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1

Causes of Death by Age

<1 

 Congenital malformations, deformations, and chromosomal anomalies

 Disorders related to short gestation and low birth weight

 SIDS

 Maternal complications of pregnancy

2

 1-4 years Causes of death

 Accidents (unintentional Injuries)

 Congenital anomalies

 Assault (homicide)

 Malignant neoplasms

 Heart diseases

3

Causes of death

 5-9 years

 Accidents (unintentional Injuries)

 Malignant neoplasms

 Congenital anomalies

 Assault (Homicide)

 Diseases of the heart

4

Causes of death 10-14 years

 Accidents (unintentional injuries)

 Malignant neoplasms

 Assault (homicide)

 Intentional self-harm (suicide)

 Congenital anomalies.

5

Predisposing factors to birth injuries

– Cephalopelvic disproportion

– Difficult labor (Breech presentation)

– Prematurity

6

Birth Injuries

• Cranial injuries

– Caput succedaneum

– Cephalohematoma

– Skull fractures

– Intracranial hemorrhage

7

Birth • Peripheral nerve injuries

– Brachial palsy

– Facial nerve palsy

8

most common birth injury

Clavicle Fx 

9

22q11.2 Deletion Syndrome

Velocardiofacial Syndrome

 Di George Syndrome 

10

Velocardiofacial Syndrome

– Congenital heart disease (outflow tracts)

– Palatal abnormalities/Facial dysmorphism

– Developmental delay

Deletion of 22q11.2

11

 Di George Syndrome

– Thymic hypoplasia – impaired T-cell immunity

– Parathyroid hypoplasia - hypocalcemia

12

KLINEFELTER‟S SYNDROME

(XXY,XXXY etc.)

– Testicular atrophy • Sterility

– Eunuchoid with:

• Gynecomastia

• Reduced facial, body and pubic hair.

Prone to breast cancer,extragonadal germ cell t., and

autoimmune diseases.

13

ENVIRONMENTAL

– Maternal/Placental Infections 2-3% of birth defects what infections?

• Rubella

• Toxoplasmosis

• Syphilis

• CMV

• HIV

14

– The most common congenital malformations

• Cleft lip/palate

• Neural tube defects

15

Pathogenesis of congenital malformations

1. Timing of the prenatal insult has an important impact on both the occurrence and the type of malformation produced.

2. Genes that regulate morphogenesis may be the target of teratogens.

– Homeobox (HOX) genes

– Sonic hedgehog gene

16

Sonic Hedgehog Gene defect causes

holoprosencephaly

17

Cyclopamine causes

holoprosencephaly

18

Homeobox Gene defect causes

limb, vertebral and craniofacial abnormalities.

19

Valproic acid mimics what 

Homeobox Gene defect

causes valproic acid

20

Retinoic acid (acne) causes

CNS, cardiac and craniofacial abnormalities including cleft lip and palate. May interfere with TGFβ (palatogenesis)

21

Malformations

 Primary structural abnormality with poor formation of tissue due to a localized error that occurs during development.

22

Malformations - examples

• Polydactyly& Syndactyly

• Cleftlip

• Cleftpalate

• Congenital heart disease

23

Disruption

• Structural defect caused by secondary destruction of or interference with a previously normally formed part.

24

Disruption example

Amniotic bands

entanglement followed by the tearing apart or amputation of a normally developed structure.

– Interruption of blood supply leading to infarction, necrosis, and/or resorption of structures distally.

25

Deformation

Localized or generalized compression of the growing fetus by abnormal biomechanical forces.

• Arises later in fetal life than do malformations

26

most common cause of deformation

Uterine constraint

27

Factors for deformations

Factors –

Maternal

» First pregnancy

» Small uterus

» Leiomyomas

Fetal

Multiple fetuses

Oligohydramnios

Abnormal presentation

28

Potter Sequence

A image thumb
29

Oligohydramnios (= lack of amniotic fluid) due to:

• Renal agenesis/ maldevelopment

• Amniotic fluid leak

• Uteroplacental insufficiency

30

Oligohydramnios causes

• Pulmonary hypoplasia

• Amnion nodosum

• Fetal compression

– Worsens pulmonary hypoplasia

– Breech presentation

– Altered facies

– Positioning defects of feet and hands

31

What are the most common malformation syndromes  

– Down syndrome - 1:660

– XXY syndrome - 1:500 males

32

Preterm is considered what 

<37 wks 

33

Appropriate for gestational age (= AGA):

Is a birth weight between

10th and 90th percentile for GA. (gestational age) 

34

Low-birth weight (LBW) infants

 <2,500 g at birth

– Premature

and/or

– IUGR for their gestational age i.e. SGA.

35

Fetal causes of growth restriction

– Chromosomal disorders (17%)

– Congenital malformations

– Congenital infections (eg. TORCH)

36

Placental causes of fetal growth restrictions

– Placenta previa

– Placental abruption

– Placental infarction

37

Maternal causes of fetal growth restrictions

– Toxemia of pregnancy

– Chronic hypertension

– Alcoholism, narcotic abuse and smoking

– Drugs (dilantin)

– Malnutrition (esp. prolonged hypoglycemia)

38

SMOKING is associated with what birth defects 

• Spontaneous abortion

• Premature labor

• Low birth weight

• SIDS

• Placental abnormalities

39

Major risk factors for Prematurity

• Premature rupture of membranes

• Intrauterine infections

• Structural abnormalities of the uterus, cervix, placenta

• Multiple gestation

40

APGAR score 

A image thumb
41

How often is APGAR administered 

1min and 5 min 

1min- tests post toleration to birthing 

5min- tests toleration to new environment

42

Complications of Prematurity

• Hyaline membrane disease ( Respiratory distress syndrome)

• Necrotizing Enterocolitis

• Intraventricular and germinal matrix hemorrhage

• Long term sequelae, including developmental delay

43

Leading cause of morbidity and mortality among premature infants

Respiratory Distress Syndrome (RDS) of the New Born

(hylaine membrane disease) 

44

Risk factors for Respiratory Distress Syndrome (RDS) of the New Born

• Prematurity

• Perinatal asphyxia

• Maternal diabetes

• Cesarean section before onset of labor

• Twin gestation

• Male sex

45

Microscopic alterations in RDS timeline

First several hours- Necrotic cellular debris in terminal bronchioles and alveolar ducts

 If survives for 12-24 hours: Smooth homogenous pink membranes lining terminal and respiratory bronchioles and alveolar duct •Membranes are composed of necrotic alveolar type II pneumocytes and fibrin; neutrophilic inflammatory reaction is not associated with these membranes

infantdiesafter several days,: reparative changes, including proliferation of type II pneumocytes and interstitial fibrosis, is seen.

46

Prevention of RDS 

• Delay labor until lung matures

• Induce maturation (steroids)

• Evaluate amniotic fluid phospholipids

47

Long term sequelae of RDS 

– Retrolental fibroplasia (retinopathy of prematurity) - oxygen toxicity - vascular endothelial growth factor (VEGF)

– Bronchopulmonary dysplasia

48

Bronchopulmonary dysplasia

Decrease in alveolar septation resulting in large, simplified alveolar structures and a dysmorphic capillary configuration.

49

Bronchopulmonary dysplasia caused by

Most likely caused by an arrested development of alveolar septation at the so-called saccular stage of development.

50

Contributing Factors to Bronchopulmonary dysplasia

• Hyperoxemia

• Hyperventilation

• Prematurity

• Inflammatory cytokines (IL1β, IL6 and IL8)

• Vascular maldevelopment

51

Prevention of Bronchopulmonary dysplasia

gentler ventilation,

glucocorticoids and prophylactic surfactant

52

Bronchopulmonary dysplasia pathology

• Hyperplasia and squamous metaplasia of bronchial epithelium

• Peribronchial fibrosis

• Fibrotic obliteration of bronchioles

• Overdistended alveoli.

53

Neonatal Necrotizing Enterocolitis

Disease of premature infants along with term infants of low birth weights (small for gestational age)

54

Neonatal Necrotizing Enterocolitis (NEC) 

 Predisposing factors

– Intestinal ischemia

– bacterial colonization of the gut

– administration of formula feeds

 

55

Neonatal Necrotizing Enterocolitis (NEC)

CLinical features 

Preterm or SGA infant with history of asphyxia requiring ventilation develops signs of obstruction after oral feedings have begun

• Abdominal distension, bloody stools, shock, DIC progressing to death

56

Neonatal Necrotizing Enterocolitis (NEC)

Diagnosis

– Abdominal radiographs show dilated loops of bowel

– pneumatosis intestinalis

57

Neonatal Necrotizing Enterocolitis (NEC)

Pathology involves what parts of GI

Typically involves terminal ileum, caecum and right colon

58

Microscopy signs in Neonatal Necrotizing Enterocolitis (NEC)

• Mucosalcoagulative necrosis extending into and often through the submucosa and muscular layers

• Small air filled spaces beneath mucosa – pneumatosis intestinalis

59

Neonatal Necrotizing Enterocolitis (NEC) 

Complications 

• Early – sepsis, shock, acute tubular necrosis, DIC, intestinal perforation

• Delayed – short gut syndrome, malabsorption, strictures.

60

Neonatal Intraventricular hemorrhage

Bleeding into the germinal matrix with extension into ventricles and beyond

61

Germinal Matrix

source of nerve cells in embryo and fetuses (up to 33 weeks of gestation.)

62

Neonatal Intraventricular hemorrhage

in long term survivors 

cavitations or pseudocysts surrounded by hemosiderin laden macrophages and gliosis.

 

 

63

Neonatal Intraventricular hemorrhage complication 

Hydrocephalus 

64

Physiological Jaundice

Elevated unconjugated bilirubin during first week of life.

 

65

Physiological Jaundice

2 functionally distinct periods

– Phase I – lasts 5 days in term infants and 7 days in preterm infants.

• Serum bilirubin level may reach 12-15 mg/dl

– Phase II – decline of serum bilirubin levels , lasts for 2 weeks.

66

Characterization of Pathological Jaundice

– Clinical jaundice appearing in first 24 hours

– Total bilirubin > 15 mg/dl ( Hyperbilirubinemia)

– Conjugated bilirubin > 2 mg/dl

67

Unconjugated Hyperbilirubinemia seen in

– Fetomaternal blood group incompatibility (Hemolytic Disease of the newborn)

– Crigler-Najjar syndrome type I & II

68

Conjugated Hyperbilirubinemia seen in

– Biliary atresia

– Neonatal hepatitis

69

Hemolytic disease of newborn

• Erythroblastosis Fetalis

• Antibody induced hemolytic disease in the newborn that is caused by blood group incompatibility between mother and fetus.

• Most common antigens – Rh (D) and ABO blood group antigens

70

Hemolytic disease of newborn

Pathogenesis

• Fetal RBCs reach maternal circulation in last trimester or during child birth

• Sensitization of mother to the foreign antigens – development of antibodies that can freely traverse the placenta to the fetus and cause hemolysis.

• Hemolysis leads to progressive anemia – intrauterine cardiac failure – Edema.

71

Hemolytic disease of newborn end results 

• Death in Utero – most extreme form of disease

• Hydrops Fetalis – most severe form in live born infants.

• Kernicturus – bilirubin encephalopathy

72

Findings in Hydrops Fetalis

• Atautopsy– hepatosplenomegaly and bile stained organs

• Microscopically–

– Erythroblastic hyperplasia of the bone marrow

– Extramedullary hematopoiesis in the liver, spleen.

73

Pathology – Kernicturus

disorder of newborns in which very high levels of unconjugated bilirubin bind to, and injure the immature neurons of the CNS

• Characterized by bile staining of the brain, particularly of the basal ganglia and brain stem.

74

Kernicturus dx

• Amniocentesis – high levels of bilirubin

• Human antiglobulin test (Coombs test) – Positive on fetal cord blood.

75

Kernicturus tx

– Exchange transfusion – Phototherapy

76

Prevention of Kernicturus

Human anti D globulin within 72 hours of delivery

77

Crigler-Najjar Disease

• Type I

recessively inherited disease

• Characterized by complete absence of UDP-glucuronyltransferase activity.

• Unremitting unconjugated hyperbilirubinemia leading to bilirubin encephalopathy.

• Most patients die within first year of life

78

Crigler-Najjar Disease

• Type II 

• Characterized by partial decrease in the activity of UDP-glucuronyltransferase activity.

• Hepatocytes have the capacity to synthesize this enzyme on treatment with Phenobarbital.

79

• Most frequent cause of chronic cholestasis in infants and children

• Most common indication for liver transplantation in this age group.

Biliary Atresia

80

Biliary Atresia

• Complete obstruction of the lumen of the extrahepatic biliary tree within the first three months of life.

• 1:10,000 live births

81

Biliary Atresia

Embryonic or fetal type – 20%

aberrant intrauterine development of the extrahepatic biliary tree

– early onset neonatal cholestasis

– No jaundice free period after physiological jaundice

– Associated congenital anomalies (malrotation of abdominal viscera, congenital heart disease)

82

Biliary atresia Perinatal type

– Normally developed biliary tree is destroyed following birth (virus induced injury to biliary epithelium)

– Late onset neonatal cholestasis (4-8 weeks)

– Jaundice free interval

– No associated congenital anomalies

83

Biliary Atresia

Morphology

• Inflammation and fibrosing stricture of the hepatic and common bile ducts

• Periductal inflammation of intrahepatic bile ducts – progressive destruction of intrahepatic biliary tree

• Features of extrahepatic biliary obstruction – Marked bile ductular proliferation

– Portal tract edema and fibrosis

– Parenchymal cholestasis

84

Biliary Atresia Prognosis

• 75% survival if operated in first 60 days of life

• 20-30% survival if operated after 90 days of life

• 80% survival with transplantation.

85

Idiopathic Neonatal Hepatitis

What is seen... excludes all other causes of hepatitis 

• Giantcell transformation. (diffuse prominent)

• Ballooning

• Acidophilic degeneration

• cholestasis

86

SIDS Risk factors 

75% of SIDS deaths have no associated risk factors.

 

A image thumb
87

Environmental risk factors for SIDS 

A image thumb
88

SIDS Pathogenesis

Multifactorial

• 1. Vulnerable infant

• 2. Critical developmental period in

homeostatic control. (arousal and cardiorespiratory)

• 3. One or more exogenous stressors (hypercarbia/hypoxia/thermal stress)

89

SIDS pathology

• Multiple petechiae (80%) in Thymus,

visceral/parietal pleura and epicardium.

• Lungs: Congestion +/- pulmonary edema

• Hypoplasia of arcuate nucleus in the brain stem.

• Decrease in brain stem neuronal populations in some cases.

90

SIDS Infectious differentials 

– Viral myocarditis

– Bronchopneumonia

91

SIDS

Congenital differentials 

– Congential aortic stenosis

– Anomalous origin of coronary artery from pulmonary artery

92

SIDS (Differential diagnosis)

• Genetic/Metabolic Defects

– Long QT syndrome (SCNSA + KCNQ1 mutations)(Sodium and potassium channel abnormalities.) 1%

– Fatty acid oxidation disorders (MCAD, LCHAD, SCHAD mutations) 5%

– Histiocytoid cardiomyopathy (MTCYβ mutations)

– Abnormal inflammatory responsiveness

(Partial deletion of C4a and C4b)

93

After how many weeks does the female amniotic fluid become bacteriocidal

20 wks 

94

Fetal and Perinatal Infections - Pathways

• Ascending from the vagina and cervix.

• Hematogenous dissemination from the placenta.

• Maternal to fetal transfusion at delivery(Hepatitis B and HIV)

• Direct contact at birth.

• From the environment post-partum.

• Accidental introduction at the time of

procedures - amniocentesis.

95

Ascending Infection

Fetus acquires infection by

– Inhalation of infected amniotic fluid

– Passage through birth canal

96

• Fetal birth infections

– Chorioamnionitis

– Funisitis

– Pneumonia

– Sepsis

– Meningitis

 

97

Infections Acquired by the Hematogenous Route

• TORCHinfections.

• Congenital syphilis.

• Parvovirus B19.

• Human Immunodeficiency  Virus(HIV).

• Other infections(Listeria, parasitic  infections).

98

O= OTHER INTRAUTERINE INFECTIONS

Syphilis

Listeria monocytogenes (late-onset sepsis)

Adenovirus (rare)

Varicella (rare)

Enterovirus

SLAVE

99

TORCH Agents

Transmission

• Hematogenous through the placenta.

• Herpes simplex infection is an exception to this as most infections are due to:

– Direct contact at the time of delivery.

– Ascending infection.

100

TORCH Infections

Common Manifestations

 SGA infants.

 CNS changes:

 Hydrocephalus.

 Microcephaly.

 Periventricular calcification.

Pneumonitis

 Petechiae

Hepatomegaly with jaundice

 Splenomegaly

 Bony changes resembling osteomyelitis

 Chorioretinitis

101

Rubella Embryopathy

 Eye and heart Manifestations 

• Ocular lesions:

– Cataracts.

– Corneal changes. 

– Microphthalmia.

• Cardiac lesions:

– Patent ductus arteriosus.

– Septal defects.

102

Cystic Fibrosis

An autosomal recessive systemic disorder of exocrine glands characterized by

– Chronic pulmonary disease

– Deficient exocrine pancreatic function

– Other complications of inspissated mucus in a number of organs, including the small intestine, liver and the reproductive tract.

103

Cystic fibrosis pathogenesis

• Gene on chromosome 7 (7q31.2) encodes for a protein called the CF transmembrane conductance regulator (= CFTR).

• Phosphorylation of CFTR by protein kinase A using cAMP controls the chloride channel in the apical membranes of eccrine glands.

104

Types of Mutations in cystic fibrosis

 In 70 % cases – 3 base pair deletion that results in loss of a phenylalanine residue at amino acid position 508(∆F508).

• The remaining patients exhibit multiple (more than 800) different mutations.

105

Cystic Fibrosis

Lung

 Plugging of submucosal tracheobronchial mucous glands and ducts.

• Obstruction of bronchioles with mucus, associated with marked hyperplasia and hypertrophy of the mucus-secreting cells.

106

LUng infections from CF

– Chronic bronchitis.

– Bronchiectasis.

– Lung abscesses.

107

Cystic Fibrosis

Pancreas

• In this organ, there is the same mucous obstruction of ducts accompanied by:

– Secondary dilatation and cystic changes of the distal ducts and atrophy of secretory cells.

– Fibrosis.

– Destruction of parenchyma.

• These effects result in chronic pancreatitis in 85% of patients with CF.

108

Cystic Fibrosis

Clinical Features

• Discovered between age of 2-12 months.

• Child presents with symptoms of malabsorption secondary to pancreatic insufficiency:

– Foul-smelling steatorrhea.

– Malnutrition • Edema

• Hypoalbuminemia

– Failure to thrive.

109

CYSTIC FIBROSIS

CLINICAL (CONTD.)

• Two clinical clues in children:

– Nasal polyps

– Rectal prolapse

110

Cystic Fibrosis

Diagnosis

• Pilocarpine sweat test

– Normal sweat: chloride = 10 mEq/L.

– CF sweat, severe variant: chloride >60 mEq/L.

– CF sweat, mild variant: chloride = 40-60 mEq/L

• Genetic diagnosis

111

Phenylketonuria

• Autosomal recessive disorder characterized by

– Progressive mental retardation caused by a deficiency of the hepatic enzyme phenylalanine hydroxylase.

112

PKU pathogenesis

• Point mutation in the PAH gene on 12q.

• Deficiency of Phenylalanine Hydroxylase (PAH) results in

– Hyperphenylalaninemia

– Formation of Phenylketones

• Hyperphenylalaninemia causes irreversible brain damage

– Complete interference with amino acid transport system in brain

– Inhibiting the synthesis of neurotransmitters

113

PKU clinical features 

• Affected infant is normal at birth

• Mental retardation develops within few months

• Tend to have fair skin, blond hair and blue eyes.

• Mousy odour

114

Galactosemia

An autosomal recessive deficiency of Galactose -1-phosphate uridyl transferase, the enzyme that catalyzes the conversion of galactose to glucose.

 

Infants fed milk rapidly develop hepatosplenomegaly, jaundice and hypoglycemia.

• Cataracts and Mental retardation.

115

Galactosemia

• M/E –

extensive and uniform fat

accumulation in liver and marked bile ductal proliferation, cholestasis and fibrosis.

 

116

Dubin-Johnson syndrome

Autosomal recessive disease characterized by chronic or intermittent jaundice and accompanied by a „black‟ liver.

• Defective transport of conjugated bilirubin from hepatocytes to canalicular lumen

• Associated defect in hepatic excretion of

coproporyphrins

117

Dubin-Johnson syndrome

pathology m.e

accumulation of coarse, iron free, dark brown granules in hepatocytes and Kupffer cells.

118

Dubin-Johnson syndrome 

path EM 

pigment is located in lysosomes and it appears to be composed of polymers of epinephrine metabolites, not bilirubin pigment

119

Rotor Syndrome

• Familial conjugated Hyperbilirubinemia

defect in the excretion of conjugated bilirubin into the biliary canaliculi with the bilirubin being absorbed into the blood.

120

Rotor Syndrome

jaundice, attacks of intermittent epigastric discomfort and occasionally abdominal pain, and fever.

121

Rotor syndrome path

low-grade pigment deposition, dissociation of liver cells, occasional necrotic foci, and fibrin precipitation.

122

Common Malignant Neoplasms of Infancy and Childhood

A image thumb
123

Special Predisposing Factors child cancers 

Chromosomal and genetic syndromes.

• Congenital immunodeficiency syndromes.

• >200 genetic syndromes are associated with an increased susceptibility to cancer.

– Down syndrome (Trisomy 21) - Acute leukemia.

– Deletion 13q - Retinoblastoma.

– Wiskott Aldrich syndrome - Lymphoma.

– Agammaglobulinemia - Acute lymphoblastic leukemia (= ALL).

124

Common “Small, Round, Blue Cell” Tumors of Childhood

• Lymphoma/Leukemia

• Medulloblastoma(CNSneoplasm)

• Neuroblastoma

• Rhabdomyosarcoma (Sarcoma) – Embryonal

– Alveolar

• Wilmstumor

• Bonetumors

– Ewing‟s sarcoma/PNET – Small cell osteosarcoma

125

Neuroblastoma general characterisitcs 

poorly differentiated tumor arising from primitive neural crest cells

  • normally give rise to the adrenal medulla and sympathetic ganglia.

  • Second most common solid malignant tumor in children.

  • Before age of 5

  • Germline mutation in ALK gene – familial predisposition to neuroblastoma.

126

Neuroblastoma clinical features

• < 2 years - Mass in abdomen, mediastinum, or other sites, fever, weight loss

• Older children – Signs of metastatic disease – bone pain, respiratory or gastrointestinal symptoms.

• Blueberry muffin baby – disseminated neuroblastoma – multiple cutaneous metastasis with deep blue discoloration of the skin

127

Neuroblastoma gross pathology

• 40 % arise in adrenal medulla.

• Remainder arise anywhere along the sympathetic chain

– paravertebral region of the

abdomen (25%)

– posterior mediastinum (15%). .

• Size varies from minute nodules to tumors weighing >1 kg in weight

• With increasing size, areas of: – Necrosis.

– Hemorrhage.

– Cyst formation.

• Gross calcification in 40-50%.

128

 Homer-Wright Pseudo rosette

the tumor cells are concentrically arranged about a central space filled with neuropil. No lumen.

 

Found in neuroblastomas

129

Neuroblastoma Microscopy

Small, round, blue cell tumor with sheets of small, primitive-appearing cells with dark nuclei, scant cytoplasm, and poorly defined cell borders

130

Neuropil 

a faintly eosinophilic fibrillary material that corresponds to neuritic processes of the primitive neuroblasts.

 

131

Neuroblastoma spreads to

• Bone.

• Lymph nodes.

• Liver.

• Bone marrow.

• Subcutaneous tissue.

132

Neuroblastoma dx

• Elevated blood levels of catecholamines

• Elevated urine levels of catecholamine metabolites

– Vanillylmandelic acid (VMA)

– Homovanillic acid (HVA)

• X –ray abdomen – calcification in tumor can be picked up

133

Neuroblastoma Prognostic factors

• Age of the patient

– < 1 year excellent prognosis – 1-5 years – intermediate

– > 5 years – poor prognosis

• Deletion distal 1p and gain of distal 17q - poor prognosis

• N-myc amplification – extrachromosomal double minute chromatin bodies or homogenously staining regions (HSR) on other chromosomes – poor prognosis

• Telomerase overexpression - poor prognosis

• Tyrosine kinase receptor A (Trk-A) – increased expression indicates good prognosis

134

Nephroblastoma (Wilms Tumor)

malignant embryonal neoplasm derived from nephrogenic blastemal cells

• Most common primary renal tumor of childhood

• Peak incidence – 2-5 years of age

135

Wilms patho

• 10% cases associated with

– WAGR syndrome – deletion of WT1 gene

– Denys-Drash syndrome –dominant, negative inactivating mutation of WT1 gene

– Beckwith-Wiedemann syndrome – mutation of putative WT2 gene – overexpression of IGF2 protein

– Mutations of β-catenin gene (10% of sporadic

WT)

136

Beckwith-Wiedemann Syndrome

• Macroglossia

• Omphalocele

• Gigantism

• Adrenal cortical cytomegaly

• Visceromegaly

• Islet cell hypertrophy

• Renal medullary dysplasia

137

Denys-Drash Syndrome

• Gonadal dysgenesis

• Renal abnormalities

• WT-1 gene mutation

• 90% chance of Wilms‟ tumor

138

ANIRIDIA (WAGR S.)

 

• Aniridia

• Genitalabnormalities • Mentalretardation

• WT-1(11p13)

• 33%ChanceofWilms

139

Nephrogenic rests- precursor lesion

Seenintherenal parenchyma adjacent to approximately 40% of unilateral tumors and nearly 100% of bilateral tumors

140

Wilms microscopy

Triphasic pattern: Embryonal tumor – recapitulates the normal development of the kidney.

• Blastema – sheets of small round blue cells

• Stroma – fibrocytic or myxoid in nature. May have striated muscle.

• Epithelium - abortive tubules and glomeruli

141

Anaplastic Subtype (5% of WT)

Characterized by:

• Cells with hyperchromatic nuclei, >3 times larger than those in adjacent cells of similar type.

• Enlarged, bizarre, multipolar mitoses.

Correlates with acquired TP53 mutations

142

Anaplastic Subtype 

Clinical presentations

• Usually comes to clinical attention due to the detection of an abdominal mass by a parent when bathing or clothing a child.

• Other common presentations:

– Abdominal pain.

– Hematuria.

– Hypertension.

– Acute abdominal crisis secondary to traumatic rupture.

143

Wilms spread

• “3L‟s”:

– Regional lymph nodes.

– Lungs.

– Liver.

• Metastatic sites other than these three sites are unusual and should suggest other diagnoses

144

Most common intraocular malignant neoplasm of childhood.

Retinoblastoma 

145

Retinoblastoma genetics 

• 40% congenital - RB1 gene - multiple tumors – bilateral

• 60% sporadic-unifocal, unilateral.

146

Age retinoblastoma 

Within first 2 years 

147

Retinoblastoma

Presentation

– White pupil (= leukocoria).

– Squint (= strabismus).

– Poor vision.

– Spontaneous hyphema (= hemorrhage into the anterior portion of the eye).

– Red, painful eye.

148

• Composed of small round cells with large hyperchromatic nuclei and scant cytoplasm.

• Flexner-Wintersteiner rosettes- Clusters of cuboidal tumor cells arranged around a central lumen

Microscopy 

REtinoblastoma 

149

Retinoblastoma course 

• Extension into optic nerve and/or subarachnoid space (CSF) with intracranial spread.

• Invasion of blood vessels, especially in the highly vascular choroid, with subsequent hematogeneous metastases.

• Frequent complication is secondary glaucoma

150

Retinoblastoma

Prognosis

• Always fatal if untreated.

• 90% survival with early diagnosis and modern therapy.

 

151

In inherited retinoblastomas, patients have an increased susceptibility to other malignant tumors:

– Osteogenic sarcoma.

– Ewing sarcoma/PNET.

– Pinealoblastoma.

152

Teratomas

• Most arise in

sacrococcygeal region

153

Teratoma pathology 

 75%-composedof histologically mature tissue elements

• 12%malignant

• 13%immature

– Proportion of immature elements important.

≤ 4 months - benign

At 1year 50% malignant

At 5years 100% malignant