4. Disease of Infancy and Childhood (Ch 10) Flashcards
1
Q
What are the four time spans to group disorders?
A
the neonatal period- first 4 weeks life
infancy- first year of life
Toddler/preschool- age 1-4
School age- age 5-15
2
Q
The US is ranked 31st in infant mortility rates among the developed nations in the western hemisphere. About 5.3 in every 1000 americans die during pregancy, what about among african americans?
A
12.4 / 1000
3
Q
What is any deviation from or interruption of the normal structure or function of a part, organ, or system of the body as manifested by characteristic symptoms and sign; the etiology pathology and prognosis may be knonw or unknown?
A
Disease
4
Q
What is a derangement or abnormality of function; a morbid physical or mental state / condition?
A
Disorder
5
Q
What is any new and abnormal growth; specifically a new growth of tissue in which the growth is uncontrolled and progressive?
A
Neoplasm
6
Q
What is a set of symptoms that occur together; a symptom complex; the sum of signs of any morbid state?
A
Syndrome
7
Q
Under what two situations can apoptosis occur? Give an example for each
A
Physiologic situations such as destruction during embryogenesis, withdrawl of hormons, cell loss, cells that are no longer useful
Pathologic Situations: DNA damage, accum of misfolded proteins, cell death by infection, duct obstruction
8
Q
What are anatomic defects that are present at birth but some such as cardiac defects and renal anomalies may not become clinically apparent until years later?
A
Congenital abnormalities
9
Q
Determine which age group the following causes of death (most common to least) fall under... Accidents Malignant neoplasms congenital malformations influenza / pneumonia
A
Age 5-9 yrs
10
Q
Determine which age group the following causes of death (most common to least) fall under... Accidents Congenital malformations Assault Malignant Neoplasms Disease of heart
A
Age 1-4
11
Q
Determine which age group the following causes of death (most common to least) fall under…
Congenital malformations
DOs related to short gestation and low birth weight
Sudden Infant death syndrome SIDS
—–Respiratory Distress of newborn
A
Younger than 1 year
12
Q
Determine which age group the following causes of death (most common to least) fall under... Accidents Malignant Neoplasms Suicide Assault Congenital malformations
A
Age 10-14 years
13
Q
What represents primary errors of morphogenesis in which there is an *intrinsically abnormal developmental process due to a single gene or chormosomal defect and are commonly multifactorial in origin?
A
Malformation
14
Q
What are some examples of malformations? 4
A
Polydactyly
Syndactyly
Congenital heart defects/anencephaly
Holoprosencephaly (penis nose)
15
Q
What is a result from secondary destruction of an organ or body region that was previously normal in development, thus arising from EXTERNAL disturbance in morphogenesis?
A
Disruption
16
Q
What is an example of disruption which denotes rupture of amnion with resultant formation of bands that encircle or attach to parts of the fetus? NOT heritable, NOT associated with increase risk in future pregs (unlike malformations)
A
Amniotic Bands
17
Q
What also represent an extrinsic disturbance of development rather than intrinsic, due to localized or generalized compression of the growing fetus by ABNORMAL biochemical forces, leading to structural abnormalities?
A
Deformations
18
Q
What is the most common cause of deformation?
between 35-38 weeks fetus is growing and uterus is not- can cause compression, due to maternal factors like first pregnancy, small uterus, leiomyomas, Fetal/placental factors like oligohydramnios, multiple fetuses.
A
Uterine constraint
19
Q
what is a cascade of anomalies triggered by one initiating abberation, half of the time due to congenital anomalies singly, the remaining d/t multiple congenital anomilies.
A
Sequence
20
Q
A good example of sequence caused by one initiating abberation is potter sequence. Explain the cause of the sequence and what it causes (5)…?
A
Renal agenesis/amniotic leak cause OLIGOhydramnios causes fetal compression resulting in..
- pulmonary hypoplasia
- Compressed/altered facies
- Clubfeet / abnormalities of hands
- Breech positioning
- Amnion Nodosum
21
Q
What is amnion nodosum and what can be assumed if it is seem upon autopsy?
A
They are nodules in the amnion due to oligohydramnios = potter sequence
22
Q
What is a constellation of congenital anomalies that cannot be explained on the basis of a single, localized, initiating defect?
A
Malformation syndrome
23
Q
What refers to the complete absence of an organ and its associated primordium?
A
Agenesis
24
Q
What closely related term to agenesis, referes to the absence of an organ, but one that occurs due to failure of growth of the existing primordium?
A
Aplasia
25
What describes the absence of an opening, usually of a hollow visceral organ such as the trachea or intestine?
Atresia
26
The common known causes of congenital anomolies can be grouped into 3 categories: genetic, environmental and multifactoral. What falls under each category?
genetic: chromosomal aberration 10-15% / mendalian 2-10%
environmental: Maternal infection 2-3%, maternal disease state 6-8%, teratogen 1%
multifactoral - 20-25%
***40-60 of abnormalities remain unknown
27
Thalidomide used in the past as a tranquilzer showed 50-80% fetus with limb abnormalities. Alcohol consumption is a teratogen which can lead to growth retardation, facial anomalies (microcephaly, short palpebral fissures, maxillary hypoplasia), and psychomotor disturbances, together known as?
Fetal alcohol syndrome
***No philtrum between lip and nose!
Low IQ
28
There are two general principles of developmental pathology which are releveant regardless of the etiologic agent. The first is?
The timing of the prenatal teratogenic insult has an important impact on the occurence and type of anomaly produced
29
The intrauterine development of humans is divided into two phases 1- embyonic period during first 9 weeks, 2- fetal period for remainder. In the early embryonic period (first 3 weeks after fert) injurious agents cause damage and death. Between the third and ninth weeks, what can occur?
the embryo is extremely susceptible to teratogenesis, with PEAK sensitivity occuring during 4th-5th week**!
30
After 9 weeks, during fetal period the child is not as susceptible to teratogenic agents but instead the fetus is susceptible to?
growth retardation/injury to alreadu formed organs
31
```
List during which weeks is the critical periods of development for the fetus...
CNS
Heart
Arms
Eyes
Legs
Teeth
Palate
External genetalia
Ears
```
```
CNS 3-6
Heart 3-6
Arms 4-7
Eyes 4-8
Legs 4-7
Teeth 6-8
Palate 6-9
External genetalia 7-9
Ears 4-9
```
32
The second general principle of developmental pathology: The interplay between environmental teratoens and intrinsic genetic defects is examplified by the fact that features of dysmorphogenesis caused by environmental insults can often be recapitulated by genetic defects in the pathways targeted by these teratogens. What are three general examples?
Cyclopamine
Valproic Acid
Retinoic acid (Vitamin A-retinol)
33
Valproic acid is an antiepileptic drugs that can lead to valproic acid embryopathy, which is due to a mutation where?
homeobox proteins (HOX)
34
A vitamin A derivative that is require for normal development and differentiation is retinoic acid. When there is excess it can lead to?
it is teratogenic and causes CNS, cardiac, cleft lipi/palata and limb abnormalities
35
What is defined by a gestational age less than 37 weeks, and is the second most common cause of neonatal mortality, behind congeital abnormalities?
Prematurity (premature infant is considered under 37months)
| *12% of all live births are premature
36
What are the 3 subcategories of preterm/ premature births which are base on gestational age?
extremely preterm less than 28weeks
Very preterm between 28 and 32 weeks
Moderate to late preterm 32 to 37 weeks
37
There are major risk factors for prematurity, including preterm premature rupture of placental membranes PPROM. PPROM is responsible for 1/3 of preterm deliveries. What is the major difference between PPROM and PROM?
PPROM occurs before 37 weeks with higher risk
| PROM occurs after 37 weeks and involves decreased risk
38
Another risk factor for prematurity is intrauterine infection which causes about 25% of preterm births. this is a major cause of?
preterm labor with and without itnact membranes
39
The third risk factor for prematurity is uterus/cervix/placental abnormalities which include uterine distortion, compromised structural cerivcal support, placenta previa, and abruptio placentae. What is the 4th risk factor that increases incidence of premature birth?
Having Multiple gestations (twin pregnancy)
40
Infants that are undergrown from where they should be for their gestational age (small for gestation age SGA) in which they are below 10th percentile for gestation age suffer from?
fetal growth restriction which may result from fetal, maternal or placental abnormalities
41
Some of the fetal causes of fetal growth restriction include chromosomal disease, congenital anomalies, congenital infections. Most common infections responsible for FGR are the TORCH group of infections which are?
ToxOplasmosis
Rubella
Cytomegalovirus
Herpesvirus
*will see proportional FGR meaning all organs are similarly effected
42
Some placental abnormalities can lead to fetal growth restriction such as uteroplacental insufficiency resulting from umbilical-placental vascular anomalies, placental abruptions, placenta previa, placental thrombosis, and placental infection--- causing what type of FGR?
Placental causes FGR to result in asymetic/ disproportionate growth retardation of the fetus, sparing the brain
43
Maternal abnormalities also can lead to FGR, most commonly conditions that result in decreased placental blood flow. This includes preeclampsia, hypertension. Also thrombphilias. What are 3 avoidable maternal factors?
smoking, alcohol intake, narcotic abuse
44
What are two major hazards/ diseases that comes along with prematurity?
neonatal respiratory distress syndrome (RDS)
| Necrotizing entercolitis
45
There are many causes of respiratory distress in the newborn the most common cause is _____ which is also known as _________ because of the deposition of a layer of hyaline proteinaceous material in the peripheral airspaces of infants who succumb to this condition.
RDS
=
hyaline membrane disease
46
In untreated infants (no surfactant) there is characteristic presentation; preterm with appropriate weight for age, resusitation at birth but normal breathing after few minutes, thne problems in 30 minutes leading to? 5
```
cyanosis
respiratory distress
fine rales
hypoxemia
*ground glass picture upon CXR
```
47
Immature lungs is what RDS develops from. The younger the gestation age (28weeks) the more likely of having RDS. The fundamental defect in RDS is a deficiency in?
pulmonary surfactant
48
Surfactant consists of two groups of surfactant associated proteins; defesnse and surfactant proteins. What are in each category?
Defense proteins: SP-A, SP-D
| Surfactant proteins: SP-B, SP-C, surfactant lipids (can measure these in amniocentesis*)
49
Surfactant decreases surface tension and allows alveoli to stay open with less pressure. Surfactant production is produced by _____ and is accelerated after the 35th week of gestation.
Type II pneumocytes (alveolar cells)
50
Without surfactant, the lungs collapse with each breath, working just as hard as they did for their first breath. What mutations cause congenital deficiency of surfactant?
SFTPB and SFTBC gene mutations
51
The lecithin-sphingomyelin L/S ratio can be measure in the amniotic fluid. If the ratio is greater than 2 it indicates the fetal lungs are mature. If it is lower than that it can lead to immature lungs, why do we care?
we can easily fix the lack of surfactant by providing glucocorticoids to the mother which can increase surfactant production (diabetic mothers have high insulin which counteracts steroids = dec. surfactant production)
52
Along with glucocorticoids, prolactin, thyroxine and what other agent modulates surfactant production?
TGFB
*Note: labor increases surfactant production so if the mother is planned C section make sure to give steroid before hand for adequate surfactant production
53
Upon gross examination of the lungs they are red purple, solid airless like the liver. Microscopically alveoli are poorly developed. When the infant passes necrotic material is incorporated with what?
eosinophilic hyaline membranes (fibrin+necrotic cells) lining the respiratory bronchioles, alveolar ducts and alveoli
54
In RDS after exogenous surfactant administration after birth, recovery begins in 3-4 days. OXygen is required, but high concentration for prolong times leads to what two complications?
Retrolental fibroplasia ROP-retinopathy of prematurity
Bronchopulmonary dysplasia
* not as frequent anymore
55
There are two phases of retrolental fibroplasia, 1 is during hyperoxia in which VEGF is decreased and the second phase is hypoxia when bb goes back to room O2, causing?
VEGF to increase, resulting in increased blood vessel formation
56
The major abnormality with bronchopulmonary dysplasia is striking decrease in alveolar septation (large alveoli), caused by reversible impairment in the development of alveolar septation. Possibly due to proinflammatory cytokines released by the dysplasia, including?
TNF, IL1, IL6, IL8 which arrest alveolar development
57
What is most common in premature infants with the incidence of disease increasing with very low birth weight infants (<1500gm)? 2500 cases occur annually...
Necrotizing enterocolitis NEC
58
NEC is multifactorial, along with prematurity ist is postulated that there is a postnatal insult such as bacteria, leading to tissue destruction. What mediatory has been implicated in increasing mucosal permeability by promoting enterocyte apoptosis and compromising intercellular tight junctions--- fuel to the fire?
Platelet activating factor PAF
59
The clinical course of NEC is fairly typical, with the onset of bloody stools, abdominal distention, and development of circulatory collapse. Radiographs demostrate gas within the intestinal wall known as?
pneumatosis intestinalis **Most common diagnostic sign**
| GOLF BALLS IN INTESTINE
60
Necrotizing enterocolitis typically involves the terminal ileum, cecum, and right colon although any part may be involved. The segment is distended, friable and congested- gangrenous with perforation and peritonitis. What is the treatment?
60% require resection of necrotic segments but post surgery delevop necrosis and strictures from fibrosis
61
Fetal and perinatal infections are acquired through one of two primary routes- transcervically (ascending) or?
transplacentally (hematologic)
62
Most parasitic and viral infections and a few bacterial infections gain access to the fetal bloodstream transplacentally via the?
chorionic villi
63
What are the two primary routes that perinatal infections are acquired?
parvovirus B19
| TORCH
64
Parvovirus 19 which causes erythema infectiosum or 'fifth disease of childhood' in immunocompetent older children, can infect 1-5% of seronegative pregnant women- most are normal. In the abnormal response to parvovirus 19 what is seen?
it can induce spontaneous abortion, stillbirth, hydrops fetalis and congenital anemia
65
What has a particular tropism for erythroid cells, and diagnostic viral inclusions can be seen in early erythroid progenitors in infected infants?
Parvovirus B19
66
What is another group of infections that leads to perinatal infection, which provoke fever, encephalitis, chorioretinitis, hepatosplenomegaly, pneumonitis, myocarditis, hemolytic anemia, and vesicular or hemorrhagic skin lesions?
TORCH (Toxoplasmosis, Other, Rubella, CMV, Herpes/HIV) - early in gestation
- can lead to mental retard, cataracts, cardiac anomalies and bone defects as well
67
What refers to accumulation of edema fluid in the fetus during intrauterine growth? Can be immune due to hemolytic anemia of the newborn (d/t Rh- in mom) or nonimmune which is more common now, with many causes.
Fetal hydrops
68
The intrauterine fluid accumulation can be variable, from progressive generalized edema of the fetus to more localized degrees of edema such as isolated pleural and peritoneal effusions or postnuchal fluid accum... what are examples for both?
generalized edema = hydrops fetalis
| localized like in postnuchal fluid accum = cystic hygroma
69
What is a hemolytic disease caused by blood group antigen incompatibility between mother and fetus? This reaction occurs in second and subsequent pregnancies in a Rh negative mom and Rh+ father.
Immune hydrops
70
The major antigens known to induce clinically significant immunologic reactions in immune hydrops is?
Rh antigens and th ABO blood groups
71
Initial exposure to to Rh antigen evokes the formation of IgM Abs that unlike IgG, dont cross placenta; so Rh disease is uncommon with the first pregnancy. Only which antigen is the major cause of Rh incompatibility?
D antigen
72
The incidence of maternal Rh isoimmunization has decreased significantly since the use of what immune globulin which contains anti-D antibodies?
Rhesus immune globulin (RhIg)
73
ABO incompatibility is slightly different from that cauased by differences in Rh antigens. which occurs in 20-25% of preganancies. Almost all cases happen in?
A or B fetuses and O mothers
| *lysis of infant RBC is minimal but there is not effective protection against ABO reactions
74
What are the two main consequences of excessive destruction of red blood cells in the neonates?
Anemia and Jaundice
75
Anemia is the direct result of red cell loss, more severe can result in hypoxic injury to heart and liver. Heart hypoxia leads to cardiac failure and liver hypoxia leads to drop in proteins which leads to what?
edema (reduced oncotic pressure cause reduced proteins) and anasarca (severe swelling) AS SEEN IN HYRDROPS FETALIS
76
Jaundice develops in patients with immune hydrops fetalis due to excessive RBC breakdown, which produced unconjugated bilirubin which builds up and can form what?
CNS damage and kernicterus (yellow discoloration most prominent along basal ganglia deep to ventricles)
77
What are the three majors causes of nonimmune hydrops?
cardiovascular defects, chromosomal anomalies and fetal anemia
78
In hydrops associated with fetal anemia, fetus and placenta are pale with enlarged liver and spleen. In the liver there is extramedullary hematopoiesis and in many other tissues. What is the reason for the increased hematopoeitic activity?
due to the large numbers of red cells with reticulocytes, normoblasts and erythroblast
===== Erythroblastosis fetalis (left shift in RBC)
79
Structural and functional CV problems can result in intrauterine cardiac failure and hydrops as well as chromosomal abnormalities like?
turner's syndrome, trisomy 18/21 d/t CV probs
80
Fetal anemia not due to Rh or ABO antibodies can also result in hydrops... such as alpha thalassemia deficiency seen in severe anemia**most common, transplacental parvo B19 infection, and?
twin twin transfusion all can cause nonimmune hydrops
81
Inborn errors of metabolism are rare disease that are Xlinked or autosomal recessive which give rise to?
metabolic disorders
82
What are three genetic disorders of metabolism, two of which have early diagnosis and another because it is the most common potentially lethal disease in caucausian decent?
Phenylketonuria
Galactosemia
Cystic Fibrosis
83
```
All of the following are what?
abnormal body odor
deafness
hydrops
coma
seizures
poor feeding
jaundice
cataract*
cherry red macula
glaucoma
myopathy*
abnormal mobility
albinism
```
Clinical abnormalities that suggest inborn errors of metabolism
84
Phenylketonuria (PKU) is most common among scandinavian descent. It is an autosomal recessive disorder caused by a deficiency of of what enzyme?
phenylalanine hydroxylase (PAH) and hyperphenylalaninemia
85
Infants with PKU are normal at birth and at 6 months are mentally retarded, who if left untreated are unable to walk, have seizures, eczema and what other thing?
decreased pigmentation of skin hair - no melanin becuase no tyrosine is converted from phenyalanine
*musty odor in urine
86
Maternal PKU is commonly passed onto their children, even though the mother may be asymptomatic- child may have mental retardation, microcephaly and congenital heart disease even if it is heterozygous. What is it imperative that mothers with PKU do during conception?
maternal phenylalanine intake is restricted prior to conception and during preganancy -- because Phenyalanine / its metabolites are teratogens at high levels
87
Some with greater thatn 6% functional phenyalalnine hydroxylase have milder disease known as benign hyperphenylalaninemia. Why is this important to know?
may have positive screening tests but do not develop stigma of PKU
88
What variant form of PKU occurs in 2% of people and cannot be trated by dietary restriction of phenyalanine?
mutation in cofactor tetrahydrobiopterin BH4
89
What is an autosomal recessive disorder of galactose metabolism resulting from accumulation of galactose-1-phosphate in tissues?
Galactosemia
*no mental retardation
90
There are two variants of galactosemia, the first is in galactokinase which is more rare and mild form, where galactose cannot become G-1-P. What is the most common form and more severe?
total lack of galactose-1-phosphate uridyl transferase (GALT)
91
GALT absence in galatosemia leads to accumulation of galactose -1-phosphate in liver spleen, *lens of eye*, kidneys, heart muscle, cerebral cortex and erythrocytes. An alternative pathway forms lead to the production of what two things which also are deposited in the mentioned tissues?
galactitol
| galactonate
92
The clinical picture of galatosemia is variable, but the eyes liver and brain get most of the damage. Hepatomegaly occurs early due to fatty change***and fibrosis, CNS changes including loss of nerve cells, gliosis and edem particularly in the dentate nuclei of the cerebellum and olivary nuclei of the medulla, and what other IMPORTANT finding?
Opacification of the lens (CATARACTS) due to osmoticall active galactitol accumulation
93
Galactosemia children fail to thrive, vomiting and diarrhea appear after milk digestion, jaundice and hepatomegaly within first week, cataracts after a few weeks and within first 6-12 months what occurs?
mental retardation-not as severe as PKU
94
Accumulation of galactose and galactose-1-phosphate in the kidney leads to aminoaciduria, an increase in escherichia coli septicemia. hemolysis and coagulopathy in newborn period as well... How is this treated?
can be prevented or ameliorated by early removal of galactose in the first 2 years of life - might show later in life problems like speech disorder and gonadal failure
95
Cystic fibrosis (mucoviscidosis) is the most common lethal genetic disease that affects caucasian populations, with an incidence rate of?
1 in 2500 (with a carrier rate of 1 in 20)
96
CF is a inherited DO of ion transport that affects fluid secretions in exocrine glands and in epithelial lining of the respiratory, GI, and reproductive glands. Abnormal viscous secretions obstruct organ passages resulting in what clinical features? 7
```
Chronic lung disease from recurring lung infections
pancreatic insufficiency
steatorrhea
malnutrition
hepatic cirrhosis
intestinal obstruction
male infertility
```
97
The primary defect in CF results from abnormal function of an epithelial chloride channel protein encoded by what gene on which chromosome?
cystic fibrosis transmembrane conductance regulator (CFTR) gene on 7q31.2
98
the interaction of CFTR and the ENaC channel, on the apical surface of exocrine epithelial cells- responsible for sodium uptake from the luminal fluid (making hypotonic fluid)- has possible the most?
pathophysiologic relevance in cystic fibrosis
99
ENaC is usually inhibited by CFTR, but in CF, ENaC activity increases, markedly augmenting sodium uptake across the apical membrane. What is the one exception to the ENaC rule?
in the sweat ducts, ENaC activity decreases, causing increase Na in the sweat (cause increase ENaC causes Na reabsorption)
100
In respiratory and intestinal epithelium, CFTR is important player for active luminal secretion of Cl, mutations of CFTR lead to loss of chloride secretion into the lumen, lumen Na absorption increases resulting in?
increase passive water reabsorption from lumen, lowering the water content of the surface fluid layer coating muscosal cells
101
The pathogenesis of respiratory and instestinal complications in cystic fibrosis seems to stem from an isotonic but low volume surface fluid layer, leading to what in the lungs?
dehydrated mucociliary action and accumulation of hyperconcentrated viscid secretions that obstruct air passages = inc. pulmonary ***infections
102
What does the most common mutation in the CFTR gene result in?
defective protein folding in the golgi/ER and degredation of CFTR before it reaches the cell surface
103
CFTR regulates transport of bicarbonate ions with SCL26. In SOME CFTR mutants, Cl is okay but bicarb regulation is bad, leading to acidic fluids when they should be alkaline. This decreases luminal pH, which can lead to what common feature seen in classic CF?
Pancreatic insuffieciency- is virtually always present when there are CFTR mutations with abnormal bicarbonate conductance
104
Environmental mutations and genetic mutations can both modify frequency and severity of organ manifestations in CF. Examples of some modifier genes include interferon related developmental regulator 1 IFRD1, transforming growth factor b TGFB1 and?
mannose binding lectin 2 (MBL2)
*presence increase chance of exogenous infections
105
In all variants of CF, sweat glands are morphologically unaffected. Pancreatic abnormalities occur in 85-90%. In more severe cases the ducts are completely locked cuasing atrophy of exocrine glands and fibrosis. This loss of pancreatic exocrine secretion does what?
impairs fat absorption and the associated vitamin A deficiency contributes to squamous metaplasia of the lining of pancreatic epithelia
**note all fat soluble vitamins may be deficient
106
Sometimes in CF viscid plugs of mucus may be found in the small intestines causing small bowel obstructions leading to?
meconium ileus
107
Hepatic steatosis is not uncommon with CF< overtime focal biliary cirrhosis develops, which in 10% of patients leads to?
diffuse hepatic nodularity
108
The pulmonary changes of CF are the most serious complications- causing secondary obstruction and infection of the air passageways; bronchioles are distented or dilated with superimposed?
infections giving rise to chronic bronchitis and bronchiectasis
109
What are the three most common organisms responsible for lung infections?
staphylococcus aureus
haemophilus influenzae
pseudomonas aeruginosa - frequent and causes chronic inflammation
110
Becoming increasingly more common, what pseudomonads, which has 9 different species, are the most common in CF patients?
Burkholderia cepacia complex OR
**B. Cenocepacia
111
In 95% of males, azoospermia and infertility is common, with congenital absence of what?
bilaterally have no vas deferens
112
5-10% of clinical cases of CF occur at or soon after birth due to meconium ileus. Exocrine pancreatic insufficiency is determined severe or mild based on what?
severe CFTR mutations on both alleles F508x2
severe/mild mutation
mild/mild mutation which can lead to no pancreatic problems
113
Cardiorespiratory complications like lung infection, obstructive pulm dz, and cor pulmonale are MCC of death. If you have mild CFTR there is no lung involvement. Severe CFTR by age 18 80% have infeection with pseudomonas. What occurs in 10-25% of people with CF?
recurrent nasal polyps
| liver dz around puberty
114
Diagnosis of CF includes one or more characteristic phenotypic features or a history of CF in family or a positive newborn screening test result AND ?
increased sweat chloride concentration on 2+ checks
or identification of two cystic fibrosis mutations
or demonstration of abnormal epithelial nasal ion transport
115
What is defined as sudden death of an infant under 1 year of age which remains unexplained* after a thorough case investigation including performance of a complete autopsy, examination of death scene and review of clinical history?
SIDS - sudden infant death syndrome
(crib death)
**diagnosis of exclusion
116
SIDS is the leading cause of death between 1mo and 1 year in the US. Mostly between 2-4 months die how?
at night at home after a period of sleep
117
Infants who die of SIDS have a variety of findings that are not present in all cases. The most common finding in 80% of cases are what? Which are usually present on the thymus, visceral and parietal pleura and epicardium...
Petechiae
118
The lungs of SIDS are typically congested with microscopic vascular engorgement and pulmonary edema. The importance of postmortem examination rests in identifying other causes of SUID such as congenital anomaly, genetic disorder and unsuspected infection- any of which would exclude?
SIDS and rule out the unfortunate possibility of traumatic child abuse
119
SIDS is a multifactorial condition, a triple risk model of SIDS has been proposed which postulates the intersection of three overlapping factors including 1 vulnerable infant, 2 critical developmental period in homeostatic control 3...?
exogenous stressor
120
The most compelling hypothesis for vulnerable infant is that SIDS reflects a delayed development of ?
arousal and cardiorespiratory control
*problems in serotonin system of medulla oblongata*
121
Infants born preterm and under weight are at increased risk, including being male sex. SIDS of previous child has 5fold increase of reoccurence and WHAT must be ruled out?
traumatic child abuse must be excluded
122
Most SIDS babies have had hx of respiratory tract infection. What is the missing link between Upper respiratory infections, the prone position and SIDS?
laryngeal chemoreceptors- inhibits cardiorespiratory reflex
* these are augmented by infections and prone position which increase volume secretion and impairs swalling/clearance of airways = death
123
Maternal smoking during pregnancy increases SIDS risk, along with young maternal age, frequent childbirths and ?
inadequate prenatal care
*COKE
124
What position of sleeping is the ONLY safe way to sleep?
SUPINE sleeping
125
SIDS is far from the only cause of sudden unexplained infant death SUID. Wht are the most common cause of sudden unexplained deaths?
infections like viral myocarditis or bronchopneumonia, followed by congenital abnormaliteis
(*5 SUIDs are via fatty acid oxidation DOs)
126
Benign tumors are more common than cancers. Most benign tumors are of little concner but on occasion they cause serious complications d/t location or rapid growth. What are the two tumor-like categories?
heterotopia (choristoma)
| Hamartoma
127
What term is used for normal cells or tissues that are present in abnormal locations? Ex: pancreatic tissue found in the wall of stomach or adrenal in kidney.
Heterotopia (choristoma) - no clincal significance
128
What term refers to an excessive, focal overgrowth of cells and tissues native to the organ in which it occurs? Examples are hemangiomas, cysts in kidneys/ovaries, etc.
Hamartoma
129
The most common neoplasms of of childhood are soft-tissue tumors of mesenchymal derivation. This contrasts in adults in which the most common tumors come from?
epithelial origin
130
What is the most common tumor of infancy which present as cavernous and capillary, with capillary being more cellular in adults?
hemangioma
131
Hemangiomas in children are located on the skin-face and scalp, larger lesions called portwine stains. They regress by themselves and sometimes can represent what?
hereditary DO- Hippel-Lindau disease
132
Lymphatic tumors such as _______ are hamartomatous or neoplastic, whereas others seem to represent abnormal dilations of preexisiting lymph channels known as?
lymphangiomas
Lymphangiectasis
133
What are characterized by cystic and cavernous spaces, occuring in neck, axilla, mediastinum, increase in size after birth possibly enroaching on other structures?
lymphangiomas
134
What present as diffuse swelling of an extremity, with deformation occuring as spongy, dilated subcutaneous and deeper lymphatics, not progressive / does not extend past original location?
lymphangiectasis
135
What tumors occur in infants and children ranging from sparesly cellular proliferation of spindle shaped cells (fibromatosis) to richly cellular lesions indistinguisable from fibrosarcomas occur in adults (congeital infantile fibrosarcomas)?
fibrous tumors
136
A characteristic chromosomal translocation t(12;15)(p13;q25) has been described in congenital infantile fibrosarcomas which results in generation of a what?
ETV6-NTRK3 fusion transcript = diagnostic marker**
137
Teratomas have 2 peaks in incidence: the first is at 2 years of age and the second in late adolesence or early adulthood. What are the most common teratoma of childhood accounting for 40% + cases occuring in 1 in every 20-40k births?
sacrococcygeal teratoma
138
If there is more mature teratomas there is less likely for malignancy, malignant potential correlates positively with?
and increase in the amount of immature tissue
139
What are the four most common neoplasms that exhibit sharp peaks in incidence in children younger than 4 years old?
Leukemia
retinoblastoma
neuroblastoma
Wilms Tumor (nephroblastoma)
140
Histologically, many of the malignant non-hematopoietic pediatric neoplasms are unique. In general, they tend to have more primitive embryonal undifferentiated appearance, and are characterized by sheets of cells, with small round nuclei, and frequently show features of organogenesis specific to the site of tumor origin. What are these tumors designated by and why?
Designated by -blastoma because of the apparent identification of the tissue origin
141
CHildhood tumors are referred to as small round blue cell tumors. These include wilms tumor, neuroblastoma and more. If the anatomic site of origin is known, diagnosis is usually possible on?
histologic grounds ALONE
142
Sometimes for a diagnosis one needs chromosome analysis, immunoperoxidase stains or EM. What are the most important tumors in this chapter?
neuroblastoma
| wilms tumor
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What term includes tumors of the sympathetic ganglia and adrenal medulla that are derived from primordial neural crest cells populating these sites?
Neuroblastic tumor
144
Neuroblastic tumors demonstrate features including spontaneous and therapy-induced differentiation of primitive neuroblasts into mature elements, spontaneous tumor regression and a ?
wide range of clinical behavior and prognosis
** neuroblastoma is most important of neuroblastic tumor family
145
What is the most common extracranial solid tumor of childhood and the most frequently diagnosed tumor of infancy?
neuroblastoma
146
Neuroblastoma occur 1 in 7000 births, 700 a year in the US. diagnosis is made around 18mos, most are sporadic, 1% familial- in which these cases there are?
neoplasms of the adrenals or multiple primary autonomic sites
147
What has been identified as a major cause of familial predispostion to neuroblastoma?
germline mutations in the anaplastic lymphoma kinase ALK gene
148
Neuroblastoma longterm prognosis is 5 year survival rate of 40%, with children younger than 18mos having a better?
prognosis than children diagnosed older than 18mos
149
The most frequent childhood cancers are in the hematopoietic system, nervous tissue, soft tissue, bone and kidney while in adults the most common sites are? 5
```
skin
lung
breast
prostate
colon
```
150
40% neuroblastomas occur in the adrenal medulla, the rest occur along the sympathetic chain (paravertebral region and posterior mediastinum). Size rangles from in situ lesions to large masses. in situ lesions occur 40x more than tumors and what usually happens?
regress leaving a fibrous scar
151
The background of histology of neuroblastoma demonstrates a faintly eosinophilic fibrillary material (NEUROPIL) that corresponds to neuritic processes of primitive neuroblasts. What can typically be found in which the tumor cells are concetrically arranged about a central space filled w neuropil?
Rosettes or HOMER-WRIGHT psuedorosettes
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Stage 1: complete gross excision with no mets to LN
Stage 2A: incomplete gross excision with no mets to LN
Stage 2B: incomplete gross excision with met to LN
Stage 3: unresectable w LN involved
Stage 4: tumor w dissemination to LN, bone marrow, liver skin and other organs
Stage 4S: ?
(staging for neuroblastomas)
Stage 4S: special, localized primary tumor w dissemination limited to skin, liver and/or bone marrow - infants younger than 1 year old
153
60-80% of kids present with stage 3/4 and only 20-40% present with stage 1,2A/B, or 4. What is paramount important for determining prognosis?
the staging system- international neuroblastoma staging system INSS
154
In childen under 2, neuroblastomas present with large abdominal masses, fever and weight loss. In older children they may not come to attention until metastasis occurs including?
bone pain, respiratory symptoms or GI issues, ***periorbital region is common metastatic site (also in blood/lymph)
155
Infants with multiple cutaneous metastasis cause deep blue discoloration of the skin, earning what name?
blueberry muffin boy
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90% of neuroblastomas regardless of location produce catecholamines which are important diagnostic features of the tumor. Elevated levels of catecholamines in the blood and elevated levels of what metabolites in urine is diagnostic?
elevated urine levels of vanillylmandelic acid VMA and homovanillic acid (HVA) **
** these are degredation products of catecholamines
157
Age and stage are most important determinations of outcome for neuroblastomas, if the stage is 1, 2A, 2B, or even 4S and age under what?
18 months (1&2 stages irregardless of age)
158
Morphology is an independent prognostic variable in neuroblastomas. The mitosis-karyorrhexis index is favorable when <200/5000 cells and unfavorable when >200/5000 cells. Eveidence of what morphology favors prognosis?
evidence of schwannian stroma and gangliocytic differentiation
159
What in neuroblastomas is a molecular event that has possible the most profound impact on prognosis, particullary when it occurs in tumors that would otherwise portend a good outcome?
MYCN oncogene amplification
160
The presence of MYCN makes the tumor high risk. It is located on chromosome 2. It is present in 20-30% of primary tumors-- Kaplan-Meier plot shows what?
significantly decreased 3 year survival from time of diagnosis in those patients with the MYCN amplification (90% without vs. 10% with MYCN).
161
What of the tumor cells correlates with outcome in children less than 2 years of age but loses its independent prognostic significance in older children?
Ploidy
162
The two categories of ploidy in neuroblastomas are near-diploid and hyper-diploid. Which is worse?
Near diploid tumors are genomically instable with multiple chromosomal abberations- decreasing prognosis
Hyperploidy are relatively banal karyotype with better prognosis
163
One form of segmental chromosomal abberation associated with near diploid tumors is ________, which involves localized fragmentation of a chromosome segment followed by random assembly of the fragments. (which can amplify MYCN and other oncogenes)
chromothripsis
164
FISH uses DNA probes that recognize sequences specific to particular chromosomal regions. This process can be used to detect what on chromosomes?
extrachromosomal double minute chromosomes or homogeneously staining regions on other chromosome like MYCN amplifications!
165
What afflicts approximately 1 in 10,000 children in the US, making it the most common primary renal tumor of childhood and the fourth most common pediatric malignancy in the US?
Wilms tumor
166
Peak incidence for wilms tumor is between 2 and 5 years. About 5-10% of wilms tumors involve both kidneys, either synchronous or metachronous. What is the difference
Wilms tumor can affect both kidneys:
1. at the same time = synchronous
2. one is affected before the other = metachronous
167
Most children with wilms tumors present with ______ that may be unilateral or when very large, may extend across the midline and down into the pelvis.
large abdominal mass
168
Hematuria, pain in the abdomen after traumatic incident, intestinal obstruction, and hypertension are other common presentations. In a considerable amount of these patients presenting, what is seen?
pulmonary metastases
169
Most with wilms are cured, what histology remains a critical determinant of adverse prognosis?
anaplastic histology
170
There have been increased risk of forming bone and soft tissue sarcomas with wilms tumors, as well as leukemia and what other two things?
breast cancer
lymphomas
*mostly due to radiation to cancer field
171
Grossly, wilms tumors present as large solitary, well circumscribed mass. On cut section tumor is soft homogenous, tan/gray with hemorrhage, cysts and necrosis. Wilms is characterized by attempts to recapitualte stages of nephrogenesis. The classic triphasic combination of stages of neprhogenesis is?
is of blastemal (small blue cells), stromal, and epithelial (tubules) cell types
172
In 5% of wilms tumors, anaplasia is seen which is the presence of large hyperchromatic, pleomorphic nuclei and?
abnormal mitoses, which correlates with the presence of TP53 mutations (which are resistant to chemotherapy)
173
Risk of wilms tumor is increased with 3 recognizable groups of congenital malformations associated with DISTINCT chromosomal loci, what are they?
WAGR / WAGI syndrome
Denys-Drash syndrome
Beckwith-Wiedeman syndrome
174
WAGR syndrome is characterized by Wilms tumor (33%), Aniridia, Gential anomalies, mental Retardation. What gene and choromsome deletions cause this?
deletions 11p13
wilms tumor associated gene WT1
PAX6 (provides instructions for making a protein that is involved in the early development of the eyes, brain, spinal cord and pancreas)
175
Aniridia = no iris, if a patient has WT1 gene but no PAX6 then will see aniridia, What happens after the first hit of WT1 gene ?
usually a second hit occurs as a frameshift/nonsense mutation in the second allele
176
Denys-Drash syndrome has a 90% risk for Wilms. It is characterized by gonadal dysgensis and early onsey nephropathy leading to renal failure. How does wilms occur?
there is a dominant negative missense mutation in WT1,,, also increase risk of gonadoblastoma d/t disruption of gonadal development
177
Beckwith-Wiedemann syndrome is characterized by enlargement of body organs; macroglossia, hemihypertrophy, omphalocele, adrenal cytomegaly. This syndrome is an example of nonclassic tumorigenesis because?
it is caused by genomic imprinting on WT2 (11p15.5)
**causes overgrowth cause leads to overexpression of IGF-2
178
Some ppl with beckwith-wiedmann syndrome have CDKN1C mutation- a cell cycle regulator (p57) that broadly inhibits multiple CDKs, causing an increased risk of hepatoblastoma, rhabdomyosarcoma, adrenal cortical tumors and?
pancreatoblastoma
179
What are putative precursor lesions of Wilms tumors and are seen in th renal parenchyma adjacent to 25-40% of unilateral tumors and 100% in bilateral tumors?
Nephrogenic Rests
180
Why is it important to document nephrogenic rests associated with Wilms tumors?
because these patients are at an increased risk of developing Wilms tumors in the contralateral kidney and require frequent surveillance
