1. CONGENITAL MALFORMATION, TERATOLOGY
Dr. Nandor Nagy
Semmelweis University, Faculty of Medicine, Department of Human Mprh and Dev Biol
Developmental disorders present at birth are called congenital anomalies, birth defect or congenital malformation.
Teratology is the science that studies the causes, mechanisms,
and patterns of abnormal development.
Major anomalies are more common in early embryos (up to 15%) than they are in newborns (3%).
Most severely malformed embryos are spontaneously aborted during first 6 to 8 weeks

2. Malformation is a primary structural defect resulting from a localized error of morphogenesis
Disruption is specific abnormality that results from disruption of normal developmental processes It depends on time not on agent
Deformation is an alteration in shape / structure of previously normally formed part
Syndrome is a recognized pattern of malformations with a given etiology.

3. Teratology, Congenital Anomalies
Basic Principles
Critical periods of human development
Most vulnerable when cell division, cell differentiation, and morphogenesis peaks !!!!
Brain development: 3-16 weeks
Dosage of the drug or chemical
Genotype of the embryo
Genotype = genetic constitution
Brain – even after this – brain is still differentiating and growing rapidly – at least the first 2 years – ALCOHOL FETAL SYNDROME

5. Congenital Anomalies Genetic Factors Environmental Factors
Chromosome abnormalities
Environmental Factors
Drugs
Viruses
Multifactorial Inheritence (MI)
Genes + environment
50 – 60% - etiology is unknown
Most = MI

6. Causes of congenital anomalies
Envitonmental sources
(teratogens)
genetic sources
Developmental abnormalities

7. Causes of congenital anomalies

8. Genetic Causes Genetic Factors Common: 6-7% of zygotes
Display similar phenotypes
Initiate anomalies by, e.g. biochemical means
Subcellular
Cellular
Tissue level
2 types of changes
Numerical & Structural
The changes may affect
Sex-chromosomes
Autosomes
Both types
Many defective zygotes, blastocysts, 3-week embryos abort spontaneously – chromosomal abnormalities = at least 50%
Mechanism – ID/similar to causal mechanisms initiated by the teratogen – drug.
2 Types of changes in chromosomal complements
Changes can affect….autosomes = all chromosomes BUT the sex chromosomes
BOTH
Phenotypes – Down syndrome – look more alike than siblings

9. Genetic Causes Trisomy 13 Trisomy 21 (1:800) Down syndrome
Extra chromosome is present for number 13
Multiple abnormalities; occurs in about 1 out of every newborns
Brain defects – seizures, apnea, deafness & eye abnormalities
Trisomy 21 (1:800)
Down syndrome
>35 age at pregnancy – higher risk
Tris 13 – most will die in first month – multiple causes – 1/5000 live births – most cleft lip or cleft palate – 80% = congenital heart defects
Most – normal children!!
If >40 – amniocintesis / chorionic villus sampling
>44 – chance of DS = 1/25

10. HoxD13 mutation (polysyndactylia)

11. Drugs: Thalidomid (Contergan),
Thalidomide, 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione, was developed by German pharmaceutical company Grünenthal. It was sold from 1957 to 1961 in almost 50 countries under at least 40 names .
Thalidomide was chiefly sold and prescribed during the late 1950s and early 1960s to pregnant women, as an antiemetic to combat morning sickness and as an aid to help them sleep. Before its release, inadequate tests were performed to assess the drug's safety, with catastrophic results for the children of women who had taken thalidomide during their pregnancies.
From 1956 to 1962, approximately 10,000 children were born with severe malformities, including phocomelia, because their mothers had taken thalidomide during pregnancy.

12. abnormally short limbs with toes sprouting from the hips and flipper-like arms. Other infants had eye and ear defects or malformed internal organs

13. Pharmochemical Teratogens
Alcohol
Fetal Alcohol Syndrome
Thin upper lip
Short palpebral fissures
Flat nasal bridge
Philtrum
Mental retardation
Brain is susceptible throughout gestation
FAS – born to chronic alcoholic mothers
Thin upper lip
Short palpebral fissures
Flat nasal bridge
Short nose
Philtrum – vertical groove in medial part of upper lip poorly formed
Most common cause of mental retardation – especially if the drinking is associated with malnutrition - takes skill to make an accurate dx – mild – severe
Safest = total abstinence!!!

14. Fetal Alcohol Syndrome
Fetal brain
Fetal Alcohol Syndrome
Normal

16. fetal alcohol syndrome, also known as fetal alcohol spectrum disorder
fetal alcohol syndrome, also known as fetal alcohol spectrum disorder. This disorder affects 2 in 1000 live-born infants . Consumption of amounts of alcohol as low as 80g per day (i.e., between two and three shots of a grain liquor such as rum) during the 1st month of pregnancy can cause significant defects, and it has been suggested that even a single binge may be teratogenic. Common components of the disorder include defects of brain and face development, namely, microcephaly (small head), short palpebral fissures (eye openings), epicanthal folds (folds over eye lids), a low nasal bridge with a short nose, flat midface, minor external ear anomalies, and jaw anomalies including a thin upper lip with indistinct philtrum and micrognathia (small jaw). Chronic consumption of even quite small amounts of alcohol later in pregnancy can result in other, less-destructive effects, such as some degree of growth retardation and minor physical defects.

17. A VITAMIN

18. DES= diethylstilbestrol catastrophe

20. Environmental Teratogens
Mercury poisoning
E.g. Minamata Bay Disease
From 1932 to 1968 – illegally dumped - estimated 27 tons of mercury compounds into Minamata Bay – town consists mainly of farmers and fisherman – diet consists mainly of fish – developed the symptoms of methyl mercury poisoning
Fetus is very sensitive to mercury’s effects – many of the CNS effects are similar to cerebral palsy = loss of movement – range: very bright – completely retarded
Well protected in the uterus – environmental agents = teratogens – maternal exposure
Minamata = industrial disease
Minamata - small industrial town in Japan – dominated by the Chisso corporation – Japanese – “chisso” = nitrogen – made fertiliser – then petrochemicals and plastics - From 1932 to 1968 – illegally dumped - estimated 27 tons of mercury compounds into Minamata Bay – town consists mainly of farmers and fisherman – diet consists mainly of fish – developed the symptoms of methyl mercury poisoning
Fetus is very sensitive to mercury’s effects – many of the CNS effects are similar to cerebral palsy = loss of movement – range: very bright – completely retarded

21. Environmental Teratogens
Lead
Enter through placenta
Accumulate in fetal tissue
Abortions, fetal anomalies, IUGR, functional deficits
Nicotine
Constrict uterine blood vessels – decrease uterine blood flow
Less O2 and nutrients
Impair cell growth – adverse mental development

22. Environmental Teratogens
Parasites
Cats play host to Toxoplasma gondii
Parasite oocysts appear in feces
Severe fetal CNS anomalies
Mental retardation
Blindness
Be very careful when handling the litter tray – may ingest!!

23. Infectious Agents Teratogens
Rubella
German or Three-Day Measles
First trimester – most serious
(glaucoma, heart deffects, mental ret.)
Cytomegalovirus (CMV)
Herpes Simplex Virus (HSV)
Varicella
Human Immunodeficiency Virus (HIV)
Toxoplasmosis
Congenital Syphilis
EYES – glaucoma, cataracts, retinopathy
EARS – loss
BRAIN – psychomotor retardation, mental retardation
HEART – congenital heart defects

24. Radiation Teratology High levels of ionizing radiation
> 25, 000 millirads
Diagnostic levels of radiation?
The WW II atomic bombing of Japan
Most vulnerable period: 8-16 weeks post-fertilization
Severe mental retardation
Commonly believed – large dosages – harm the developing CNS – BUT – no conclusive proof that human congenital anomalies are caused by DIAGNOSTIC levels of radiation.
Injure embryonic cells – cell death – chromosome injury, retard mental development and physical growth.
Past – hundreds – several 1000’s of rads – pregnant women – CA of cervix – malformed / killed
BOMB:
After week 16 – most neuronal proliferation is complete – decreased risk of mental retardation

25. Mechanical Factors (external trauma) as Teratogens
Mechanical forces
Restrict the mobility of the fetus
Cause prolonged compression in an abnormal posture
E.g. congenital dislocation of hip
clubfoot
Malformed uterus
Protect the embryo from most external trauma

26. Maternal Factors as Teratogens
Maternal diseases
Diabetes mellitus
No specific diabetic embryopathic syndrome
Macrosomia
Holoprosencephaly
Sacral agenesis
Vertebral, limb & congenital heart anomalies
Lead to a higher risk – DM – with persistent hyperglycemia + ketosis – part. During embryogenesis = 2-3* higher birth-defects

27. Mechanical Factors as Teratogens
Amniotic fluid
Absorb mechanical forces
Oligohydramnios
Significantly reduced fluid-quantity
Mechanically induced deformations of the limbs
Knee hyper-extends
Amniotic bands
Rings formed from amnion rupture
Local constriction during fetal growth
Intrauterine amputations