EMBRYOLOGICAL DEVELOPMENT AND DYSMORPHOLOGY

1. EMBRYOLOGICAL DEVELOPMENT AND DYSMORPHOLOGY Dr. E.M. Honey Department of Genetics University of Pretoria

6. 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

7. 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%

8. 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

9. 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

11. 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

13. Pathogenesis of congenital abnormalities • 3. Deformation – an abnormal mechanical force which distorts an otherwise normal structure Example: Mild talipes(club foot)

15. 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

19. 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

20. Clinical presentation of congenital malformations • Sequence: Consequence of a cascade of events initiated by a single primary factor Example: Potter sequence

21. 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

22. 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 Susceptible stages of development

24. 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 Teratogen

25. 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 - Thalidomide as an example

26. 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 Teratology - retinoic acid as example

27. 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

28. Maternal illness Maternal infections Drugs and toxins Alcohol and smoking Common teratogens

29. Diabetes mellitus Phenylketonuria Epilepsy Hyperthermia Hypothyroidism Hypertension Common teratogensMaternal illness

31. Toxoplasmosis Rubella Cytomegalovirus Herpes simplex Varicella zoster Syphilis Human Parvovirus B19 HIV Common teratogensMaternal infections

32. Alcohol Anti-coagulants - Warfarin Anti-convulsants - Phynetoin, Valproic acid Antibiotics - Streptomycin/Tetracycline Psychiatric drugs - Lithium Illicit drugs - cocaine/ heroin/ smoking Hormones -estrogens Common teratogensDrugs and Chemicals

33. 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 Fetal alcohol syndrome

34. 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 Ionizing radiation

35. 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.