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Birth Defects
Shun Zhu, Department of Cellular and Genetic Medicine
A Boy with Down Syndrome
Outline
 Introduction
 Genetic Defects
 Neural Tube Defect
 Mouth/facial defects
 Limb defects
 Congenital Heart Defects
 Summary
Introduction
What are birth defects?
 Birth defects ARE abnormalities of structure or function
of the body that are present at birth
 Structural birth defects
 Functional birth defects
 Birth defects ARE NOT impairment of body function or
structure due to adverse influences to which the infant
has been subjected at birth – birth injuries
Structural Birth Defects
 related to how a body part/structure looks
 Cleft lip/palate
 Heart defects, e.g. misshaped valves
 Abnormal limbs, e.g. clubfoot
 Neural tube defects, e.g. spina bifida
Functional Birth Defects
 related to how a body part/structure works
 Central Nervous System problems, e.g. Down syndrome
 Sensory problems, e.g. blindness
 Metabolic disorders, e.g., phenylketonuria (PKU)
 Degenerative disorders, e.g. muscular dystrophy
A Collection of Birth Defects
How common are they?
In the US/world, ~3% babies born with a
birth defect
http://www.cdc.gov/
Top 6 Common Birth Defects
 Genetic defects (e.g. Down syndrome): 6,916 babies
per year
 Mouth/facial defects (cleft lip): 6,776 babies per year
 Heart defects: 6,527 babies per year
 Musculoskeletal defects (including arm/leg defects):
5,799 babies per year
 Stomach/intestinal defects: 2,883 babies per year
 Eye defects: 834 babies per year
CDC, Morbidity and Mortality Weekly Report, Jan. 6, 2006; vol 54: pp 1301-1305.
Causes-Misconceptions
 In ancient times, birth defects were seen as warnings or
punishments from the gods
 In some parts of the world, it was believed that
unsatisfied wish of a pregnant woman will cause a birth
mark
Causes-The Truth
 Faulty genes can cause birth defects
 Gene mutations, Chromosome aberration
 Adverse environment
 Exposure to chemical, physical and biological factors
 Interactions between genes and environment
 Unknown
Example of ExposuresThalidomide
 Perhaps the most notorious case of a drug that caused
defects
 It was brought on to the market first in West Germany by the
company Grünenthal after inadequate testing
 Treat pregnancy reaction like sickness but cause limb defects
Other Examples

Tetracycline may affect the long bones and teeth

Anticonvulsant medicines for epilepsy may cause hare lip, limbs defects, and CHDs

Moderate alcohol use in pregnancy may cause subtle brain damage to the developing fetus

Smoking during pregnancy may cause events like premature delivery and low birth weight

The rubella virus, Cytomegalovirus which causes German measles, can cross the placenta and
cause a range of defects

Cytomegalovirus can also causes birth defects

Herpes simplex causes heart defects and deafness (4weeks 61%, 5-8weeks 26%, 9-10weeks 6%)

Bacteria such as salmonella, present in undercooked meat (especially chicken), and listeria (found
in some cheeses), can cause problems for the continuation of the pregnancy

Parasite Toxoplasma can cross the placenta, leading to hydrocephalus or chorioretinitis

X-rays and radiation may affect the baby’s central nervous system
Vulnerabilities At Various
Development Stages
Genetic Defects
Down Syndrome
1 in 1000 babies
Down Syndrome-John
Langdon Down1828-1896
 The first to describe down syndrome
 Originally named as mongolian idiocy
About Down Syndrome
 Also know as Down’s syndrome or Trisomy 21
 A genetic disorder caused by the presence of all of, or
part of chromosome 21
 The most common chromosome abnormality, 1 in 1000
babies
Mechanisms of TrisomyNondisjunction
Symptoms
http://www.mun.ca/biology/scarr/MGA2-11-17_Down.html
Symptoms
Tests and Diagnosis
 Screening tests can indicate the likelihood a mother is
carrying a baby with Down syndrome
 Diagnostic tests can identify whether your baby has
Down syndrome
Pregnancy Timeline
Screening Tests
The first trimester combined
test
 Blood test: measures the levels of pregnancyassociated plasma protein-A (PAPP-A) and the
pregnancy hormone known as human chorionic
gonadotropin (HCG). Abnormal levels of PAPP-A and
HCG may indicate a problem with the baby.
 Ultrasound: measure a specific area on the back of
your baby's neck. This is known as a nuchal
translucency screening test. When abnormalities are
present, more fluid than usual tends to collect in this
neck tissue.
Integrated screening test
 First trimester: includes a blood test to measure PAPP-A
and an ultrasound to measure nuchal translucency.
 Second trimester: the quad screen measures your
blood level of four pregnancy-associated substances:
alpha fetoprotein, estriol, HCG and inhibin A.
 The results are combined to estimate the risk that your
baby has Down syndrome with the same level of
detection as the first trimester combined test but with a
lower false-positive rate
Cell free fetal DNA test
 Circulating freely in the maternal blood stream
 Can be sampled by venipuncture as a non-invasive
prenatal diagnosis
http://www.gelab.com.tr/
Diagnostic Tests
Amniocentesis

A sample of the amniotic fluid
surrounding
the
fetus
is
withdrawn through a needle
inserted into the mother's
uterus

This sample is used to analyze
the chromosomes of the fetus

Usually performed in the
second trimester, after 15
weeks of pregnancy

A slight risk of miscarriage, and
risk increases if done before 15
weeks
Chorionic Villus Sampling
 Cells are taken from the
placenta to analyze the
fetal chromosomes
 Typically performed in the
first trimester, after 10
weeks of pregnancy
 Appears to carry a
somewhat higher risk of
miscarriage than second
trimester amniocentesis
Cordocentesis
 Fetal blood is taken from
a vein in the umbilical
cord for chromosomal
defects exam
 Performed between 18
and
22
weeks
of
pregnancy
 Carries a significantly
greater risk of miscarriage
than does amniocentesis
or CVS
Marfan Syndrome
1 in 5000 babies
About Marfan Syndrome
 A genetic disorder that affects connective tissue,
which holds other tissues together
 Can affect many body systems, including the heart,
blood vessels, bones, eyes, lungs and skin but not
intelligence
 Can be mild or severe. May be present at birth or
become apparent in childhood or in adult life
Marfan Syndrome-Symptoms
 Affected individuals are
tall, slender and loosejointed
 Arms, legs, fingers and
toes often are unusually
long
 Usually have long,
narrow faces, and their
teeth are generally
crowded
Marfan Syndrome-Causes

Mutations in the FBN1 gene encoding
fibrillin-1 on chr15, which form thread
like filaments called microfibrils

Microfibrils become part of the fibers
that provide strength and flexibility to
connective tissue.

Microfibrils store molecules called
growth factors

Mutations in FBN1 reduce the amount
of functional fibrillin-1 that is available
to form microfibrils or store growth
factors, leading to instability of tissues
and overgrowth
Isogai et al., Journal of Biological Chemistry, 278, 2750-2757, 2003
Cri du chat Syndrome
1 in 50,000
Cri du chat Syndrome
 Its name is a French term (call of the cat) referring to
the characteristic cat-like cry of affected children
 Also known as chromosome 5p deletion syndrome
 A rare genetic disorder due to a missing part (deletion)
of chromosome 5
Autism
1 in 68 babies
About Autism
 A neurodevelopmental
disorder characterized by
impaired
social
interaction, verbal and
non-verbal
communication,
and
restricted and repetitive
behavior
 The rate of autism are
estimated at about 1-2
per
1,000
people
worldwide
Autism-Causes
 A complex disorder whose core aspects have distinct
causes that often co-occur
 Has a strong genetic basis, although the genetics of
autism are complex: it is unclear whether Autism is
explained more by rare mutations with major effects, or
by rare multigene interactions of common genetic
variants
 Environmental factors are also contributors to Autism
Neural Tube Defect
Neural Tube Defect (NTD)
Spina Bifida
1 in 1000 babies
Spina Bifida
 A condition that affects the spine and a type of neural
tube defect (NTD)
 Can happen anywhere along the spine if the neural
tube does not close all the way
 Might cause physical and intelectual disabilities that
range from mild to severe
Three Types of Spina Bifida
Spina Bifida Occulta: is a small gap in the spine, no opening or sac
Meningocele: a sac of fluid without spinal cord
Myelomeningocele: a sac of fluid with spinal cord (most serious)
http://www.cdc.gov/ncbddd/spinabifida/facts.html
Causes of Spina Bifida
 Largely unknonwn, generally caused by the interaction
of multiple genetic and environmental factors
 Could be related to the genetic variations of
MTHFR
gene,
which
encodes
the
enzyme
methylenetetrahydrofolate reductase
Tests and Diagnosis
 Blood test: tests how much alpha-fetoprotein (AFP ) has
passed into the mother’s bloodstream from the baby.
A high level of AFP might indicate spina bifida
 Ultrasound: a type of image for the unborn baby,
which may indicate whether the baby has spina bifida
in a straightforward way
 Amniocentesis: takes a small sample of the amniotic
fluid surrounding the baby. Higher than average levels
of AFP in the fluid might indicate spina bifida
Anencephaly
1 in 10,000 babies
Anencephaly
 As the neural tube forms and closes, it helps form the
baby’s brain and skull, spinal cord, and back bones
 Anencephaly happens if the upper part of the neural
tube does not close all the way
 A serious type of neural tube defect in which a baby is
born without parts of the brain and skull
 Usually happens during the first month of pregnancy
 Almost all babies with Anencephaly will die shortly after
birth
Anencephaly
Encephalocele
1 in 5000 babies
Encephalocele
 A sac-like protrusion or
projection of the brain and the
membranes that cover it
through an opening in the skull
 Happens when the neural tube
does not close completely
 The result is an opening in the
midline of the upper part of
the skull, the area between the
forehead and nose, or the
back of the skull
How to prevent NTD?
 Causes of most NTDs are largely unknown
 But there are ways for women to reduce the risk of
having a baby with spina bifida.
 Take folic acid every day. Folic acid prevents most cases
of spina bifida
 Others, like vitamins, and dietary or herbal supplements
 Avoid overheating your body. Treat any fever
About Folic Acid
Mouth/facial defects
Facial Development
 A baby’s head forms early during pregnancy. To make
the face, body tissue and special cells from each side
of the head grow toward the center of the face and
join together. This joining of tissue forms the facial
features, like the lips and mouth.
Cleft Lip / Cleft Palate
1 in 700 babies
Cleft Lip / Cleft Palate

Cleft Lip: The lip forms between
the fourth and seventh weeks
of pregnancy. A cleft lip
happens if the tissue that
makes up the lip does not join
completely before birth.

Cleft Palate: The roof of the
mouth (palate) is formed
between the sixth and ninth
weeks of pregnancy. A cleft
palate happens if the tissue
that makes up the roof of the
mouth does not join together
completely.
Limb defects
Club Foot
1 in 1000 babies
About Club Foot
 Also called congenital talipes equinovarus (CTEV)
 The affected foot appears to have been rotated
internally at the ankle
 Causes are largely unknown, but may be related to
PITX1-TBX4 transcription pathways
 With treatment, the vast majority of patients recover
completely during early childhood
Dobbs and Gurnett J Pediatr Orthop B. 21, 7-9, 2012
Treatments
 Ponseti method: stretching and casting
 French method: stretching, taping and splinting
 Surgery: in severe conditions when stretching
treatments don’t work, clubfoot can be treated with
surgery
Polydactyly
1 in 500 babies
About Polydactyly
 Polydactyly means
“many” “fingers”
 It may occur in three
places of the hand
 on the small finger side most common (ulnar)
 on the thumb side - less
common (radial)
 in the middle of the
hand - least common
(central)
Potentail Genetic Causes
 Mutations in Sonic
hedgehog (shh) genes
 Shh genes plays a key
role in regulating
vertebrate
organogenesis
Lettice et al., Dev. Cell, 22, 459-467, 2012
Congenital Heart
Defect (CHD)
1 in 100 babies
Congenital Heart Defect
 CHDs are present at birth
and can affect the structure
of a baby’s heart and the
way it works
 Affect how blood flows
through the heart and out to
the rest of the body
 Vary from mild (such as a
small hole in the heart) to
severe (such as missing or
poorly formed parts of the
heart)
 Causes are largely unknown
http://www.cdc.gov/ncbddd/heartdefects/facts.html
Major Types of CHD











Atrial Septal Defect
Atrioventricular Septal Defect
Coarctation of the Aorta
Hypoplastic Left Heart Syndrome
Pulmonary Atresia
Tetralogy of Fallot
Total Anomalous Pulmonary Venous Return
Transposition of the Great Arteries
Tricuspid Atresia
Truncus Arteriosus
Ventricular Septal Defect
http://www.cdc.gov/ncbddd/heartdefects/facts.html
Coarctation of the Aorta
 Part of the aorta
narrower than usual
is
 A critical congenital
heart defect, the baby
may need surgery or
other procedures soon
after birth
Pulmonary Atresia
 Missing pulmonary valve,
which is the valve that
controls blood flow from the
right ventricle (lower right
chamber of the heart) to the
main pulmonary artery (the
blood vessel that carries
blood from the heart to the
lungs)
 In babies with this defect,
blood has trouble flowing to
the lungs to pick up oxygen
for the body
Ventricular Septal Defect
 A
ventricular
septal
defect (VSD) is a birth
defect of the heart in
which there is a hole in
the wall (septum) that
separates the two lower
chambers (ventricles) of
the heart
Summary
 Birth defects have various forms affecting nearly every
part of the body
 Birth defects have complex causes, including both
genetic and environmental factors
 The risks of having babies with birth defects can be
minimized with proper measures
Final Exam
 When: 1PM, Jan. 19 (Monday)
 Where: F2305
Thank You!