Transcript embryological development and dysmorphology

EMBRYOLOGICAL
DEVELOPMENT AND
DYSMORPHOLOGY
Dr. E.M. Honey
Department of Genetics
University of Pretoria
Introduction
• Normal development from fertilization to birth (38 weeks) is an
extremely complex process.
• Divided into 3 stages:
1. Pre-embryonic – 1 to 19 days
2. Embryonic – 17 to 56 days
3. Fetal stage – 56 days till birth
• All organs originates from three germ layers:
a. Ectoderm
b. Mesoderm
c. Endoderm
• All above processes under genetic and environmental control
Causes of congenital
abnormalities
Genetic
Chromosomal
Single gene
Multifactorial
Subtotal
Environmental
Drugs and chemicals
Infections
Maternal illness
Physical agents
Subtotal
Unknown
Total
6%
7,5%
20-30%
30-40%
2%
2%
2%
1%
5-10%
50%
100%
Aetiology of congenital abnormalities
• 1. Single gene defects – unifactorial/ Mendelian
inheritance(Autosomal dominant, autosomal recessive, Xlinked recessive)
• 2. Multifactorial inheritance – genetic and
environmental influences
• 3. Chromosomal abnormalities – numerical or structural
• 4. Teratogens
• 5. Constraint
Pathogenesis of congenital abnormalities
• 1. Malformation – primary structural defect of
an organ which results from an inherent
abnormality in development
Example: Cleft palate, neural tube defect
Pathogenesis of congenital abnormalities
• 2. Disruption – an abnormal structure of an organ
or tissue as a result of external factors disturbing
the normal developmental process – include
ischaemia, infection or trauma
Example: Amniotic band syndrome
Pathogenesis of congenital abnormalities
• 3. Deformation – an abnormal mechanical force
which distorts an otherwise normal structure
Example: Mild talipes(club foot)
Pathogenesis of congenital abnormalities
• 4. Dysplasia – an abnormal organisation of cells
into tissue in all parts of the body in which that
particular tissue is present
Example: Ectodermal or skeletal dysplasia
Clinical presentation of congenital
malformations
• Syndromes: Consistent patterns of abnormalities
for which there will often be a known underlying
cause
Example: Down syndrome – chromosomal
Van der Woude syndrome – single
gene
Amniotic band syndrome –
disruption
Clinical presentation of congenital
malformations
• Sequence: Consequence of a cascade of events
initiated by a single primary factor
Example: Potter sequence
Clinical presentation of congenital
malformations
• Association: Certain malformations tend to occur
together but can not be explained on the basis of a
sequence or a syndrome
Example: VACTERL association
Susceptible stages of development
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1st trimester
0-17 days: pre-differentiation
pre-implantation
not susceptible
18-30 days:early differentiation
highly susceptible
31-60 days: advancing
organogenesis
susceptibility continually
lessening
2nd trimester
decreasing susceptibility
3rd trimester
minimal susceptibility
Teratogen
A teratogen is either a drug,
chemical, infectious agent or
physical agent, maternal
disease or metabolic agent,
that by acting on the
developing fetus, causes a
structural or functional
abnormality( congenital
malformation or birth
defect) present at birth
Teratology - Thalidomide as an example
• Given as sedative to
pregnant women in 1950s
• Limb reduction defects in
fetus when exposed
between 4 and 8 weeks
• Damaging tissue in
progress zone of the
developing limb bud
• Effect is specific
• Otherwise a safe drug
Teratology - retinoic acid as example
• Serious birth defects when
fetus exposed in utero
• Use in certain skin
diseases(acne) and
leukaemia - Ro-accutane
• Endogenous retinoids
component of signalling
pathways used to pattern
the brachial arches
• Extreme caution in
multivitamin
supplementation
Principles of teratology
• Stage sensitivity
- pre-implantation
- embryonic period
- fetal period
• Organ susceptibility
• Window of action
• Dose response relationship
• Genetic differences in susceptibility
• Teratogenesis and malformation patterns
Common teratogens
• Maternal illness
• Maternal infections
• Drugs and toxins
• Alcohol and smoking
Common teratogens
Maternal illness
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Diabetes mellitus
Phenylketonuria
Epilepsy
Hyperthermia
Hypothyroidism
Hypertension
Common teratogens
Maternal infections
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Toxoplasmosis
Rubella
Cytomegalovirus
Herpes simplex
Varicella zoster
Syphilis
Human Parvovirus B19
HIV
Common teratogens
Drugs and Chemicals
• Alcohol
• Anti-coagulants - Warfarin
• Anti-convulsants Phynetoin, Valproic acid
• Antibiotics Streptomycin/Tetracycline
• Psychiatric drugs Lithium
• Illicit drugs - cocaine/
heroin/ smoking
• Hormones -estrogens
Fetal alcohol syndrome
• Children born to mothers
who have consistently
consumed large quantities
of alcohol during
pregnancy
• Unsure about the level that
is “safe”
• Recommended all women
should try to abstain from
alcohol intake completely
• Genetic susceptibility
Ionizing radiation
• Survivors of the Japanese
atomic bomb and large
doses for therapeutic
purposes
• Causes breaks in DNA
• Variety of anomalies
- central nervous system
- cleft palate
- malformations of limbs,
skeleton or viscera
Conclusion
• Different teratogens often cause very specific patterns of
birth defects.
• Exposure to environmental agents should be avoided
during pregnancy.
• Benefit of giving a drug should be weighed againt the
possible harmfull effects.