Ch. 10 - Diseases of Infancy and Childhood Flashcards
1
Q
what kills children globally?
A
#1 = malnutrition #2 = infections (pneumonia, diarrhea, malaria)
2
Q
perinate
A
around time of birth
3
Q
neonatal period
A
first four weeks of life
4
Q
infancy
A
first year of life (death during this period is most often due to SIDS, congenital anomalies and prematurity)
5
Q
congenital anomalies
A
morphologic defects that are present at birth, but may not become clinically apparent until years later. term means “born with” – but does not imply or exclude a genetic basis for birth defect
• most common cause of mortality in the first year
6
Q
malformations
A
: represent primary errors of morphogenesis, in which there is an intrinsically abnormal developmental process
• usually associated with multiple genetic loci (multifactorial) and not eh result of a single gene or chromosomal defect
• i.e. congenital heart defects, anencephaly (absence of brain)
7
Q
dirsuptions
A
result from secondary destruction of an organ or body region that was previously normal in development; disruptions arise from extrinsic disturbance in morphogenesis
• amniotic bands
• these are NOT heritable
8
Q
deformations
A
like disruptions, also represent an extrinsic disturbance of development rather than an intrinsic error of morphogenesis. They are due to localized or generalized compression of the growing fetus by abnormal biomechanical forces, leading eventually to a variety of structural abnormalities
• ex. uterine constraint – most common cause of deformations – in 35th-38th week
• could be due to maternal factors (i.e. small or deformed uterus), fetal or placental factors (oligohydramnios, multiple fetuses)
• ex. club feet seen in Potter sequence
9
Q
Potter’s sequence
A
problems with kidneys/amniotic leak –> oligohydramnios –> fetal compression –> pulmonary hypoplasia, flat face, positioning defects of hands and feet, breech presentations
10
Q
sequence?
A
a cascade of anomalies triggered by one initiating aberration
• ex. oligohydramnios (or Potter) sequence
• Causes of oligohydramnios: amniotic rupture, uteroplacental insufficiency from maternal HTN or toxemia, renal agenesis in fetus
• nodules in the amnion are frequently present: amnion nodosum
11
Q
amnion nodosum
A
nodules on the fetal surface of the amnion, and is frequently present in oligohydramnios.
12
Q
syndrome
A
a constellation of congenital anomalies, believed to be pathological. In contrast to a sequence, it cannot be explained on the basis of a single, localized initiating defect
• most often caused by single etiologic agent, such as viral infection or chromosomal abnormality that affects multiple tissues
13
Q
agenesis
A
complete absence of an organ – and its associated primordium (primordium = organ/tissue in its earliest recognizable stage of development)
14
Q
aplasia
A
- imcomplete/defective development, no organ development
- only most rudimentary organ present due to failure of development of the primordium
15
Q
atresia
A
: the absence of an opening – usually a hollow visceral organ – such as trachea or intestine
16
Q
hypoplasia
A
incomplete development/decreased size of an organ with decreased numbers of cells
17
Q
hyperplasia
A
enlargement of an organ due to increased number of cells
18
Q
hypertrophy/hypotrophy
A
increase or decrease in size (rather than number of cells in an organ)
19
Q
dysplasia
A
an abnormal organization of cells (in the context of malformations) – not neoplasia
20
Q
causes of death in children under 1 year?
A
- congenital malformations
- disorders related to short gestation
- SIDS
21
Q
causes of death of children ages 1-4?
A
- accidents
- congenital malformations
- malignant neoplasms
22
Q
causes of death children ages 5-14?
A
- accidents
- malignant neoplasms
- homicide
23
Q
cause of death children ages 15-24?
A
- accidents
- homicide
- suicide
24
Q
most comon birth defects?
A
Trisomy 21 (Down syndrome) and cleft palate/cleft lip
25
if pinna of ear is deformed?
look for other morphologic abnormalities, because these are being formed from weeks 4-10
26
holoprosencephaly
most common defect of forebrain and midface – due to loss of function in Hedgehog signaling pathways
- a cephalic disorder in which the prosencephalon (the forebrain of the embryo) fails to develop into two hemispheres.
27
achondroplasia
most common form of short-limb dwarfism –
caused by gain of function mutations in FGFR3 – which is a negative regulator of bone growth –
activating this mutation exaggerates the physiologic inhibition.
28
Rubella virus
o at risk period: shortly after conception → 16 weeks gestation
o “Rubella syndrome”: cataracts, heart defects, deafness and mental retardation [heart defects include- persistent ductus arteriosus, pulmonary aa. hypoplasia/stenosis, ventricular septal defect, tetralogy of Fallot]
29
cytomegalovirus
o most common fetal viral infection
o at risk period: second trimester
o because organogenesis is completed at end of first trimester, congenital malformations are more rare
o virus induced injury on formed organs is severe
o see damage to CNS: mental retardation, microcephaly, deafness, hepatosplenomegally
30
trimesters
```
First trimester (week 1-week 12)
Second trimester (week 13-week 28)
Third trimester (week 29-week 40)
```
31
thalidomide
chemical that causes limb abnormalities due to downregulation of wingless (WNT) signaling pathway through upregulation of endogenous WNT repressors.
- was used against nausea and to alleviate morning sickness in pregnant women.
- infants were born with malformation of the limbs (phocomelia)
32
alcohol during pregnancy?
see sublet cognitive and behavioral defects in fetus called fetal alcohol spectrum disorders (FASDs) – causes growth retardation, microcephaly, atrial septal defect, short palpebral fissures and maxillary hypoplasia (“fetal alcohol syndrome”)
33
radiation during pregnancy?
o exposure to heavy doses during organogenesis causes malformations like microcephaly, blindness, skull defects, spina bifida
34
diabeticembryopathy
: maternal hyperglycemia-induced fetal hyperinsulinemia results in increased body fat, mm mass, and organomegaly (fetal macrosomia); cardiac anomalies, neural tube defects and CNS malformations
35
fetal macrosomia
organomegaly - seen with maternal diabetes
36
multifactorial inheritence
(interaction between two or more genes of small effect, with environmental factors)
• arise as a result of inheritance of multiple genetic polymorphisms that confer a “susceptibility phenotype”
• ex. congenital dislocation of the hip – shallow acetabular socket and laxity of supporting ligaments are genetically determined, where as breech position is environmental factor
37
embryonic period
(first 9 weeks of pregnancy)
• Early embryonic period (first three weeks): injurious agent damages cells causing abortion or allowing ebryo to recover without developing defects
• Between 3rd and 9th weeks – the embryo is extremely susceptible to teratogenesis: the peak sensitivity is b/w fourth and fifth weeks – during this period organs are being crafted out of germ cell layers
38
fetal period
(week 10- birth): follows organogenesis – is marked by further growth and maturation of the organs, with reduced susceptibility to teratogenic agents
• fetus is susceptible to growth retardation or injury in already formed organs
39
cyclopamine
teratogen from CA lily – pregnant ewes that eat it produce lambs with craniofacial abnormalities and holoprosencephaly and “cyclopia” – due to inhibitor of Hedgehog signaling
40
valproic acid
anti-epileptic that disrupts expression of homeobox proteins (HOX) genes – these are necessary for patterning of limbs, vertebrae and craniofacial structures. Mutations in HOX family genes are responsible for congenital anomalies that mimc valproic acid embryopathy
41
abscence of retinol
Vitamin A (retinol) is essential for normal dev. and differentiation – absence causes malformations in eyes, GI system, CV system, diaphragm and lungs.
42
xs retinol
But excess causes retinoic acid embryopathy: includes CNS, cardiac and craniofacial defects such as cleft lip/palate. May be due to dysregulation of TGF-beta pathway
43
AGA/SGA/LGA
preterm
posterm
```
AGA = appropriate for gestational age
SGA = small for gestational age- associated with FGR
LGA = large for gestational age - assoc. w/ maternal diabetes
preterm = infants born before 37 weeks
post-term = infants born after 42 week
```
44
prematurity
= less than 37 weeks; it is the second most common cause of neonatal mortality, behind congenital anomalies
45
PPROM
preterm premature rupture of placental membranes
• clinical risk factors: prior history of preterm delivery, vaginal bleeding, maternal smoking, low socioeconomic status, poor maternal nutrition
• Polymorphisms in TNF (immune regulation) and Matrix metalloproteinases 1,8,9 (collage breakdown) have been associated with PPROM
• pathophys. of PPROM includes inflammation of placental membranes and enhanced collagen degradation by MMPs
46
PROM
spontaneous ROM occurring after 37 weeks gestation – associated risk to fetus is greatly reduced
47
PPROM and intrauterine infections
: major cause of preterm labor without intact membranes
• inflammation of the placental membranes (chorioamnionitis) and inflammation of the fetal umbilical cord (funisitis) result from intrauterine infection
• Most common organisms: Ureaplasma urealyticum, Mycoplasma hominis, Gardnerella vaginalisis, Trichomonas, gonorrhea, and Chlamydia
• Infection results in TLR activation by bacterial lipopolysaccharide resulting in inflammation-induced preterm labor. Furthermore signals produced by some TLRs (i.e. TLR4) deregulte prostaglandin expression, which in turn induces uterine smooth mm. contraction
48
chorioamnionitis
inflamm. of placental membranes
49
funisitis
inflamm. of fetal umbilical cord
50
three reasons for PPROM?
intrauterine infections
uterine,cervical and placental abnormalities
multiple gestation
51
hazards of prematurity
* Hyaline membrane disease (neonatal RDS)
* necrotizing enterocolitis
* sepsis
* intraventricular hemorrhage
* mental development delay
52
FGR
Fetal growth restriction (FGR) commonly underlies SGA – results in intrauterine growth retardation: three causes
1. Fetal influences: chromosomal disorders, congenital anomalies, congenital infections (TORCH organisms, commonly responsible for FGR – toxoplasmosis, rubella, cytomegalovirus, herpesvirus)
2. Placental Influences:
• uteroplacental insufficiency: may result from umbilical placental vascular anomalies, placental abruption, placenta previa (insertion in the cervix), placental thrombosis/infarction/infection or multiple gestations
• placental causes of FGR tend to result in asymmetric growth retardation with relative sparing of the brain
• Confined placental mosaicism: genetic mosaicism confined to the placenta is a cause of FGR – if the mutation occurs later and within dividing trophoblast or extraembryonic progenitor cells in the ICM
3. Maternal influences:
• decreased placental blood flow
• vascular diseases, i.e. preeclampsia (toxemia of pregnancy = high blood pressure of pregnancy) and chronic HTN, inherited thrombophilias (ex. Factor V Leiden mutation)
• narcotic abuse, alcohol intake, heavy cigarette smoking, maternal malnutrition (prolonged hypoglycemia)
53
TORCH
(TORCH organisms, commonly responsible for FGR – toxoplasmosis, rubella, cytomegalovirus, herpesvirus)
54
preeclampsia
• vascular diseases, i.e. preeclampsia (toxemia of pregnancy = high blood pressure of pregnancy) = maternal influence of FGR
55
hyaline membrane disease
RDS = • called hyaline membrane disease because of the deposition of a layer of hyaline proteinacecous material in the peripheral airspaces of infants who succumb to this condition
Waxy-appearing layers of hyaline membrane line the collapsed alveoli of the lung.
56
RDS associations?
• presents in preterm and AGA: strong associations with male gender, maternal diabetes, C-sections
57
general presenation of RDS?
• Within a few minutes they have rhythmic breathing, within 30 minutes breathing becomes more difficult, within a few hours cyanosis becomes evident
IRDS begins shortly after birth and is manifest by tachypnea, tachycardia, chest wall retractions (recession), expiratory grunting, nasal flaring and cyanosis during breathing efforts.
* fine rales are heard over both lung fields
* CXR shows uniform densities called “ground-glass picture”
58
dx of IRDS?
The diagnosis is made by the clinical picture and the chest xray, which demonstrates decreased lung volumes (bell-shaped chest), absence of the thymus (after about 6 hours), a small (0.5–1 mm), discrete, uniform infiltrate (sometimes described as a "ground glass" appearance or as of recently described as "diffuse airspace and interstitial opacities") that involves all lobes of the lung, and air-bronchograms
59
Etiology of IRDS?
* Results from lungs being immature
* incidence is inversely proportionate to gestational age
* Fundamental defect is due to deficiency of pulmonary surfactant → increased surface tension in the alveoli → more pressure required to keep the alveoli patent and aerated → deficiency causes lungs to collapse with each successive breath so infants must work hard with each successive breath → “stiff atelectactic lungs”
60
mutations of surfactant genes?
• surfactant mutations in : SFTPB or SFTBC genes
61
when is surfactant produced? what hormones?
• surfactant production by type II alveolar cells is accelerated after the 35th week of gestation in fetus – thus premature babies are at greater risk
• hormones modulating synthesis: Cortisol, Insulin, prolactin, thyroxine, TGF-B. Role of glucocorticoids is important
o increased uterine stresss → increased corticosteroid release → lower risk of developing RDS
o labor is also known to increase surfactant synth
62
morphology of IRDS?
• Lungs are solid, airless, reddish purple and sink in water
• microscopically alveoli are poorly developed and are collapsed
• necrotic cellular debris can be seen in the terminal bronchioles and alveolar ducts, it becomes incorporated into the membranes which are largely made of fibrin → causing formation of hyaline membrane
• see neutrophilic inflamm. rxn with these membranes
Note: Atelectasis = collapsed lung
63
clinical course of IRDS?
* Clinical tx has improved with use of exogenous surfactant
* analysis of amniotic fluid phospholipids provides a good estimate of level of surfactant in the alveolar lining
* surfactant has been shown to help infants as young as 26-28 weeks
* antenatal corticosteroids decrease neonatal morbidity and mortality when administered to mothers with premature delivery at 24-34 weeks
64
oxygen toxicity
a hazard of therapy caused by O2 freee radicals – high concentrations of O2 administration for prolonged periods cause two well known complications:
o retrolental fibroplasia aka “retinopathy of prematurity” in the eyes
o bronchopulmonary dysplasia (BPD):
65
retinopathy of prematurity
o retrolental fibroplasia aka “retinopathy of prematurity” in the eyes
• retinopathy is due to sharp decrease in VEGF, which serves as a survival factor for endothelial cells and promotes angiogenesis
• during hyperpoxic phase of RDS, VEGF is decreased, causing endothelial cell apoptosis
66
BPD
o bronchopulmonary dysplasia (BPD):
• need at least 28 days of O2 therapy in an infant who is beyond 36 weeks to be called BPD
• BPD is airway epithelial hyperplasia and squamous metaplasia, alveolar wall thickening, and peribronchial as well as interstitial fibrosis
• see decrease in alveolar septation (large simplified alveolar structures) and a dysmorphic capillary configuration
• caused by the reversible impairement in the development of alveolar septation in the saccular stage
• Contributing factors: hyperoxemia, hyperventilation, prematurity, inflamm cytokines (TNF, IL-1B, IL6, IL8), vascular maldevelopment
• infants who succumb to BPD have dysmorphic capillaries and reduced levels of VEGF
• infants who recover are at risk of developing patent ductus arteriosus, intraventricular hemorrhage, necrotizing enterocolitis
67
NEC
* NEC is most common in premature infants – occurs in 1 out of 10 low birth weight infants
* **breakdown of mucosal barrier allows transluminal migration of gut bacteria → inflammation → mucosal necrosis → increased bacterial entry → culminates in sepsis and shock
* Clinical Features: bloody stools, abdominal distention, development of circulatory collapse.
* Pneumatosis intestinalis: abdominal radiographs show gas within the intestinal wall
* NEC typically involves the terminal ileum, cecum and right colon
* infected segment is distended, friable, congested and gangrenous
* see mucosal coagulative necrosis, ulceration, bacterial colonization and submucosal gas bubbles
* infants that survive surgery will often have post-NEC strictures: ;fibrosis caused by the healing process.
68
what inflamm. mediator of NEC?
inflammatory mediators: Platelet activating factor (PAF)- increases mucosal permeability by promoting enterocyte apoptosis and compromising intercelluluar tight junctions
69
pneumatosisintestinalis
abdominal radiographs show gas within the intestinal wall (seen in NEC)
70
transcervical/ascending infection
* most bacteria and a few viral (herpes simplex II) infections
* fetus acquires infection by inhaling infected amniotic fluid into lungs shortly after birth, or by passing through infected birth canal during delivery
* fetus infected by inhalation → most commonly get pneumonia, sepsis, meningitis
71
transplacental infection
Transplacental (Hematologic) Infections:
• most parasitic (toxoplasma, malari) and viral infections with a few bacterial (Listeria, treponema) gain access to fetal bloodstream transplacentally via chorionic villi
- Parvovirus B19
- TORCH groups
• infection may result in spontaneous abortion, stillbirth, hydrops fetalis, and congenital anemia
72
P-virus B19
• Parvovirus B19: causes erythema infectiosum (“fifth disease” Fifth disease is an illness caused by a virus that leads to a rash on the cheeks, arms, and legs)
ex. of transplacental infection
73
what do TORCH infections cause?
• TORCH group of infections: evoke fever, encephalitis, chorioretinitis, hepatosplenomegaly, pneumonitis, myocarditis, hemolytic anemia, vesicular/hemorrhagic skin lesions
- seen transplacentally
74
causes of newborn sepsis?
* early onset: within first 7 days of life
* late onset: from 7 days to three mos: most often due to Listeria and Candida
* usually acquired shortly before birth → pneumonia, sepsis and meningitis
* group B streptococcus is most common for early-onset sepsis (most common cause of bacterial meningitis
75
fetal hydrops
= refers to accumulation of edema fluid in the fetus during intrauterine growth
- “immune hydrops” due to hemolytic anemia caused by Rh blood group incompatibility b/w mother and child used to be the number one cause
- “nonimmune hydrops” has now emerged as the principle disease
76
hydrops fetalis
generalized edema of the fetus
77
cystic hygroma
a birth defect due to a growth that occurs in the head and neck – could be due to postnuchal fluid accumulation
- often due to lymphatic lesion
- benign but disfiguring
78
immune hydrops
a hemolytic disease caused by blood group incompatibility b/w mother and fetus
• hemolytic disease results when fetus inherits red cell antigenic determinants from father that are foreign to the mother
• Fetal red blood cells may reach the maternal circ. during the last trimester of pregnancy when cytotrophoblast is no longer present as a barrier or during childbirth → mother becomes sensitized to foreign Ag → build up Abs that will affect her second pregnangy
• D antigen is the major cause of Rh incompatibility
79
ABO incompatability and Rh protection?
Concurrent ABO incompatibility protects the mother against Rh immunization b/c feta RBCs are promptly coated and removed by anti-A/B IgM Abs that do not cross the placenta
80
what causes immune hydrops?
* Hemolytic disease develops only when the mother has experienced a significant transplacental bleed
* Initial exposure to Rh Ag evokes formation of IgM abs, so Rh disease is uncommon with first pregnancy. Exposure during next pregnancy → brisk IgG Ab response and risk of immune hydrops
81
ABO hemolytic disease?
• only 1 in 200 cases of hemolytic disease req. treatment b/c:
o most anti-A/B Abs are of IgM type and don’t cross placenta
o neonatal RBCs express blood group Ags A and B poorly
o many cells other than RBCs express and and B ags and absorb some of the transferred ab
• ABO hemolytic disease occurs nearly exclusively in infants of group A or B who are born of group O mothers: certain O group women have IgG Abs against A and B → thus firstborn may be affected
82
how does hemolysis --> hydrops fetalis?
o Anemia → may result in hypoxic injury to heart and liver → decreased plasma protein synthesis
o cardiac hypoxia → cardiac decompensation and failure
o reduced plasma oncotic pressure and increased hydrostatic pressure in circulation → generalized edema (anasarca) → hydrops fetalis
Jaundice:
o develops b/c hemolysis produces unconj. bilirubin → kernicterus
83
anasarca
generalized edema
84
when is non-immune hydrops seen?
* major causes: cardiovascular defects, chromosomal anomalies, fetal anemia
* seen with Turner syndrome, and trisomies 21 and 18: usually due to underlying cardiac defects
* turner phenotype:
* alpha thalassemia
* Parvovirus B19
85
turner phenotype
abnormalities of lymphatic drainage from neck → postnuchal fluid accumulation (cystic hygromas)
86
alpha thalassemia
severe fetal anemia --> non-immune hydrops
87
Parvovirus B19 --> fetal hydrops?
virus gains entry into erythroid precursors, replicates, leads to apoptosis of RBC progenitors → isolated RBC aplasia
88
morphology of hydropsfetalis?
* intrauterine fluid accumulation
* fetal anemia hydrops → both fetus and placenta are characteristically pale, and liver and spleen are enlarged from cardiac failure and congestion, and bone marrow shows compensatory hyperplasia of erythroid precurors, and extramedullary hematopoiesis
* in peripheral circulation see large number of immature RBC’s = erythroblastosis fetalis
* Kerinecterus → CNS damage, brain is enlarged, edematous and brigh yellow color in basal ganglia, thalamus and cerebellum (bilirubin level >20)
89
clinical features of fetal hydrops?
* minimally affected infants: pallor, hepatosplenomegally, jaundice
* ill neonates: intense jaundice, generalized edema, signs of neurologic involvement
90
how are inborn errors of metabolism inherited?
• most inborn errors are rare, they are inherited and most commonly autosomal recessive or X-linked
91
PKU?
• due to abnormalities of phenylalaline metabolism → hyperphenylalaninemia
• Cannot convert phyenylalaline → tyrosine
f
92
causes of PKU?
* Autosomal recessive – PKU caused by bi-allelic mutation of gene encoding PAH enzyme (phenylalaline hydroxylase)
* degree of hyperphenylalaninemia is inversely related to residual enzyme activity
93
benign hyperphenylalaninemia
only modest elevations of blood phenylalaline, but does not develop classic PKU
• hepatic PAH system converts uneeded phen. through PAH, BH4 and DHPR (though 98% of cases are due to PAH deficiency)
94
how does PAH work?
• hepatic PAH system converts uneeded phen. through PAH, BH4 and DHPR (though 98% of cases are due to PAH deficiency)
95
BH4 deficiency
BH4 is imp. in neurotransmission, thus patients with BH4 problems show neurologic damage that does not stop despite decreased phenylalaline → these PKU variants cannot be treated by dietary control of Phe alone
96
classic PKU sx
”: due to deficiency in in PAH → phenylacetic acid causes strong musty or mousy odor
o xs PHE causes brain damage
o by 6 mos, see severe mental retardation if untreated
o 1/3 of children cannot walk and talk
o see seizures, neurologic abnormalities, decreased pigmentation of hair and skin and eczema
o however, this can be avoided with Phe restriction in early life
97
maternal PKU
• children born to women with maternal PKU → metabolites corssing placenta → mental retardation, microcephalic and congenital heart disease
o it is necessary that maternal dietary restriction of PHE be initiated before conception and continued throughout pregnancy
98
galactosemia
* autosomal recessive disorder
* cannot convert lactose → glucose and galactose (occurs in intestinal microvilli via lactase) → galactose is then broken to glucose
99
GALT deficiency
* most common cause of galactosemia *
results in accumulation of galactose-1-phosphate in liver, spleen, lens, kidneys, heart mm, cerebral cx and erythrocytes
• alternative metabolic pathways activated → production of galactitol and galactonate which accumulate in tissues
100
galactokinase deficiency
* rare variant * deficiency of galactokinase → less severe progressionnot associated with mental retardation
101
clinical presentation in galactosemia
variable, due to heterogeneity of mutations
• most damage in liver, eyes and brain
• hepatomegaly: due to fatty change in liver
• Opacification of lens (cataract development): due to lens absorbing water and swelling with accumulated galactitol
• CNS problems: loss of nerve cells, gliosis, edema
• infants “fail to thrive from birth”
102
what infection more comon with galactosemia
E. coli septicemia
103
ddx of galactosemia
* if there is a reducing sugar other than glucose present in the urine (aka galactose 1 phosphate)
* assay of GALT activity
* Early removal of galactose from diet for the first 2 years of life can control problems and prevent cataracts and liver damage
* however older patients often still develop speech disorder and gonadal failure and ataxic gait
104
CF
a disorder of ion transport in epithelial cells that affects fluid secretion in exocrine glands and the epithelial lining of the respiratory, GI and reproductive tracts
• abnormally viscous secretions → obstruction of organs → chronic lung disease secondary to recurrent infections, pancreatic insufficiency, steatorrhea, malnutrition, hepatic cirrhosis, intestinal obstruction and male infertility
• most common lethal genetic disease affecting Caucasians
105
transmission of CF
• Follows an autosomal recessive transmission , but even heterozygote carriers have a higher incidence of respiratory and pancreatic disease
106
CFTR gene
. The primary defect in CF is due to abnormal fn. of epithelial Cl- channel protein encoded by the cystic fibrosis transmembrane conductance regulator gene (CFTR gene)
o the two transmembrane domains form a channel through which Cl- passes, Activation of CFTR channel is mediated by cAMP, followed by ctivation of protein Kinase A → phosphorylation → ATP binding and opening/closing of channel
107
ENaC
ENaC is situated on the apical surface of exocrine epithelial cells: uptake of sodium from luminal fluid → luminal fluid to be hypotonic
• ENaC is inhibited by normally functioning CFTR
• in CF, ENaC activity increases → increasing sodium uptake across the apical membrane → dehydrated mucus in the GI tract and pulmonary
• in sweat glands, ENaC activity decreases in CF, causing hypertonic luminal fluid containing high sweat chloride and high sodium content → “salty sweat”
108
loss of CFTR in sweat glands
The major fn. of CFTR in sweat gland ducts is to reabsorb luminal Cl- and Na+ via the ENaC.
• in loss of CFTR → decreased reabsorption of sodium chloride → hypertonic sweat
109
loss of CFTR in airways
The major fn. of CFTR in the respiratory and intestinal epithelium is active luminal secretion of Cl-.
• loss of CFTR see reduced Cl- secretion into lumen → passive water reabospriton from the lumen → lowers water content of surface fluid layer coating mucosal cells → defective mucociliary action, accumulation of hyperconcentrated viscid secretions that obstruct air passages and lead to recurrent infections
o there is no difference in the salt concentration of the surface fluid layer coating the resp. and intestinal mucosal cells in normal individuals versus those with CF.
o the pathogenesis in CF comes from an isotonic, but low volume surface fluid layer
110
how does CFTR mediate bicarb ion tranpsort?
CFTR mediates transport of bicarbonate ions via anion exchangers called SLC26, which are coexpressed on apical surface with CFTR
• in some CFTR mutations, bicarbonate transport is abnormal, while Cl- transport remains normal
• Alkaline fluids are normally secreted into tissues, while acidic fluids are secreted by epithelia harboring the mutant CFTR alleles
• results in decreased luminal pH → increased mucin precipitation → plugging of ducts → increased binding of bacteria to plugged mucins
111
class I CF
- Class I: defective CFTR protein synthesis, complete lack of CFTR on apical surface
112
class II CF
Class II: Abnormal protein folding, processing, trafficking – most commonly due to deletion at ΔF508 (mutation found in 70% of cases): associated with complete lack of CFTR protein on apical surface of cells
113
class III CF
Class III: defective regulation: mutations prevent activation of CFTR by preventing ATP binding and hydrolysis. There is a normal amount of CFTR on apical surface, but it is not functional.
114
class IV CF
Class IV: Deceased conductance: mutations in transmembrane domain of CFTR, which forms the ionic pore. there is normal CFTR at apical membrane but with reduced function = milder phenotype
115
class V CF
- Class V: Reduced abundance: mutations affecting intron splice sites of CFTR promoter: normal amount of CFTR, but with reduced function = milder phenotype
116
class VI CF
Altered regulation of separate ion channels: CFTR is involved in regulation of multiple ion channels, mutations here affect regulatory role
117
severity of CF? classes?
```
2 severe (Class I,II,III) mutations → produce absence of CFTR → “classic” CF
• see pancreatic insufficiency, sinopulmonary infections, GI symptoms, male infertility, hepatic cirrhosis
```
“Mild mutation” (Class IV/V) on one or both alleles → less severe phenotype
Note: patients who present with a variety of unrelated clinical phenotypes may also harbor CFTR mutations. Which includes idiopathic chronic pancreatitis, idiopathic bronchiectasis, obstructive azoospermia caused by bilateral absence of vas deferens. Most of these patients do not demonstrate other features of CF despite the presence of bi-allelic CFTR mutations that are classified as nonclassical or atypical CF
118
genetic modulators in CF?
• severity of pulmonary problems in CF associated with polymorphic variants at mannose binding lectin 2 (MBL2) and TGFβ1: TBFβ is an inhibitor of CFTR
mutations in ΔF508
119
Pseudomonas aeruginosa
species that colonizes the lower resp tract in patients with CF.
o static mucus creates hypoxic environment in airway surface fluid → production of alginate → allows for formation of a biofilm that protects the bacteria from Abs and antibiotics allowing them to evade host defenses and cause chronic lung disease
120
pancreatic abnormalities in CF?
present in 85-90% of patients with CF
• in milder cases, may result in accumulation of mucus in small ducts with dilation of exocrine glands
• in severe cases, ducts are completely plugged, causing atrophy of exocrine glands and progressive fibrosislatrophy of exocrine prtion of pancreas → impaired fat absorption, avitaminosis A→ squamous metaplasia of lining of ducts of pancreas
(usually ΔF508 mutation) → protein and fat malabsoprtion and loss in fecal
• malabsorption see large, foul-smelling stools, abdominal distention, poor weight gain
• deficiency of fat soluble vitamins (A,D,K)
• hypoproteinemia → generalized edema
• in pancreas sufficient phenotype don’t see these things → have excellent growth and development
• Idiopathic Chronic pancreatitis: see abdominal pain
121
meconium ileus changes in CF?
= small bowel obstruction in infants with CF due to mucus plugs found in small intestines
122
liver problems seen in CF?
occurs late in hx of CF
• asymptomatic hepatomegaly
• obstruction of common bile duct →abdominal pain and acute onset of jaundice
• diffuse biliary cirrhosis
bile canaliculi are plugged → ductular proliferation and portal inflammation
• hepatic steatosis
• focal biliary cirrhosis
123
salivary glands in CF?
glands show dilation of ducts, squamous metaplasia of lining, glandular atrophy followed by fibrosis
124
pulmonary changes in CF?
: most serious portion of this disease
• viscous mucus secretions of submucosal glands in respiratory tree → obstruction → infection of air passages
• distended bronchioles with thick mucus: hypertrophy and hyperplasia of mucus secreting cells
• severe chronic bronchitis and bronchiectasis
• lung absesses may develop
• Staph aureus, Hemophilius influenza, Pseudomonas aeruginosa (P. aeruginosa is the most common)
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clinical features in CF?
- meconium ileus often seen in babies
- Exocrine pancreatic insufficiency
- Endocrine pancreatic insufficiency: non-classical
- Cardiorespiratory Complications:
- Liver Disease: occurs late in hx of CF
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greatest cause of death from CF in US?
cardiorespiratory disases
* persistent lung infections, obstructive pulmonary disease, cor pulmonale (Cor pulmonale is failure of the right side of the heart brought on by long-term high blood pressure in the pulmonary arteries and right ventricle of the heart. - results in ~80% of CF deaths)
* P. aeruginosa seen most commonly in infections
* individual w/ one sever and one mild gene → see late-onset mild pulmonary disease, and often no pancreatic problems
* “Adult onset idiopathic bronchiectasis” linked with CFTR mutations
* recurrent sinonasal polyps
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criteria for ddx of CF?
One or more characteristic phenotypic features,
o OR a history of cystic fibrosis in a sibling,
o OR a positive newborn screening test result
AND
• An increased sweat chloride concentration on two or more occasions
o OR identification of two cystic fibrosis mutations,
o OR demonstration of abnormal epithelial nasal ion transport
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SIDS
is a “cause of death” because it is not entirely figured out yet
• “SIDS” = the natural death of an infant under age 1 which remains unexplained through case investigation
• infant usually dies while asleep, mostly in the prone or side position, hence term “crib death”
Epidemiology:
• leading cause of death in first year in the US, third leading in overall deaths after congenital anomalies and diseases of prematurity
• 90% of cases occur in first 6 mos
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maternal risk factors for SIDS
* young maternal age
* maternal smoking
* drug abuse of either parent: marijuana for father, opiates/cocaine for mother
* short intergestational intervals
* no prenatal care
* low socioeconomic group
* African-american or American Indian ethnicity (low socioeconomic status?)
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infant RF for SIDS
* brain stem abnormalities: delayed development of arousal and cardiorespiratory control
* prematurity and low birth weight
* male sex
* multiple births
* SIDS in prior sibling
* antecedent respiratory infections
* germline polymorphisms in ANS genes
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environmental RFs for SIDS
* prone/side sleeping position
* sleeping on soft surface
* hyperthermia
* co-sleeping in first 3 mos
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morphology of SIDS
* Multiple Petechiae: most common finding: present on thymus, visceral, parietal pelura and epicardium
* lungs are congested, see vascular enlargement w/ or w/out pulmonary edema
* histologic evidence of a recent infection, though not severe enough to cause death
* CNS demonstrates astrogliosis of brain stem and cerebellum
* hypoplasia of arcuate nucleus in brain stem, or decrease in brain stem neuronal populations
* persistence of hepatic extramedullary hematopoiesis and periadrenal brown fat (due to chronic stress/hypoxemia?)
* autopsy fails to provide clear COD
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pathogenesis of SIDS
* multifactorial condition
* triple risk model: 1. vulnerable infant, 2. critical development period in homeostatic control 3. an exogenous stressor
* SIDS reflects a delayed development of “arousal” and cardiorespiratory control: the brain stem and medulla oblongata are necessary to respond to hypoxia encountered during stress. The serotnergic system of the medulla is implicated in these “arousal” responses – abnormalities in serotonin-dependent signaling in the brainstem may underly SIDS
* laryngeal chemoreceptors: have emerged as a link b/w RTI and prone position, when stimulated they elicit an inhibitory cardiorespiratory reflex. stimulation of the chemoreceptors is augmented by RTIs which increase the volume of secretions, and by the prone position, impair swallowing and clearing of airways – if infant has impaired arousal, then this inhibitory cardiorespiratory reflex could be fatal.
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heterotopia
(choristoma): applied to microscopically normal cells/tissues that are present in abnormal locations
o ex. pancreatic tissue found in wall of stomach
o usually have little significance
o rarely they are sites of true neoplasms
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hamartoma
excessive, focal overgrowth of cells and tissues native to the organ where they occur
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hemangioma
* most common tumors of infancy
* most are located on skin – usually face and scalp
* produce flat/elevated irregular red-blue masses = aka “port wine stains”
* May enlarge along with growth of child, but in many cases they spontaneously regress
* these ae seen however in von Hippel-Lindau syndrome
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lymphangioma
haratomatous or neoplastic, characterized by malformations of the lymphatic system, and are seen in cystic and cavernous spaces.
o Lesions may occur in skin but are usually seen in deep regions of neck, axilla, mediastinum and retroperitoneal tissue
o histologically benign, but may increase in size thus encroaching on vital structures
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lymphangiectasis
derived from preexisting lymph channels
o present as diffuse swelling of a part or all of an extremity
o cause distortion and deformation
o the lesion is NOT progressive , and are difficult to correct for surgically
- dilation of lymph vessels
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two types of fibrous tumors?
Fibromatosis: cellular proliferations of spindle shaped cells
congenital-infantile fibrosarcomas: cellular lesions indistinguishable from fibrosarcomas in adults
o often arise due to generation of ETV6-NTRK3 fusion transcript – which can serve as an important dianogstic marker
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ETV6-NTRK3 seen in blood?
congenital-infantile fibrosarcomas: cellular lesions indistinguishable from fibrosarcomas in adults
o often arise due to generation of ETV6-NTRK3 fusion transcript – which can serve as an important diagnostic marker
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teratomas
* may occur as benign, mature teratomas, or indeterminate/immature teratomas, or as malignant teratomas
* seen usually at 2 y/o and second in late adolescence/early adulthood
* congenital neoplasms: seen at 2 y/o
benign cystic teratoma: seen in children 1-4 mos.
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sacrococcygeal teratomas
most common teratomas of childhood (~75% are mature)
| • most benign teratomas are seen in young infants, whereas children w/ malignant lesions tend to be older
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malignant tumors seen in children
* most frequent childhood cancers arise in hematopoietic system, nervous tissue, soft tissues, bone and kidney
* Most common in children under 10 years: leukemia, retinoblastoma, neuroblastoma, Wilms tumor hepatoblastoma, rhabdomyosarcoma, teratoma, CNS tumors
* *** Leukemia accounts for more deaths in children younger than 15 years than all other tumors combined
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- blastoma
malignant non-hematopoietic pediatric neoplasms have a more primitive (embryonal) appearance and are characterized by sheets of cells with small, round nuclei = “small round blue cell tumors” : neuroblastoma, nephroblastoma (Wilms tumor), lymphoma, rhabdymyosarcoma, meduloblastoma, retinoblastoma
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neuroblastic tumors
tumors of sympathetic ganglia and adrenal medulla that are derived from primordial neural crest cell populating these sites
* see spontaneous or therapy-induced differentiation of primitive neuroblasts into mature elements
* spontaneous tumor regression
* wide range of clinical behavior and prognosis- mirroring extent of histologic differentiation
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neuroblastomas
are most common extracranial solid tumor of childhood, and most frequently diagnosed tumor of infancy (1 in 7000 live births)
• children younger than 18 mos have much better prognosis
• 40% of neuroblastomas arise in the adrenal medulla – remainder occur along sympathetic chain, pelvis, neck and brain
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ALK gene
Anaplastic lymphoma kinase (ALK) gene: germline mutations in ALK gene have been identified as a major cause of familial predisposition to neuroblastoma
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in situ lesions
minute nodules of neuroblastomas – reported to occur 40x more frequently than clinically overt
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different sizes/shapes of neuroblastomas?
* in situ lesions: minute nodules of neuroblastomas – reported to occur 40x more frequently than clinically overt tumors – the majority of which will clinically regress, leaving only calcification or fibrosis in the adult
* neuroblastomas can also be large masses that weight more than 1 kg in weight, thus the size is variable
* some neuroblastomas are sharply demarcated by a fibrous pseudo-capsule, while others are infiltrative and composed of soft, gray-tan tissue
* larger tumors have areas of necrosis, cystic softening and hemorrhage
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morphology of neuroblastomas?
small, primitive appearing cells with dark nuclei, scant cytoplasm and poorly defined cell borders growing in solid sheets.
karyorrhexis/nuclear breakdown
neuropil = background eosinophilic material
pseudorosettes: rosettes that are found in concentrically arranged about a central space filled with neuropil
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ganglioneuroblastoma
tumor with various stages of ganglion cell maturation and neuroblasts
o Schwannian stroma: see schwann cells and fibroblasts along with ganglion cell maturation = prerequisite for designation of ganglioneuroblastoma and ganglioneuroma
o The presence of Schwannian stroma is associated with favorable outcome
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where do neuroblastomas metastasize?
liver, lungs, bone marrow and bones
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Staging of Neuroblastomas
* Stage 1: Localized tumor with complete gross excision, with or without microscopic residual disease; representative ipsilateral nonadherent lymph nodes negative for tumor (nodes adherent to the primary tumor may be positive for tumor).
* Stage 2A: Localized tumor with incomplete gross resection; representative ipsilateral nonadherent lymph nodes negative for tumor microscopically.
* Stage 2B: Localized tumor with or without complete gross excision; ipsilateral nonadherent lymph nodes positive for tumor; enlarged contralateral lymph nodes, which are negative for tumor microscopically.
* Stage 3: Unresectable unilateral tumor infiltrating across the midline with or without regional lymph node involvement; or localized unilateral tumor with contralateral regional lymph node involvement.
* Stage 4: Any primary tumor with dissemination to distant lymph nodes, bone, bone marrow, liver, skin, and/or other organs (except as defined forstage 4S).
* Stage 4S (“S” = special): Localized primary tumor (as defined for stages 1, 2A, or 2B) with dissemination limited to skin, liver, and/or bone marrow; stage 4S is limited to infants younger than 1 year.
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stages NB
1, 2a, 2b, 4s = good
3,4 = bad
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NB age prognosis
18 mos = bad
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NB histology
schwannianstroma/gangliocytic differentiation = good
mitosis/karorrhexis >2///5000 cells = bad
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DNA ploidy for NBs
hyperdiploid/near-triploid = good
near-diploid = bad
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N-Myc for NB
not amplified = good
| amplified = bad
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chromsome 17q gain
no gain = good
| gain = bad
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chromosome 1p loss
no loss = good
| loss = bad
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chromosome 11q loss
no loss = good
| loss = bad
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TRKA expression
present = good thing
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TRKB expression
absent = good thing
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telomerase expression in Nb
low/absent = good
| highly expressed = bad
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how do neuroblastomas present?
* in children under 2 y/o, neuroblastomas present with large abdominal masses, fever and possibly weightloss
* in older children, they may not come to attn. until metastases cause bone pain, resp. sx, GI complaints
* Proptosis (forward displacement of eyes)
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blueberry muffin baby
neuroblastomas in neonates may present with multiple cutaneous metastases that cause deep discoloration
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best diagnostic feature of neuroblastoma?
• 90% of NB’s produce catecholamines: imp for diagnostic feature in blood:
o look for vanillymandelic acid [VMA] and homovanillic acid [HVA] in blood
o HTN is not as frequent than seen in pheochromocytomas
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ganglioneuromas
tend to produce asymptomatic mass lesions or sx related to compression
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determinants of outcome:
* NBs of stage 1,2A,2B have excellent prognosis, irrespective of age (Exception: tumors exhibiting amplification of the N-MYC oncogene)
* 4S: Infants with localized primary metastases to liver, bone marrow and skin are special, b/c its not uncommon to see it regress spontaneously
* Children younger than 18 mos have excellent prognosis regardless of stage of neoplasm
* children older than 18 mos fall into “intermediate” risk category
N-MYC amplification always means high risk!
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ploidy of Nb
correlates with children less than 2 years of age, but loses indep. prognostic sig. in older children
• near-diploid = worse prognosis
o more aggressive, harbor generalized genomic instability with unbalanced translocations and rearrangments
• hyper-diploid/near-triploid = better prognosis due to NBs with hyperploidy having an underlying defect in mitotic machinery, leading to chromosomal nondisjunction and near-triploidy
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Wilm's tumor
* most common renal tumor of childhood, 4th most common pediatric malignancy in US
* peak age is 2-5 y/o, and 95% occur before age 10
bilateral tumors seen in 5-10%
o synchronous- tumor involving both kidneys
o metachronous: one kidney affected after the other
o bilateral tumors have median age of onset at 10 mos, - often due to patients harboring a germline mutation in one of wilms tumor predisposing genes
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4 types of Wilm's tumors?
1. WAGR syndrom (WT1 gene/PAX6)
2. Denys-Drash syndrome (WT1 gene)
3. Beckwith-Wuedemann syndrome (WT2 gene/imprintining of IGF-2)
4. sporadic Wilm's tumor
* note: syndromic tumors generally affect the kidney and gonads!
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WAGR syndrome
Wilms tumor, aniridia (absence of iris), genital anomalies, mental retardation
carry deletion of 11p13
WTI gene and PAX6 both located on chromosome 11
o patients with restricted PAX6 → aniridia
o patients with restricted WT1 → Wilms tumor
mutation of WT1 gene represents the “first hit” to formation of Wilms tumor. Nonsense or frameshift mutation causes “second hit” in development of Wilms tumor
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Denys-Drash syndrome
* see gonadal dysgenesis (male pseudoherm) and early onset nephropathy → renal failure (due to diffuse mesangial sclerosis)
* patients have anvormalities in WT1 gene due to dominant-negative missense mutation,
* Wilm’s tumor only results when there is bi-allelic inactivation of WT1
* increased risk of development of gonadoblastomas
* WT1 encodes a DNA binding txn factor that is expressed in kidney and gonads during emryogenesis, thus the WT1 protein is critical for normal renal and gonadal development:
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BWS
Beckwith-Wiedemann syndrome (BWS):
• see enlargement of body organs (organomegally), macroglossia, hemihypertrophy, omphalocele(infants intestines/organs stick out in bellybuttong) and abnormal large cells in adrenal cx
• a model for genomic imprinting
• WT2 gene: contains genes that are normally only expressed from one of parental alleles with imprinting of the other – development of BWS is due to imprinting patterns
o loss of imprinting of IGF-2 (usually only expressed by father) → overexpression of IGF-2
o uniparental paternal disomy: deletion of mothers allele, and duplication of txn. active paternal allele in tumor
o explains features of overgrowth in BWS, since IGF-2 is a embryonal growth factor
Patients with BWS are at increased risk of developing hepatoblastoma, pancreatoblastoma, adrenocortical tumors, rhabdomyosarcomas
• Recent studies have also shown B-Catenin (WNT pathway signaling) gain –of –function mutations to cause Wilms tumors
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nephrogenic rests
* putative precursor lesion of Wilms tumors, seen in renal parenchyma adjacent to tumors
* arises in 100% of all bilateral Wilm’s tumors, and 25-40 % of unilateral tumors
* important to document presence of nephrogenic rests b/c patients are at an increased risk of developing Wilms tumors in contralateral kidney and require surveillance for many years
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morphology of wilms tumor?
• grossly presents as large, solitary, well-circumscribed mass (though 10% are bilateral)
• tumor is soft, homogenous, tan-gray, with occasional foci of hemorrhage, cyst formation and necrosis
• Microscopically see stages of nephrogenesis: see triphasic combination of blastemal, stromal and epithelial cell types
• sheets of small blue cells with few distinctive features
• 5% of tumors are anasplastic: see large, hyperchromatic pleomorphic nuclei with abnormal mitoses
o presence of anaplasia correlates to p53 mutations (keeps the cells from apoptosing) – loss of p53 explains unresponsiveness of anaplastic cells to cytotoxic chemotherapy
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clinical features of wilm's tumor?
• most children present with large abdominal mass, that may be unilateral, or extend across pelvis
• hematuria, pain in abdomen, intestinal obstruction and appearance of HTN are all common patterns
• in many children pulmonary metastases are present at time of primary dx
• Most patients with Wilms can expect to be cured
• anaplastic histology remains critical determinant for adverse prognosis
• furthermore, loss of material on chromosomes 11q and 16q, and gain of 1q = adverse prognosis
• increased relative risk of developing second primary tumors, including bone and soft tissue sarcomas, leukemia and lymphomas and breast cancers
o some are due to point mutations, while others are because of radiation administered for treatment, thus radiation needs to be used judiciously in treatment of this and other childhood cancers
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what age do ME's not sign death certificate?
less than 20 weeks
| less than 500 gms
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hyaline membranes of RDS?
composed of fibrin and type II pneumocytes, with little inflammation
Type I pneumocytes makes up about 90-95% and are involved in the gas exchange between the alveoli and blood.
Type II pneumocytes function is to secrete surfactant, which decreases surface tension within the alveoli.
interstitium is very dilated
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retrolental fibroplasia and BPD
problems with oxygen therapy
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what are hazards of prematurity?
1. hyaline membrane disease
2. NEC
3. perinatal infections
4. sepsis
5. intraventricular hemorrhage
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causes of non-immune hydrops?
CV: malformations, tachyarrhythmia, high-output failure
chromosomal: turner, trisomy 21/18
thoracic causes; cystic adenomatoid malformation, diphargmatic hernia
alpha thalassemia, parvovirus B19, immune hydrops, twin to twin transfusion, cytomegalovirus, syphilis, toxoplasmosis
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most common malignant tumor ages 0-9?
1. Acute lymphoblastic leukemia
2. retinoblastoma
3. neuroblastoma (most common SOLID tumor)
