Birth DefectsShun 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 Exposures- Thalidomide 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 Syndrome1 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 Trisomy-Nondisjunction

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 pregnancy-

associated 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 Syndrome1 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 loose-jointed

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

Autism1 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 Bifida1 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 sacMeningocele: a sac of fluid without spinal cordMyelomeningocele: 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

Anencephaly1 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

Encephalocele1 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 Palate1 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 Foot1 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

Polydactyly1 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 is narrower than usual

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!