Diseases of infancy and childhood Flashcards
what are the four time spans in the development of the infant
neonatal period–> first 4 weeks of life
infancy–> first year of life
age 1-4 years
age 5-14 years
what is the most common cause of mortality in the first year of life
birth defects
what are malformations
primary errors of morphogenesis
intrinsically abnormal development process
multiple genetic loci
what is a disruption
secondary destruction of an organ or body region that was previously normal in development
extrinsic disturbance
amniotic bands - classic example
can be caused by environmental agents
not heritable
what is a deformation
extrinsic disturbance of development
fundamental to this is localized or generalized compression of the growing fetus by abnormal biomechanical forces
commonly caused by uterine constraint
factors leading to this include: first pregnancy small uterus malformed uterus leiomyomas
oligohydramnios
multiple fetuses
abnormal fetal presentation
example is clubfeet
what is a sequence
cascade of anomalies triggered by one initiating aberration
Potter sequence:
oligohydramnios caused by leakage of amniotic fluid, uteroplacental insufficiency (caused by maternal HTN or toxemia) and renal agenesis in the fetus (b/c fetal urine is a major constituent of amniotic fluid)
oligohydramniosis causes compression of the newborn infant which causes:
- flattened facies
- positional abnormalities of the hands and feet
- dislocated hips
- poor growth of chest wall and lungs
- nodules in the amnion (amnion nodosum)
what is a syndrome
constellation of congenital anomalies that are pathologically related and cannot be explained on the basis of a single, localized, initiating defect
most often caused by a single etiologic agent, such as a viral infection or chromosomal abnormality
which then affects Several tissues
agenesis
complete lack of an organ
and its primmordium
aplasia
absence of an organ but one due to failure of development of the primordium
atresia
absence of an opening
usually of a hollow visceral organ such as the trachea and intestine
hypoplasia
incomplete development of decreased size of an organ with decreased number of cells
hyperplasia
enlargement of an organ due to increased numbers of cells
what are the three major categories of causes of congenital abnormalities
genetic
environmental
multifactorial
unknown
what is holoprosencephaly
the most common developmental defect of the forebrain and midface in humans
the hedgehog signaling pathway plays a critical role in the morphogenesis of these structures and there is loss of function of these components in patients with a family history of holoprosencephaly
single gene mutation
what is achondroplasia
what is the cause
mechanism
the mot common form of short limb dwarfism
caused by gain of function mutations in fibroblast growth factor (FGFR3)
FGFR3 protein is a negative regulator of bone growth and the activating FGFR3 mutations in achondroplasia are thought to exaggerate this physiologic inhibition, resulting in dwarfism
single - gene mutation
what viruses are associated with anomalies
rubella cytomegalic inclusion disease herpes simplex varicella-zoster influenza mumps HIV enterovirus
***age at which the infection occurs in the mother is critically important
what is the at risk age for rubella infection?
what are the fetal defects associated with this infection
extends from shortly before conception to the sixteenth week of gestation
defects:
cataracts
heart defects (persistent ductus arteriosus, pulmonary artery hypoplasia or stenosis
ventricular septal defect, tetralogy of fallot)
deafness
metal retardation
***congenital rubella syndrome
intrauterine infection with cytomegalovirus ….
when is the fetus most at risk for this….
what are the outcomes
most common fetal viral infection
the highest at-risk period is the second trimester of pregnancy
b/c organogenesis is completlet by the end of the first trimester, congenital malformations occur less frequently than in rubella
involvement of the CNS is a major feature
mental retardation
microcephaly
deafness
hepatosplenomegaly
what are some drugs/chemicals that are teratogenic
thalidomide folate antagonists androgenic hormones alcohol anticonvulsants warfarin 13-cis retinoic acid (acne)
thalidomide causes what to occur
what is the mechanism
limb abnormalities
downregulation of the developmentally important wingless (WNT) signaling pathway through upregulation of endogenous WNT repressors
these drugs are used to treat neoplasms
what are the effects alcohol has on development
fetal alcohol spectrum disorders
growth retardation microcephaly atrial septal defect short palpebral fissures maxillary hypoplasia
mechanism:
affects the developmental signaling pathways –> retinoic acid and hedghog
what are the effects of radiation exposure during organogenesis
microcephaly
blindness
skull defects
spina bifida
what are the effects of maternal diabetes
results in:
increased body fat, muscle mass, and organomegaly (fetal macrosomia)
cardiac anomalies
neural tube defects and other CNS malformations
this is called diabetic embryopathy
multifactorial causes of abnoramlities
arise as a result of inheritance of multiple genetic polymorphisms that confer a susceptibility phenotype
the interaction of this phenotype and the environment is then required before the disorder manifests
what is the embryonic period
first 9 weeks of pregnancy
what is the fetal period
after 9 weeks and terminating at birth
in the early embryonic period (first 3 weeks after fertilization) what can occur
an injurious agent damages either enough cells to cause death and abortion or only a few cells –> allowing the embryo to recover without developing defects
what is significant about the time b/w the third and 9th weeks in the embryo’s development
when is the peak sensitivity during this period
the embryo is EXTREMELY susceptible to teratogenesis
peak sensitivity–> b/w the 4th and 5th weeks during which time the organs are being crafted out of the germ cell layers
what occurs during the fetal period
further growth and maturation of the organs
reduced susceptibbility to teratogenic agents
fetus is susceptible to growth retardation or injury to already formed organs
what does cyclopamine cause
what is the mechanism
derived from “California lily”
craniofacial abnormalities including holoprosencephaly and cyclopia (single fused eye)
inhibitor of hedgehog signaling in the embryo
what is valproic acid normally used for
what is the mechanism for its teratogenic actions
anti-epileptic
disrupts expression of HOX (transcription factors) (homeobox)
the genes encoding HOX proteins have a 190 nucleotide motif, dubbed the homeobox, which binds DNA in a sequence-specific fashion
HOX proteins in humans have been implicated in the patterning of limbs, vertebrae, and craniofacial structures
what is all-trans-retinoic acid essential for
what happens in its absence during embryogenesis (vitamin A deficiency)
what occurs with excessive retinoic acid
vitamin A (retinol) is essential for normal development and differentiation
its absence during embryogenesis resultis in multiple organ systems affected –> eyes, GU, CV, diaphragm, lungs… etc.
in excess–> CNS, cardiac and craniofacial defects (cleft lip, cleft palate)
Cleft palate is caused by retinoic-acid mediated deregulation of components of the TGF-beta signaling pathway (involved in palatogenesis)
critical period of development for CNS
heart
eyes
ears
CNS- 3-5 weeks
heart 3.5-6.5
eyes- 4.5-8.5
ears- 4.5- 9.5
critical period of development for arms legs teeth/palate external genitalia
arms/legs –> 4.5-8 weeks
teeth/palate–> 6.75-9
external genitalia–> 7.5-9.75
above or below what percentile for a given gestational age are children considered SGA or LGA
below 10th percentile or above 90th percentile
what is premature
less than 37 weeks
second most common cause of neonatal mortality
rate of premature babies is actually increasing and is around 12 percent
what are the major risk factors for prematurity
preterm premature rupture of placental membranes (before 37 weeks)
intrauterine infection
- seen with inflammation of placental membranes and fetal umbilical cord
- common organisms include ureaplasma urealyticum, mycoplasma hominis, gardnerella vaginalis, treichomonas, gonorrhea, chlamydia
- HIV and malaria
- TLR-4 activation by bacterial lipopolysaccharide is one of the initiating events in inflammation-induced preterm labor (TLR-4 deregulates prostaglandin expression which in turn induces uterine smooth muscle contractions)
uterine, cervical and placental structural abnormalities
multiple gestations (twins)
what are the hazards of prematurity
hyaline membrane disease (neonatal resp distress syndrome)
necrotizing enterocolitis
sepsis
intraventricular hemorrhage
developmental delay
what are the fetal influences resulting in FGR (fetal growth restriction)
despite an adequate supply of nutrients
chromosomal disorders -triploidy -trisomy 18 -trisomy 21 trisomy 13 -deletions and translocations
congenital anomalies
congenital infections TORCH group of infections -toxolasmosis -rubella -cytomegalovirus -herpesvirus -syphyilis
typically these infants are SGA and symmetric - all organ systems are similarly affected
what are the placental influences that occur with FGR
uteroplacental insufficiency
causes: umbilical-placental vascular anomalies (single umbilical artery) placental abruption placenta previa placental thrombosis and infarction placental infection multiple gestations
tend to be ASYMMETRIC growth retardation of the fetus and viewed as a downregulation of growth in the latter half of gestation b/c of limited availability of nutrients or oxygen
what is genetic mosicism confined to the placenta…
cause of FGR
usually mosaicism is caused by genetic mutations after the zygote has formed
occurs later and within the dividing trophoblast or extraembryonic progenitor cells of the inner cell mass
common to see trisomy 7
what are the maternal influences in FGR
decreased placental blood flow is the most common
- preclampsia
- chronic HTN
what are some causes of neonatal respiratory distress syndrome ?
excessive sedation of the mother fetal head injury during delivery aspiration of blood or amniotic fluid intrauterine hypoxia brought about by coiling of the umbilical cord about the neck hyaline membrane disease
hyaline membrane disease
deposition of a layer of hyaline proteinaceious material in the peripheral airspaces of infants who succumb to this condition
presentation: preterm and AGA male gender maternal diabetes c- section
usually a steady breathing rhythm occurs, but then within 30 minutes breathing becomes difficult and cyanosis may occur
fine rales
ground-glass picture on chest X-ray
etiology and pathogenesis of RDS (neonatal respiratory distress syndrome)
immaturity of the lungs
deficiency in pulmonary surfactant
SP-A and SP-D in surfactant
role in pulmonary host defense and innate immunity
SP-B and SP-C
reduction of surface tension –> less pressure is then required to keep the lungs patent and hence aerated
what produces surfactant
type II alveolar cells
what hormones modulate surfactant synthesis
growth factors–> cortisol, insulin, prolactin, thyroxine and TGF-Beta
intrauterine stress and FGR increase corticosteroid release… what is the signficance of this
this lowers the risk of developing RDS
surfactant synthesis is supressed by the compensatory high blood levels of insulin in infants of diabetic mothers, which counteracts the effects of steroids. this may be why infants with diabetic mothers have higher risk of developing RDS
why does C-section cause increased risk for RDS
b/c labor is known to increase surfactant synthesis
what is the path that leads to formation of hyaline membranes i nthe lungs in RDS
prematurity–> reduced surfactant synthesis, storage and release–> decreased alveolar surfactant
increased alveolar surface tesnion–> atelectasis –> uneven perfusion and hypoventilation
hypoxemia and CO2 retention–> acidosis –> pulmonary vasoconstriction–> pulmonary hypoperfusion –> endothelial and epithelial damage —>
plasma leak into alveoli–> fibrin and necrotic cells (hyaline membrane)
this leads to a increased diffusion gradient
oxygen toxicity causes what two common things
high concentrations of oxygen administered for prolonged periods cause 3 complications
retrolental fibroplasia: eyes
-due to changes in VEGF expression which is induced by hypoxia
bronchopulmonary dysplasia:
associated with disregulation of cytokines causing arrested pulmonary development
-infants with BPD have dysmorphic capillaries and reduced levels of VEGF
necrotizing enterocolitis
PAF- platelet activating factor : causes increasing mucosal permeability by promoting enterocyte apoptosis and compromising intercellular tight junctions
there is a breakdown of mucosal barrier functions and transluminal migration of bacteria occurs
clinical course: bloody stools abdominal distention circulatory collapse gas in the intestinal wall on radiographs
transcervical infections
most bacterial, some viral infection acquired this way
caught by either inhaling infected amniotic fluid in to the lungs shortly before birth or by passing through an infected birth canal
pneumonia, sepsis, and meningitis are the most common sequelae in a fetus infected via this route
transplacental infection (hematologic)
most parasitic, and viral infections and some bacterial gain access to the fetal bloodstream transplacentally via the chorionic villi
parovirus B19- high affinity for erarly erythroid progenitor cells
TORCH group of infections causing: fever, encephalitis choriorteinitis hepatosplenomegaly pneumonitis myocarditis hemolytic anemia vesicular or hemorrhagic skin lesions
