EMBRYOLOGICAL DEVELOPMENT AND DYSMORPHOLOGY
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Transcript of EMBRYOLOGICAL DEVELOPMENT AND DYSMORPHOLOGY
EMBRYOLOGICAL DEVELOPMENT AND DYSMORPHOLOGY
Dr. E.M. HoneyDepartment of GeneticsUniversity 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 6% Single gene 7,5% Multifactorial 20-30% Subtotal 30-40%Environmental Drugs and chemicals 2% Infections 2% Maternal illness 2% Physical agents 1% Subtotal 5-10%Unknown 50%Total 100%
Aetiology of congenital abnormalities
• 1. Single gene defects – unifactorial/ Mendelian inheritance(Autosomal dominant, autosomal recessive, X-linked 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
• 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 astructural or functionalabnormality( congenitalmalformation or birthdefect) 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 teratogensMaternal illness
• Diabetes mellitus• Phenylketonuria• Epilepsy• Hyperthermia• Hypothyroidism• Hypertension
Common teratogensMaternal infections
• Toxoplasmosis• Rubella• Cytomegalovirus• Herpes simplex• Varicella zoster• Syphilis• Human Parvovirus B19• HIV
Common teratogensDrugs 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.