These arise from an extrinsic disturbance in morphogenesis / development.

These are common problems, affecting approx: 2% of newborn infants

Pathogenesis:- There is localized or generalized compression of the
growing fetus by abnormal biomechanical forces, leading to a variety of
structural abnormalities. The most common underlying factor responsible for
deformations is uterine constraint. Between the 35th and 38th weeks of
gestation, rapid increase in the size of the fetus outpaces the growth of the
uterus, and the relative amount of amniotic fluid (which normally acts as a
cushion) also decreases which results in uterine constraint .
Several factors are there which cause uterine constraint .
Maternal factors include first pregnancy, small uterus, malformed
(bicornuate) uterus, and leiomyomas.
Fetal or placental factors include oligohydramnios, multiple fetuses, and
abnormal fetal presentation.
 Sequence
A sequence is a cascade of anomalies
triggered by one initiating aberration, which
is extrinsic.
e.g. Oligohydramnios (decreased amniotic fluid)
sequence, caused by a variety of maternal,
placental, or fetal abnormalities.
 Sequence
Causes of oligohydramnios include
* Chronic leakage of amniotic fluid because of rupture of the
amnion
* Uteroplacental insufficiency resulting from maternal HTN or
severe toxemia, and
* Renal agenesis in the fetus (because fetal urine is a major
constituent of amniotic fluid).
The fetal compression results in flattened facies
and abnormalities of the hands and feet, hips may
be dislocated.
Growth of the chest wall and the lungs is also
compromised so that the lungs are frequently
hypoplastic.
 Oligohydramnios (Potter) Sequence
 Oligohydramnios (decreased amniotic fluid)
 Renal agenesis
 Amniotic leak

 Fetal Compression
 flattened facies
 club foot
 Pulmonary hypoplasia

 Breech Presentation
 The Oligohydramnios “Sequence”

Amnion nodosum are nodules on the fetal surface of the amnion,

and is frequently present in oligohydramnios
 Infant with Oligohydramnios sequence

Infant with oligohydramnios sequence. Note the flattened facial

features and deformed right foot (talipes equinovarus), and
nodules on the amnion (amnion nodosum)
 Syndrome
It is a constellation of congenital anomalies,
believed to be pathologically related.

Syndromes are most often caused by a single

etiologic agent, such as a viral infection or
specific chromosomal abnormality, which
simultaneously affects several tissues.
 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
CAUSES OF CONGENITAL ANOMALIES
* Genetic
 karyotypic aberrations
 single gene mutations
* Environmental
 infection
 maternal disease
 drugs and chemicals
 irradiation
* Multifactorial

Unknown (majority of the cases)

Genetic Causes

 Karyotypic abnormalities
 80-90% of fetuses with aneuploidy die in utero
 trisomy 21 (Down syndrome) most common karyotypic
abnormality (21,18,13)
 sex chromosome abnormalities next most common
(Turner and Klinefelter)
 autosomal chromosomal deletion usually lethal
 karyotyping frequently done with aborted fetuses
with repeated abortions
 Single gene mutations
Environmental causes
Maternal Viral Infection
 Rubella (German measles)
 risk period - first 16 weeks of 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 risk period - second trimester
 central nervous system infection predominates
Drugs and Chemicals

 13 cis-retinoic acid (acne agent)

 warfarin

 angiotensin converting enzyme inhibitors (ACE I)

 anticonvulsants

 oral diabetic agents

 Thalidomide

 Alcohol

 Tobacco
Diabetes Mellitus
 Fetal Macrosomy (>10 pounds)
 maternal hyperglycemia increases insulin
secretion by fetal pancreas, insulin acts with
growth hormone effects
 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
PATHOGENESIS OF CONGENITAL ANOMALIES

The pathogenesis of congenital anomalies

is complex and still poorly understood, but
the general principles of developmental
pathology are relevant regardless of the
etiologic agent.
The timing of the prenatal teratogenic
insult has an important impact on the
occurrence and the type of anomaly
produced .
 The intrauterine development of humans
can be divided into two phases:
 Embryonic period
 weeks 1- 9 of pregnancy
 organogenesis occurs in this period

 Fetal period
 weeks 9 to 38
 marked by further growth and maturation
Disorders of Prematurity
 Prematurity
Prematurity defined as gestational age < 37 wks
Second most common cause of neonatal mortality (after
congenital anomalies)

Infants born before completion of the normal gestation

period have higher morbidity and mortality rates than
full-term infants

A system of classification that takes into account both

birth weight and gestational age has been adopted.

Based on birth weight, infants are classified as follows

Based on birth weight, infants are classified
as follows
• Appropriate for gestational age (AGA)
– Infants whose birth weight falls between the 10th and the 90th
percentiles for a given gestational age are considered AGA
• Small for gestational age (SGA)
• Large for gestational age (LGA)
- whereas those who fall above or below these norms are classified
as LGA or SGA, respectively
• Preterm
– born before 37 weeks (<2500 grams)
• Post-Term
– born after 42 weeks
Prematurity and Fetal growth restriction
Causes for prematurity
-Preterm premature rupture of fetal membranes
(PPROM)
-Intrauterine infection
-Uterine, cervical, and placental abnormalities
-Multiple gestation
 Hazards of Prematurity
* Hyaline membrane disease (Neonatal respiratory
distress syndrome)
* Necrotizing enterocolitis
* Sepsis
* Intraventricular hemorrhage
*Long-term complications, including
developmental delay.
 Neonatal Respiratory Distress Syndrome
(RDS)
 RDS also previously referred to as HMB (Hyaline
Membrane Disease)
 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
Pathophysiology of respiratory distress syndrome
 RDS Pathology
 Gross
 solid and airless (no crepitance)
 sink in water
 appearance is similar to liver tissue*

 Microscopic
 atelectasis and dilation of alveoli
 hyaline membranes composed of fibrin
and cell debris line alveoli (HMD former
name)
 minimal inflammation
 Hyaline membrane disease.

There is alternating atelectasis and dilation of

the alveoli. Note the eosinophilic thick hyaline
membranes lining the dilated alveoli.
 Necrotizing Enterocolitis
 Incidence is inversely proportional to
gestational age
 approaches 10% with severe prematurity
 2000 cases yearly in USA
 Pathogenesis
 not fully understood
 intestinal ischemia

 inflammatory mediators

 breakdown of mucosal barrier

 Necrotizing Enterocolitis

A, Postmortem examination in a severe case of NEC shows the entire small bowel is markedly distended with a
perilously thin wall (usually this implies impending perforation). B, The congested portion of the ileum
corresponds to areas of hemorrhagic infarction and transmural necrosis microscopically. Submucosal gas bubbles
(pneumatosis intestinalis) can be seen in several areas (arrows), caused by gas forming bacteria.
Perinatal Infection
 Perinatal Infection
Infections of the embryo, fetus, and neonate are
manifested in a variety of ways

In general, fetal and perinatal infections are

acquired through one of the following routes
1) Transcervically (also referred to as ascending) or
2) Transplacentally (hematologic)
3) Occasionally, infections occur by a combination of
the two routes in that an ascending microorganism
infects the endometrium and then the fetal
bloodstream via the chorionic villi.
 Perinatal Infection
 Transcervical (ascending)
 inhalation of infected amniotic fluid
 pneumonia, sepsis, meningitis
 commonly occurs with PROM (Preterm rupture of membranes )
 passage through infected birth canal
 herpes virus– caesarian section for active herpes
 Transplacental (hematogenous)
 mostly viral and parasitic
 HIV—at delivery with maternal to fetal transfusion
 TORCH
 parvovirus B19 (Fifth), erythema infectiosum
 bacterial
 Listeria monocytogenes
Tumors and Tumor-like Lesions
of Infancy and Childhood
 TUMORS
Benign

Malignant
 BENIGN
 Hemangiomas
 Lymphatic Tumors
 Fibrous Tumors
 Teratomas (also can be malignant)
 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
Congenital Capillary Hemangioma

At birth Two years

after spontaneous regression
 Teratomas
 Composed of cells derived from more
than one germ layer, usually all three
 Sacrococcygeal teratomas
 most common childhood teratoma
 frequency 1:20,000 to 1:40,000 live births

 4 times more common in boys than girls

 Aproximately 12% are malignant

 often composed of immature tissue
 occur in older children
 Sacrococcygeal Teratoma

Note the size of the lesion compared with that of the infant
 MALIGNANT
Neuroblastic
Tumors
Wilms Tumor

(The TWO tumors comprise the vast majority of

pediatric SOLID (non hematopoietic) malignant tumors)
 Incidence and Types
The most frequent childhood cancers arise
in the hematopoietic system, nervous
tissue (including the central and sympathetic nervous
system, adrenal medulla, and retina), soft tissues,
bone, and kidney.

This is in sharp contrast to adults, in whom

the skin, lung, breast, prostate, and colon
are the most common sites of tumors.
Small Round Blue Cell Tumors
 Frequent in pediatric tumors
 Differential diagnosis
 Lymphoma
 Neuroblastoma
 Wilms tumor
 Rhabdomyosarcoma
 Ewings tumor
 Diagnostic procedures
 immuno stains
 electron microscopy
 chromosomal analysis and molecular markers
 Neuroblastomas
 Second most common malignancy of
childhood (650 cases / year in USA)
 Neural crest origin
 adrenal gland – 40 %
 Non adrenal (sympathetic ganglia) – 60%

 In contrast to retinoblastoma, most are

sporadic but familial forms do occur
 Median age at diagnosis is 22 months
 Neuorblastoma Morphology
 Small round blue cell tumor
 Neuorpil (background eosinophilic fibrillary material that
corresponds to neuritic processes of the primitive
neuroblasts) formation
 rosette formation ( Homer-Wright pseudorosettes can be
found in which the tumor cells are concentrically arranged
about a central space filled with neuropil )
 immunochemistry – neuron specific enolase (NSE)
 EM – secretory granules (catecholamine)
 Usual features of anaplasia
 high mitotic rate is unfavorable
 evidence of Schwann cell or ganglion
differentiation favorable
 Neuroblastoma

**

Adrenal neuroblastoma. This tumor is composed of

small cells embedded in a finely fibrillar
*Neuropil
matrix.
**Homer-Wright Rosettes
 Wilms Tumor
 Most common primary renal tumor of
childhood
 Incidence 10 / million children < 15 years
 Usually diagnosed between age 2-5
 5 – 10 % are multi-focal, i.e., bilateral
 synchronous
 metachronous

Synchronous means “occurring at the same time”.

Metachronous means NOT occurring at the same time, but one after another
 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
 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
Wilms Tumor

Wilms' tumor in the

lower pole of the
kidney with the
characteristic
tan-to-gray color and
well-circumscribed
margins.
 Wilms Tumor

A, Wilms tumor with tightly packed blue cells consistent with the blastemal component
and interspersed primitive tubules, representing the epithelial component. Although
multiple mitotic figures are seen, none are atypical in this field.
B, Focal anaplasia was present in this Wilms' tumor in other areas, characterized by
cells with hyperchromatic, pleomorphic nuclei and abnormal mitoses.