Chapter 10: Diseases of Infancy and Childhood Flashcards Preview

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1

Primary errors of morphogenesis, in which there is an intrinsically abnormal developmental process defines?

Malformations

2

Secondary destruction of an organ or body region that was previously normal in development; thus arising from extrinsic disturbancs in morphogenesis defines what?

Classic example?

- Disruptions

Amniotic bands, denoting rupture of amnion w/ resultant formation of "bands" that encircle, compress, or attach to parts of developing fetus

3

What is the most common underlying factor for the development of deformations in newborns?

Example of common deformation seen in Potter sequence?

- Uterine constraint: size of fetus outpaces the growth of uterus (35th-38th week)

- Deformations are caused by abnormal biomechanical forces

- Club feet is deformation seen in Potter sequence

4

What is the classic example of a sequence?

Due to what and what abnormalities are produced?

- Oligohydramnios (Potter) sequence

- Decreased amniotic fluid --> flattened facies and positional abnormalities of hands and feet; dislocated hips; hypoplastic lungs

Nodules (amnion nodosum) in the amnion of frequently present

5

Malformations, disruptions, or deformations that set into motion secondary effects in other organs is known as?

sequence = cascade of anomalies triggered by one initiating aberration

6

A constellation of congenital anomalies, believe to be pathologically related, but cannot be explained on the basis of a single, localized, initiating defect defines what?

Malformation syndrome

7

What is frequently present in Oligohydramnios (or Potter) sequence?

Nodules in the amnion (amnion nodosum)

8

Differentiate agenesis from aplasia

Agenesis: complete absence of an organ AND its associated primordium (absent primordium)

Aplasia:  absence of an organ but one that occurs due to failure of growth of the existing primordium (primordium exists)

9

What are the most common microbes to cause congenital abnormalities during development? (hint: mnemonic = TORCH)

T - Toxoplasmosis

O - Other - Syphillis

R - Rubella

C - CMV

H - Herpes/HIV

10

Maternal hyperglycemia-induced fetal hyperinsulinemia results in what disorders in the fetus? (Diabetic embryopathy)

- Macrosomia (organomegaly and increased body fat and muscle mass)

- Cardiac anomalies

- Neural tube defects

- CNS malformations

*The major defects in diabetic embryopathy

11

What 7 drugs/chemicals have been known to cause congenital anomalies in humans?

1) Alcohol

2) Folic acid antagonists

3) Androgens

4) Phenytoin

5) Thalidomide

6) Warfarin

7) 13-cis-retinoic acid

12

What is the most common genetic cause of congenital malformations?

What common malformations are included in this category?

Multifactorial inheritance

- Cleft lip, cleft palate, and neural tube defects

13

Major morphological abnormalities occur during which weeks of embryonic development?

Weeks 3-7

14

Between which weeks is the embryo extremely susceptible to teratogenesis?

Peak sensitivity when?

- Extremely sensitive = Weeks 3-9

- Peak sensitivity4-5th week

15

Teratogens during the 4th and 5th weeks of gestation affect every body system except for?

Teeth, palate, and genitalia

16

The antiepileptic drugs, Valprotic acid, disrupts expression of what developmentally critical TF?

Causes what?

- Disrupts HOX proteins that help limb pattern developmentvertebrae, and craniofacial structures

- Mutations in the HOX family of genes are responsible for congenital anomalies that mimic features observed in valproic acid embryopathy

17

Thalidomide, once used as a tranquilizer in Europe, causes an extremely high incidence of?

Limb malformations

18

Infants born to mothers treated with retinoic acid for severe acne have which predictable phenotype (retinoic acid embryopathy)?

CNS, cardiac, and craniofacial defects (cleft lip and cleft palate)

 

19

The craniofacial defects (cleft lip and palate) which result from retinoid acid embryopathy are a result of?

Retinoic acid-mediated deregulation of the TGF-B signaling pathway

20

What defines prematurity?

Second most common cause of?

- Gestational age less than 37 weeks

- Second most common cause of neonatal mortality

21

What are the 4 risk factors associated with prematurity?

1) PPROM (before 37 weeks = most serious)

2) Intrauterine infections (major cause)

3) Structural abnormalities (uterine, placental, and cervical)

4) Multiple gestations (twin pregnancy)

22

What are the most common microorganisms implicated in intrauterine infections leading to preterm labor?

Ureaplasma urealyticum

Mycoplasma hominis

Gardnerella vaginalis

Trichomonas

- Gonorrhea

Chlamydia

My Garden Gnomes Trick Unpleasant Children

23

What is the molecular mechanism by which intrauterine infections induce preterm labor?

- Endogenous TLRs bind bacterial compounds

- Produce signals which deregulate prostaglandin expression, in turn producing smooth muscle contractions

24

Which fetal conditions cause Fetal Growth Restriction (FGR)?

Infections by what agents?

- Chromosomal disorders,

- Congenital anomalies

- Congenital infections (TORCH = most commonly responsible)

25

Infants who are SGA because of fetal factors usually have which type of growth restriction?

Also referred to as?

Symmetric growth restriction (also referred to as proportionate FGR) = all organ systems are similarly affected

26

Placental causes of FGR tend to result in what type of growth retardation of the fetus?

Asymmetric (or disproportionate) growth retardation w/ relative sparing of the brain

27

What are the most common maternal abnormalities/conditions associated with SGA infants?

Vascular diseases = Preeclampsia (toxemia of pregnancy) and Chronic HTN

- Thrombopilias (i.e., acquired antiphospholipid antibody syndrome)

- Narcotic abuse, alcohol intake, and heavy cig smoking

- Maternal malnutrition (i.e., prolonged hypoglycemia)

28

What is found deposited in the peripheral airspaces of infants who succumb to Respiratory Distress Syndrome (RDS)?

Hyaline proteinaceous material 

29

What are the strong associations with RDS?

- Male gender

- Maternal diabetes

- C-section

30

What are the major morphological features of RDS?

Cyanosis

Fine rales over both lung fields

Ground-glass on X-ray

31

Which surfactant-associated proteins play a role in pulmonary host defense?

Which are involved in reduction of surface tension at the air-liquid barrier?

- SP-A and SP-D are involved in host defense (innate immunity)

- SP-B and SP-C + Surfactant lipids are involved in reducing surface tension

32

What hormones and GFs are responsible for modulating the synthesis of Surfactant?

Which is particularly important?

- Prolactin

- Insulin (suppresses synthesis)

Cortisol (particularly important)

- Thyroxine

- TGF-B

*Role of glucocorticoids are particularly important

33

Conditions associated with intrautrerine stress and FGR that increase corticosteroid release have what effect on infants developing RDS?

Can be counteracted by?

- Lowers the risk of developing RDS

- Compensatory high levels of insulin in infants of diabetic mothers, counteracts the effects of steroid and suppresses surfactant synthesis

34

What are the 2 complications of prolonged therapy with high concentration of ventilator-administered oxygen for RDS?

1) Retrolental fibroplasia 

  - Phase I: VEGF is decreased = endothelial apoptosis

  - Phase II: VEGF levels rebound upon return to hypoxic room air ventilation,                      inducing retinal vessel proliferation

2) Bronchopulmonary dysplasia --> increased levels of pro-inflammatory cytokines --> decreased alveolar septation

35

What are the morphological characteristics of RDS?

- Lungs normal size, solid, airless, and reddish-purple in color

- Alveoli poorly developed and collapsed -- atelectasis

- Necrotic cells (type II pneumocytes) seen early and later incorporated within eosinophilic hyaline membranes also composed of fibrin

36

Bronchopulmonary dysplasia as a result of high concentrations of ventilator-administered oxygen is caused by potentially reversible impairment in the development of alveolar septation at what stage?

Saccular stage

37

Infants who recover from RDS are also at increased risk for developing what other complications associated with pre-term birth?

- Patent ductus arteriosus

- Intraventricular hemorrhage

- Necrotizing enterocolitis

38

Most cases of Necrotizing Enterocolitis are associated with?

Enteral feeding

39

Which inflammatory mediator is commonly seen in Necrotizing Enterocolitis?

Function?

- PAF

- Increasing mucosal permeability by: 

   - Promoting enterocyte apoptosis and

   - Compromising intercellular tight junctions

40

Abdominal radiographs in infants with Necrotizing Enterocolitis often show?

Pneumatosis intestinalis (gas within intestinal wall)

41

Necrotizing enterocolitis typically involves which structures?

Terminal ileum

Cecum

Right colon

42

What are the 2 primary routes in which fetal and perinatal infections are acquired?

1) Transcervically (also called ascending)

2) Transplacentally (hematologic)

43

Most bacterial and few viral (herpes simplex II) are acquired via which route?

Cervicovaginal route

44

Most parasitic (toxoplasma, malaria), viral, and few bacterial infections (Listeria, Treponema) gain access to the fetal bloodstream how?

Transplacental (Hematologic) via Chorionic Villi

45

Parvovirus B19 has a particular tropism for which cells?

Seen how diagnostically?

- Erythroid cells

- Diagnostic viral inclusions can be seen in early erythroid progenitors 

46

TORCH group of infections evoke similar clinical and pathologic manifestations including?

- Fever

- Encephalitis

- Chorioretinitis

- Hepatosplenomegaly

- Pneumonitis

- Myocarditis

- Hemolytic anemia

- Vesicular or hemorrhagic skin lesions

47

Most common cause of early-onset sepsis as well as early-onset meningitis?

Group B streptococcus

48

What are the major antigens known to induce clinically significant immunologic reactions leading to Immune Hydrops?

Certain of the Rh antigens and the ABO blood groups

49

Of the numerous antigens included in the Rh system, which antigen is the major cause of Rh incompatibility?

D antigen

50

The incidence of maternal Rh isoimmunization has decreased significantly since the use of?

When is it administered?

 

- Rhesus immune globulin (RhIg) containing anti-D antibodies

- Administered at 28 weeks and within 72 hours of delivery to Rh-negative mothers

51

ABO hemolytic disease occurs almost exclusively in which infants and mothers?

Occurs during what pregnancy?

- Infants of group A or B who are born to group O mothers

- Can occurs during the first pregnancy, unlike in Rh-mediated immune hydrops

52

What are the 3 major causes of nonimmune hydrops?

1) Cardiovascular defects

2) Chromosomal anomalies (Turner syndrome - cystic hygromas + trisomies 21/18 - CV problems)

3) Fetal anemia

53

In some parts of the world (i.e., Southeast Asia), what is the most common cause of severe fetal anemia ---> nonimmune hydrops?

Homozyogous α-thalassemia, resulting from deletion of all four α-globin genes

54

Transplacental infection by which virus is rapidly emerging as an important cause of hydrops?

Parvovirus B19

55

In hydrops associated with fetal anemia, both the fetus and placenta are characteristically pale; what organ morphologies are seen?

Major morphologic feature of the liver?

- Liver and spleen are enlarged from cardiac failure and congestion

Extramedullary hematopoiesis present in liver, spleen, and LNs

56

Increased numbers of RBCs, including reticulocytes, normoblasts, and erythroblasts seen in hydrops due to fetal anemia culminates to what?

Erythroblastosis fetalis

57

What is the most serious threat in fetal hydrops?

Morphological features?

- CNS damage, known as kernicterus (toxicity of bilirubin)

- Brain is enlarged and edematous, and when sectioned has a bright yellow , particularly the basal gangliathalamuscerebellum, cerebral gray matter, and SC

58

Classic Phenylketonuria is distinctively common in which populations?

Uncommon in?

Inheritance pattern?

- Common in Scandinavian descent

- Uncommon in African American and Jews

- Autosomal Recessive

59

PKU is caused by a severe deficiency of what enzyme?

Converts phenylalanine to?

- Phenylalanine hydroxylase (PAH) = AR

- Needed for conversion of Phenylalanine ---> Tyrosine

60

What is clinical findings and timeline seen in patients suffering from PKU?

 

- Normal at birth but develop rising plasma phenylalanine level, impairing brain development

- Present w/ Musty or Mousy odor to urine

- Usually by 6 months, there is severe mental retardation

61

If PKU is left untreated, what is seen in 1/3 and 2/3 of these patients?

What other major clinical consequences/findings?

- 1/3 of these children never able to walk

- 2/3 cannot talk

- Seizures, decreased pigmentation of hair/skin, and eczema

62

Explain how female PKU patients are able to reach adulthood and what occurs when they decide to have a child.

What is maternal PKU?

- Female PKU pts, if tx w/ dietary restriction early in life, reach childbearing age and are clinically asymptomatic; most have hyperphenylalaninemia due to dietary tx being discontinued after reaching adulthood

- Maternal PKU results from the teratogenic effects of phenylalanine or its metabolites that cross the placenta and affect specific fetal organs during development

63

How can the teratogenic effects of phenylalanine be avoided in children being born to mothers with PKU?

Imperative that maternal dietary restriction of phenylalanine be initiated BEFORE conception and continued throughout pregnancy

64

An infant presents with strong musty/mousy odor to the urine, what do you suspect?

PKU

65

What is responsible for the decreased pigmentation of the skin and hair seen in patients with PKU?

- Phenylalanine is not converted to tyrosine

- Tyrosine is a precursor of melanin

66

Clinically why is it important to recognize benign hyperphenylalaninemia?

How is it determined if you are dealing with benign vs classic PKU?

 

- These individuals may hav a positive screening test but do not develop the severe symptoms seen in classical PKU

- Measurement of serum phenylalanine is necessary to differentiate; classic PKU will have levels five-fold or more above normal

67

While 98% of PKU is attributable to mutation in PAH, how can the other 2% be accounted for?

Why is this clinically important?

- Abnormalities in the synthesis or recycling of the cofactor tetrahydrobiopterin (BH4)

- Clinically important to recognize these variant forms because they cannot be treated by dietary restriction of phenylalanine

68

Galactosemia results from the accumulation of ______ in tissues

Galactose-1-phosphate

69

2 variants of galactosemia have been identified, which enzyme is missing in the most common form and which in the more rare form?

Which reaction in the sequence is each involved in?

- Galactose-1-phosphate uridyl transferase (GALT) of reaction 2 = most common

- Galactokinase in the more rare form and is involved in reaction 1

70

The rare variant of galactosemia involving reaction 1 and the enzyme galactokinase leads to?

Milder form of the disease NOT associated with mental retardation

71

Which tissues does galactose-1-phosphate accumulate in?

What are the products of the alternative metabolic pathways that are activated?

- Liver, spleen, lens of the eye, kidneys, heart muscle, cerebral cortex, and erythrocytes

Galactitol (polyol metabolite of galactose) and Galactonate also accumulate in the tissues

72

What are the major effects on the liver, eye, and CNS in patients with Galactosemia?

Liver: early damage leads to fatty change hepatomegaly; later scarring resembles cirrhosis of alcohol abuse

Eye: opacification of the lens (cataracts), due to accumulation of galactitol causing an increased osmotic pressure

CNS: loss of nerve cells, gliosis, and edema, particularly in the dentate nuclei of the cerebellum and olivary nucleus of the medulla

73

An infant presents with failure to thrive since birth. Since starting feeding of milk he has began to vomit and experience diarrhea. At the end of his first week of life he is Jaundiced w/ marked Hepatomegaly.

Based on these symptoms what do you suspect?

Galactosemia

74

When does cataracts seen in patients with Galactosemia develop?

Within a few weeks of life

75

Accumulation of galactose-1-phosphate in the kidney impairs what?

Leads to?

Impairs amino acid transport ---> aminoaciduria

76

Depressed neutrophil bactericidal activity in Galactosemia leads to increased frequency of?

Escheria coli septicemia

77

Older patients with Galactosemia, even those with dietary restrictions, present later in life with?

Speech disorder

Gonadal failure (especially premature ovarian failure)

Ataxia (less common)

78

What are the clinical features of Cystic Fibrosis?

- Chronic lung disease secondary to recurrent infections

- Pancreatic insufficiency

- Steatorrhea

- Malnutrition

- Hepatic cirrhosis

- Intestinal obstruction

- Male infertility

79

What is the most common lethal genetic disease that affects the Caucasian population?

What is the carrier frequency?

- Cystic fibrosis

- Carrier frequency 1 in 20

80

What do heterozygote carriers of cystic fibrosis have higher incidences of?

Respiratory and Pancreatic disease

81

Although, CTFR regulates multiple ion channels and cellular processes, which has the most pathophysiologic relevance in cystic fibrosis?

What is its normal function vs. in CF?

- Epithelial sodium channel (ENaC)

- ENaC is inhibited by normally functioning CFTR

- In CF, ENaC activity increases, markedly increasing Na+ uptake across the apical membrane --> increased Na+ and water reabsorption leading to dehydration of the mucus layer coating epithelial cells in the airway

82

What is the one exception to the activity of the ENaC in patients with cystic fibrosis?

Forms the basis of what significant clinical finding?

- In human sweat ducts, ENaC activity decreases in CF

- Hypertonic luminal fluid containing high sweat sodium chloride (the sine qua non of classic CF) is formed

- Basis for the "salty" sweat that mothers can often detect in their affected infants

83

The pathogenesis of respiratory and intestinal complications in cystic fibrosis seems to stem from?

An isotonic but low-volume surface fluid layer

84

Pancreatic insufficiency in classic CF is virutally always due to the regulation of _______ by the CFTR

HCO3 (bicarbonate)

85

Polymorphisms in what genes whose products modulate neutrophil function act as modifier loci for the severity of pulmonary disease in cystic fibrosis?

Mannose binding lectin 2 (MBL2)

Transforming growth factor β1 (TGFB1)

- Interferon related developmental regulator 1 (IFRD1)

86

What is the morphology of the sweat glands in all variants of CF patients?

Morphologically unaffected

87

The production of _______, a mucoid polysaccharide capsule, by colonizing bacteria, permits the formation of a biofilm that protects bacteria and produces chronic destructive lung disease in patients with CF

Alginate

88

What pancreatic abnormalities are seen morphologically in CF?

- Accumulation of mucus in small ducts (mild cases)

- Ducts completely plugged, causing atrophy of exocrine portion of pancreas, leaving only islets w/ fibrofatty stroma (severe cases)

- Loss of exocrine pancrease --> fat malabsorption --> Vit A deficiency ---> Squamous metaplasia of ducts

89

Thick viscid plugs of mucus may be found in the small intestine of infants with CF, which sometimes cause a small bowel obstruction known as?

Meconium ileus

90

What are the 3 most common organisms responsible for the lung infections in CF?

1) Staphylococcus aureus

2) Haemophilus influenzae

3) Pseudomonas aeruginosa

91

What is found in 95% of the males with CF who survive to adulthood?

 

- Azoospermia and inferitility

- Congenital bilateral absence of Vas deferns is common

92

What is the gold standard for diagnosis of CF?

Sequencing the CFTR gene

93

What's the difference between SIDS and SUID?

SIDS = sudden death of an infant under 1 yo which remains unexplained after a thorough investigation and autopsy

SUID = sudden death in infancy w/ an unexpected anatomic or biochemical basis discernable at autopsy

* SIDS accounts for 50% of the cases of SUID in the United States

94

Leading cause of death in the United States of infants between 1 month and 1 year old?

SIDS

95

What ages do most cases of SIDS occur?

Which sex is at increased risk?

- First 6 months of life

- Most between ages of 2-4 months

- Males have greater risk

96

What is the most common finding at postmortem examination in infants who have died of suspected SIDS?

Location?

Multiple petechiae on the thymusvisceral and parietal pleura, and epicardium

97

What are the 2 main consequences of immune hydrops?

1) Anemia

2) CNS --> Kernicterus

98

What is seen in 85-90% of patients wth cystic fibrosis and is associated with that type of CFTR mutations?

- Exocrine pancreatic insufficiency

- "Severe" CFTR mutations on BOTH alleles

99

Cystic fibrosis patients with exocrine pancreatic insufficiency may have what clinically significant problems?

- Protein and fat malabsorption ---> large, foul-smelling stools, abdominal distention, poor weight gain)

- Faulty fat absorption may induce fat-soluble vitamin (ADEK) deficiencies

- Hypoproteinemia may be severe enough to cause generalized edema

100

Upon postmortem examination of an infant who has died from SIDS you would suspect to potentially see what in the upper respiratory system (larynx and trachea)?

How does this affect your autopsy?

- May see some histologic evidence of recent infection

- Changes are NOT sufficiently severe to account for death and should NOT detract from the diagnosis of SIDS

101

What kind of solution in sweat ducts with CFTR mutation?

Extra NaCl where?

Hypertonic solution w/ extra NaCl in the lumen (basis for the "salty" sweat)

 

102

Polydactyl, congenital heart defects, anencephaly, cleft lip/palate are examples of?

Malformations

103

Uterine constraint is a type of what?

What is an example?

Deformation

Club foot in Potter sequence

104

What is the "triple risk" model (i.e., 3 overlapping factors) in the pathogenesis of SIDS?

1) A vulnerable infant

2) Critical developmental period in homeostatic control

3) Exogenous stressor

105

Amniotic bands are an example of what?

Disruption

106

What are 4 enviornmental stressors associated with SIDS? (hint: most of them have to do with sleep)

1) Prone/side sleeping positions 

2) Sleeping with parents first 3 months 

3) Sleeping on soft surfaces 

4) Thermal stress

107

What are 3 organs in SIDS cases where petechiae are found?

Lungs 

Thymus 

Heart

108

What are normal cells in an abnormal location called?

Heterotropia (choristoma)

109

What is the most compelling hypothesis for the greatest risk factor that makes an infant vulnerable to SIDS? (i.e delayed development of?)

Which abnormality may be the underlying basis for SIDS in some infants?

- SIDS reflects a delayed development of "arousal" and cardiorespiratory control

- Abnormalities in serotonin-dependent signaling in the brain stem may be the underlying basis for SIDS in some infants

110

What has emerged as the putative "missing link" between upper respiratory tract infections, the prone position, and SIDS?

Why?

- Laryngeal chemoreceptors

- Stimulation of the receptors is augmented by respiratory tract infections -> increase volume of secretions and prone position impairs swallowing and clearing of the airways

111

How does SIDS in a prior sibling play a role in the development of SIDS in a newborn?

Fivefold relative risk of recurrence

112

What maternal/paternal risk factors have been identified and linked to SIDS?

- Smoking during pregnancy

- Drug abuse in either parent (i.e., paternal marijuana and maternal opiate)

- Young maternal age

- Frequent childbirths

- Inadequete prenatal care

- African American and American Indian Ethnicity (Socioeconomic status?)

113

What is an excessive focal overgrowth of tissue native to the organ, but does not follow the architecture of the orignal tissue called?

Hamartoma

114

Most common neoplasm of childhood is derived from?

In adults?

Children = soft-tissue tumors of mesenchymal derivation

Adults = have an epithelial origin

115

Most common tumor of infancy?

Hemangioma

116

Hemangiomas in children are of what type?

Located on what body surfaces?

What are their morphological characteristics?

- Capillary and cavernous hemangiomas

- Most are located in the skin, particularly on the face and scalp

- Produce flat to elevatedirregularred-blue masses; some of the flat larger lesions are referred to as port-wine stains.

117

Although most hemangiomas spontaneously regress, some may represent one facet of what hereditary disorder?

von Hippel-Lindau disease

118

How does lymphangiectasis usually present in children?

Diffuse swelling of part or all of an extremity; considerable distortion and deformation may occur as a consequence of the spongy, dilated subcutaneous and deeper lymphatics

119

What is the characteristic chromosomal translocation which has been described in congenital-infantile fibrosarcomas?

Results in generation of which fusion transcript, which can be used as a diagostic marker?

- t(12;15)

ETV6-NTRK3 fusion transcript --> Signals thru RAS and PI-3K/AKT

*Was an exam question!*

120

What are the most common teratomas of childhood?

Most common in what sex?

- Sacrococcygeal teratomas

- Females to males (4:1)

121

When are the 2 peaks in incidence for Teratomas?

1) At 2 years of age

2) In late adolescence or early adulthood

122

Lymphangiomas are characterized by _______ and _______spaces?

Histologically?

- Cystic and cavernous spaces

- Histologically benign, tend to increase in size after birth

123

The malignant potential of Teratomas correlates with the amount of?

Immature tissue

124

How does age affect the malignancy potential of Teratomas?

- Most benign teratomas are encountered in younger infants (<4 mo.)

- Children with malignant lesions tend to be older

125

What are the 5 most common sites of childhood cancer?

- Hematopoietic system

- Nervous system (i.e., central and sympathetic, adrenal, medulla, retina)

- Soft tissues

- Bone

- Kidney

126

Which cancer accounts for more deaths in children younfer than age 15 years than all of the other tumors combined?

Leukemia; principally acute lymphoblastic leukemia

127

Why are many tumors of childhood frequently designated by the suffix        -blastoma?

Frequently show features of organogenesis specific to the site of tumor origin

128

Due to their primitive histologic appearance many childhood tumors have been collectively referred to as?

Small round bue cell tumors

129

Neuroblastic tumors includes tumors of?

Derived from?

- Sympathetic ganglia and adrenal medulla

- Derived from primordial neural crest cells

130

Germline mutations in which gene have been identified as a major cause of familial predisposition to neuroblastoma?

Anaplastic lymphoma kinase (ALK) gene

131

What is the median age at diagnosis for Neuroblastomas?

18 months

132

40% of neuroblastomas arise in the?

What about the remainder?

- Adrenal medulla (40%)

- Remainder occur anywhere along sympathetic chain, especially paravertebral region of abdomen and posterior mediastinum

133

Which type of neuroblastoma is reported to occur 40x more frequently than clinically overt tumors?

In situ lesions (minute nodules)

134

Histologically the background of neuroblastomas often demonstrates a faintly eosinophilic fibrillary material called what?

What is typically found?

Neuropil

- Rosettes (Homer-Wright pseudorosettes) are seen in which tumor cells are concentrically arranged about a central space filled with neuropil

135

Neuroblastomas will show positive immunohistochemical reactions for what?

Neuron-specific enolase

136

What is the histologic prerequisite for the designation of gangloneuroblastoma and gaglioneuroma?

- Presence of mature Schwann cells and fibroblasts

Ganglion cell in and of themselves do not fufill the criteria

137

Documenting the presence of schwannian stroma and gangliocytci differentiation in Neuroblastomas is important why?

Associated with a favorable outcome

138

What is the common presentation for neuroblastomas in children <2 yo?

How about older children?

<2 year = large abdominal masses, fever, and possible weight loss, blueberry muffin baby 

Older children = bone pain, respiratory sx's, or GI complaints

139

In neonates, disseminated neuroblastomas may present with multiple cutaneous metastases that produce what characteristic?

Deep blue discoloration of the skin (Blueberry muffin baby)

140

90% of neuroblastomas regardless of location produce?

Catecholamines (similiar to Pheochromocytomas)

141

What important diagnostic indicator is found elevated in the blood of patients with neuroblastomas?

In the urine?

Catecholamines in the blood

- VMA and HVA in the urine

142

How does age play a role in the prognosis of Neuroblastomas?

- Children younger than 18 months have excellent prognosis

- Children older than 18 months fall into the "intermediate" risk category

143

Amplification of what in neuroblastomas has the most profound and negative impact on prognosis?

MYCN oncogene

144

Which ploidy of neuroblastoma cells is associated with a better prognsis in children younger than 2?

Hyper-diploid (whole chromosome gains)

145

What is the most common primary renal tumor in childhood and the 4th most common pediatric malignancy in the United States?

Wilms Tumor

146

When is the peak incidence of Wilms Tumor?

95% occur before what age?

- Peak incidence = 2-5 y/o

- 95% occur before the age of 10

147

5-10% of Wilms tumors affect the kidneys via what pattern?

What type of mutation?

- Involve both kidneys

- Either simultaneously (synchronous)

- Or one after the other (metachronous)

Germline mutation in one of the genes (first hit)

148

What is WAGR syndrome and how likely are these patients to develop a Wilms Tumor?

Wilms tumor

Aniridia

Genital anomalies

Retardation

- 33% chance 

149

Patients with WAGR syndrome carry what chromosomal deletion?

What relevant genes are found on this chromosome?

Germline deletions of 11p13

WT1

PAX6

150

Patients with deletion of PAX6, but functional WT1 will develop?

Sporadic aniridia

*Not at increased risk for Wilms tumors.

151

What constitutes the "first" and "second" hit in WAGR syndrome for the development of a Wilms tumor?

- Germline WT1 deletion = "first" hit

- Nonsense or frameshift mutation in the second WT1 allele = "second" hit

152

What is the risk for Wilms tumors in Denys-Drash syndrome?

What is the mutation?

- 90%

- Dominant-negative missense mutation in zinc-finger region of WT1 protein, affecting its DNA-binding properties

153

What are the clinical features of Denys-Drash syndrome?

- Gonadal dysgenesis (male pseudohermaphroditism)

- Early-onset nephropathy ---> renal failure

154

What is the characteristic glomerular lesion seen in patients with Denys-Drash syndrome?

Diffuse mesangial sclerosis

155

What other kind of tumors are patients with Denys-Drash syndrome at an increased risk for developing?

Germ cell tumors called gonadoblastomas

156

WT1 protein is critical for what?

Normal renal and gonadal development

157

What are the clinical features of Beckwith-Wiedmann syndrome?

- Organomegaly

- Macroglossia

- Hemihypertrophy

- Omphalocele (intestines outside body at birth)

- Abnormal large cells in the adrenal cortex (adrenal cytomegaly)

158

Beckwith-Wiedmann syndrome (BWS) is an example of what type of mechanism of tumorigenesis?

What chromosome?

- Genomic imprinting

- Chromosome 11

159

Which specific imprinting abnormalities are implicated in BWS?

What important gene is found in this region and has to strongest relationship to tumor predisposition in BWS?

- Specific "WT2" imprinting abnormalities

- Insulin-like growth factor-2 (IGF-2)

160

Patients with Beckwith-Wiedemann syndrome are also at increased risk for developing what?

- Hepatoblastoma

- Pancreatoblastoma

- Adrenocortical tumors

- Rhabdomyosarcomas

161

Other than the presence of mutations in WT1, what else has been implicated in Wilms Tumors and may act synergistically?

β-catenin belonging to the WNT signaling pathway

162

Which precursor lesions are seein in the renal parenchyma adjacent to 25-45% of unilateral Wilms tumors and nearly 100% of those that are bilateral? 

Why is it important to document their presence in resected specimens?

- Nephrogenic rests

- Important because patients are at an increased risk of developing Wilms Tumors in the contralateral kidney and require frequent surveillance for many years

163

Classic triphasic combination of blastemal, stromal, and epithelial cell types in observed in the vast majority of what lesions?

Those of Wilms tumors

164

Presence of anaplasia in Wilms Tumors is associated with?

Why is it important for prognosis?

TP53 mutations and emergence of resistance to chemotherapy

165

What type of tumor is this?

How can you tell?

- Wilms Tumor

- Soft, homogenous, and tan-to-gray

166

A child presents with pain in the abdomen after running into a tree, on PE a large abdominal mass is found unilaterally, he is also experiencing hematuria, and he appears to be hypertensive.

What do you suspect?

A Wilms Tumor

167

What type of metastases is also commonly present in children presenting with a Wilms Tumor?

Pulmonary metastases

168

Which chromosomal mutations are associated with poor prognosis of WIlms Tumors?

- Loss of genetic material on chromosomes 11q and 16q

Gain of chromosome 1q