Chapter 10: Diseases of Infancy and Childhood Flashcards
1
Q
Primary errors of morphogenesis, in which there is an intrinsically abnormal developmental process defines?
A
Malformations
2
Q
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?
A
- Disruptions
- Amniotic bands, denoting rupture of amnion w/ resultant formation of “bands” that encircle, compress, or attach to parts of developing fetus
3
Q
What is the most common underlying factor for the development of deformations in newborns?
Example of common deformation seen in Potter sequence?
A
- 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
Q
What is the classic example of a sequence?
Due to what and what abnormalities are produced?
A
- 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
Q
Malformations, disruptions, or deformations that set into motion secondary effects in other organs is known as?
A
A sequence = cascade of anomalies triggered by one initiating aberration
6
Q
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?
A
Malformation syndrome
7
Q
What is frequently present in Oligohydramnios (or Potter) sequence?
A
Nodules in the amnion (amnion nodosum)
8
Q
Differentiate agenesis from aplasia
A
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
Q
What are the most common microbes to cause congenital abnormalities during development? (hint: mnemonic = TORCH)
A
T - Toxoplasmosis
O - Other - Syphillis
R - Rubella
C - CMV
H - Herpes/HIV
10
Q
Maternal hyperglycemia-induced fetal hyperinsulinemia results in what disorders in the fetus? (Diabetic embryopathy)
A
- Macrosomia (organomegaly and increased body fat and muscle mass)
- Cardiac anomalies
- Neural tube defects
- CNS malformations
*The major defects in diabetic embryopathy
11
Q
What 7 drugs/chemicals have been known to cause congenital anomalies in humans?
A
1) Alcohol
2) Folic acid antagonists
3) Androgens
4) Phenytoin
5) Thalidomide
6) Warfarin
7) 13-cis-retinoic acid
12
Q
What is the most common genetic cause of congenital malformations?
What common malformations are included in this category?
A
- Multifactorial inheritance
- Cleft lip, cleft palate, and neural tube defects
13
Q
Major morphological abnormalities occur during which weeks of embryonic development?
A
Weeks 3-7
14
Q
Between which weeks is the embryo extremely susceptible to teratogenesis?
Peak sensitivity when?
A
- Extremely sensitive = Weeks 3-9
- Peak sensitivity = 4-5th week
15
Q
Teratogens during the 4th and 5th weeks of gestation affect every body system except for?
A
Teeth, palate, and genitalia
16
Q
The antiepileptic drugs, Valprotic acid, disrupts expression of what developmentally critical TF?
Causes what?
A
- Disrupts HOX proteins that help limb pattern development, vertebrae, and craniofacial structures
- Mutations in the HOX family of genes are responsible for congenital anomalies that mimic features observed in valproic acid embryopathy
17
Q
Thalidomide, once used as a tranquilizer in Europe, causes an extremely high incidence of?
A
Limb malformations
18
Q
Infants born to mothers treated with retinoic acid for severe acne have which predictable phenotype (retinoic acid embryopathy)?
A
CNS, cardiac, and craniofacial defects (cleft lip and cleft palate)
19
Q
The craniofacial defects (cleft lip and palate) which result from retinoid acid embryopathy are a result of?
A
Retinoic acid-mediated deregulation of the TGF-B signaling pathway
20
Q
What defines prematurity?
Second most common cause of?
A
- Gestational age less than 37 weeks
- Second most common cause of neonatal mortality
21
Q
What are the 4 risk factors associated with prematurity?
A
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
Q
What are the most common microorganisms implicated in intrauterine infections leading to preterm labor?
A
- Ureaplasma urealyticum
- Mycoplasma hominis
- Gardnerella vaginalis
- Trichomonas
- Gonorrhea
- Chlamydia
My Garden Gnomes Trick Unpleasant Children
23
Q
What is the molecular mechanism by which intrauterine infections induce preterm labor?
A
- Endogenous TLRs bind bacterial compounds
- Produce signals which deregulate prostaglandin expression, in turn producing smooth muscle contractions
24
Q
Which fetal conditions cause Fetal Growth Restriction (FGR)?
Infections by what agents?
A
- 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 ganglia**, **thalamus**, **cerebellum**, **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 **P****henylalanine ---\> 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** (**p****olyol 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 **thymus**, **visceral** 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 **elevated**, **irregular**, **red-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?
**W**ilms tumor
**A**niridia
**G**enital anomalies
**R**etardation
- 33% chance
149
Patients with WAGR syndrome carry what chromosomal deletion?
What relevant genes are found on this chromosome?
- **Germline** deletions of **11p13**
## Footnote
**- *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**
