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Transcript
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 • • • 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 • • • • • • Diabetes mellitus Phenylketonuria Epilepsy Hyperthermia Hypothyroidism Hypertension Common teratogens Maternal infections • • • • • • • • 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.