Infancy and Childhood - D. Padla

8/19/2019 Infancy and Childhood - D. Padla

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Pathology 3.6

Diseases of Infancy and ChildhoodDr. Padla

October 1, 2013

UTLINE

Causes of death related with age

Congenital anomalies

. Disorders of prematurity

.

Perinatal infections

Fetal Hydrops

.

Inborn Errors of Metabolism and other Genetic Disorders

I.

SIDS

II. Tumors

I.CAUSE OF DEATH RELATED WITH AGE

ble 1. Most Common Causes of Death in US

Under 1 year (Infancy) Rate /100,000

1. Congenital malformations, deformations,

chromosomal abnormalities

685.2

2. Disorders related to short gestation & low

birth weight

3. Sudden infant death syndrome

4. Newborns affected by maternal

complications of pregnancy

5.

Respiratory distress of newborn6. Accidents (unintentional injuries)

7.

Bacterial sepsis of newborn

8.

Intrauterine hypoxia and birth asphyxia

9. Diseases of the circulatory system

Under 1-4 year

29.9

1. Accidents and adverse effects

2. Congenital malformations, deformations,


3.

Malignant neoplasms

4.

Homicide and legal intervention

5. Diseases of the heart

6.

Influenza and pneumonia

Under 5-14 year

16.8


2. Malignant neoplasms

3.

Homicide and legal intervention

4.

Congenital malformations, deformations,


5. Suicide

6. Diseases of the heart

Under 15-24 year

80.1


2. Homicide

3.

Suicide4. Congenital malformations, deformations,


5.

Malignant neoplasms

6.

Diseases of the heart

Source: (Minimo et al. National Vital Statistics 55:19,2007)

ote: Accidents and adverse effects are not so much common in infancy

t it becomes the most common cause of death in the succeeding age

oups.

II.CONGENITAL ANOMALIES

Congenital anomalies are morphologic defects that are present at

Malformations

o Disorder of morphogenesis that are intrinsic to the infant/fe

o It is “within” the fetus (Genetically determined)

Figure 1.(L) syndactyly; (R) polydactyly

Syndactyly : two or more digits are fused together . Polydactyly : prese

supernumerary digits on hand

Disruptions

o Results from secondary destruction of an organ or body

that was previously normal in development.

o Arise from an extrinsic disturbance in morphogenesis

Figure 2. Disruption of morphogenesis by amniotic band

Note: Disruption and deformation are extrinsic to the fetus

Deformations

o

Localized or generalized compression of the growing fetabnormal biochemical factors

o Maternal

includes pregnancy, small uterus, malformed uterus

leiomyomas.

o Fetal (placental)

multiple fetuses and abnormal placental presentation

Figure 3. Malformation brought by homeobox gene.

Left: Cleft palate. Right: Cyclops eye

Sequence

o Effects of initial pathology; follows previous defec

development(e.g. oligohydramnios)

o Cascade of anomalies triggered by one initiating aberration.

o Manifestations are related to each other

o “Domino effect”


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PATHOLOGY 3.6

Figure 4. Oligohydramnios due to a very small amount of amniotic fluid

It is characterized by inward and downward turning of the foot(Talipesequinovarus) and a flattened brain. This is termed as Potter sequence or

Oligohydramnios sequence. Note flattened facial features and deformed

right foot

Figure 5. Pathogenesis of oligohydramnios

The causes of hydramnios are Amniotic leak, Renal Agenesis (Baby doesn’t

ave kidneys) and others. In renal agenesis, baby has no kidneys, therefore

the fetus doesn’t produce urine. The urine of the fetus contributes to the

amniotic fluid inside the uterus that is why renal agenesis can be a factor

causing oligohydramnios.

Syndrome: involvement of many organ that are not related

sequentially (Rubella syndrome: congenital heart disease, cataract,

mental retardation).

o Manifestations are unrelated to each other

Agenesis: absence of primordium (organ) usually due to infection and

environmental factor during organogenesis

Aplasia: primordium(organ) that fails to develop

Atresia: absence of an opening usually of a hollow visceral organ

Hypoplasia/Hyperplasia: lesser/greater number of cell

Hypotrophy/Hypertrophy: lesser/greater size of cell

Dysplasia: there is increase in the number of cells but the structural

arrangement do not follow the normal configuration. Examples are

adenoma of the liver, cyst of the kidney, hemangioma, fibroma and

terratoma. Disorganization of cell that causes congenital anomaly

ble 2. Causes of Congenital Anomalies. Chromosomal aberration and

endelian inheritance is an example of congenital malformation.

GENETIC Frequency (%)

Chromosomal aberrations 10-15

Mendelian inheritance 2-10

ENVIRONMENTAL

2-3

Maternal/placental Infections

(rubella, toxoplasmosis, syphilis, CMV, Herpes*)

Maternal Disease States

(diabetes, phenylketonuria, endocrinopathies)

6-8

Drugs and Chemicals

(alcohol, folic acid antagonists, androgens,

phenytoin, thalidomide, warfarinj, 13-cis-retinoic

acid, etc)

1

Irradiations 1

MULTIFACTORIAL 20-25

UNKNOWN 40-60

Note: Thalidomide – drug used to treat anxiety disorders as tranqu

They were given to pregnant mothers decades ago. It is found

teratogenic that is why we do not give this to pregnant mothers now

Babies who were born to mothers who were taking this drug

phocomelia (loss of extremeties). This occurs because of the disrup

the signaling pathway of developmental genes (Wingless Sig

Pathway). It is also given as an anti-neoplastic drug.

Pathogenesis of Congenital Anomalies

Timing o Early embryonic period

1st

3 weeks after fertilization: Injurious agent damages

enough cells to cause death and abortion or only few

presumably allowing the embryo to recover.

There will be no congenital anomaly but abortio

happen. If the fetus survives, since it is still too ear

fetus can progress to develop completely.

3rd

week- 9th

week: embryo is extremely suscepti

teratogenesis. During this period, organs are being c

out of the germ cell layers.

o Fetal Period

Futher growth and maturation of the organs

Critical period: Reduced susceptibility to teratogens but

fetus is susceptible to growth retardation and injuryComplex interplay

o Environment and genetic make-up

III.DISORDERS OF PREMATURITY

A. Causes of Prematurity and Fetal growth restriction

Premature birth – occurs when the baby is delivered early than t

term age of 9 months or 37 to 42 weeks

PROM – Premature Rupture of Membrane

o Occurs when the bag of water ruptures after 37 wee

gestation but before 42 weeks

o What happens during PROM?

Amniotic sac contains amniotic fluid where baby floats insid

uterus. Normally, during the full term, when the mother g

labor, the bag of water spontaneously ruptures during labo

the baby comes out. During PROM, the bag of water ru

without labor or contraction of the uterus. This is very dang

before it will predispose to ascending infection and can

compression of the fetus. The most concern is infection.

o PPROM- Preterm Premature Rupture of Membrane

Occurs when the bag of water ruptures before the 37

of gestation.

This will also lead to ascending infection

Fetal Growth Restrictions

o There are various causes why the baby will be smaller than n

o Causes can be fetal, placental and maternal. May include:

Lack of proper nutrition- a complex cause of sma

gestational age-fetus.

Maternal smoking

Inability of the placenta to provide sufficient bloo

nutrient

Fetus can also be larger than normal such as in cases when the m

has diabetes.

B. Neonatal Respiratory Distress Syndrome

Characterized by prematurity of the lungs

Also called Hyaline Membrane Disease

The Alveolar Type 2 pneumocytes are immature and are not pro

surfactant needed to reduce surface tension of lung fluid. W

surfactant, the lung collapses, causing distress.


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PATHOLOGY 3.6

Classical manifestation of the disease:

o A Premature infant manifests with distress immediately after birth.

The APGAR score, which describes how live or sick the baby is, is

very low. The baby requires resuscitation and initially responds,

but returns to distress after a while. The lungs become collapsed

and atelectiatic, solid instead of spongy.

o This usually happens for three days. If the baby survives the critical

3-day period, the pneumocytes will recover and be able to

produce surfactant. If the baby does not survive, the autopsy will

show collapsed lung with hyaline membrane. This is why NeonatalRespiratory Distress Syndrome is also called Hyaline Membrane

Disease.

Other causes of respiratory distress in newborn:

a) Excessive sedation of the mother

b) Fetal head injury during the delivery

c) Aspiration of blood of amniotic fluid

d) Intrauterine hypoxia

Figure 6. Pathophysiology of RDS.

his shows how the hyaline membrane develops in the respiratory passages,

alveolar ducts and alveolar sacs.

Figure 7. Hyaline Membrane Disease.

This shows atelectiasis and dilation in the alveoli. The alveolar sacs

sappear and are replaced by cells. The hyaline membrane lines the alveolar

sacs. Those alveolar sacs which remain are hyperinflated or overdilated

(compensatory emphysema) because the baby is struggling to inhale.

ecause of the hyaline membrane, there is still no exchange of CO2 and O2.

the baby survives the critical 3-day period, the hyaline resorbs and normal

reathing ensues. There are also other forms of management such as giving

of surfactant or oxygen therapy.

C. Necrotizing Enterocolitis

o The premature baby is given enteral feeding (tube feeding) in

bacteria or infection is introduced.

Figure 8. Necrotizing enterocolitis

Manifestations of the infection:

o Presence of blebs or air sacs within the mucosa of the intest

o On Xray, it has a characterized appearance called Pneum

Intestinalis.

o Increase in the chemical mediators of inflammation parti

Platelet Activating Factor (PAF). The PAF increases permeab

the tight junctions between the epithelial cells, leading to en

bacteria and possible progression to gangrene.

IV. PERINATAL INFECTIONS

Figure 6. Transplacental/Hematologic Spread of Infection

Two(2) ways by which the root of infection may infect the fetus

perinatal infections:

1.

Transplacental (hematologic)

o The infection crosses the placental barrier from the mother

fetus.

o The infecting agent (e.g., bacteria, virus) enters throug

chorionic vili to the fetus.

o PATHWAY of INFECTION:

The mother has infectionThe maternal blood ente

placenta through openings in the endometrium of the

surrounding the fetus At the placental implantation

endometrium, the maternal blood enters the placenta

The fetal blood also enters the placenta and circulates a

the chorionic vili. (Note: Chorionic villi are blood capil

vessels of the fetus in the placenta. They are us

pathologists as histologic markers of placental tissue

cases such as abortion.)

The mother’s blood is also inside the placenta, aroun

chorionic vili. So, the exchange of gas and nutrient ha

between the maternal blood circulating the placenta a

chorionic vili which contains the fetal blood. (Note tha

is no direct between fetal and maternal circulation.)

In summary:

MotherPlacentaChorionic ViliUmbilicusB


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PATHOLOGY 3.6

Transcervical (Ascending)

o PATHWAY of INFECTION

The infection goes through the cervix and then ultimately to

the amniotic sac The amniotic sac becomes infected,

creating amnionitis The infection contaminates the

amniotic fluid The baby inhales the infection into the lungs

TYPES OF SEPSIS BASED ON ONSET OF DISEASE

o Early Onset – When the baby manifests the disease within 7 days

of life

Group B Streptococcus is the most common infective agent

causing meningitis, pneumonia and sepsis

o Late Onset – When the baby manifest the disease after 7 days of

life

Listeria and Monilla fungal infections are more common

Characterized by long latent period

V. FETAL HYDROPS

Fetal hydrops refers to the accumulation of edema fluid in the fetus

during intrauterine growth.

NON IMMUNE HYDROPS (Parvovirus B19)

o Suprresion of RBC proliferation Anemia Compensatory

increase in rate of pumping by heart Increase blood volume

Increase Hydrostatic pressure Edema Fetal Hydrops

Figure 7. Bone marrow from infant with parvovirus B19. e (arrows) indicate 2 large erythroid precursors with large nucleus, due to

viral intranuclear inclusions, and a peripheral rim of residual chromatin.

IMMUNE HYDROPS

o Destruction of RBC

o Hemolytic disease caused by blood group incompatibility between

mother and fetus.

o For example: Rh incompatibility (Mother: Rh- and Fetus: Rh+)

Mother is sensitized by fetal Rh+ antigen during 1st

pregnancy

producing IgM Antibodies that does not pass placental barrier.

Hence, no hemolytic destruction of RBC.

During 2nd

pregnancy, re-exposure to same antigen produces

IgG Antibodies that cross placental barrier, causing hemolytic

destruction of fetal RBC. o 2 Mechanisms:

1. Anemia: Direct result of red cell loss.

Hemolytic Anemia Compensatory increase in rate of

pumping by heart Increase blood volume Increase

Hydrostatic pressureEdema Fetal Hydrops

2. Jaundice: Develops because hemolysis produces

unconjugated bilirubin.

Can produce Kernicterus if bilirubin passes blood-brain

barrier Hypoalbuminemia Decrease in Oncotic

pressure Extravasation of fluid Edema Fetal

Hydrops

Figure 8. Pathogenesis of immune hydrops fetalis

Note: On the subsequent pregnancy, the IgG crosses the placenta atta

to the Rh+ erythrocyte causing hemolysis. Unconjugate bilirubin, whi

lypophilic, crosses the blood brain barrier and causes kernicterus causin

manifestation.

Figure 9. (A) hydrops fetalis (B) cystic hygroma – fluid

accumulation is particularly prominent in the soft tissues of the neck,

because of non-development of lymphatic channels.

Figure 10. Kernicterus.

This is the a picture of midbrain that controls the vegetative, respirato

cardiocvascular function. Destruction of this region will lead to fet

consequences in the baby

Figure 11. Islands of extramedullary hematopoeisis. Liver.

This is due to the compensation to restore the normal amount of bloo

to hemolysis.


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PATHOLOGY 3.6

ble 3. Immune Hydrops and Non-immune hydrops

Reason CharacteristicHematopoeitic

Response

Immune

Hydrops

Rh Incompatibility Destruction of RBC Bone Marrow

Hypercellularity/

Hyperplasia

With Extramedullary

hematopoesis

Non-

Immune

Hydrops

Parvovirus B19 Suppression of RBC

proliferation

Bone Marrow

Aplasia/ Hypoplasia

Without Extramedullary

hematopoeisis

VI.INBORN ERRORS OF METABOLISM AND OTHER GENETIC DIISORDERS

Phenylketonuria: Abnormalities of phenylalanine metabolism

o Phenylalanine hydroxylase deficient (nausea, vomiting, mental

retardation) – error in metabolizing phenylalanine protein leading

to its accumulation in the system. Metabolites are produced from

this which causes symptoms such as mental retardation (due to

metabolic derangement)

o Phenyl acetic acid accumulation – excreted in urine and sweat

which gives the infant a mousy odor which is distributed

throughout the body

o

Screening fos this condition is important – early diagnosis canprevent the occurrence and further complications of the disease

by not giving phenyalanine rich food to the baby

Figure 12. Phenylalanine hydroxylase system

Galactosemia: autosomal recessive disorder of galactose metabolism.

o Most common and severe: Reaction 2 will not take place

o Lacks the enzyme that digest galactose present in themilk leading

to Galactose 1- phosphate accumulation

o Manifestations:

Mental retardation (brain) - yhis is due to the accumulation of

the metabolites produced

Cataract (eye)

Hepatomegaly (liver)

o Don’t give galactose in the diet in the first 2 years of life.

o Milk of the mother contains lactose that will be broken down by

lactase to become galactose and lactose which will worsen the

manisfestation. Thus other sources of nutrition should be

considered, at least in the first two years.

Figure 13. Pathway of galactose metabolism

Figure 14. Galactosemia in liver causing fibrosis and fatty change th

causing hepatomegaly.

Cystic Fibrosis (Mucoviscidosis): Disorder of ion transport in epi

cells that affects fluid secretion in exocrine glands and the ep

lining of the respiratory, gastrointestinal, and reproductive tracts;

o Cystic Fibrosis Gene regulates the chloride and other ion

pass through the ion channel. It is not so much important

metabolic reaction during brain development thus, it doe

cause mental retardation.

o Caucasian> African Americans, Asians, Hispanics

Figure 15. Chloride channel defect in sweat duct.

This is responsible for the salty taste of the baby.

o Cystic fibrosis associated gene: Normal Structure

The primary defect in cystic fibrosis results from

abnormal function of an epithelial chloride channel p

ecroded by the cystic fibrosis transmembrane condu

regulator (CFTR) gene on chromosome 7q31.2

o CFTR regulates multiple additional ion channels and c

processes. Interaction of CFTR with epithelial sodium ch

(ENaC) has possibly the most pathophysiologic relevance infibrosis. ENaC is responsible for sodium uptake from the lu

fluid rendering it hypotonic.

o In cystic fibrosis, ENaC activity increases markedly augm

sodium uptake across the apical membrane. In human sweat

ENaC activity decreases therefore a hypertonic lumina

containing high sweat chloride and high sodium content is f

(salty sweat).

o Functions of CFTR are tissue specific therefore mutations ar

tissue specific.

o Respiratory and intestinal epithelium

CFTR is an avenue for active luminal excretion of chlorid

mutations result in loss or reduction of chloride secretio

the lumen.


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PATHOLOGY 3.6

increase passive water reabsorption from the lumen,

lowering the water content of the surface fluid layer coating

mucosal cells.

In the lungs, dehydration leads to defective mucociliary

action and the accumulation of hyperconcentrated, viscid

secretions.

o Gene: CFTR

Class I – Defective protein synthesis

complete lack of CFTR protein

Class II - Abnormal protein folding, processing, trafficking

defective processing of the protein from the

endoplasmic reticulum to the Golgi apparatus.

Does not become fully folded and glycosylated

Class III - Defective regulation

prevent activation of CFTR by preventing ATP binding

and hydrolysis

Class IV – Decreased conductance

reduced function of CFTR

Class V - Reduced abundance

reduced amount of normal protein

Class VI – Altered regulation of separate ion channels

affect regulatory role of CFTR

Figure 16. Clinical manifestations of mutations in CFTR gene.

Two severe mutations are associated with the classic cystic fibrosis

phenotype while the presence of a mild mutation on one or both alleles

results in a less severe type.

Figure 17. CF changes in pancreas.

Hyperconcentrated fluid will cause the obstruction of the duct causing

latation of exocrine glands (digestive glands) which contains acids that are

orrosive. The acid will extravasate in the surrounding gland causing fibrosis.

This will result to the fibrous thickening in the interspaces of the dilated

glands. This will result in digestive enzyme insufficiency, malnutrion,

malabsortion, and hypovitaminosis.

Figure 18. Lungs

The chloride channel and some other electrolyte will lead to the dehyd

of the lungs thus will increase the lungs susceptibility to infection

Clinical features of cystic fibrosis.

1. Chronic sinopulmonary disease manifested by

2. Gastrointestinal and nutritional abnormalities, including

3.

Salt-loss syndromes: acute salt depletion, chronic metabolic acido

4. Male urogenital abnormalities resulting in obstructive azoosp

(congenital bilateral absence of vas deferens)

Criteria for diagnosis of cystic fibrosis

One or more characteristic features,o OR, a history of cystic fibrosis in sibling

o OR, a positive newborn screening test result

AND

An increased sweat chloride concentration on 2 or more occasion

o or, identification of 2 cf mutations

o or, demonstration of abnormal epithelial nasal ion transport

Abnormalities suggesting inborn errors of metabolism

GENERAL

o dysmorphic features, deafness, self-mutilation, abnorma

abnormal body and urine odor, hepatosplenom

cardiomegaly, hydrops

NEUROLOGIC

o

hypotonia or hypertonia, coma, persistent lethargy, seizuresGASTROINTESTINAL

o poor feeding, recurrent vomiting, jaundice

EYES

o cataract, cherry red macula, dislocated lens, glaucoma

MUSCLE, JOINTS

o myopathy, abnormnal motility

VII.SUDDEN INFANT DEATH SYNDROME (SIDS)

This is a phenomenon which is known as the killer in the young in

Autopsy (no clear cause of death)

usually dies while asleep, mostly in the prone or side position

death or cot death)

Diagnosis of exclusion – you should examine the scene of death

baby to rule out the possibility of child abuse or no harm was in

on the baby

Epidemiology

o It is the leading cause of death between age 1 month and 1 y

the USA

o third leading cause of death overall in infancy

o 90% of deaths occur during first 6 months of life (specifically

mos.)

o Prolonged apnea, marked change in color or muscle ton

choking or gagging are considered risk factors.

Morphology

o Multiple petechiae on the thymus, visceral and parietal pleu

epicardium are common


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PATHOLOGY 3.6

o Recent infection in the upper respiratory tract

o astrogliosis of the brain stem and cerebellum

o hypoplasia of the arcuate nucleus

Pathogenesis

o Vulnerable infant

delayed development of “arousal” and cardiorespiratory

control

o Maternal Risk factors

born before term or low birth weight

o

Environment

side sleeping positions, sleeping on sofa surfaces and thermal

stress

f the cause of death is not clear then it is known as unclassified infant

ath syndrome and not a condition of sudden infant death syndrome

SK FACTORS ASSOCIATED WITH SIDS

PARENTAL

o Young maternal age (


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PATHOLOGY 3.6

Staging

o Stage 1: Localized tumor with complete gross excision, with or

without microscopic residual disease

o Stage 2A: Localized tumor with incomplete gross resection.

Representative ipsilateral nonadherent lymph nodes negative for

tumor microscopically.

o Stage 2B: Localized tumor with or without complete gross

excision, ipsilateral nonadherent lymph nodes positive for tumor.

Enlarged contralateral lymph nodes, which are negative for tumor

microscopically.o Stage 3: Unresectable unilateral tumor infiltrating across the

midline with or without regional lymph node involvement; or

localized unilateral tumor with contralateral regional lymph node

involvement.

o Stage 4: Any primary tumor with dissemination to distant lymph

nodes, bone, bone marrow, liver, skin, and/or other organs (except

as defined for stage 4S).

o Stage 4S ("S" = special): Localized primary tumor (as defined for

Stages 1, 2A, or 2B) with dissemination limited to skin, liver,

and/or bone marrow; Stage 4S is limited to infants


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PATHOLOGY 3.6

B. WILM’S TUMOR

Pathogenesis & Genetics

o WT1 encodes a DNA-binding transcription factor that is expressed

within several tissues during embryogenesis. It is critical for

normal renal and gonadal development

o Children with Beckwith-Wiedemann syndrome

characterized by enlargement of body organs, macroglossia,

hemihypertrophy, omphalocele, and abnormal large cells in

the adrenal cortex.

Morphologyo Nephrogenic rests- are putative precursor lesions of Wilms tumors

and seen in the renal parenchyma.

Figure 25. Wilm’s tumor; gross

Clinical Features

o large abdominal mass that may be unilateral or may extend across

the midline and down into the pelvis.

o Hematuria, abdominal pain

o Anaplastic histology remains a critical determinant of adverse

prognosis

Figure 26. Triphasic Histology of Wilm’s tumor

hase 1: Small blue rounded cells/blastimal cells, Phase 2: Epithelial cell that

leads to abortive tubules, Phase 3: spindle shaped mesenchymal cells

…Because your SMILE is my LIFE

Edited by: Rei Israel Manlulu

When God places a burden upon you,

He places His arms underneath you.

“Come to me, all you who are weary and burdened, and I will give

you rest. Take my yoke upon you and learn from me, for I am

gentle and humble in heart, and you will find rest for your souls.

For My yoke is easy and My burden is light.”

(Matthew 11:28-30)

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Infancy and Childhood - D. Padla