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.