Teratology Flashcards
Top 2 causes of infant mortality (up to age 4)
Birth defects
Preterm/Low birthweight
What % of zygotes and pregnancies result in normal, healthy babies?
25% zygotes
<50% pregnancies
Gestational milestones in order
Implantation Primitive streak Early Differentiation Organogenesis Ends Usual Parturition
When does birth defects start in gestation?
Primitive streak onwards
6 weeks
Why do you have to know the gestational period of a women before giving pills?
primitive streak (6 weeks) to organogensis end (50 weeks) is birth defects
Intercellular Signals
Message sent by inducer Spatial proximity received by compentent population ∆ developmental state Maturational or stability
What allows for internal rearrangement in humans?
We have time in gestation, development schedules, populations of cell
What is the dynamic nature of embryonic development?
There is a small period of time to go back before going forward
Ability to adjust to changing conditions
How much do we not know about the cause of birth defects?
50%
developmental plasticity
ability of a single gene to express +1 phenotype based on environmental conditions
(BMI >27; T2D, CHD)
Reason to advocate early prenatal care
What causes chromosomal abnormaities typically?
nondisjunction during gametogenesis
How much ova are aneuploid in humans mostly?
15%, increases in maternal age
How else can aneuploid happen?
nondisjunction during cleavage: results in mosaicism of zygote
Signs of Trisomy 21/Down Syndrome
Brachycephaly
flat nasal bridge
upward slanding palpebral fissures
Simian crease
Fatality in Trisomy 21/Down Syndrome
75% spontaneous abort
20% still born
Survivors survive into 50’s
Trisomy 18/Edward Syndrome Signs
Flexed digits
Micrognathia
Low set, malformed ears
prominent occiput
Fatality in Trisomy 18/Edward Syndrome
50% spontaneously abort
survival rarely past 6 month
Signs of Patau Syndrome/Trisomy 13
Cleft lip/palate
Sloping forhead
CNS malformations
Polydactyly
Fatality of Patae Syndrome/Trisomy 13
50% spontaneously abort
Rarely survive beyond 6 months
Signs of Turner syndrome/45, X
Lymphedema
Lack of secondary sex characteristics
Webbed neck
broad chest
Fatality of Turner Syndrome/45, X
1% embryos survive
X missing in Turner’s syndrome
Paternal X usually
47, XXX
Normal female appearance
fertile
20% mentally retarded
47, XXY/Klinefelter Syndrome
Male small testes aspermatogenesis long legs intelligence deficit gynecomastia
47, XYY
Normal male appearance
tall
Triploidy 3N
Intrauterine growth retardation
Small trunk
large head
What typically causes triploidy 3N
dispermy
Fatality of triploidy 3N
live births are extremely rare
Tetraploidy 4N
Abort very early
probs due to failure of cytoplasmic cleavage or chromosomal segration at first mitotic cleavage division
Nonhomologous DNA translocation caused by
radiation, drugs, chemicals, viruses
balanced vs unbalanced translocation
balanced: non DNA lost or added - less severe
unbalanced - more severe
Cri du chat syndrome
deletion of short arm of chromosome 5
Cri du chat syndrome or deletion of short arm of chromosome 5 results in
microcephaly
severe mental retardation
heart anomalies
Duplications can exist as (3)
- Tandem repeat within chromosome
- attached to a chromosome
- As a separate fragment
Duplications compared to deletions
More common
Less harmful
Inversions
Segment of chromosome is reversed
2 types of chromosomal inversion
ParAcentric: single arm
Pericentric: both arms, including the centromere
What happens in inversion
interes with homolgous recombination and segration during meiosis
Isochromosomes
centromere divides dransversely intead of longitudinally
Most common structural defect of X chromosome
Isochromosomes
When can mutations not be deliterious?
When good (evolution) When silent: no effect on protein function or impair function of a redundant gene
What disease has a problem with sonic hedgehog?
Holoprosenscephaly
What happens in holoprosencephaly?
Failure of forebrain to completely separate into 2 lobes
leads to a wide range of brain, skull and facial defects
(form cleft lip to cyclopia/hypertolorism with proboscis)
Dwarfism disease name
Achondroplasia: FGFR3
Predisposition for suceptibility or resistance in embryo genotype oftem due to
plymorphisms in drug netabolizing enzymes
phenytoin/dilantin
Fetal hydantion (dilantin) syndrome
Phenytoin stuck in toxic epoxide intermediate without epoxide hydrolase
Fetal hydantion (dilantin) syndrome signs
5% of fetuses IUGR microcephaly mental retardation altered facies underdeveloped nails
∆s in women during pregnancy
50% increase in plasma volume "" CO "" GFR ↓ systemic vacular resistance " plasma protein binding Altered salts and mineral metabolism Greater pulmonary ventilation
Toxicities to embryo (3) from mother toxicity
- aminopterin
- methyllmercury
- polychlorinated biphenyls (eh)
Toxicity to embryo in stress (3)
steroidal hormones
ethanol
cigarette smoking
Toxicity to embryo without significant maternal effects (4)
- Thalidomide
- Accutane
- Diethylstilbestrol
- Ionizing radiation
Preeclampsia
blood vessels in uterus constrict
Restricts blood supply to placneta and increases bp in mother
associated with ↓ VEGF in maternal blood
What decreases incidence of preeclampsia
periconecptual multivitamins
Risk of birth defects in poor glucose control vs normally
10% to 3%
Maternal diabetes associated with (3)
- Macrosomia (large baby)
- Spina bifida
- Heart, Skeletal, Urinary, reproductive, and digestive tract defects
Hyperthermia in mother happens in situations of (3)
Fever,
extremely vigorous exercise,
hot tub/sauna
What and when: hyperthermia
3-4 weeks gestation when the neural tube is closeing
increased risk of neural tube defects
(including spina bifida to anencephaly)
Phenylketonuria (PKU)
defect in phenylalanine metabolism (phylalanine hydroxylase)
PKU controlled by
avoiding certain foods high in phenylalinine (meat, fish, eggs, dairy products, nuts, lentis, aspartame)
Excess Phe
abnormal brain development and mental retardation
heart defects
behavior problems
Difference between malformation and deformation?
Deformation is late in gestation and caused by physical changes
Septate Uterus can cause:
- club foot
- hip dislocation
- skull deformation
- reduction defects of limbs, face
Oligohydramnios
Low level of amniotic fluid often due to renal agenesis or amnion lea
Prader Willi Syndrome
Paternal exposure of hydrocarbon
15q deletion
Prader Willi Syndrome results in
hypothalamic dysfunction
hyperphagia
obesity
etc
What can somewhat protect the fetus?
Maternal IgG but not well, infections mild or asymptomatic in mother may seriously damage the fetus
Rubella Virus/German Measles trad of clinical signs
- Cataract
Hearing defect
Patent ductus arteriosis
Rubella VIRUS/German Measles sensitivity period
Earlier = greater risk
up to 5 weeks of gestation
Most common VIRAL infection at birth in US
Cytomegalovirus
1/2 of infected infants with cytomegalovirus get: (4)
- Hearing loss
- Mental disability
- Impaired liver function
- Poor growth
Do cytomegalovirus infants get problems at birth?
10% are asymptomatic at birth and manifest problems within first few years of life
What type of infection is toxoplasma gondii
Protozoan
How is the protozoan infection of toxoplasma gondii spread?
via raw meat and cat feses
early exposure = greater risk
Symptoms of toxoplasma gondii (10% at birth): (3)
- Eye infections
- enlarged liver and spleen
- jaundice
Symptoms of toxoplamsa gondii if later due to reactivation of latent infection
- Eye infections
- vision impairment (retinochoroiditis)
- hearing loss
- learning disabilities
What type of infection is Treponema pallidum (syphilis)
Spirochete bacteria
When/How can treponema pallidum (syphilis) be treated?
antibiotic treatment of maternal syphilis before 16 weeks gestation
Effects of treponema pallidum?
- Stillbirth/neonatal death
- Dental anomalies
- Deafness
- Mental retardation
- Skin, bone lesions
- Meningitis
Do birth defects have pathognomonics?
NO those are unique to a single cause/etiology
birth defect anamolies ARE NOT
What things can cause spina bifida as a characteristic not a pathognomonics
- genetic mutation
- methotrexate
- valproic acid
- maternal diabetes
- hyperthermia
- Folate Deficiency
Methylmercury in shellfish yielded
itai-itai, convulsions, psychosis, coma, death
in utero: neurological and behavioral disturbances
instability of neck, convulsions, mental retardation, microcephaly, brain damage
How does methylmercury cause harm?
Stabilizes microtubules, interferes with neuronal cells proliferation and migration
PCBs (polychlorinated biphenyls)
Used in insulators, hydraulic fluids, plastic pains until ‘77
continued input into environment via disposal of PCB containing products
PCDFs (polychlorinated dibenzofurans) - CAUSE OF DEFECTS
byproducts of incineration, smelting, steel production, burning fossil fuels, manufacture of chlorinated compounds, bleaching of pulp and paper
PCDDs (polychorinated dibenzo-p-dioxin)
same as PCDF
TCDD = most infamous of all HAH congener = was in defoliant Agent Orange
PCDFS (POLYCHLORINATED DIBENSOFURANS) effects
Prematurity, low birth weight, neonatal death Growth abnormalities Neurological damage Hyperpigmentation Chloracne Gum and dental disorders Rock bottom heel Sperm defects
Fetal alcohol syndrome (FAS)
A set of physical and mental birth defects stemming from in utero alcohol exposure
Fetal alcohol spectrum disorders (FASD)
Umbrella term describing range of fetal alcohol effects
NOT a clinical diagnosis
What is the leading PREVENTABLE cause of mental retardation and birth defects?
FASD
(1 in 100)
(1 in 1000 FAS)
Societal cost: 5.4 billion annually
FAS characteristics
Mental Retardation Small head circumference Facial abnormalities: reduced, indistinct philtrum, thin upper lip, epicanthal folds short palpebral fissures, maxillary hypoplasia, poor frontonasal process development Growth deficits Microcephaly Heart liver, kidney defects Vision and hearing problems
FAS features from later exposure
Motor function hyperactivity memory, attention, and judgement problems language problems difficulties in school
Most sensitive period for FAS
1st month of gestation (risky b/c many don’t know they’re pregnant until the 2nd month)
But functional deficits can result from THRU OUT gestation
FAS characteristics mechanism of action
Excessive cell death (especially neurons)
Decreased cell proliferation
Altered cell migration (especially neural crest)
Loss of cell adhesion
Altered neuronal/glial interactions
Altered differentiation
Thalidomide
caused teratogenicity if taken when pregnant
Still used for treating leprosy, cancer, certain types blindness
Thalidomide effects
Quadruple amelia
Phocomelia
Retinoids
Similar to Vitamin A
teratogenic
dangerous b/c fine for girls but 1/2 of pregnancies are unplanned
Retinoid Development Toxicity
Craniofacial defects Heart malformations Thymic defects Cleft palate Eye and ear deformities CNS defects
Sensitivity period for retinoids
3-5 weeks gestation
critical period for cranial neural cret specification
Effects of retinoids from
Disruption of HOX gene expression and subsequent effects on cranial and cardiac neural crest cells (and somite-derived structures)
Amniocentesis
Invasive Prenatal Screening Performed at 13 weeks gestation Fetal cells isolated from small volume of amniotic fluid Genetic/karyotypic analysis Risk of miscarriage 1:300
Chorionic villus sampling
Invasive prenatal screening Performed at 8-10 weeks gestation Chorionic villus cells collected Genetic/karytypic analysis Risk of miscarriage 1:100
Ultrasound
Non-invasive so used more than the invasive ones
Nuchal translucency ultrasound
Performed at 9-13 weeks gestation
Increased thickness of nuchal fold >3mm
indicates lymphedema and correlates with trisomy 13, 18, 21
Possible risk of neural architecture disturbance so don’t use too much
Maternal serum analysis
Non-Invasive Prenatal Screening at 15 weeks AFP, Estriol, ß-hCG maternal blood has 6 fetal cells/mL mostly trophoblasts Fetal cells differ from maternal cells by surface receptors and methylation patters cloned, genetic karyotypic analysis performed no risk of miscarriage
High AFP in mother serum =
neural tube defects
other combinations = various trisomies
Conditions associated with smoking
spontaneous abortion, preterm delivery, delivery problems, Intrauterine Growth Retardation (IUGR)/Low birth weight
Altered infant bp
Anamolies with smoking
Extra digits among children of african descent
Webbing between digits among caucasion males
Not sure about these though
Stopping smoking most likely helps decrease infant mortality by
decreasing premature births (17%, 4.5K)
Should women gain weight in pregnancy?
Yes, if stop smoking +5-7, its healthy
