embryological development and dysmorphology
DESCRIPTION
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 - PowerPoint PPT PresentationTRANSCRIPT
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.