Pediatric Pathology

Pathogenesis of congenital anomalies: Intrauterine development – 2 phases

▪ Embryonic period  1st 9 weeks of pregnancy

o 1-3 weeks after fertilization
 Injurious agent damages cells  death & abortion
o 3rd – 9th weeks
 Embryo is susceptible to teratogenesis
o 4th – 5th weeks (peak sensitivity)
 Organs crafted out of germ cell layers

Causes of congenital anomalies

▪ Genetic
o Ch. Aberrations (10-15% frequency)
- A 25-year-old woman is G5, P0, Ab4. All of her previous pregnancies ended in
spontaneous abortion in the first or second trimester. She is now in the 16th week of
her fifth pregnancy and has had no prenatal problems. Laboratory findings include
maternal blood type of A positive, negative serologic test for syphilis, and immunity to
rubella. Which of the following laboratory studies would be most useful for determining
a potential cause of recurrent fetal loss in this patient? Amniocentesis with
chromosomal analysis
o Mendelian inheritance (2-10% frequency)
▪ Environmental
o Maternal/placental infections (2-3% frequency)
 Rubella, toxoplasmosis, syphilis, CMV, HIV
 A neonate born at 36 weeks’ gestation manifests severe hydrops fetalis, hepatosplenomegaly, generalized icterus, and scattered
ecchymoses of the skin. Laboratory studies show a hemoglobin concentration of 9.4 g/dL and platelet count of 67,000/mm3.
Ultrasound of the head shows ventricular enlargement. Death occurs 14 days after birth. At autopsy, there is extensive
subependymal necrosis, with microscopic evidence of encephalitis. Within the areas of necrosis, there are large cells containing
intranuclear inclusions. Congenital infection with which of the following organisms is most likely to produce these findings?
Cytomegalovirus
 A 5-year-old boy presents with a maculopapular rash. On physical examination, the rash affects the palms and soles. Cracks and
fissures are noted around the mouth and anus. There is funduscopic evidence of interstitial keratitis. Mild hepatosplenomegaly
is present. The anterior tibial bones exhibit an outward curvature. What is the most likely etiology of these clinicopathologic
findings? Syphilis
o Maternal disease states
 Diabetes, PKU
- A 25-year-old primigravida has an uncomplicated prenatal course. She gives birth
to a 4500-g boy whose Apgar scores are 8 and 10 at 1 minute and 5 minutes.
Shortly after birth, he develops irritability with seizure activity. On examination, the
infant is normally developed with no anomalies. The lungs are clear to auscultation.
Laboratory studies show serum Na+, 145 mmol/L; K+, 4.2 mmol/L; Cl–, 99 mmol/L;
CO2, 25 mmol/L; urea nitrogen, 0.4 mg/dL; and glucose, 18 mg/dL. Which of the
following pathologic findings is most likely to be present in the pancreas of this
infant? Islet hyperplasia
- An infant is born following premature delivery. Multiple external congenital
anomalies are noted. The infant exhibits a seizure soon after birth. The blood
glucose is 19 mg/dL. Which of the following maternal diseases is the most likely
cause for the observed findings in this infant? Diabetes mellitus, type 2
o Drugs and chemicals
 Alcohol, folic acid antagonists, androgens, phenytoin, thalidomide, warfarin, 13-cis-retinoic acid
- A 28-year-old high school teacher, who is pregnant, presents with severe acne on the face and is concerned that these will disfigure her face.
Before she visited the doctor, she does an Internet search and finds that a compound related to Vitamin A has proven effective in the treatment
of acne. However, her obstetrician is reluctant to prescribe it because he thinks that it may cause fetal malformations. The teratogenic effect of
this medication is most likely related to which of the following processes? Disruption of the pattern of expression of homeobox genes
o Retinoic acid embryopathy, which is characterized by cardiac, neural, and craniofacial defects, is believed to result from the ability of
retinoids to down-regulate the transforming growth factor beta (TGF-β) signaling pathway and affect the expression of homeobox
(HOX) genes.
o Irradiations
▪ Multifactorial (20-25% frequency)
- In the year 1000 ce, an infant with difficulty nursing since birth is brought to Abul Qasim al-Zahrawi, who works in Cordoba, Andalusia (present-day Spain).
The boy infant is the product of a normal term pregnancy. On physical examination the only abnormality is the lack of fusion between the lateral nasal
prominence and the maxillary prominence. The cleft is repaired. There is no family history of birth defects, and the mother’s other two children are healthy
with no apparent abnormalities. This clinical picture is most likely the result of which of the following conditions? Multifactorial inheritance
- The parents of a 2-year-old boy with hyposadias (urethra opens on the ventral aspect of the penis) visit a genetic counselor to discuss the chances that a
similar birth defect will occur in their future offspring. This birth defect shows which of the following patterns of inheritance? Multifactorial
- A 50-year-old man with a history of type 2 diabetes mellitus asks about the chances that his children will inherit this metabolic disorder. The patient is told
that he has a genetic disease that shows which of the following patterns of inheritance? Multifactorial
▪ Unknown (40-60% frequency)

1|P a g e
Common congenital anomalies

▪ Polydactyly – one or more extra digits

▪ Syndactyly – fusion of digits
o (Mutation of GLI3)
▪ Amniotic bands – rupture of amnion with resultant formation of “bands” that encircle, compress, or attach
to parts of the developing fetus
- A 31-year-old woman, G3, P2, has had an uneventful pregnancy except for lack of any fetal
movement. She has a spontaneous abortion at 20 weeks’ gestation and delivers a stillborn boy. On
examination at birth, the fetus has an abdominal wall defect lateral to the umbilical cord insertion; a
short umbilical cord; marked vertebral scoliosis; and a thin, fibrous band constricting the right upper
extremity. A radiograph is shown in the figure. None of the woman’s other pregnancies, which ended
in term births, were similarly affected. Which of the following is the most likely cause of these findings? Early amnion disruption
o This is a classic example of an embryonic disruption that leads to the appearance of congenital abnormalities. Fibrous bands and possible
vascular insults may explain such findings, which fall within the spectrum of a limb–body wall complex that includes amniotic band syndrome.
▪ Oligohydraminos/Potter sequence – Decreased amniotic fluid
- A 16-year-old primigravida in her 18th week of pregnancy has not felt any fetal movement, and an ultrasound is performed. The amniotic fluid index is
markedly decreased. Both fetal kidneys are cystic, and one is larger than the other. There is no fetal cardiac activity. The pregnancy is terminated, and a
fetal autopsy is performed. Findings include multicystic renal dysplasia, hemivertebra, anal atresia, tracheoesophageal fistula, and lungs that are equivalent
in size to 14 weeks’ gestation. Which of the following errors in morphogenesis most likely led to the appearance of the fetal lungs? Deformation
o The lungs are hypoplastic (small) because of deformation caused by an oligohydramnios sequence. The malformation (anomaly) that initiated
the sequence in this case was multicystic renal dysplasia because the kidneys formed little fetal urine, which is passed into the amniotic cavity to
form the bulk of the amniotic fluid. There was no disruption in this case. Teratogens may produce anomalies, but these are uncommon. The
spectrum of findings in this case is consistent with the VATER association (vertebral defects, imperforate anus, tracheoesophageal fistula, and
radial and renal dysplasia)
Renal Agenesis

▪ Absence of kidneys
▪ Can be unilateral or bilateral
▪ Bilateral is incompatible with life
▪ Oligohydramnios
▪ Leads to Potter’s syndrome/sequence
▪ Potter facies –wide-set eyes, low-set floppy ear and a broad-flat face
- A 31-year-old woman, G1, P0, has noticed very little fetal movement during her pregnancy. At 36 weeks’
gestation, she gives birth to an infant with the facial features and positioning of extremities shown in the
figure. Soon after birth, the infant develops severe respiratory distress. Which of the following conditions
affecting the infant best explains these findings? Renal Agenesis
- A 20-year-old primigravid woman is in the third trimester and has felt minimal fetal movement. An ultrasound scan shows bilaterally
enlarged echogenic kidneys and a markedly decreased amniotic fluid index. She gives birth to a stillborn male fetus at 33 weeks’
gestation. At autopsy, there are deformations resulting from marked oligohydramnios, including flattening of the facies, varus
deformities of the feet, and marked pulmonary hypoplasia. Microscopic examination of the liver shows multiple epithelium-lined
cysts and a proliferation of bile ducts. Which of the following is the most likely renal disease in this fetus? Autosomal recessive
polycystic kidney disease
Ectopia Cordis

▪ Heart is present in an abnormal position

▪ Commonly exposed in the thorax due to maldevelopment of the sternum
▪ Associated with other congenital heart defects
▪ High mortality

Klippel Feil syndrome

▪ Short neck due to malformation of the cervical vertebra

▪ Head appears to rest on the shoulders
▪ Often there are associated other abnormalities

Accessory Ribs/Cervical rib

▪ Extra ribs, usually in the cervical region

▪ Can press on the brachial plexus- weakness of hand muscle
Subclavian vessels compression- weak radial pulse during abduction and external rotation of the shoulder

Congenital Diaphragmatic Hernia

▪ Defect in the development of the diaphragm produces a defect through which abdominal contents can herniate into the thorax
▪ Causes Pulmonary Hypoplasia
▪ 8% of congenital anomalies

First Arch Syndrome

▪ Results from abnormal development of the 1st pharyngeal arch Caused by lack of migration of neural crest cells into the 1st arch
▪ Various facial anomalies
▪ Treacher Collins syndrome (mandibular facial dystosis) & Pierre Robin syndrome
o Autosomal dominant

2|P a g e
Treacher Collins’ syndrome

- Affects the face “horizontally”

- The mandible will be hypoplastic along with hypoplastic zygomatic arches,
abnormal hair growth on cheek, malformed ears, and coloboma of lower
eyelid

Pierre Robin Syndrome:

- Affects the face “vertically”

- The mandible will be hypoplastic
along with glossoptosis and U-
shaped palate

Cleft Lip & Cleft Palate

1st Arch derivatives –
▪ Common abnormalities Mandible;
▪ Combined cleft lip & palate – 50%
▪ Isolated cleft palate – 30%
▪ Isolated cleft lip – 20%
▪ Multifactorial cause
▪ Genetic Cause
o Trisomy 13
o Van der Woude syndrome (lower lip
pits, cleft lip with or without cleft
palate, and cleft palate alone (CP).
▪ Teratogens:
o Anticonvulsants – Phenytoin
o Alcohol
o Smoking
o Vit B complex deficiency
- A 17-year-old primigravida gives birth at 37 weeks’ gestation. Her Hgb A1C is 6%. The birth weight is 2350 g. On physical examination,
the infant has multiple congenital abnormalities including single umbilical artery, cleft lip, and spina bifida occulta. Which of the
following is the most likely risk factor for these findings? Teratogen
- The parents of an infant with cleft lip and palate (infant shown in the image) visit a genetic counselor to discuss the chance that a
similar birth defect will occur in their future offspring. In addition to teratogen exposure and multifactorial inheritance, which of the
following is an important cause of this error of morphogenesis? Structural chromosomal abnormality

Consequence of Cocaine Abuse

▪ CNS
o Mood elevation  irritability, anxiety, depression  suicide
o Cerebral infarcts in newborns of addicted mothers
o Epileptic seizures & respiratory arrest
- A 19-year-old man is found unconscious and taken to the emergency department. On physical examination, his temperature is 41.2 C, pulse is 103/min,
respirations are 27/min and shallow, and blood pressure is 145/100 mm Hg. He develops an intractable cardiac dysrhythmia
and dies. At autopsy, the heart is slightly enlarged; microscopically, the distal coronary arteries are thickened. Sections of the
brain show a 2-cm area of hemorrhage in the right superior parietal lobe and a 0.5-cm hemorrhage in the medulla. There is a
partially cystic, 1-cm area with brown discoloration in the left anterior frontal lobe. This clinical picture is most likely to have
developed by usage of which of the following substances? Cocaine
Effects of Cocaine

▪ Increased circulating catecholamine levels  vasoconstriction

▪ Acute hemorrhages & infarction in brain
▪ Ischemic changes in the heart
▪ Intra-nasal use
o Nasal congestion
o Ulceration
o Septal perforation
▪ Intravenous use
o Viral infections (HIV or HBV)
o Risk of acute infective endocarditis
▪ Burn injury
o Due to volatile inflammable substances
▪ Pregnant mothers using cocaine
o LBW babies
o Increased risk for placental abruption
o Risk of amniotic fluid embolism

3|P a g e
 o ARDS
o DIC
▪ Cocaine Psychosis
o Excited delirium
o Rhabdomyolysis
 Increase in creatine kinase & myoglobinuria
 No RBCs in urine
 Myoglobin++ in urine

Birth Weight & Gestational Age

▪ Infants born between 37-42 weeks = term

o Term infants usually weigh greater than 2,500 gm
▪ Infants born before 37 weeks = preterm
o Infant wt. 2300 gm/34 weeks  likely to be physiologically immature
o RDS, transient hyperbilirubinemia
▪ Infants born after 42 weeks = post-term

Based on birth weight, infants are classified as:

▪ Appropriate for gestational age (AGA)

o Birth wt. between 10th & 90th percentiles
▪ Small for gestational age (SGA)
o Birth wt. < 10th percentile
- A healthy 21-year-old primigravida gives birth at 36 weeks following rupture of membranes. Apgar scores are 8 at 1 minute and 9 at 5 minutes. The infant
weighs 2000 g (4.4 lb) and on examination has no congenital anomalies noted. The head size is normal but other body measurements are decreased. Which
of the following risk factors during pregnancy most likely led to these findings? Cigarette smoking
- A 20-year-old woman gives birth at term to an infant weighing 1900 g. On physical examination, the infant’s head size is normal, but the crown-heel length
and foot length are reduced. There are no external malformations. Throughout infancy, developmental milestones are delayed. Which of the following
conditions occurring during gestation would most likely produce these findings? Pregnancy-induced hypertension
o Differential: The infant is small for gestational age because of intrauterine growth retardation (IUGR). The asymmetric growth with normal head
size suggests a maternal or placental cause in later gestation. Fetal problems, such as chromosomal abnormalities (Down syndrome), infections
(cytomegalovirus), and erythroblastosis, are likely to produce symmetric growth retardation. Fetal hydrops can accompany congenital infections
and erythroblastosis, which may artificially increase fetal weight. Infants born to diabetic mothers are likely to be larger than normal
(macrosomia) for gestational age.
▪ Large for gestational age (LGA)
o Birth wt. > 90th percentile

APGAR score

▪ Evaluate physiologic condition/responsiveness of newborn infants & chances of survival

▪ Scoring
o 5 parameters to be scored
o Evaluation at 1 minute & at 5 minutes
o A total score of 10  an infant in the best possible condition
▪ Correlation b/w APGAR score and mortality during 1st 28 days of life is impressive

Evaluation of Newborn Infant

Sign 0 1 2

Heart rate Absent Below 100 Over 100

Respiratory effort Absent Slow, irregular Good, crying

Muscle tone Limp Some flexion Active motion

of extremities

Response to catheter in No response Grimace Cough or sneeze

nostril (tested after
oropharynx is clear) Alveoli have not
developed
Color Blue, pale Body pink, Completely pink completely
Extremities Interstitium - more
blue prominent

Preterm Infants: Immaturity of organ systems

▪ Lungs immaturity
o Wall
 Thick-walled alveolar septae
 Increased connective tissue
o Alveoli
4|P a g e
  Eosinophilic proteinaceous precipitate (hyaline membrane)
 Occasional squamous cells
 Development continues after birth up to 8 years
▪ Kidneys
o Sub-capsular zone
 Primitive glomeruli
 Primitive tubules
o Deeper glomeruli & tubules
 Well formed
 Function is usually adequate
o Outer cortex of fetal kidney below capsule – nephrogenic zone (primitive dark blue cells where development of
glomeruli and tubules is taking place)

Prematurity

▪ Major risk factors for prematurity

o Preterm rupture of placental membranes (PROM) – MCC of prematurity (30-40%)
o Structural abnormalities – uterus, cervix, and placenta
o Multiple gestation (twin pregnancy)
o Intrauterine infection (25% of preterm births)
 Chorioamnionitis (inflamed placental membranes)
 Funisitis (inflammation of umbilical cord)
 Most common micro-organisms
 Ureaplasma
 A 17-year-old primigravida has an uneventful pregnancy until 25 weeks, when she notes absence of fetal movement for a
day. On examination, her temperature is 37° C, pulse is 80/ min, and blood pressure is 115/80 mm Hg. No fetal heart tones
are present. An ultrasound examination shows no apparent fetal anomalies. The next day she develops premature rupture
of fetal membranes, and the next day a stillborn fetus is delivered. Examination of the placenta shows normal size for
gestational age, but microscopic analysis shows that neutrophils have infiltrated the chorion and amnion. What is the most
likely diagnosis? Ureaplasma urealyticum infection
 Ureolyticum
 Mycoplasma
 Hominis
 Gardnerella vaginalis
 Trichomonas
 Gonorrhea
 Chlamydia

Birth injuries

▪ Important cause of infant morbidity & mortality

▪ Predisposing factors
o LGA infants, cephalo-pelvic disproportion, inappropriate use of forceps, hasty deliveries
▪ Most Common injuries
o Clavicular fracture, facial nerve injury, brachial plexus injury, intracranial injury, humeral fracture, lacerations

Caput succedaneum (“crosses suture”)

▪ Progressive accumulation of interstitial fluid in soft tissues of scalp

▪ Effects – edema, congestion, swelling at site where head begins to enter lower uterine canal

Cephalhematoma

▪ Hemorrhage into scalp

▪ Underlying skull fracture
▪ Predisposing conditions
o Hastened delivery
o Inappropriate use of forceps
o Prolonged labor w/ disproportion between size of fetal head and birth canal

Intracranial hemorrhages

▪ MC birth injury
o Excessive molding of head or sudden pressure changes in its shape
▪ Predisposing factors
o Prolonged labor
o Hypoxia
o Hemorrhagic disorders
o Intracranial vascular anomalies

Hyaline Membrane Disease

▪ Synonyms:
o Respiratory distress syndrome of newborn

5|P a g e
 o Neonatal Respiratory Distress Syndrome (NRDS)
▪ Complication of premature birth
▪ More premature the infant, more likely for HMD to occur
o Gestational age < 28 weeks - 60% incidence
▪ M:F = 1.5-2:1
▪ Surfactant plays a dual function of:
o preventing alveolar collapse during breathing cycle
o protection of the lungs from injuries and infections caused by foreign bodies and pathogens

Pathogenesis

▪ Deficiency of surfactant
o Lecithin or phosphatidylcholine
▪ Synthesis of lecithin
o Type II pneumocytes
▪ Measurement of surfactant
o In amniotic fluid
o Lecithin/sphingomyelin ratio (L/S ratio > 2 indicates adequate surfactant
▪ Fetal lung maturity
o Measuring concentration of surfactant phospholipids in amniotic fluid
o Ultrasound
o Administration of corticosteroids to mother if delayed delivery cannot be achieved
- A 19-year-old woman, G2, P1, has a screening fetal ultrasound at 20 weeks’ gestation that shows no abnormalities. Premature labor leads to an emergent
vaginal delivery at 31 weeks. Soon after birth, the neonate develops respiratory distress requiring intubation with positive pressure ventilation. Which of
the following prenatal diagnostic tests could have best predicted this neonate’s respiratory distress? Phospholipid level in amniotic fluid
- A 30-year-old pregnant woman visits her obstetrician for prenatal care and eventual delivery. The patient volunteers that two of her three children had
“yellow jaundice” at birth. Her youngest girl had been severely jaundiced and had been given two blood transfusions. Prenatal laboratory tests indicate that
the mother is blood type O, Rh negative, whereas her husband is blood type A, Rh positive. The obstetrician samples amniotic fluid at 36 weeks of gestation
to ascertain whether the fetus is mature enough for preterm delivery. Quantitative analysis of which of the following was most likely used as an indicator of
fetal lung maturity? Lecithin

Deficiency of surfactant

▪ Prematurity -Reduced synthesis

▪ Delivery by cesarian section -Lack of cortisol-induced stress associated with vaginal delivery
▪ Maternal diabetes -Inhibitory effect of fetal insulin on surfactant production in response to maternal hyperglycemia
- A 38-year-old primigravida has premature rupture of membranes at 36 weeks’ gestation, necessitating
delivery. At birth, the infant is noted to have a two-vessel umbilical cord, a cleft lip, a heart murmur, and spina
bifida. Which of the following factors is most likely to increase the risk of hyaline membrane disease in the
infant? Diabetes mellitus, type 1
o The hyperinsulinism in the fetus of a diabetic mother suppresses pulmonary surfactant production.
Corticosteroids stimulate surfactant production in type II pneumocytes. Infection may increase the
risk of premature birth, but it does not significantly affect surfactant production. The risk for major
malformations, called diabetic embryopathy, is 6% to 10% in infants born to mothers with diabetes
mellitus; but there is no set pattern to the anomalies, and similar embryopathies are not seen in
gestational diabetes. So the cause for anomalies here is unknown.
▪ Multiple births
▪ Excess sedation of mother- decrease respiration of infant

Pathophysiology

▪ Deficient surfactant  poorly functioning type II pneumocytes

o → high surface tension, atelectasis, and ventilation-perfusion mismatching
▪ Further complicated by immature pulmonary parenchyma → poor ventilation-perfusion matching
o rib cage unable to support collapsed lungs
- In a study of lung maturation, the amount of surfactant at different gestational ages is measured. Investigators
find that the amount of surfactant in the developing lung increases between 26 and 32 weeks’ gestation, with progression of lung architecture to a saccular
alveolar configuration. This increase in surfactant is most likely related to which of the following developmental events? Maturation of type II alveolar
epithelial cells
Gross

▪ Size  normal
▪ Reddish purple (liver-like)
▪ Solid & airless
▪ Sink in water

Microscopy

▪ Atelectasis alternating with dilated alveoli

▪ Eosinophilic hyaline membrane
o Fibrin, cell debris from necrotic alveolar epithelial cells
▪ Congestion, focal hemorrhages, dilated lymphatics
▪ No inflammation
- 25-year-old woman gives birth at 28 weeks’ gestation. The newborn girl has initial Apgar scores of 5 and 6 at 1 and 5 minutes, but within 1 hour, she
6|P a g e
 experiences severe respiratory distress and appears cyanotic. A chest radiograph shows a bilateral ground-glass appearance in the lungs. She is treated with
assisted ventilation and nutritional support and seems to improve for 24 hours, but then becomes progressively more cyanotic, develops seizures, and dies
4 days after birth. At autopsy, the newborn’s lungs have the microscopic appearance shown in the figure. Which of the following conditions initiates the
development of these findings? Immaturity of lungs
Clinical Features

▪ OFTEN NORMAL AT BIRTH

▪ Symptoms few hours after birth
o Dyspnea
o Tachypnea
o Nasal flaring
o Use of accessory muscles of respiration
o Expiratory grunt
o Cyanosis
▪ Prognosis
o Overall mortality- 20-30% in newborns<28 weeks gestation

Laboratory findings

▪ X-ray
o Ground-glass reticulo-granular densities
▪ Biochemistry
o Lecithin-sphingomyelin ratio < 2

Course

▪ Uncomplicated case
o Respiratory distress continues for 48 – 72 hours
▪ Type II pneumocytes increase production of surfactant

Treatment

▪ Artificial surfactant replacement

▪ Oxygen
o Bronchopulmonary dysplasia
 Decrease in alveolar number
 Alveolar hypoplasia
o An infant is born prematurely at 32 weeks’ gestation to a 34-year-old woman with gestational diabetes. On physical examination, the infant is at
the 50th percentile for height and weight and there are no congenital anomalies. The infant requires 3 weeks of intubation with positive
pressure ventilation and dies of sepsis at 4 months of age. At autopsy, the lungs show bronchial squamous metaplasia with peribronchial fibrosis,
interstitial fibrosis, and dilation of airspaces. Which of the following conditions best explains these findings? Bronchopulmonary dysplasia
 Sustained, high-dose oxygen therapy delivered with positive pressure ventilation can cause injury to immature lungs, leading to the
chronic lung disease known as bronchopulmonary dysplasia.
o Retrolental fibroplasia/retinopathy of prematurity (ROP)

Prevention

▪ Mature lungs
o Delay labor  corticosteroids

Phenylalanine metabolism

- An 18-month-old, light-skinned African American child has a developmental delay

characterized by mental retardation and inability to walk. The child’s urine has a distinctly “mousy” odor.
On physical examination, there is no lymphadenopathy or hepatosplenomegaly. Laboratory studies show
hemoglobin, 14 g/dL; platelet count, 302,700/mm3; WBC count, 7550/mm3; glucose, 80 mg/dL; total
protein, 7.1 g/dL; albumin, 5 g/dL; and creatinine, 0.5 mg/dL. A mutation involving a gene that encodes
which of the following enzymes is most likely to be present in this child? Phenylalanine hydroxylase
- A 20-year-old woman misses a menstrual period, and her pregnancy test is positive. This
pregnancy is planned. She was diagnosed with phenylalanine hydroxylase deficiency at birth and was
placed on a special diet until she was 12 years old. Her physical development has been normal and she
has obtained a degree from Universidad de Buenos Aires. Which of the following treatment plans is most
appropriate for this pregnancy? Special diet for the mother
- A 10-month-old boy who was adopted from an orphanage in Eastern Europe presents for a
physical examination. His parents believe that he is failing to meet developmental milestones. The child is
fair skinned and has blond hair. On physical examination, the patient is noted to have a “mousy” odor.
Laboratory studies demonstrate an inborn error of amino acid metabolism. To prevent mental
retardation, this patient should be placed on a special diet that lacks which of the following essential
amino acids? Phenylalanine

7|P a g e
Phenyl Ketonuria

▪ Inheritance: AR disorder
▪ Enzyme deficiency - Phenylalanine hydroxylase
o ↑Phenylalanine and its by products are Neurotoxic
o ↓Tyrosine
▪ Clinical Features:
o Mental retardation, microcephaly
o Mousy odor (phenylalanine converted into phenylacids)
o ↓pigmentation (melanin derives from tyrosine) – fair skin and blonde hair
 Must be exposed to phenyllanine (milk) before phenylalanine is increased)
▪ Rx:
o Restrict phenylalanine; avoid sweeteners containing phenylalanine (e.g., NutraSweet)
o Add tyrosine to diet
 Pregnant women with PKU must be on a phenylalanine free
 diet or newborns will be mentally retarded at birth

Homocystinuria

▪ Deficient enzyme - Cystathionine synthase

▪ ↑Homocysteine and methionine
▪ ↓Cystathionine
▪ Clinical features
o Mental retardation
o Vessel thrombosis (homocysteine)
o Lens dislocation, arachnodactyly

Cystic Fibrosis

▪ Most important AR pediatric disorder

▪ Thick mucus secretions
o Systemic disorder of exocrine glands
o Involves both mucus-secreting & sweat glands

Etiology of Cystic Fibrosis

▪ CF gene - Localized to a single locus on long arm of chromosome 7

▪ CFTR
o Gene product – Protein
o CF transmembrane conductance regulator
o Chloride channel that fails to be activated by cAMP
▪ Mutation - delta F508
o at 508th amino acid
o Homozygous -Most severe
- A 21-year-old primigravida gives birth to a term infant after an uncomplicated pregnancy. The infant is of normal height and weight, and no anomalies are
noted. The infant fails to pass meconium. Laboratory studies show an elevated sweat chloride level. Genetic testing indicates that a critical protein coded by
a gene is missing one phenylalanine amino acid in the protein sequence. Which of the following types of gene mutations is most likely to produce these
findings? Three-base pair deletion
- A 29-year-old woman has a history of steatorrhea and recurrent pulmonary infections since childhood. She experiences a fracture, and the radiograph
shows osteopenia. Laboratory studies show an abnormal sweat chloride level. Neither parents nor siblings are affected. Genetic studies show a mutation in
a gene encoding for chloride ion channel. Which of the following inheritance patterns is her disease most likely to have? Autosomal recessive
- An 11-year-old child has had increasing episodes of diarrhea for the past 3 years. The child’s stools are bulky and foul-smelling. The child also has a history
of multiple respiratory tract infections. On physical examination, vital signs include temperature of 38.1° C, pulse of 80/min, respirations of 20/min, and
blood pressure of 90/55 mm Hg. On auscultation, diffuse crackles are heard over both lungs. Laboratory findings include quantitative stool fat of greater
than 10 g/ day. Sputum cultures have grown Pseudomonas aeruginosa and Burkholderia cepacia. Which of the following inborn errors of metabolism is
most likely present in this child? Impaired epithelial cell transport of chloride ion
- A 15-year-old girl has had a fever and productive cough for the past 4 days. She was born at term, but developed abdominal distention in the first week of
life from meconium ileus. She has had frequent bouts of pneumonia with cough productive of thick mucoid sputum for 8 years. Sputum cultures have
consistently grown Pseudomonas aeruginosa. Each new bout of pneumonia is longer and increasingly nonresponsive to antibiotics. On physical
examination, her temperature is now 38.2° C. Which of the following is the most important factor causing increasing frequency and severity of her
Pseudomonas infections? Formation of respiratory epithelial biofilms
- A clinical study is performed involving male subjects with infertility. Some of these patients are found to have bilateral agenesis of the vas deferens along
with a history of recurrent respiratory tract infections, steatorrhea, and biliary cirrhosis. Genetic analysis reveals polymorphisms of mannose-binding lectin
2 (MBL2) and transforming growth factor beta 1 (TGFβ1) genes. An abnormality involving which of the following laboratory tests is most likely to be found
in these infertile men? Sweat chloride
-
Pathophysiology

▪ Defect in cAMP-regulated chloride transport across apical membranes of affected epithelial cells
▪ Membrane ion channel protein mutated
▪ % of normal residual CFTR function correlates with extent of disease

8|P a g e
Sweat Gland

▪ Impairment of transport
o Failure of resorption of chloride through duct epithelial cells
o →elevated sweat chloride level
▪ Elevated sweat chloride > 60 meq/L along with symptoms is diagnostic
o Normal – 10 meq/L

Clinical Features

▪ Chronic sino-pulmonary disease

o Persistent colonization/infection with Staph.aureus, H.influenzae, Pseudomonas aeruginosa
o Chronic cough and sputum production
o Airway obstruction (Wheezing and air trapping)

Gastrointestinal abnormalities

▪ Meconium ileus
o Due to lack of pancreatic enzyme secretion
▪ Distal intestinal obstruction syndrome

Pancreas

▪ Pancreatic insufficiency
o Steatorrhea
▪ Recurrent pancreatitis
▪ Pancreas cystic fibrosis changes  dilated ducts w/ mucin & parenchymal glands  atrophic, replaced by fibrous tissue

Hepatic

▪ Chronic hepatic disease

Nutritional

▪ Failure to thrive (protein-calorie malnutrition)

▪ Hypoproteinemia, edema
▪ Complications secondary to fat-soluble vitamin deficiency

Necrotizing Enterocolitis

▪ Predisposing conditions
o Most commonly in premature infants
o Common in very LBW infants (<1500 gm)
▪ Clinical features
o Symptoms usually do not appear until after oral feeding is instituted
o Introduction of bacteria  tissue destruction
▪ Intestinal ischemia due to
o Generalized hypoperfusion or reduction of blood flow to intestines
▪ Inflammatory mediators, platelet activating factor Abdominal
o Increases mucosal permeability X-ray - Gas within
o Permits transluminal migration of gut bacteria intestinal wall
  inflammation  mucosal necrosis (pneumatosis intestinalis)
  sepsis & shock
▪ Clinical course of NE
o Onset
 Bloody stools
 Abdominal distention & pain
 Circulatory collapse
 Hypotension
- A 17-year-old primigravida gives birth at 34 weeks’ gestation to a male infant of low birth weight. The infant is given
exogenous surfactant and does not develop respiratory distress. On the third day of life, physical examination reveals
hypotension, abdominal distention, and absent bowel sounds, and there is bloody stool in the diaper. A radiograph shows
pneumatosis intestinalis and abdominal free air. Surgical removal of the bowel is performed. Which of the following
conditions is most likely to be present in this infant? Necrotizing Enterocolitis
- Which of the following would be the most likely complication related to anoxia and acidosis? Necrotizing enterocolitis
▪ Gross Site
o Terminal ileum, cecum, right colon
o Figure B: Congested portion of ileum – areas of hemorrhagic infarction & transmural
necrosis. Submucosal gas bubbles (pneumotasis intesintalis) seen (arrows)
▪ Pathology
o Involved segment-distended, friable, congested, or frankly gangrenous
▪ Complications
o Intestinal perforation w/ peritonitis
Entire small bowel is markedly distended with a
perilously thin wall

9|P a g e
Fetal Hydrops

▪ Accumulation of edema fluid in fetus during intrauterine growth

▪ Causes – multiple

Pathogenesis

▪ Intra-uterine fluid accumulation from progressive, generalized edema of fetus (hydrops fetalis) to more localized degrees of edema
o Isolated pleural & peritoneal effusions
o Post-nuchal fluid accumulation (cystic hygroma)
▪ Classification
o Immune hydrops
o Non-immune hydrops
o A 23-year-old woman has reduced fetal movement at 19 weeks’ gestation. Fetal ultrasound scan is performed and shows marked soft tissue fluid
collections. The maternal Coombs test is negative. TORCH titers are unremarkable. Which of the following additional findings is most likely to be
observed with this ultrasound examination? Endocardial cushion defect
 Nonimmune hydrops fetalis may be due to cardiac failure in utero, with cardiac defects leading to high output congestive heart
failure. Cardiac defects may occur in association with other anomalies and may be part of chromosomal aneuploidies (chromosomes
13, 18, 21, and XO).

Immune Hydrops

▪ Erythroblastosis fetalis
o Antibody induced hemolytic disease
o Blood group incompatibility b/w mother & fetus
▪ ABO and Rh (D) antigenic systems may be involved
▪ Clinical features
o Jaundice
o Erythroid hyperplasia
o Extra-medullary hematopoiesis w/ hepatosplenomegaly edema
▪ Treatment
o Phototherapy or exchange transfusions (severe cases)
▪ Prevention
o Administration of human anti-D globulin
- The risk for fetal and neonatal accumulation of edema fluid in soft tissues is increased in Mayan mothers whose spouse is of European ancestry. Firstborn
infants are affected, and the risk increases with subsequent pregnancies. Neonatal Coombs test is positive, with both IgG and IgM antibodies present.
Which of the following blood groups are these Mayan women most likely to have? D
- A 20-year-old woman, G3, P2, has a screening ultrasound at 18 weeks’ gestation that shows hydrops fetalis but no malformations.
The woman’s two previous pregnancies ended at term in live births. The current pregnancy results in a live birth at 36 weeks.
Physical examination shows marked hydrops of the neonate and placenta. Laboratory studies show a cord blood hemoglobin level
of 9.2 g/dL and total bilirubin concentration of 20.2 mg/dL. Which of the following laboratory findings is most likely to be present in
this case? Positive Coombs test result on cord blood
- The patient delivers a female at 37 weeks of gestation with evidence of severe generalized edema (neonate shown in the image).
The baby is given exchange transfusions with Rh-negative cells but subsequently dies. Which of the following best describes the
pathogenesis of anasarca in this baby? Congestive heart failure.
o Erythroblastosis fetalis is a hemolytic disease of the newborn caused by maternal antibodies against fetal erythrocytes.
Erythroblastosis fetalis does not ordinarily occur during the fi rst pregnancy, because the quantity of fetal blood
necessary to sensitize the mother is introduced into her circulation only at the time of delivery, too late to affect the
fetus. However, when the sensitized mother again bears an Rh-positive fetus, much smaller quantities of fetal D antigen
can elicit an increase in IgG antibody titer. This cycle is exaggerated in multiparous women, and the severity of
erythroblastosis tends to increase progressively with each succeeding pregnancy. However, even after multiple
pregnancies, only 5% of Rh-negative women are ever delivered of infants with erythroblastosis fetalis. The severity of erythroblastosis fetalis
varies from a mild hemolysis to fatal anemia, and the pathological findings are determined by the extent of the hemolytic disease. Hydrops
fetalis refers to the most serious form of erythroblastosis fetalis, and is characterized by severe edema secondary to congestive heart failure
caused by severe anemia.

Parvovirus B19

▪ Causes 5th disease in mother

▪ Effects
o Spontaneous abortion/still birth
o Hydrops fetalis
o Congenital anemia
▪ Diagnostic viral cytopathic effect
o Late erythroid progenitor cells of infected infants
o Can cause destructions of erythroid leading to pure red cell aplasia – low red cell count and anemia while the WBC and platelet count are normal
o A 3-year-old boy dies in an automobile accident. At autopsy, the right lung is markedly shrunken. Dissection shows that the right main stem
bronchus ends blindly in nondescript tissue composed of rudimentary ducts and connective tissue. This finding represents an example of which
of the following errors of morphogenesis? Aplasia
 Aplasia is the absence of an organ coupled with persistence of the organ anlage or a rudiment. Thus, aplasia of the lung refers to a
condition in which the main bronchus ends blindly in nondescript tissue composed of rudimentary ducts and connective tissue.
▪ The name “5th disease” derives from its historical classification as the fifth of the classical childhood skin rashes

10 | P a g e
 o Measles
o Scarlet fever
o Rubella
o Duke’s disease
o 5th disease
o Roseola
- A 19-year-old primigravida who has had an uncomplicated pregnancy undergoes a screening ultrasound at 16 weeks’
gestation that shows no abnormalities. At 18 weeks, the woman develops a mild rash on her face. She gives birth to a
stillborn, severely hydropic male infant at 33 weeks. At autopsy, there are no congenital malformations, but
cardiomegaly is present. From the histologic appearance of the bone marrow shown in the figure, which of the
following is the most likely cause of these findings? Infection with parvovirus B19
Diagnosis of parvovirus B19

▪ Antibodies produced by immune system in response to parvovirus B19

▪ IgM antibody to parvovirus B19 detected
o S/O recent infection

Fetal Alcohol Syndrome

▪ Cause
o Maternal ethanol consumption (only 1 drink/day)
o Acetaldehyde – metabolite of ethanol crosses placenta  brain damage
▪ Growth/development defects
o Microcephaly
o Facial dysmorphology
o Malformations – Brain, CVS
▪ Affected infants
o Growth retardations, microcephaly, ASD, short palpebral fissures, maxillary hypoplasia
- A newborn boy delivered at 38 weeks is small for gestational age. Physical examination shows microcephaly, frontal bossing, long and narrow forehead,
hypotelorism, maxillary and mandibular hypoplasia, narrow palpebral fissures, thin elongated philtrum, vermilion border of the upper lip, dental
malocclusion, saddle nose, tooth enamel hypoplasia, and uvular hypoplasia. Ocular problems include microphthalmia, corneal clouding, coloboma,
nystagmus, strabismus, and ptosis. A systolic murmur is heard on auscultation, and echocardiography shows a membranous ventricular septal defect.
Which of the following conditions is most likely to produce these findings? Fetal Alcohol Syndrome
- A 4-year-old girl presents for a preschool physical examination. The child has a small head circumference, thin upper lip, and low-bridge nose. She shows
evidence of mild mental retardation. Her parents state that she is often “emotional.” Which of the following maternal causes of birth defects most likely
accounts for these clinicopathologic findings? Alcohol abuse
- A neonate was noted to have mild growth retardation and facial dysmorphology. The mother was a known abuser of several substances. This infant’s
problem most likely resulted from maternal intake of which of the following? Alcohol

Sudden Infant Death Syndrome (SIDS)

▪ Sudden & unexpected death of an infant < 1 year of age

▪ Death remains unexplained
o After a complete autopsy, examination of scene of death, review of case history
▪ Epidemiology
o Incidence ~ 8000 deaths/yr in USA
o Age – b/w 2-4 months
▪ Increased risk
o In prone sleeping position

Pathology

▪ By definition nothing at autopsy that could cause death

▪ Thymic or pleural petechiae
▪ Microscopic abnormalities
o In brainstem nuclei
▪ Findings may be identical to suffocation
▪ Diagnosis of SIDS in children < 1 month or > 6 months should be made w/ caution
▪ Current recommendation of supine sleeping position have reduced incidence by 40%
- A 5-month-old male infant died suddenly and unexpectedly. Scene investigation reveals the infant was prone with no airway obstruction or evidence of
trauma. Gross and microscopic examination at autopsy reveals only petechiae of mesothelial surfaces. Which of the following neurotransmitters that
involves signaling within brainstem medullary arousal centers is most likely implicated in the pathogenesis of this infant’s death? Serotonin
o The most likely cause of death here is sudden infant death syndrome (SIDS). Other causes of death must be excluded by careful examination and
interviews with caretakers. By definition, there are no significant gross or microscopic autopsy findings. Infants with congenital anomalies or
infections are unlikely to appear healthy, feed well, or gain weight normally. Though the cause for SIDS is unknown, abnormalities of
serotonergic neural pathways in the medulla oblongata, and a respiratory tract stressor (sleeping prone) may put vulnerable infants at risk.
Abnormalities in medullary centers that regulate responses to noxious stimuli such as hypoxia, hypercarbia, and thermal stress may lead to
absence of cardiorespiratory and reflexive responses that normally maintain homeostasis.
- An 4-month-old African American boy is found dead in his crib one morning. The distraught parents, both factory workers, are interviewed by the medical
examiner and indicate that the child had not been ill. She finds no gross or microscopic abnormalities at autopsy, and the results of all toxicologic tests are
negative. The medical examiner tells the parents she believes the cause of death is sudden infant death syndrome (SIDS). This conclusion is most likely
based on which of the following factors? No abnormalities at autopsy

11 | P a g e
Tumors

▪ 2nd most common cause of death between age 4-14

▪ Benign tumors
o More common than malignant tumors

Hemangiomas

▪ MC tumors of infancy
o Architecturally ~ adults
▪ Location in children
o Skin of face & scalp
o Port-wine stains
 Flat-to-elevated, irregular, red-blue masses
▪ Clinical course
o May enlarge along w/ child’s growth
o Spontaneous regression; cosmetic significance
o May be a part of von Hippel-Lindau disease
- A 3-year-old child’s mother notes that a large port wine stain on the left side of the child’s face has not diminished in size since birth. This irregular, slightly
raised, red-blue area is not painful, but is very disfiguring. Histologically, this lesion is most likely composed of a proliferation of which of the following tissue
components? Capillaries
Lymphangiomas

▪ Cystic spaces lined by endothelial cells

▪ Locations
o Neck, axilla
▪ Course
o May enlarge when spaces fill w/ lymphatic fluid

Teratomas

▪ Benign, well-differentiated cystic lesions (mature teratomas)

▪ Immature teratomas
▪ Malignant teratomas
o usually admixed with another germ cell tumor component, i.e. Endodermal sinus tumor
▪ Two peaks in incidence
o 1st at ~2 years of age
 Congenital neoplasms
o 2nd in late adolescence or early adulthood
 More slowly growing

Sacrococcygeal teratomas

▪ MC teratomas of childhood
▪ ~ 10% associated w/
o Congenital anomalies primarily defects of hindgut and cloacal region
▪ Other midline defects
o i.e. meningocele, spina bifida
▪ Histology: most of them are benign tumor composed of tissue derived from all 3 germ cell layers; excellent prognosis after resection
- A 28-year-old woman, G1, P0, has an uncomplicated pregnancy until 28 weeks’ gestation, when she develops uterine contractions and has premature
rupture of membranes. An ultrasound reveals a lesion with the representative gross appearance shown in the figure. Which of the following is the most
likely diagnosis of this lesion? Teratoma

Other site for teratomas in childhood

▪ Testis
▪ Ovaries
▪ Various midline locations
o Mediastinum
o Retroperitoneum
o Head & neck

Commonest Pediatric tumors

▪ Neuroblastoma
▪ Retinoblastoma
▪ Wilms tumor
▪ Hepatic tumors
▪ Malignant bone tumors
▪ Soft tissue sarcoma
▪ Germ cell/gonadal tumors

12 | P a g e
Malignant Tumors

Malignant pediatric neoplasms are unique

▪ More primitive (embryonal)

▪ Microscopic appearance
o Sheets of cells w/ small, round nuclei
o Feature of organogenesis specific to site of tumor origin
o Because of this, frequently designated by the suffix-blastomas
▪ Example
o Nephroblastoma (Wilms tumor)
o Hepatoblastoma
o A longitudinal study of pediatric neoplasia is performed. Infants born at term with no abnormalities and no family history of malignancies are
identified and followed. Which of the following neoplasms is most likely to be diagnosed in the first year of life in this cohort? Hepatoblastoma
o Neuroblastoma

Small round blue cell tumors

▪ Many childhood tumors - Collectively referred to as small round blue cell tumors
▪ Differential diagnosis
o Neuroblastoma
o Wilms tumor
o Lymphoma
o Rhabdomyosarcoma
o Ewing sarcoma/primitive neuroectodermal tumor

Neuroblastoma

▪ Tumors of sympathetic ganglia and adrenal medulla

▪ Origin
o Primordial neural crest cells
▪ Incidence
o 2nd most common solid malignancy of childhood after brain tumors
o 7-10% of all pediatric neoplasms
▪ Median age at diagnosis
o 22 months
▪ Urine VMA level are high
- The mother of a 6-month-old boy notices that he has a palpable abdominal mass. On physical examination, the infant has a temperature of 37.8° C, and he
is at the 33rd percentile for weight. An abdominal CT scan shows a solid 5.5-cm mass involving the right adrenal gland. Laboratory studies show that 24-
hour urine levels of homovanillic acid (HVA) and vanillylmandelic acid (VMA) are increased. The adrenal gland is excised surgically; the histologic
appearance of the mass is shown in the figure. Which of the following features of this lesion is most likely associated with a poor prognosis? MYCN (NMYC)
gene amplification
o Amplification of the MYCN (NMYC) oncogene occurs in about 25% of neuroblastomas, and the greater the number of copies, the worse the
prognosis. This amplification tends to occur in neuroblastomas with a higher stage or with chromosome 1p deletions.
Site of occurrence

▪ In childhood
o ~40% arise in adrenal medulla
o Remainder – anywhere along sympathetic chain
o 25% paravertebral region of abdomen
o Posterior mediastinum
▪ Clinical course
o Most silent lesions
o *spontaneous regression  focus of fibrosis or calcification in the adult

Gross

▪ Size
o Varies from minute nodules (in situ lesions)
o Large masses > 1 kg in weight
▪ Margins
o Often sharply demarcated w/ a fibrous pseudo-capsule
o Infiltrative and invade surrounding structures-kidneys, renal vein, and vena cava, & envelop aorta

Classic neuroblastomas

▪ Background
o Eosinophilic fibrillary material (neurophil)
 Neuritic processes of primitive neuroblasts
▪ Malignant cells
o **Homer-right rosettes
o Tumor cells – concentrically arranged about a central space filled w/ neurophil
▪ Positive for neuron-specific enolase
▪ EM: small, membrane-bound, cytoplasmic catecholamine containing secretory granules

13 | P a g e
Retinoblastoma

▪ Most common primary intraocular malignancy of children

▪ Cell of origin- Neuronal
▪ Inheritance of a germ-line mutation of one RB allele
▪ Age
o May be present at birth
o Usually < 2 years of age
- 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? Germline mutation
Epidemiology

▪ Sporadic in ~60% of cases

o Sporadic cases are unilateral and monocentric in origin Retinoblastoma
▪ Familial in ~ 40% of cases seen as "white
o Familial cases are frequently bilateral and multicentric in origin White pupil" (leucocoria)
▪ Demonstrates homozygous deletion of Rb gene (located on chr 13 at band q14) pupil on fundoscopy

Pathogenesis

▪ Both hereditary and sporadic types is identical

▪ Both undifferentiated and differentiated elements may be present Cross section of
▪ Undifferentiated form eyeball- Large
o Collections of small, round cells with hyperchromatic nuclei white mass pushing
into vitreous

Flexner Wintersteiner Rosettes

▪ Clusters of cuboidal or columnar cells arranged around a central lumen

▪ Nuclei are displaced away from lumen
▪ Reflect photoreceptor differentiation

Differential: Homer Write Rosettes in Neuroblastoma

▪ Radial arrangements of cells around a central tangle of fibrils (rosette)

Nephroblastoma (Wilms Tumor)

▪ Epidemiology
o Age
 Most common renal tumor in children (2-5 years)
▪ No risk factors
o ~ 90% cases are sporadic and unilateral
▪ Clinically
o Abdominal mass or abdominal pain (if tumor ruptures)
▪ Tumor suppressor genes
o WT-1 (11p13)
o WT-2 (11p15)

Gross

▪ Large, solitary, well-circumscribed mass

▪ 10% - Bilateral or multicentric at time of diagnosis
▪ Cut section
o Soft, homogeneous
o Tan to gray
o Occ. foci of hemorrhage, cyst formation, necrosis

Triphasic histology of Wilms Tumor

▪ Stromal component
o Spindle-shaped cells
▪ Epithelial component
o Immature tubules or glomeruli
▪ Blastemal component
o Tightly packed blue cells
- A 3-year-old child has become less active over the past 2 months. On physical examination an abdominal mass is palpable on the left. A urinalysis shows
hematuria. Radiographic studies show an 8-cm mass in the left retroperitoneal space. The mass is excised and on microscopic examination shows a triphasic
combination of blastemal, stromal, and epithelial cell types. The child is doing well 10 years later. Which of the following most likely related to the
pathogenesis of this child’s neoplasm? Nephrogenic rests
o Nephrogenic rests can be found in the renal parenchyma adjacent to a Wilms tumor. They are presumed precursor lesions because they may

14 | P a g e
 share genetic alterations with the adjacent Wilms tumor. There is an increased risk of developing Wilms tumors in the contralateral kidney if
such rests are present. Anaplasia in Wilms tumor suggests a poor prognosis, but overall the cure rate is 90%.
- A 4-year-old girl has complained of abdominal pain for the past month. On physical examination, she is febrile, and palpation of the
abdomen shows a tender mass on the right side. Bowel sounds are present. Laboratory studies show hematuria without proteinuria.
Abdominal CT scan shows a 12-cm, circumscribed, solid mass in the right kidney. A rightsided nephrectomy is performed; the gross
appearance of the mass is shown in the figure. What is the most likely diagnosis? Wilms tumor
Clinical Features

▪ Large abdominal mass

o Unilateral; very large- May extend across midline and down into pelvis
▪ Other patterns of presentation
o Hematuria, pain in abdomen after some traumatic incident, intestinal obstruction, hypertension
▪ Prognosis
o Generally good
 even with high stage disease
o Multi-focal anaplasia
 Enlarged hyperchromatic nuclei, atypical mitosis
 Associated with a poor prognosis

Denys-Drash Syndrome

▪ Gonadal dysgenesis
▪ Male pseudohermaphroditism
▪ Renal glomerular sclerosis
▪ WT-1

WAGR Syndrome

▪ Wilms tumor
▪ Aniridia
▪ Genital abnormalities
▪ Mental retardation (33% risk of tumor)
▪ Abnormality on chr. 11p13 (WT-1, tumor suppressor gene)
- A 2-year-old boy is noted to have absence of the iris bilaterally, cryptorchidism, hypospadias, and mental retardation. His mother has observed that the
child has an enlarging abdomen over the past 3 months. On physical examination, there are palpable abdominal masses. An abdominal CT scan shows
bilateral adrenal enlargement and pancreatic enlargement. There is a 6-cm solid mass in the left kidney. Which of the following congenital disorders is the
most likely diagnosis? WAGR syndrome

Becwith-Wiedmann Syndrome

▪ Hemi-hypertrophy
▪ Renal cysts
▪ Adrenal cytomegaly
▪ Genetic locus – 11p15.5 (WT-2)
o Increased incidence of Wilms & other tumors

Anomalies of the female reproductive tract

▪ Double Uterus with double vagina – complete lack of fusion of the Müllerian duct & the sinovaginal bulbs
▪ Bicornuate uterus – partial fusion of the Müllerian duct
o The uterus has 2 horns entering a common vagina
▪ Vaginal Atresia – vaginal lumen is blocked
o when only the inferior part of the vaginal plate fails to canalize, it is called as an imperforate hymen

Ambiguous Genitalia

▪ Female pseudo hermaphrodite – 2 ovaries

o MCC is congenital adrenal hyperplasia (CAH)
o 46XX genotype
o Excessive exposure to androgens during pregnancy results in virilization of the female fetus
▪ Male pseudo hermaphrodite – 2 testis
o 46XY
o Deficiency of MIF, testosterone
o Androgen insensitivity syndrome (testicular feminization syndrome) – failure of end organs to respond to DHT
 Blind vagina, no uterus & ovaries
 XY but has a female phenotype
▪ True Hermaphrodite – ovary &/or testis or ovotestis
o Rare condition
o Persons usually have a 46XX karyotype
o Have both testicular & ovarian tissue
o Most are reared as females
▪ Mixed gonadal dysgenesis – testis plus streak gonad
▪ Pure gonadal dysgenesis – bilateral streak gonads

15 | P a g e
Small round cell/Blue cell tumors : Childhood tumor - sheets of primitive cells with scanty cytoplasm

16 | P a g e