Froberg --Diseases of Infancy and Childhood—3.22.10
Objectives:
•Learn basic epidemiology of childhood causes of death
•Learn factors contributing to intra-uterine growth retardation
(IUGR)
•Understand the pathophysiology of Respiratory Distress
Syndrome (RDS)
•Know the major factors related to metabolic inherited diseases
of childhood, SIDS, and benign & malignant neoplasms of
childhood
Causes of Death & Age
•Under 1 yr  IUGR, RDS, congenital anomalies, SIDS,
pneumonia
•1-4 yrs  injuries, congenital anomalies, malignant
neoplasms, homicide
•5-9 yrs  injuries, malignant neoplasms, congenital
anomalies, homicide
•10-14 yrs  injuries, malignant neoplasms, suicide,
homicide
•15-24 yrs  injuries, suicide, homicide (all traumatic
stuff)
Birth Weight and Gestational Age
•AGA=appropriate for gestational age,
SGA=small,
LGA=large
•10-90th percentile = AGA
•Before 37th week = preterm, >42 = post-term
–1500gm infant at 32 weeks has mortality risk
of ~20%
–700gm infant at 32 weeks has mortality risk
of 65%
-mortality is more related to weight than
gestational age.
Mortality is related to gestational age, but birth weight is more
important for infants of the same gestational age.
-So for a 32 week infant of 700 g the expected mortality
is 63%, while for a 1750 g infant of the same gestational
age the expected mortality is ~6%. Neonatal intensive
care has improved the survival of preterm infants.
IUGR
•Underlies SGA, detect by US
•Factors relating to IUGR:
–Fetal - trisomies, congenital anomalies & infections
(symmetric growth retardation-Type I)
–Placental - uteroplacental insufficiency, thrombosis,
infarction, abruption, placenta previa, confined
placental mosaicism (placenta can have division of
DNA) (disproportionate growth retardation-Type II)
–Maternal - most common: includes toxemia, HTN,
malnutrition, ETOH, smoking, narcotics, teratogens
(often cause learning disabilities, cerebral
dysfunction)
1
Organ Immaturity: Problem of preterm regardless of weight
–Lungs - alveoli mature late in gestation (7th month),
alveoli lined by cuboidal epith prior to 26-32 weeks,
septa thick, reach full compliment of alveoli by 8 yrs
(develop slowly over yrs)
–Brain - smooth surface, soft, nerve fibers poorly
myelinated
–Liver - large but physiologically immature, jaundice
esp in low birth wt infants (def bilirubin glucuronyl
transferase, etc)
Infant Mortality
•20.0 per 1000 population in 1970  7.5 per 1000 in
1995
•Rate for blacks >twice whites: 14.9/1000 compared to
6.3/1000
•US infant mortality ranks 21st among industrialized
nations
Socioeconomic factors underlie the frequency of low birth
weight babies (worse in SE)
Congenital Anomalies
•In 3% of newborns, major cause of M&M in 1st yr
•Definitions:
–Malformations - intrinsic abnl occurring during
development, ex. Anencephaly
–Deformations - arise later in fetal life, alteration in
structure from mechanical factors (small uterus,
leiomyomata) or fetal-placental (abnl presentation,
multiple births, oligohydramnios, ex. Clubfeet)
More Definitions
•Disruptions - 2 interference with previously normal organ or
region, ex amniotic bands
•Sequence - pattern of cascade anomalies, ex. Potter’s sequence:
renal agenesis  oligohydramnios  pulmonary hypoplasia
•Other terms: agenesis - organ & primordium absent; aplasia failure of organ development; atresia - absent opening;
hypoplasia -  # of cells; hyperplasia -  # of cells; dysplasia abnl organization
Amniotic Band
An amniotic band has interrupted development of a lower
extremity (arrow). Placenta is present to the right.
Causes of Malformation
1. Genetic - include karyotypic aberrations, single gene
mutations, multifactorial
–Abnl karyotype in 10-15% of live-born infants with
congenital malformations; frequency - Down,
Klinefelter, Turner, Patau syndromes
–Usually arise during gametogenesis, so not familial
–Single gene mutations - Mendelian, uncommon (210%) - Marfan syndrome
–Multifactorial - interaction with environment (2025%) (cleft lip/palate)
2. Environmental - infections (TORCH), maternal disease states
(diabetes), drugs (thalidomide)
Infections -rubella in 1st trimester can cause cataracts,
heart defects, deafness (50% in 1st month of gestation)
Froberg --Diseases of Infancy and Childhood—3.22.10
CMV - most common cause of fetal viral
infection, can cause MR, deafness,
hepatosplenomegaly
thalidomide - limb malformations (50-80%), amelia &
phocomelia (underdeveloped limbs)
ETOH - growth retardation, microcephaly, ASD
Examples of Toxicants associated with impairment of fetal
growth
-drugs of abuse: cigarette, ethanol, heroin
-Rx: glucocorticoids, propranolol, phenytoin, warfarin
-infectious agents: Herpes simplex, CMV, rubella,
toxoplasmosis
Malformations:
Timing - critical to type & severity of malformation
-early embryogenesis - 1st three weeks death more
likely
-organogenesis - weeks 3-9 most susceptible to
teratogens
Teratogens & genetic defects may act on cell
proliferation, migration, differentiation or damage
formed organs - affect growth factors (WT-1, TGF-)
-Hox (homeobox) genes interact with multiple
downstream genes, hence is a regulator of
morphogenesis, can be affected by retinoids - temporal
& spatial expression of retionic acid-binding proteins
may affect morphogenesis
3-9 wks you will see greatest effects of insult
Forms of vitamin A are necessary for normal development but in
excess can cause malformations
-Excess renioic acid (Vit A) MS, CNS, cardaic
-Def Vit A  defects of eye, lung, cardiac
-Enters nucleus, binds to response element  alt HOX
genes  patterns of malformation
2
Perinatal infections
Ascending - transcervical leading to
–funisitis (cord) &
–chorioamnionitis (membranes),
–fetus may inhale amniotic fluid or contact microbe in
birth canal during delivery; most bacterial, few viral
•Hematological - most viral or parasitic; Treponema, Listeria,
HIV, Hep B
•Perinatal sepsis - group B Strep and E. coli lead to pneumonia
and sepsis in 4-5 days, late sepsis - Listeria and Candida
•TORCH syndrome: toxoplasma, rubella, cytomegalovirus,
herpesvirus and others (syphilis, etc.).
–Cause similar clinical & pathological picture in
newborn.
–Clinical: fever, encephalitis, chorioretinitis,
hepatosplenomegaly, pneumonitis, myocarditis,
hemolytic anemia, and vesicular or hemorrhagic skin
lesions.
–Chronic sequelae: growth & learning delays, cataracts,
cardiac anomalies and bone defects
Respiratory Distress Syndrome/Hyaline Membrane Disease
•Still common in newborn period, affects 60-70,000 infants/yr
–Risk Factors:
•excess sedation of mother  respiratory depression &
brain injury
•Prematurity  muscle & resp immaturity (1
atelectasis)
•Aspiration of blood, mucus, squames, amniotic fluid
•Umbilical cord coils  hypoxia
•Mortality previously 25,000 infants/yr, now 5,000
•CSx: usually preterm, or associated with maternal diabetes or
cesarean section
–May see resuscitation at birth  improve
–Soon develop resp distress  grunting, retraction,
cyanosis, rales on auscultation, ground-glass picture by
CXR, may progress despite ventilator assistance
•Pathogenesis: incidence ~ 1/gestational age,
60% <28 wks, 15-20% if 32-36 wks, <5% if over 37 wks
–Main defect is lack of surfactant - 75% is
phosphatidylcholine (lecithin) made by type II
pneumocytes esp after 35th week, sphingomyelin is
universal cell membrane component (use for relative
baseline)
–L/S ratio 2.0 or > in amniotic fluid = 95% chance of no
RDS, matures rapidly (1-2 days)
RDS Pathology
•Gross - lungs stiff, solid, reddish purple
•Micro - atelectasis & dilation, hyaline membranes, cell debris
•Rx: oxygen, ventilatory assistance, surfactant
•Complications: bronchopulmonary dysplasia (emphysematous
changes 2 to ventilatory injury), PDA, IVH, necrotizing
enterocolitis
•Mortality ~1/body wt
3
Froberg --Diseases of Infancy and Childhood—3.22.10
self perpetuating cycle of pathology. With this damage you get
leaky caps  fibrinogen  fibrin + necrotic cells  hyaline
membranes  thicker wall  inc diffusion gradient
The most common variant of galactosemia occurs from a lack of
galactose-1-phosphate uridyl transferase. A rare variant is due to
galactokinase deficiency
Atelectasis & dilation  uneven ventilation. Congestion of bld
vessels. hyaline membranes
Phenylketonuria (PKU)
•Autosomal recessive disorder caused by lack of phenylalanine
hydroxylase  PKU, incidence 1/20,000 births, pathogenesis
unknown
•NL at birth, rapid  serum phenylalanine  severe MR by six
months,
Only 4% of untreated PKU pts have IQ>50 or 60, also
see seizures, eczema, hypopigmentation, 2/3 unable to
talk, 1/3 unable to walk (bad!)
•Can prevent MR by restricting phenylalanine in diet
•Other forms of PKU:
–Maternal PKU: profound MR in child of non-compliant
mother with PKU (although child is heterozygote)
–Benign PKU: perinatal screen (Guthrie test) positive
but only partial def of phenylalanine, serum levels NL
(so ), don’t develop stigmata
–Other variant forms: may affect other enzymes in
cascade, some transient, some due to lack of
tetrahydrobiopterin cofactor, can see neurological
impairment with NL serum phenylalanine levels
Pathway of phenylalanine metabolism: in PKU PAH is usually
reduced or absent. However, deficiencies in BH4 or DHPR may
also lead to PKU or a positive Guthrie test.
•Newborn screening tests:
-heel stick bld collection
–Urine + FeCl3  black color in presence of
phenylpyruvate
–Guthrie test - heel stick -bacterial inhibition assay,
repeat if + and follow serum phenylalanine (1% of
newborns +, but 90% FP rate)
–Molecular tests
Galactosemia
•Autosomal recessive: classic form - lack of galactose-1phosphate uridyl transferase & accumulate substrate (some
galactokinase def.), incidence 1 per 80,000 whites
–Targets liver, brain & eyes  steatosis, cirrhosis,
cataracts, neuronal loss & gliosis (MR in severe form)
–Eye: galactose converted by aldose reductase to
galactilol  absorbs water  cataracts
Galactosemia
•Mechanism of liver & CNS damage unknown
•CSx: reluctant to nurse, Failure to thrive, Vomit & Diahhrea,
hepatomegaly, MR by 6-12 months, jaundice, neonatal sepsis (E.
coli)
•Dx: enzyme def in RBCs, heel stick for enzyme immunoassay,
can do on amniotic fluid
•Rx: restrict dietary galactose (milk)
Fibrosis & fatty liver from galactosemia
Cystic Fibrosis (not on test – see module)
Sudden Infant Death Syndrome
•“Crib Death,” sudden, unexplained death of infant <1 yr of age
after thorough investigation
1.~ 6000/yr in US, worldwide 1-5/1000 live births
2.90% in first 6 months of life (peak 2-4 months)
3.Cyanosis and cessation of respirations, most have minor
manifestations of URI
4. Risk factors: mother <20 yrs, unmarried, smoking, low
socioeconomic status, drug abuse, black race, infant prematurity,
LBW, male sex, SIDS in prior sibling
5. 1-10% have inborn error of metabolism like acyl-CoAdehydrogenase def, may be heterogeneous group of disorders
with same outcome, some homicides
6. Apnea & abnl temperature control thought to be involved,
delayed autonomic development?
7. Supine   SIDS
Tumors & Tumor-Like Lesions
•Only 2% of all malignant neoplasms occur in infancy &
childhood, but 2nd leading cause of death 4-14 yrs of age
1.Heterotopia (choristoma) - NL cells in abnl location, ex. adrenal
rests
2.Hamartoma - excessive growth of cells/tissues native to organ,
ex. Cardiac myomas & subependymal hamartomas of tuberous
sclerosis
3. Benign - may be difficult to distinguish from hamartomas, are
most common neoplasms of childhood
•Hemangiomas - most common tumor of infancy, skin of
face & scalp, flat to elevated, irregular, red-blue masses.
Very large = port-wine stains. May regress
Froberg --Diseases of Infancy and Childhood—3.22.10
spontaneously. May be part of von Hippel-Lindau
Syndrome (tumor suppressor gene in vasc
development. Hemangioblastoma of cerebellum, cysts
of organs, renal cell carcinomas, often hemangiomas as
well)
4. Teratomas - tumor composed of more than one germ cell layer,
may be benign (mature) cystic or malignant (immature) solid
masses. May be congenital.
Sacrococcygeal > head & neck, gonads, mediastinum, incidence
1/20,000, F:M is 4:1, 75% benign, may cause non-immune
hydrops fetalis (massive edema); Rx: surgery
Fetal ultrasound showing heart
chambers of 18 week of
gestation fetus
Ultrasound seven weeks later
showing a large mediastinal
mass
An island of cartilage is
surrounded by glands showing
dissolution in mature teratoma
Neuroepithelial rosette
(arrow) in benign teratoma
liver
The heart (red arrow) is
displaced by a large
mediastinal mass (black
arrow)
Tumors: Malignant Concepts
•May be related to abnl development
•May regress or cytodifferentiate
•Rx may lead to 2 malignancies
•Small , round, blue cell tumors
•Sites: hematopoetic, nervous system, soft tissue, bone
•Include neuroblastoma, lymphoma, rhabdomyosarcoma,
PNET/Ewing’s sarcoma
4
Neuroblastoma
•Most commnon malignant tumor of children <1yr, 15% of
childhood cancer deaths, 35% in 1st yr of life, 85-90% prior to
age 5
•25-35% arise in adrenal medulla, rest along sympathetic chain
(paravertebral mediastinum or abdomen, pelvis, neck, even
brain)
•Gross: soft, gray, hemorrhagic, areas of necrosis,  calcifications
•Histopath: small, round, blue-cell tumor (neuroblasts), HomerWright pseudorosettes (no lumen-fibrillar extensions), may show
some level of diffentiation (~ganglioneuroma = benign)
•Clinical: present as abdominal mass, fever & wt loss. Later may
be signs of mets (GI or resp complaints)
•Produce catecholamines (90%)  elevated urine VMA and HVA
(unlike pheochromocytomas do not typically produce
hypertension)
•Clinical:
–Prognosis: age & stage dependent 
•<1yr good regardless of stage, if <1yr and
stage I or II  95-98% 5-year survival,
• >1yr and stage III or IV  10%
–Stage IV-S (1 plus single mets to skin, liver or bone
mets)  80% 5-yr survival (4S limited to infants <1yr)
–Disseminated neuroblastoma to skin may present as
“blueberry muffin baby” (multiple hemorrhagic nodules
of skin)
•Genetics: Commonly have
–17q gain (50% of tumors) in unbalanced translocation usually
with 1q  adverse outcome
–1p deletion in region of band p36 (25-35% of tumors), site of
likely tumor suppressor gene  have worse prognosis
•25-50% of neuroblastomas have 14q del & aggressive course
•25% have amplification of N-myc oncogene, see double minutes
by karyotype  have poorer prognosis
•Hyperdiploid or near triploid tumors have a better prognosis
(divide faster), while diploid tumors have unfavorable outcome
•Neuroblastomas may spontaneously regress or differentiate
•IF nerve growth factor receptor Tyrosine Kinase A  
favorable outcome
•If  Trk A  poorer prognosis
•Trk A may play a role in maturation of tumor to ganglioneuroma
(mature neural elements)
•Cytodifferentiation may be spontaneous or following Rx
Froberg --Diseases of Infancy and Childhood—3.22.10
Retinoblastoma
•Most common malignant eye tumor of childhood
•1% of all cancer deaths to 15 yrs
•Seen in 1 of 17,000 live births
•90% diagnosed prior to age 7
•Gross: nodular mass within globe (arising from retina), do
fundoscopic exam on all neonates
•Histopath: small, round, blue-cell tumor with FlexnerWintersteiner rosettes (central lumen), histogenesis ~
retinoblasts
•Clinical: often present at birth or by 2 yrs with poor vision,
strabismus, whitish hue to pupil (cat’s eye) or eye pain, usually
fatal once spread beyond orbit
•Rx: radiation, laser photocoagulation, cryotherapy, enucleation
•Genetics: loss of Fx of retinoblastoma gene at 13q14, a tumor
suppressor gene
•Hypophosphorylated Rb binds E2F & prevents G1  S transition
of cell cycle
•Tumors sporadic or hereditary: Knudson “two-hit” hypothesis
•Sporadic  60-70% of cases, require two somatic mutations in
same retinoblast
•Familial (autosomal dominant)  have one germline and one
somatic mutation
•Rb alterations also seen in osteosarcomas, etc. Bone tumors may
follow Rx for retinoblastoma
5
Loss of Rb function leads to loss of tumor suppression & cell cycle
regulation.
Genetic alterations in retinoblastoma include large deletions seen
by karyotyping or Southern blot or by point mutations leading to
a stop codon.
Retinoblastoma: primitive neuroepithelial cells forming FlexnerWintersteiner rosettes (arrow)
Knudson two-hit hypothesis: requires one germline and
somatic mutation of the Rb gene. Sporadic forms have two
mutations within retinal cells after birth
Froberg --Diseases of Infancy and Childhood—3.22.10
Wilms Tumor
•Most common 1 renal malignancy of childhood
•Gross: solitary, gray-tan, well-circumscribed mass, 10% bilateral
•Micro: recapitulate stages of nephrogenesis, usually triphasic
with blastemal (nephroblasts), stromal and epithelial elements
•Clinical: 2-5 yrs, abdominal mass (hematuria, obstruction)
•Rx: 5-yr survival now >90% with triple therapy
8.
9.
10.
Wilms tumor at lower pole of kidney
11.
12.
13.
Wilms Tumor: triphasic histology with blastema (blue), tubular
epithlium (red) and stroma (black)
14.
15.
16.
17.
•Genetics: sporadic vs inherited, genetic alterations of 11p13
(WT-1) or 11p15.5 (WT-2). WT-1 necessary for NL
nephrogenesis
•Associated congenital malformations  risk of developing Wilms
tumor:
–WAGR syndrome: aniridia, genital anomalies, MR, &
33% chance of Wilms tumor
–Denys-Drash syndrome: gonadal dysgenesis &
nephropathy leading to renal failure
–Beckwith-Wiedemann syndrome: organomegaly,
hemihypertrophy (one side of body much larger), renal
medullary cysts, adrenal cytomegaly (WT-2 altered),
some have genomic imprinting
•Premalignant condition: nephroblastomatosis-persistent
immature nephrogenic elements (nephrogenic rest = fetal renal
tissue persistent into adult life)
Questions:
1. Disproportionate growth retardation is a characteristic
of _________. While proportionate growth retardation is a
characteristic of __________. Finally, learning disabilities,
cerebral dysfunction is often caused by _______________.
a. fetal
b. Maternal
c. placenta
2. What is the difference between disruption and
sequence?
3. What is the most common viral infection of pregnancy?
What effect does it have on the fetus?
4. Why are Hox genes important?
5. What does TORCH stand for and what effect can these
infections have on a fetus?
6. What are risk factors for Respiratory Distress
Syndrome?
7. Mother presents at 32 weeks in premature labor. The
L/S ratio is 2.3. What is chance of the baby having RDS?
Should you halt labor or is it ok for her to deliver?
6
Atelectasis & dilation, hyaline membranes, cell debris
on histological exam are characteristic of what newborn
disease?
The perinatal PKU screen (Guthrie test) on an infant is
positive, but only partial deficiency of phenylalanine is
present with normal serum levels. What is this called?
Will the baby develop stigma?
A 7 month infant is reluctant to nurse, is failing to
thrive, is vomit & diahhrea, has hepatomegaly, MR, and
jaundice. What is the most likely diagnosis?
The 4 month old male infant of a poor 16 year-old
mother who smokes is found dead in his crib. An
investigation rules out fool play. What is the most likely
diagnosis?
What is the most common location of teratomas?
An 11 month old previously health girl presents with
present as abdominal mass, fever & wt loss. What is the
most likely diagnosis?
25% of the patients described in question 13 have an
amplification of which of the following genes?
a. 17q
b. 1p
c. 13q14 d. N-myc
A 15 month old boy presents with vision loss, eye pain,
and “cat’s eye”. What is the most likely diagnosis?
Using the answers to Q14, what is the genetic origin of
this disease?
Describe the genetic differences between sporadic and
familial retinoblastomas.
What tumor often recapitulates the stages of
nephrogenesis?
Answers:
1. C, A, B
2. Disruptions - 2 interference with previously normal organ or region,
ex amniotic bands
•Sequence - pattern of cascade anomalies, ex. Potter’s sequence: renal
agenesis  oligohydramnios  pulmonary hypoplasia
3. CMV - most common cause of fetal viral infection, can cause MR,
deafness, hepatosplenomegaly
4. Hox (homeobox) genes interact with multiple downstream genes,
hence is a regulator of morphogenesis, can be affected by retinoids temporal & spatial expression of retionic acid-binding proteins may affect
morphogenesis
5. TORCH syndrome: toxoplasma, rubella, cytomegalovirus, herpesvirus
and others (syphilis, etc.).
–Cause similar clinical & pathological picture in newborn.
–Clinical: fever, encephalitis, chorioretinitis,
hepatosplenomegaly, pneumonitis, myocarditis, hemolytic
anemia, and vesicular or hemorrhagic skin lesions.
–Chronic sequelae: growth & learning delays, cataracts, cardiac
anomalies and bone defects
6. •excess sedation of mother  respiratory depression & brain injury
•Prematurity  muscle & resp immaturity (1 atelectasis)
•Aspiration of blood, mucus, squames, amniotic fluid
•Umbilical cord coils  hypoxia
7. 5% chances of RDS, she is ok to deliver
8. RDS
9. Benign PKU, no they will not develop stigma
10. Galactosemia
11. SIDS
12. sacrococcygeal
13. Neuroblastoma
14. D
15. retinoblastoma, C
16. •Sporadic  60-70% of cases, require two somatic mutations in same
retinoblast
•Familial (autosomal dominant)  have one germline and one somatic
mutation
17. Wilms Tumor