Disorders of Development

Congenital Birth Defects

Congenital Teratogenic Agents
Trisomy Disorders
Williams Syndrome
Autism.
Dr Saim Ali Soomro.
MBBS,MCCM.
Birth Defects occur during Critical Periods
in Development
1. Defects during Zygote are aborted;
2. Defects in the remaining prenatal period
are irreversible;
3. Critical Periods: a time of rapid change in
the development of the organism (i.e., system
or structure) and if interrupted will result in
permanent congenital abnormalities.
Sensitive periods in development
1. Occur prenatally and less irreversible
2. Interference will disrupt growth; may
result in subtle dysfunctions
3. Continues into post-natal period
Teratogens
- Agents that cause congenital
malformations in critical periods, and
subtle alterations in the brain during
sensitive periods
Critical Period Defect:
Cleft Palate
Irreversible congenital
abnormality affecting a
critical period (palate
development) during the
embryonic and early fetal
stages
May affect pituitary
growth as the palate and
anterior pituitary are
derived from the same
embryonic tissue.

Critical Period Defect:
Anencephaly (absence of brain)

Failure for the brain to grow
beyond the rhombencephalon.
Neonate failed to survive.
Critical Period Defect: Schizencephaly
Developmental of the brain affected during the fetal period
(i.e., growth of the forebrain). Cells either failed to migrate
or ventricular region failed to close.
Teratogens
Agents that cause
congenital
malformations
Fetal Alcohol Syndrome
Features: Growth retardation, neurodevelopmental abnormalities (fine motor
skills, LD, behavior disorders, and mental retardation in 50%). Facial
dysmorphia during embryonic period (week 4-8), CNS problems during the fetal
period (migration problems, smaller dendrites, few neurons in brain regions)
Genetic Conditions:
Chromosomal Abnormalities
Trisomy 21 (Downs Syndrome)
Trisomy of other chromosomes
Edwards Syndrome (Trisomy 18)
Pataus Syndrome (Trisomy 13)
Trisomy 21: Downs Syndrome
Non-disjunction of the 21
st
Chromosome
Anatomical Dysmorphia & Risk (Increase with
Maternal Age)
Just 1%-
20%
graphed
here
How does Trisomy
21 happen?
First, normal
development
In normal
development
mitosis proceeds
normally from the
first cell division
In Downs
Syndrome, non-
disjunction of
the 21
st

chromosome can
happen at the
first cell division
Non-disjunction of
the 21
st

chromosome cab
occur after the first
cell division
resulting in a
mosaic form of
Downs Syndrome
Faulty distribution
can occur in the egg
or sperm when the
mother or father is a
carrier.
Trisomy 18 Edwards Syndrome
Some Features of Edwards Syndrome
Facial: microcephaly, low set
malformed ears
Skeletal: webbed neck,
overlapping of fingers and
fixed flexion of fingers
CNS: severe mental
retardation, neural tube
defect, ocular
abnormalities
Respiratory: apnea



Cardiovascular problems

Gastrointestinal and
genitourinary problems

Life Span: death by 12-24
months (very few reach
adulthood)

Incidence: 0.2/1000 births

Trisomy 13: Pataus Syndrome
Features:
0.1/1000 births
Spina bifida & cleft palate
CNS: underdevelopment of
frontal lobe (fails to
divide) and corpus
callosum
Profound Mental Retardation
Extra fingers and toes, deaf
Life Span: 82% die in the
first month, 5-10% die in
first year.
Williams Syndrome Partial Deletion of
the 7
th
Chromosome
Features:
1 in 20,000 births
Neurodevelopmental delays,
cognitive deficits, LD,
ADHD
Overly friendly, social
Extremely empathic
Low muscle tone
Extremely sensitive hearing


Brain Areas Affected:
Amygdala activates more
for threatening scenes and
very little for threatening
faces. This accounts for
absence of anxiety in
interpersonal interactions
(no fear, hence over
friendliness).
Also, abnormal activity in
frontal lobe and a
disconnect with the
amygdala (except for
medial-prefrontal which is
linked to empathy and the
only structure still
connected to the amygdala)
Normal Control Williams Syndrome
Amygdala
Genetic Abnormality
of Chromosome 7:
21 genes missing
Elastin protein, made only during the prenatal period, is absent and causes vascular problems
during life; the missing elastin gene is use to identify the 21 missing genes in Williams Syndrome.
Autism
A neurodegenerative
disorder characterized by
impairment in social
interaction and
communication.

Age of onset: typically
between ages 2 and 4
(sometimes earlier)

Symptoms
Theories for Etiology and CNS Problems
Genetic alterations
Prenatal exposure to
toxins and/or viruses
Maternal and fetal
immune interactions
Vaccination with
mercury base

Amygdala less active and
area is smaller
Hippocampus is smaller
Frontal areas (medial
prefrontal region) less
active
Less activity in the
superior temporal sulcus
(involved in understanding
others)
Larger & heavier brain
suggests apoptosis failure

Microglia Activation in Autism
(white matter of the cerebellum)
Microglial cells
Brain Areas Affected in Autism: Fusiform Face
Area (FFA), Amygdala, Left Frontal Lobe, Left
Temporal Lobe, and Cerebellum
References for Photos
(slides 5,6,9,11,16,18,19,22-25)

http://images.google.com/imgres?imgurl=http://www.hallym.or.kr/~kdcp/cytogenetics/cytogen-
ds.files/c6_cleft_lip.jpg&imgrefurl=http://www.hallym.or.kr/~kdcp/cytogenetics/cytogen-
ds.htm&h=483&w=316&sz=61&tbnid=9z1GFXy5kykJ:&tbnh=126&tbnw=82&hl=en&start=61&prev=/images%3Fq%3DWilliams%2BSyndrome%26start%3D60%26svnu
m%3D10%26hl%3Den%26lr%3D%26client%3Dfirefox-a%26rls%3Dorg.mozilla:en-US:official_s%26sa%3DN

http://images.google.com/imgres?imgurl=http://cas.bellarmine.edu/tietjen/HumanBioogy/Finished%2520Images/gen12.gif&imgrefurl=http://cas.bellarmine.edu/tietjen/Hu
manBioogy/bills_developmental_abnormalities.htm&h=383&w=400&sz=117&tbnid=KbFuC4QsI4sJ:&tbnh=114&tbnw=120&hl=en&start=3&prev=/images%3Fq%3DEdw
ard%2527s%2BSyndrome%26svnum%3D10%26hl%3Den%26lr%3D%26client%3Dfirefox-a%26rls%3Dorg.mozilla:en-US:official_s%26sa%3DG

http://images.google.com/imgres?imgurl=http://www.cmu.edu/cmnews/extra/extra_art/Just_Fig1.jpg&imgrefurl=http://www.cmu.edu/cmnews/extra/extra_art/&h=421&w=
150&sz=25&tbnid=0aXX65rnVysJ:&tbnh=122&tbnw=43&hl=en&start=189&prev=/images%3Fq%3Dautism%2Bbrain%26start%3D180%26svnum%3D10%26hl%3Den
%26lr%3D%26client%3Dfirefox-a%26rls%3Dorg.mozilla:en-US:official%26sa%3DN

http://www.altcorp.com/DentalInformation/autismcytokines.htm

http://www.neuro.jhmi.edu/neuroimmunopath/Microglia%20pictures/5_lg.jpg


http://images.google.com/imgres?imgurl=http://www.fetalalcohol.com/images/face-thm.gif&imgrefurl=http://www.fetalalcohol.com/what-is-
fase.htm&h=260&w=304&sz=16&tbnid=RpmOv4g5G04J:&tbnh=95&tbnw=112&hl=en&start=6&prev=/images%3Fq%3DFetal%2BAlcohol%2BSy
ndrome%26svnum%3D10%26hl%3Den%26lr%3D%26client%3Dfirefox-a%26rls%3Dorg.mozilla:en-US:official_s%26sa%3DG

http://images.google.com/imgres?imgurl=http://www.infobiogen.fr/services/chromcancer/IntroItems/Images/tri21FaceEng.gif&imgrefurl=http://www
.infobiogen.fr/services/chromcancer/IntroItems/PolyTri21Eng.html&h=429&w=463&sz=50&tbnid=XGXbYU9uVcYJ:&tbnh=115&tbnw=125&hl=en&
start=1&prev=/images%3Fq%3DTrisomy%2B21%2Bface%26svnum%3D10%26hl%3Den%26lr%3D%26client%3Dfirefox-
a%26rls%3Dorg.mozilla:en-US:official_s%26sa%3DG