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272 Cards in this Set
- Front
- Back
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what are congenital anomalies?
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morphologic defects that are present at birth
don't have to be genetic, but can be |
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what are malformations?
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primary errors of morphogenesis in which there is an intrinsically abnormal developmental process
**not the result of a single gene or chromosomal defect** |
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what are disruptions?
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secondary destruction of an organ or body region that was previously normal in development, resulting from an extrinsic disturbance in morphogenesis
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what are amniotic bands?
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classic example of a disruption
rupture of amnion with resultant formation of "bands" that encircle, compress, or attach to parts of the developing fetus |
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what are deformations?
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localized or generalized compression of the growing fetus by abnormal biomechanical forces, leading to a variety of structural abnromalities
represents an extrinsic disturbance of development |
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what is the most common underlying factor responsible for deformations?
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uterine constraint
between 35 & 38 weeks of gestation, rapid increase in the size of the fetus outpaces the growth of the uterus, and the relative amount of amniotic fluid also decreases |
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what are the maternal factors for uterine constraint?
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first pregnancy
small uterus malformed (bicornuate) uterus leiomyomas |
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what are the fetal factors for uterine constraint?
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oligohydramnios
multiple fetuses abnormal fetus presentation |
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what type of congenital anomalies are clubfeet an example of?
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deformation
(part of Potter sequence) |
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what is a sequence?
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a cascade of anomalies triggered by one initiating aberration
example: oligohydramnios (Potter) sequence |
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what is oligohydramnios?
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decreased amniotic fluid
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what is Potter's sequence?
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the atypical physical appearance of a fetus or neonate due to oligohydramnios experienced in the womb
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what are the causes of oligohydramnios?
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chronic leakage of amniotic fluid caused by rupture of amnion
uteroplacental insufficiency resulting from maternal hypertension or severe toxemia renal agenesis of the fetus (fetal urine is a major constituent of amniotic fluid) |
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what is the classic phenotype caused by oligohydramnios-mediated compression in the newborn infant?
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flattened facies
positional abnormalities of hands and feet hips may be dislocated hypoplastic lungs nodules in amnion |
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what is amnion nodosum?
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nodules in the amnion, frequently found in oligohydramnios
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what is a syndrome?
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a constellation of congenital anomalies, believed to be pathologically related, that cannot be explained on the basis of a single, localized, initiating defect
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what is agenesis?
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complete absence of an organ and its associated primordium
**differs from aplasia, because primordium is absent** |
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what is aplasia?
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absence of an organ due to the failure of development of the primordium
**differs from agenesis, because primordium is present** |
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what is atresia?
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absence of an opening, usually of a hollow visceral organ, such as the trachea and intestine
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what is hypoplasia?
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incomplete development or decreased size of an organ with decreased numbers of cells
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what is hyperplasia?
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enlargement of an organ due to increased numbers of cells
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what is dysplasia?
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in the context of malformations, describes an abnormal organization of cells
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what are the tree categories of known causes of congenital anomalies?
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genetic
environmental multifactorial |
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what is the most common developmental defect of the forebrain and midface in humans?
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holoprosencephaly
the forebrain of the embryo fails to develop into two hemispheres |
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what is the most common form of short-limb dwarfism?
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achondroplasia
caused by gain-of-function mutation in fibroblast growth factor receptor 3 |
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what type of congenital anomalies are caused by viral infections, drugs, and irradiation to which the mother was exposed during pregnancy?
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disruptions
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when is the at-risk period for a fetus to develop malformations from rubella infection ?
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shortly before conception to the sixteenth week of gestation
greater hazard in first 8 weeks than second 8 weeks |
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what is the major tetrad of fetal defects from rubella infection?
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congenital rubella syndrome:
- cataracts - deafness - mental retardation - heart defects (persistent ductus arteriosus, pulmonary artery hypoplasia/stenosis, ventricular septal defect, tetralogy of Fallot) |
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what is tetralogy of Fallot?
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a congenital heart defect which is classically understood to involve four anatomical abnormalities (although only three of them are always present)
the most common cyanotic heart defect, and the most common cause of blue baby syndrome |
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what are the four features included in the tetralogy of Fallot?
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1) pulmonary stenosis (at or just below the valve)
2) overriding aorta (aorta is positioned directly over a ventricular septal defect, instead of over the left ventricle) 3) ventricular septal defect 4) right ventricular hypertrophy |
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what is the most common fetal viral infection?
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cytomegalovirus (CMV)
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when is the highest at-risk period for a fetus to develop congenital anomalies from cytomegalovirus (CMV) infection?
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second trimester of pregnancy
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what are the congenital malformations associated with cytomegalovirus infection?
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mental retardation
microcephaly deafness hepatosplenomegaly |
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what is the most widely used teratogen?
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alcohol
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what is the name for the spectrum of congenital problems caused by alcohol?
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fetal alcohol spectrum disorders (FASDs)
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what congenital malformations are noted in the most severely affected infants with fetal alcohol spectrum disorders?
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a classic teratogenic phenotype called fetal alcohol syndrome
- growth retardation - microcephaly - atrial septal defect - short palpebral fissures - maxillary hypoplasia |
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what two seminal developmental signalling pathways are disrupted by prenatal exposure to alcohol?
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retinoic acid
Hedgehog |
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what is often noted in babies born to smoking mothers?
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low birth weight
prone to SIDS there is also a high incidence of spontaneous abortions, premature labor, and placental abnormalities in pregnant smokers |
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what malformations are caused by exposure to heavy doses of radiation during the period of organogenesis?
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microcephaly
blindness skull defects spina bifida |
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what congenital anomalies are caused by maternal hyperglycemia-induced fetal hyperinsulinemia?
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increased body fat
increased muscle mass organomegaly (fetal macrosomia) cardiac anomalies neural tube defects CNS malformations |
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what is diabetic embryopathy?
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uncontrolled diabetes in a pregnant woman causes congenital malformations in her child
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how are multifactorial disorders manifested?
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fetus inherits a "susceptibility phenotype" but this phenotype has to interact with the environment before it can manifest
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what is congenital dislocation of the hip?
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a multifactorial disorder
a shallow acetabular socket and laxity of the supporting ligaments are genetically determined the breech position in utero (with hips flexed and knees extended) is a key environmental factor interaction of the susceptibility phenotype with the environment is necessary for the anomaly to manifest |
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what are the two phases of intrauterine development?
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1) embryonic period (first nine weeks of pregnancy)
2) fetal period (from nine weeks until birth) |
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what are the effects of injurious agents in the early embryonic period (first three weeks after conception)?
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either damages enough cells to cause death and abortion
OR damages only a few cells, presumably allowing the embryo to recover without developing defects |
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at what time is an embryo at peak sensitivity to teratogenesis?
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between the third and ninth weeks, the embryo is extremely susceptible to teratogenesis
peak sensitivity occurs between the fourth and fifth weeks (organs are being crafted out of the germ cell layers) |
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what are the risks with injurious stimuli during the fetal period (9 weeks to birth)?
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growth retardation
injury to already formed organs |
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why is valproic acid an important drug for pregnant women?
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valproic acid is an anti-epileptic drug and a recognized teratogen during pregnancy
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why is vitamin A (retinol) an important drug for pregnant women?
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vitamin A is used to treat severe acne, but excessive exposure to retinoic acid is teratogenic
predictable phenotype (called retinoic acid embryopathy): - CNS defects - cardiac defects - craniofacial defects (cleft lip and cleft palate) |
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what are the classification criteria for infants based on both birth weight and gestational age?
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appropriate for gestational age (AGA)
small for gestational age (SGA) large for gestational age (LGA) |
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at what birth weights are infants considered normal for gestational age?
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birth weight between the 10th and 90th percentiles for a give gestational age
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when are infants considered preterm?
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delivered before 37 weeks
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when are infants considered postterm?
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delivered after the 42nd week
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what are the top two most common causes of neonatal mortality?
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1) congenital anomalies
2) prematurity |
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what is PPROM?
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preterm premature rupture of placental membranes
spontaneous rupture of membranes occurring before 37 weeks' gestation |
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why is it preferable for infants to be born after 37 weeks?
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after 37 weeks, the associated risk to the fetus is considerably decreased
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what are the clinical risk factors for PPROM?
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prior history of preterm delivery
preterm labor (current pregnancy) vaginal bleeding (current pregnancy) maternal smoking low socioeconomic status poor maternal nutrition |
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what is included in the pathophysiology of PPROM?
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typically includes inflammation of placental membranes and enhanced collagen degradation by matrix metalloproteinases
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what factors determine the maternal and fetal outcomes after PPROM?
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gestation age of fetus (2nd trimester PPROM has dismal prognosis)
effective prophylaxis of infections in the exposed amniotic cavity |
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in how many preterm births is intrauterine infection present?
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25%
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what are the histologic correlates of intrauterine infection?
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inflammation of the placental membranes (chorioamnionitis)
inflammation of fetal umbilical cord (funisitis) |
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what are the most common organisms implicated in intrauterine infections leading to preterm labor?
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Ureaplasma urealyticum
Mycoplasma hominis Gardnerella vaginalis Trichomonas gonorrhea chlamydia |
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activation of what toll-like receptor has been implicated as one of the initiating events in inflammation-induced preterm labor?
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TLR-4 activation by bacterial lipopolysaccharide
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what are the hazards of prematurity?
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hyaline membrane disease
necrotizing enterocolitis sepsis intraventricular hemorrhage long-term complications (developmental delay) |
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how can fetal growth restriction be detected before delivery?
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ultrasonographic measurement of various fetal dimensions (biparietal diameter, head circumference, abdominal circumference, femur length, head-to-abdominal circumference ratio, femur length-to-abdominal circumference ratio, total intrauterine volume)
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what are fetal influences on fetal growth restriction?
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those that intrinsically reduce growth potential of the fetus despite an adequate supply of nutrients from the mother
- chromosomal disorders - congenital anomalies - congenital infections |
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what is the significance of TORCH?
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TORCH is an acronym for the microorganisms that most commonly are passed across the placental membrane
T - toxoplasmosis O - other (syphilis) R - rubella C - cytomegalovirus H - herpes virus |
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how do infants who are SGA because of fetal factors present?
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symmetric growth restriction (proportionate fetal growth restriction)
essentially, all organ systems are similarly affected |
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when is adequate placental growth extremely important?
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second half of second trimester
in third trimester, the fetus grows vigorously and places particularly high demands on the uteroplacental supply line uteroplacental insufficiency is an important cause of fetal growth restriction |
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how do infants who are SGA because of placental factors present?
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asymmetric (disproportionate) growth retardation of the fetus with relative sparing of the brain
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what is confined placental mosaicism?
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if a mutation occurs later (within a dividing trophoblast or extraembryonic progenitor cells of the inner cell mass), then a genetic abnormality results that is in the placenta only
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what are the most common factors associated with SGA infants?
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maternal conditions that result in decreased placental blood flow, especially:
- preeclampsia - chronic hypertension - inherited diseases of hypercoagulability (also lead to early pregnancy losses) - narcotic abuse - alcohol intake - heavy cigarette smoking |
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what is preeclampsia?
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a medical condition in which hypertension arises in pregnancy (pregnancy-induced hypertension) in association with significant amounts of protein in the urine
(aka toxemia of pregnancy) |
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what is the most common cause of respiratory distress in the newborn?
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neonatal respiratory distress syndrome (RDS)
aka hyaline membrane disease |
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why is RDS called hyaline membrane disease?
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a layer of hyaline proteinaceous material is deposited in the peripheral airspaces of infants who succumb to this condition
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what is the stereotyped fashion in which RDS usually presents in untreated infants?
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almost always preterm and AGA
strong, but not invariable, associations with male gender, maternal diabetes, and delivery via C-section |
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what is seen in a chest x-ray of an infant with RDS?
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uniform minute reticulogranular densities, producing a so-called ground-glass picture
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what is the prognosis for RDS?
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if therapy staves off death for the first 3-4 days, the infant has an excellent chance of recovery
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what is the most important factor in an infant developing RDS?
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immaturity of the lungs
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what is the fundamental defect in RDS?
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deficiency of pulmonary surfactant
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what are the primary components of pulmonary surfactant?
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dipalmitoyl phosphatidylcholine (lecithin)
phosphoatidylglycerol two groups of surfactant-associated proteins |
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what are the two groups of surfactant-associated proteins in pulmonary surfactant?
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SP-A and SP-D - hydrophilic; role in innate immunity
SP-B and SP-C - hydrophobic; role in reducing surface tension at the air-liquid barrier in alveoli; act in concert with surfactant lipids |
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what cells produce pulmonary surfactant?
when is this process accelerated? |
type II alveolar cells (pneumocytes)
accelerated after the 35th week of gestation in the fetus |
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describe the first few breaths of an infant with normal (healthy) lungs
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first breath requires high inspiratory pressure to expand lung
40% of residual air volume is retained after the first breath (if pulmonary surfactant levels are normal) subsequent breaths require far lower inspiratory pressure |
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describe the first few breaths of an infant with RDS
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first breath requires high inspiratory pressure to expand lung
lungs collapse due to deficiency of pulmonary surfactant subsequent breaths are equally as hard as the first |
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what is atelectasis?
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the collapse of part or (much less commonly) all of a lung
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why does a fibrin-hyaline membrane form in the lungs of an infant with RDS?
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decreased surfactant synthesis
-> decreased alveolar surfactant -> atelectasis -> uneven perfusion -> hypoventilation -> hypoxemia & CO2 retention -> reduced surfactant synthesis -> acidosis -> reduced surfactant synthesis -> pulmonary vasoconstriction -> pulmonary hypoperfusion -> endothelial damage -> plasma leak into alveoli -> fibrin & necrotic cells -> increased diffusion gradient -> hypoxemia and CO2 retention -> epithelial damage -> plasma leak into alveoli -> fibrin & necrotic cells -> increased diffusion gradient -> hypoxemia and CO2 retention -> hypoxemia & CO2 retention |
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what hormones modulate the production of pulmonary surfactant?
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cortisol **particularly imporant**
insulin prolactin thyroxine TGF-beta |
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what is the effect of intrauterine stress and fetal growth restriction on pulmonary surfactant?
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increases corticosteroids release, which subsequently increases surfactant production
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what is the effect of diabetic mothers on pulmonary surfactant?
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increases insulin release in infant, which suppresses the production of surfactant
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how do RDS lungs look on gross examination?
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normal size
solid airless reddish puple sink in water |
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how do RDS lungs look microscopically?
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poorly developed alveoli
those alveoli that are present are collapsed membranes are largely made up of fibrin admixed with cell debris derived chiefly from necrotic type II pneymocytes paucity of neutrophilic inflammatory reaction associated with membranes |
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when are lesions of hyaline membrane disease seen in stillborn infants?
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never
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what happens in the lungs of RDS infants that survive longer than 48 hours?
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reparative changes occur in the lungs
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what is the major thrust in the control of RDS?
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prevention, either by delaying labor until the fetal lung reaches maturity or by inducing maturation of the lung in the fetus at risk
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how can you clinically obtain a good estimate of the level of surfactant in the alveolar lining?
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analysis of amniotic fluid phospholipids
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in what infants should prophylactic administration of exogenous surfactant be performed?
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those that are extremely premature (26-28 weeks)
older premature infants who are symptomatic |
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what has been shown to decrease neonatal morbidity and mortality from RDS in mothers with threatened premature delivery at 24-34 weeks' gestation?
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antenatal corticosteroids
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what is the cornerstone of treatment in infants born with RDS?
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delivery of surfactant replacement therapy and oxygen
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how quickly does recovery from RDS occur in uncomplicated cases?
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3-4 days
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what is oxygen toxicity?
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high concentrations of oxygen administered for prolonged periods cause complications:
- retrolental fibroplasia - bronchopulmonary dysplasia |
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what is retrolental fibroplasia?
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aka retinopathy of prematurity
eye disease that affects prematurely born babies, thought to be caused by disorganized growth of retinal blood vessels which may result in scarring and retinal detachment |
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what is bronchopulmonary dysplasia?
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a chronic lung condition that affects newborn babies who were either put on a breathing machine after birth or were born very early (prematurely)
at least 28 days of O2 therapy in an infant who is beyond 36 weeks' post menstrual age is required to render a diagnosis of BPD |
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what are the major abnormalities in bronchopulmonary dysplasia?
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striking decrease in alveolar septation (large, simplified alveolar structures)
dysmorphic capillary configuration |
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what are the most important complications that infants who recover from RDS are at increased risk of developing?
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patent ductus arteriosus
intraventricular hemorrhage necrotizing enterocolitis |
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what causes necrotizing enterocolitis?
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prematurity
enteral feeding (suggests that some postnatal insult, like introduction of a bacteria, sets in motion the cascade culminating in tissue destruction) |
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how does platelet activating factor (PAF) figure into the pathogenesis of necrotizing enterocolitis?
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increases mucosal permeability by promoting enterocyte apoptosis and compromising intercellular tight junctions
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what is the typical clinical course of necrotizing enterocolitis?
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bloody stools, abdominal distention, and development of circulatory collapse
abdominal radiographs often demonstrate gas within the intestinal wall involved segment of colon is distended, friable, and congested, or it can be frankly gangrenous intestinal perforation with accompanying peritonitis may be seen |
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what is pneumatosis intestinalis?
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gas within the intestinal wall
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what portions of the intestines are typically involved in necrotizing enterocolitis?
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terminal ileum
cecum right colon |
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what is the treatment of necrotizing enterocolitis?
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if detected early on, can be treated conservatively
if not detected early, necrotic segments of bowel require resection (20%-60% of cases) |
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what are transcervical infections?
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aka ascending infections
fetus acquires infection either by inhaling infected amniotic fluid into the lungs shortly before birth or by passing through an infected birth canal during delivery |
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what are transplacental infections?
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aka hematologic infections
most parasitic and viral infections, as well as a few bacterial infections (Listeria, Treponema), gain access to the fetal bloodstream transplacentally via the chorionic villi |
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what infections are acquired by infants via the cervicovaginal route?
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most bacterial infections
a few viral infections (herpes simplex II) |
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what infections are acquired by infants via the transplacental route?
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most parasitic infections (toxoplasma, malaria)
most viral infections a few bacterial infections (Listeria, Treponema) |
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what are the common clinical/pathological manifestations of the TORCH group of infections?
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fever
encephalitis chorioretinitis hepatosplenomegaly pneumonitis myocarditis hemolytic anemia vesicular or hemorrhagic skin lesions if such infections occur early in gestation, may cause growth and mental retardation, cataracts, congenital cardiac anomalies, and bone defects |
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what are the two clinical groups of perinatal sepsis?
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early onset (within first 7 days of life)
late onset (from 7 days to 3 months) |
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when are most cases of early onset perinatal sepsis acquired?
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at or shortly before birth
tend to result in clinical signs and symptoms of pneumonia, sepsis, and occasionally meningitis within 4/5 days of life |
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what are most cases of late onset perinatal sepsis?
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Listeria and Candida acquired at or shortly before birth
both of these organisms follow a latent period between time of inoculation and the appearance of clinical symptoms |
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what is fetal hydrops?
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accumulation of edema fluid in the fetus during intrauterine growth
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what is hydrops fetalis?
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progressive, generalized edema of the fetus
usually a lethal condition |
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what is immune hydrops?
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a hemolytic disease caused by blood group incompatibility between mother and fetus
major antigens to cause clinically significant immunological disease: - Rh antigens - ABO blood groups |
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what is the underlying basis of immune hydrops?
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immunization of a mother by blood group antigens on fetal red cells and the free passage of antibodies (IgG) from the mother through the placenta to the fetus
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how do fetal red cells reach maternal circulation?
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during last trimester of pregnancy when the cytotrophoblast is no longer present as a barrier
during childbirth itself |
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which Rh antigen is the only major cause of disease?
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D antigen
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how does concurrent ABO incompatibility protect mothers against Rh immunization?
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fetal red cells are promptly coated and removed from maternal circulation by anti-A or anti-B IgM antibodies that do not cross the placenta
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why is Rh disease only common during the second or subsequent prenancies?
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initial exposure creates IgM antibodies
exposure during subsequent pregnancies generally lead to a brisk IgG antibody response and the risk of immune hydrops |
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how has the incidence of maternal Rh isoimmunization been decreased?
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started using Rhesus immune globulin containing anti-D antibodies
administration of RhIg at 28 weeks and within 72 hours of delivery to Rh-negative mothers significantly reduces risk for hemolytic disease in Rh-positive neonates and in subsequent pregnancies |
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how can cases of severe intrauterine hemolysis be treated when identified?
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fetal intravascular transfusions via the umbilical cord and early delivery
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why does ABO incompatibility cause hemolytic disease only rarely?
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1) most anti-A and anti-B antibodies are of the IgM type and do not cross the placenta
2) neonatal red cells express blood group antigens A and B poorly 3) many cells other than red cells express the A and B antigens and they absorb some of the transferred antibody |
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what is the cause of hydrops fetalis?
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the combination of reduced plasma oncotic pressure and increased hydrostatic pressure in the circulation (secondary to cardiac failure) results in generalized edema and anasarca, culminating in hydrops fetalis
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what are the two consequences of excessive hemolysis in the neonate?
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anemia (leading to hypoxic injury)
jaundice (leading to kernicterus) |
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what is kernicterus?
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bilirubin that passes through the blood-brain barrier binds to lipids in the brain, resulting in damage to the CNS
the damage is called kernicterus |
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what are the three major causes of nonimmune hydrops?
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cardiovascular defects
chromosomal anomalies fetal anemia |
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what is seen in hydrops fetalis mophologically?
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in hydrops associated with fetal anemia, both fetus and placenta are characteristically pale
hepatosplenomegaly cardiac failure and congestion bone marrow demonstrates compensatory hyperplasia of erythroid precursors |
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what is erythroblastosis fetalis?
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an alloimmune condition that develops in a fetus, when the IgG molecules produced by the mother pass through the placenta
among these antibodies are some which attack the red blood cells in the fetal circulation; the red cells are broken down and the fetus can develop reticulocytosis and anemia |
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what is the most serious threat in fetal hydrops?
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kernicterus (CNS damage caused by bilirubin)
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why are jaundiced children treated with phototherapy?
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the visual light oxidizes toxic unconjugated bilirubin to harmless, readily excreted, water-soluble dipyrroles
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what is the inheritance pattern of phenylketonuria (PKU)?
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autosomal recessive
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what is the defect in phenylketonuria?
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bi-allelic mutations of the gene encoding phenylalanine hydroxylase (PAH)
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what is the function of phenylalanine hydroxylase (PAH)?
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convert phenylalanine to tyrosine
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what is benign hyperphenylalaninemia?
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disease that results from mutations in PAH which result in only modest elevations of blood phenylalanine levels without neurologic damage
positive screening tests don't develop stigmata of classic PKU |
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in addition to PAH mutations, what can cause PKU?
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deficiency of tetrahydrobiopterin (BH4) (cofactor in phenylalanine metabolism)
mutation in dihydropteridine reductase (enzyme that regenerates BH4) |
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what imparts a strong musty or mousy odor to infants affected with phenylketonuria?
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abnormal metabolites of PAH that are excreted in the sweat, particularly phenylacetic acid
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what is maternal PKU?
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syndrome in which the children of a PKU patient develop mental retardation, microcephaly, and congenital heart disease, even though they are only heterozygous for the recessive mutation in PAH
happens because phenylalanine and its metabolites that cross the placenta are teratogenic to specific fetal organs during development |
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what are the symptoms of phenylketonuria?
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seizures
albinism (excessively fair hair and skin) "musty odor" to the baby's sweat and urine (due to phenylacetate, one of the ketones produced) major clinical problems later in life: microcephaly progressive impairment of cerebral function hyperactivity EEG abnormalities seizures severe learning disabilities "musty or mousy" odor of skin, hair, sweat and urine (due to phenylacetate accumulation) tendency to hypopigmentation and eczema are also observed |
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what is the inheritance pattern of galactosemia?
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autosomal recessive
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what is the first step of lactose metabolism?
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split into glucose and galactose
occurs in the intestinal microvilli performed by lactase |
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what is the major carbohydrate of mammalian milk?
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lactose
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what are the two variants of galactosemia?
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deficiency of galactokinase
deficiency of galactose-1-phosphate uridyl transferase (GALT) |
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in what tissues does galactose-1-phosphate accumulate in GALT deficiency (galactosemia)?
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liver
spleen lens of the eye kidneys heart muscle cerebral cortex erythrocytes |
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what is the effect of galactose-1-phosphate accumulation in GALT deficiency (galactosemia)?
|
alternative metabolic pathways are activated, leading to the production of galactitol (polyol metabolite of galactose) and galactonate (oxidized by-product of excess galactose)
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what are the symptoms of galactosemia (GALT deficiency)?
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jaundice and hepatomegaly (due to fatty change; occurs in first week)
cataract (galactitol accumulates and increases tonicity, leading to increased water absorption; occurs in first few weeks) nonspecific CNS changes (loss of nerve cells, gliosis, and edema) leading to mental retardation (6-12 months) failure to thrive almost from birth vomiting and diarrhea (within a few days of milk ingestion) aminoaciduria, increased frequency of fulminant E. coli septicemia, hemolysis and coagulopathy |
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where is CNS edema located in galactosemia (GALT deficiency)?
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particularly in the dentate nuclei of the cerebellum, the olivary nuclei of the medulla, and the cerebral cortex and white matter
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how can diagnosis of galactosemia be suspected and reliably determined?
|
suspected if any reducing sugar other than glucose is demonstrated in the urine
tests that directly ID the deficiency of GALT reliably diagnose |
|
|
how is galactosemia (GALT deficiency) treated?
|
most of the clinical and morphological changes of galactosemia can be prevented or ameliorated by early removal of galactose from the diet for at least the first 2 years of life
|
|
|
what is cystic fibrosis?
|
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
leads to abnormally viscous secretions which obstruct organ passages |
|
|
what are the clinical features of cystic fibrosis?
|
chronic lung disease secondary to recurrent infections
pancreatic insufficiency steatorrhea malnutrition hepatic cirrhosis intestinal obstruction male infertility |
|
|
what is the most common lethal genetic disease that affects caucasian populations?
|
cystic fibrosis
1 in 2500 live births |
|
|
what is the inheritance pattern of cystic fibrosis?
|
autosomal recessive
|
|
|
what is the primary defect in cystic fibrosis?
|
mutation in an epithelial chloride channel protein encoded by the cystic fibrosis transmembrane regulator (CFTR) gene, causing abnormal function
|
|
|
what ion channels and cellular processes can CFTR regulate?
|
outwardly rectified chloride channels
inwardly rectified potassium channels epithelial sodium channel (ENaC) gap junction channels cellular processes involved in ATP transport and mucus secretion |
|
|
where is ENaC located?
|
ENaC = epithelial Na channel
located on the apical surface of exocrine epithelial cells |
|
|
what is the function of ENaC?
|
ENaC = epithelial Na channel
responsible for Na uptake from the luminal fluid, rendering the luminal fluid hypotonic |
|
|
what is the effect of normal CFTR on ENaC?
|
CFTR = cystic fibrosis transmembrane conductance regulator
ENaC = epithelial Na channel normally functioning CFTR inhibits ENaC |
|
|
what happens to the activity of ENaC in cystic fibrosis?
|
CFTR, the mutated protein in cystic fibrosis, normally inhibits ENaC
in cystic fibrosis, ENaC activity increases, markedly augmenting sodium uptake across the apical membrane exception: in sweat ducts, ENaC activity decreases as a result of CFTR mutations |
|
|
what is the exception to excessive ENaC activity in cystic fibrosis?
|
in sweat ducts, ENaC activity decreases as a result of CFTR mutations
a hypertonic luminal fluid with high chloride and high sodium content is formed this is the sine qua non of classic cystic fibrosis |
|
|
define "sine qua non"
|
often used in regard to any sign, symptom or finding whose absence would very likely mean absence of the target disease or condition
|
|
|
what is the result of mutations in CFTR in the respiratory and intestinal epithelium?
|
CFTR = cystic fibrosis transmembrane conductance regulator
in respiratory and intestinal epithelium, mutations of CFTR (cystic fibrosis) result in loss or reduction of chloride secretion into the lumen, as well as increase of active luminal sodium absorption (due to loss of ENaC activity) both of these ion changes increase passive water reabsorption from the lumen, lowering the water content of the surface fluid layer coating mucosal cells no difference in salt concentration of surface fluid layer, but low volume of surface fluid |
|
|
what is the result of dehydration, as a result of cystic fibrosis, in the lungs?
|
leads to defective mucociliary action and the accumulation of hyperconcentrated, viscid secretions that obstruct the air passages and predispose to recurrent pulmonary infections
|
|
|
what is the classic cystic fibrosis phenotype?
|
pancreatic insufficiency
sinopulmonary infections gastrointestinal symptoms |
|
|
what is the effect of cystic fibrosis on pH of luminal fluids?
|
normal tissues secrete alkaline fluids
certain mutations in CFTR preserve chloride transportation, but instead decrease bicarbonate secretion; this causes decreased luminal pH which leads to increased mucin precipitation and plugging of ducts, increased binding of bacteria to plugged mucins |
|
|
what bacteria, in particular, colonizes the lower respiratory tract in cystic fibrosis patients?
|
Pseudomonas aeruginosa
at first intermittently and then chronically |
|
|
what is meconium ileus?
|
earliest stools of an infant (meconium) sometimes become thickened and congested in the ileum, a condition known as meconium ileus
meconium ileus is often the first sign of cystic fibrosis |
|
|
what are the three most common organisms responsible for lung infections in cystic fibrosis?
|
S. aureus
Hemophilus influenzae Pseudomonas aeruginosa |
|
|
what is found in 95% of males who survive cystic fibrosis into adulthood?
|
azoospermia and infertility
congenital bilateral absence of the vas deferens |
|
|
what are the changes in the pancreas of a cystic fibrosis patient?
|
dilation of ducts
plugging of ducts with eosinophilic mucin atrophy of parenchymal glands replacement of parenchymal glands by fibrous tissue |
|
|
define "protean"
|
in medicine, having variable symptoms and presentations
|
|
|
what is associated with pancreatic insufficiency?
|
protein and fat malabsorption and increased fecal loss
|
|
|
what are the manifestations of malabsorption?
|
large, foul-smelling stools
abdominal distention poor weight gain |
|
|
what type of pancreatic insufficiency is common in cystic fibrosis?
|
exocrine pancreatic insufficiency
endocrine pancreatic insufficiency is uncommon in cystic fibrosis |
|
|
what are the most common causes of death in patients with cystic fibrosis?
|
cardiorespiratory complications
- persistent lung infections - obstructive pulmonary disease - cor pulmonale |
|
|
describe liver disease as it relates to cystic fibrosis
|
significant liver disease occurs late in the natural history of cystic fibrosis
obstruction of the common bile duct may occur due to stones or sludge (presents with abdominal pain and acute onset of jaundice) |
|
|
what is the diagnosis of cystic fibrosis based?
|
persistently elevated sweat electrolyte concentrations (often mother makes diagnosis by recognizing infant's abnormally salty sweat)
characteristic clinical findings (sinopulmonary disease, GI manifestations) abnormal newborn screening test family history |
|
|
what is liver involvement in cystic fibrosis?
|
bile canaliculi are plugged by mucinous material, accompanied by ductular proliferation and portal inflammation
hepatic steatosis focal biliary cirrhosis, which can eventually involve the entire liver, resulting in diffuse hepatic nodularity (less than 10% of pts) |
|
|
what is the gold standard for diagnosis of cystic fibrosis?
|
sequencing of the CFTR gene
|
|
|
define SIDS
|
SIDS = sudden infant death syndrome
the 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 the death scene, and review of the clinical history |
|
|
what are the usual conditions in which an infant dies in SIDS?
|
infant usually dies while asleep, mostly in the prone or side position
aka crib death or cot death |
|
|
what is the leading cause of death between age 1 month and 1 year in the United States?
|
SIDS
|
|
|
what is the third leading cause of death overall in infancy?
|
SIDS
(follows congenital anomalies and diseases of prematurity and low birth weight) |
|
|
when do most SIDS deaths occur?
|
90% during the first 6 months of life
most between 2 and 4 months |
|
|
what is an "apparent life-threatening event"?
|
some combination of apnea, marked change in color or muscle tone, choking or gagging which were considered to put infants at risk for subsequent SIDS
|
|
|
what are the findings in infants who have died of suspected SIDS?
|
multiple petechiae (on thymus, visceral and parietal pleura, and epicardium)
vascular engorgement w/ or w/o pulmonary edema astrogliosis of brain stem and cerebellum hypoplasia of the arcuate nucleus frequent persistence of hepatic extramedullary hematopoiesis and periadrenal brown fat |
|
|
what is the "triple risk" model of SIDS that attempts to explain the multifactorial condition?
|
1) a vulnerable infant
2) critical developmental period in homeostatic control 3) exogenous stressor(s) |
|
|
what is the most compelling hypothesis to account for the vulnerable infant in SIDS?
|
delayed development of "arousal" and cardiorespiratory control
|
|
|
what part of the brain plays a critical role in the body's arousal response to noxious stimuli encountered during sleep?
|
brain stem (particularly medulla oblongata)
noxious stimuli: hypercarbia, hypoxia, thermal stress |
|
|
what epidemiologic factors are associated with SIDS?
|
preterm infants
low birth weight infants male sex maternal smoking during pregnancy young maternal age frequent childbirths inadequate prenatal care most have a history of a mild respiratory tract infection immediately prior (no single organism IDed) |
|
|
what is the link between laryngeal chemoreceptors, prone position, and SIDS?
|
laryngeal chemoreceptors usually elicit an inhibitory cardiorespiratory reflex when stimulated
stimulation is augmented by respiratory tract infections, which increase the volume of secretions, and by the prone position, which impairs swallowing and clearing of the airways even in healthy infants |
|
|
what are the environmental stressors that increase risk of SIDS?
|
prone or side sleeping positions
sleeping with parents in first 3 months sleeping on soft surfaces thermal stress |
|
|
according to the american academy of pediatrics, what is the only safe sleeping position for reducing the risk of SIDS
|
supine sleeping position
|
|
|
what is the most common cause of sudden unexpected death of babies?
|
infections
- viral myocarditis - bronchopneumonia |
|
|
how many infant deaths are caused by cancer in the US in children between age 4 and 14?
|
9%
only accidents cause significantly more deaths |
|
|
why might benign tumors cause serious complications?
|
by virtue of their location or rapid increase in size
|
|
|
define heterotopia
|
aka choristoma
microscopically normal cells or tissues that are present in abnormal locations |
|
|
define hamartoma
|
excessive, focal overgrowth of cells and tissues native to the organ in which it occurs
cellular elements are mature and identical to those found in remainder of organ, but they do not reproduce the normal architecture of the surrounding tissue |
|
|
what are the most common neoplasms of childhood?
|
soft-tissue tumors of mesenchymal derivation
|
|
|
what are the most common tumors of infancy?
|
hemangiomas
|
|
|
what types of hemangiomas can be encountered in infants?
|
cavernous and capillary
**capillary hemangiomas are often more cellular than in adults** |
|
|
where are most hemangiomas located?
|
in the skin, particularly on the face and scalp
produce flat to elevated, irregular, red-blue masses |
|
|
what are port-wine stains?
|
a vascular birthmark consisting of superficial and deep dilated capillaries in the skin which produce a reddish to purplish discoloration of the skin
can represent flat, larger lesions of hemangioma |
|
|
what happens to hemangiomas as a child grows?
|
may enlarge with the growth of the child
in many instances, they spontaneously regress |
|
|
what hereditary disorder can hemangiomas (particularly port wine stains) represent a facet of?
|
von Hippel-Lindau disease
|
|
|
what is lymphangiectasis?
|
pathologic dilation of lymph vessels
|
|
|
what usually characterizes lymphangiomas?
|
cystic and cavernous spaces
|
|
|
where are lymphangiomas located?
|
can occur in the skin
more often, they are encountered in deeper regions of the neck, axilla, mediastinum, retroperitoneal tissue, and elsewhere |
|
|
how dangerous are lymphangiomas?
|
histologically benign
tend to increase in size after birth (leads to accumulation of fluid and the budding of preexisting spaces) and so may encroach on vital structures (mediastinal structures, nerve trunks in axilla) |
|
|
how large does a lymphangiectasis get?
|
not progressive, so it does not extend beyond its original location
diffuse swelling of part or all of an extremity that creates cosmetic problems that are often difficult to correct surgically |
|
|
define fibromatosis
|
fibrous tumor in infants and children that consist of sparsely cellular proliferations of spindle-shaped cells
|
|
|
define congenital-infantile fibrosarcomas
|
fibrous tumors that infants are born with that are richly cellular and indistinguishable from fibrosarcomas occurring in adults
have better prognosis than adult fibrosarcomas |
|
|
what are mature teratomas?
|
benign, well-differentiated cystic lesions
|
|
|
what are immature teratomas?
|
cystic lesions of indeterminate potential
|
|
|
how do unequivocally malignant teratomas present?
|
usually admixed with another germ cell tumor component such as endodermal sinus tumor
two peaks in incidence: - 2 years of age - late adolescence/early adulthood |
|
|
how can teratomas presenting in late adolescence/early adulthood be congenital?
|
if they are slowly growing, you might not see any symptoms from them until later in life
|
|
|
what are the most common teratomas of childhood?
|
sacrococcygeal teratomas
|
|
|
what is the distribution of sacrococcygeal teratomas between boys and girls?
|
4 times more common in girls than in boys
|
|
|
aside from the sacrococcygeal area, what are the other sites for teratomas in childhood?
|
testis
ovaries mediastinum retroperitoneum head and neck |
|
|
what neoplasms exhibit sharp peaks in incidence in children younger than 10? (11)
|
1) leukemia (principally acute lymphoblastic leukemia)
2) neuroblastoma 3) wilms tumor 4) hepatoblastoma 5) retinoblastoma 6) rhabdomyosarcoma 7)teratoma 8) Ewing sarcoma 9) juvenile astrocytoma 10) medulloblastoma 11) ependymoma |
|
|
what is nephroblastoma?
|
Wilms tumor
|
|
|
what are small round blue cell tumors?
|
collectively, childhood tumors, because of their primitive histologic appearance
|
|
|
how do malignant neoplasms of children differ from those of adults?
|
tend to have a more primitive (embryonal) rather than pleomorphic-anaplastic microscopic appearance
often characterized by sheets of cells with small, round nuclei, and frequently show features of organogenesis specific to the site of tumor origin |
|
|
define neuroblastic tumor
|
tumors of the sympathetic ganglia and adrenal medulla that are derived from primordial neural crest cells populating these sites
|
|
|
what are the characteristic features of neuroblastic tumors as a family?
|
spontaneous or therapy-induced differentiation of primitive neuroblasts into mature elements
spontaneous tumor regression wide range of clinical behavior and prognosis |
|
|
what is the most important member of the neuroblastic tumor family?
|
neuroblastoma
|
|
|
what is the most common extracranial solid tumor of childhood?
|
neuroblastoma
|
|
|
what is the most frequently diagnosed tumor of infancy?
|
neuroblastoma
|
|
|
what is the median age at diagnosis of neuroblastoma?
|
18 months
|
|
|
what is a major cause of familial predisposition to neuroblastoma?
|
germline mutations in the anaplastic lymphoma kinase (ALK) gene
|
|
|
what is the 5-year survival for patients with the high-risk subsets of neuroblastoma?
|
40%
|
|
|
what is the size range of neuroblastomas?
|
minute nodules to large masses (>1kg in weight)
|
|
|
what happens to the great majority of neuroblastomas?
|
they spontaneously regress, leaving only a focus of fibrosis or calcification in the adult
|
|
|
how well confined are neuroblastomas?
|
some are often sharply demarcated by a fibrous pseudo-capsule
others are far more infiltrative and invade surrounding structures |
|
|
describe the histologic appearance of classic neuroblastomas
|
composed of small, primitive-appearing cells with dark nuclei, scant cytoplasm, and poorly defined cell borders growing in solid sheets
mitotic activity, nuclear breakdown (karyrrhexis), and pleomorphism may be prominent |
|
|
what is in the background of neuroblastomas?
|
faintly eosinophilic fibrillary material (neuropil)
|
|
|
what are Homer-Wright pseudorosettes?
|
neuroblastoma tumor cells that are concentrically arranged about a central space filled with neuropil
|
|
|
what are dense core granules in neuroblastoma?
|
small, membrane-bound, cytoplasmic, catecholamine-containing secretory granules containing characteristic central dense cores surrounded by a peripheral halo
|
|
|
how do neuroblastomas typically present in children under 2 years?
|
large abdominal masses
fever weight loss |
|
|
how do neuroblastomas typically present in older children?
|
typically not noticed until metastases prroduce manifestations (bone pain, respiratory symptoms, GI complaints)
|
|
|
where do neuroblastomas typically metastasize to?
|
liver
lungs bones bone marrow periorbital region (causes proptosis and ecchymosis) |
|
|
what is blueberry muffin baby?
|
in neonates, disseminated neuroblastomas may present with multiple cutaneous metastases that cause deep blue discoloration of the skin
|
|
|
what is produced by 90% of neuroblastomas that is an important diagnostic feature?
|
catecholamines
elevated blood levels of catecholamines and elevated urine levels of vanillylmandelic acid (VMA) and homovanillic acid (HVA) (metabolites of catecholamines |
|
|
how are neurblastoma and pheochromocytoma alike? how do they differ?
|
similar: both produce catecholamines
different: hypertension is much less frequent in neuroblastomas than in pheochromocytomas |
|
|
what are the most important determinants of outcome in neuroblastomas?
|
age and stage
18 months is a critical point of dichotomy in terms of prognosis (<18 mo, excellent prognosis; >18 mo, at least intermediate risk category) |
|
|
what is the molecular event that has the most profound impact on the prognosis of neuroblastoma?
|
amplification of the N-MYC ocogene
this bumps the tumor into a "high" risk category |
|
|
what is the most common primary renal tumor of childhood?
|
Wilms tumor
|
|
|
what is the fourth most common pediatric malignancy in the US?
|
Wilms tumor
|
|
|
when is the peak incidence of Wilms tumor?
|
between 2 and 5 years
95% occur before 10 years |
|
|
what is a synchronus Wilms tumor?
|
Wilms tumor that involves both kidneys simultaneously
|
|
|
what is a metachronus Wilms tumor?
|
Wilms tumors that afect the kidneys one after the other
|
|
|
what is WAGR syndrome?
|
constitutional (germline) deletion of 11p13
Wilms tumor (33%) characterized by aniridia genital anomalies mental retardation |
|
|
what is Denys-Drash syndrome?
|
dominant negative missense mutation of WT1 (wilms tumor 1 gene)
characterized by gonadal dysgenesis (male pseudohermaphroditism), and early onset nephropathy (leads to renal failure) |
|
|
development of what organs is dependent on WT1?
|
kidneys
gonads |
|
|
what is Beckwith-Wiedemann syndrome?
|
loss of genomic imprinting on 11p15.5, WT2 gene
characterized by organomegaly, macroglossia, hemihypertrophy, omphalocele, abnormally large cells in adrenal cortex |
|
|
how is insulin-like growth factor-2 transcriptionally silenced?
|
it is normally expressed solely from the paternal allele of 11p15.5, while the maternal allele is silenced by imprinting
|
|
|
to what developmentally important signalling pathway does beta-catenin belong?
|
WNT (wingless) signaling pathway
|
|
|
what are nephrogenic rests?
|
putative precursor lesions of Wilms tumors seen in renal parenchyma adjacent to 25-40% of unilateral Wilms tumors (100% of bilateral tumors)
|
|
|
why is it important to document neprogenic rests?
|
patients with nephrogenic rests are at increase risk of developing Wilms tumor in the contralateral kidney
|
|
|
how do WIlms tumors appear grossly?
|
large, solitary, well-circumscribed mass
on cut section, it is soft, homogeneous and tan to gray with occasional foci of hemorrhage, cyst formation, and necrosis |
|
|
how do Wilms tumors appear microscopically?
|
characterized by recognizable attempts to recapitulate different stages of nephrogenesis
classic triphasic combination of blastemal, stromal, and epithelial cell types is observed in the majority of all lesions blastemal component - sheets of small blue cells with few distinctive features epithelial component - abortive tubules or glomeruli stromal cells - usually fibrocytic or myxoid; sometimes skeletal muscle differentiation |
|
|
define anaplasia
|
presence of cells with large, hyperchromatic, pleomorphic nuclei and abnormal mitoses
correlates with the presence of p53 mutations and emergence of resistance to chemotherapy |
|
|
how do most children with Wilms tumors present?
|
large abdominal mass that may be unilateral or may extend across the midline and down into the pelvis
hematuria pain in the abdomen (after some traumatic incident) intestinal obstruction appearance of hypertension |
|
|
what is the prognosis for Wilms tumor?
|
most patients can expect to be cured
molecular parameters that correlate with adverse prognosis include loss of genetic material on chromosomes 11q and 16q and gain of chromosome 1q in tumor cells |
|
|
what risks are increased in individuals who survive Wilms tumors?
|
rist of developing second primary tumors
- bone and soft tissue sarcomas - leukemia - lymphomas - breast cancers |
