Birth Defects

Question 1

Birth defects

Answer 1

• congenital malformation
• structural, functional or behavioral disorder present at birth
• structural malformations due occur in 3 % of live births (1 in 33 babies)
• account for 25% of infant deaths

Question 2

Causes of birth defects

Answer 2

• there are several known causes of birth defects:
• genetic problems (chromosome abnormalities or gene mutations) cause 28% of birth defects
• environmental factors cause 3-4%
• a combination of gene and environment (called multifactorial inheritance) accounts for 20-25%
• twinning causes 1%
• however for many defects (40-45%) the cause is unknown

Question 3

Genetics of birth defects

Answer 3

• can be due to a single gene mutations
• can be due to chromosomal abnormalities
• often sporadic
• can be inherited as dominant, recessive or X-linked

Question 4

Chromosome defects alter embryonic development

Answer 4

• aneuploidy (altered chromosome number)
• structural defects: deletion, duplication, translocation
• chromosome abnormalities can be inherited or occur de novo

Question 5

Mutations in single genes can alter the development of multiple systems

Answer 5

• Axenfeld-Rieger syndrome is primarily an eye disorder, but it can also affect other parts of the body
• many affected individuals have distinctive facial features such as widely spaced eyes (hypertelorism)
• a flattened mid-face with a broad, flat nasal bridge and prominent forehead
• the condition is also associated with dental abnormalities including unusually small teeth (microdontia) or fewer than normal teeth (oligodontia)
• some people with Axenfeld-Rieger syndrome have extra folds of skin around their belly button (redundant periumbilical skin)
• estimated prevalence of 1 in 200,000 people. This condition is inherited in an autosomal dominant pattern

Question 6

Gene gene and gene-environment interactions

Answer 6

• a single rare mutation can fully account for a disease, but clinical variablilty can be observed even for determined monogenic disease, and this variability may itself involve genetic factors, the so-called modifier genes
• in contrast to monogenic traits, complex traits have many contributing genes and non-genetic influences

Question 7

Holoprosencephaly

Answer 7

• chromosome abnormalities: number and structure (trisomy 13, or 18, )
• environmental conditions: maternal diabetes, also retinoic acid and alcohol
• single gene mutations
• common malformation of the forebrain in humans
• failed or incomplete forebrain division in the third to fourth weeks of gestation: the forebrain (prosencephalon) incompletely cleaves into right and left hemispheres
• when the embryos forebrain does not divide, it causes defects in the development of the face and in brain structure and function

Question 8

Genes have been implicated in holoprosencephaly

Answer 8

• many genes have been implicated in HPE
• many of these operate in the hedgehog signaling pathway
• heterozygous deletions and nonsense, frameshift, and missense mutations in SHH predict a loss-of-function mechanism
• SHH encodes a secreted protein that functions as a morphogen and is involved in establishing cell fates at several points during development
• it is expressed in the Hensen node, the floor plate of the neural tube, the early gut endoderm, the posterior of the limb buds, and throughout the notochord
• it has been implicated as the key inductive signal in patterning of the ventral neural tube, the anterior-posterior limb axis, and the ventral somites

Question 9

Infectious agents and birth defects

Answer 9

• rubella viral infections (German measles) during pregnancy were linked to specific birth defects: congenital cataracts, deafness and congenital heart malformations
• Coxsackie (B- spontanesous abortion)
• Cytomegalovirus
• Herpes simplex
• Parvovirus
• Toxoplasmosis- found in animal feces and under cooked meats can lead to cerebral calcifications and head defects.
• Syphilis
• another complicating factor is that many infections cause fevers (hyperthermia), which can disrupt neurulation and result in neural tube defects

Question 10

Pharmacological agents can cause birth defects

Answer 10

• limb defects to the sedative thalidomide
• thalidomide was widely used in the 1950s and 1960s to treat nausea in pregnant women (morning sickness)
• was taken off the market in 1961
• mechanism of action unclear: inducing oxidative stress or disrupting angiogenesis

Question 11

Environmental factors can cause birth defects

Answer 11

• teratology is the study of birth defects
• teratogen-agents that cause birth defects
• addition to infectious agents, drugs can cross the placenta, enter the baby and impact development

Question 12

Specific environmental factors that cause birth defects

Answer 12

• infectious agents, physical agents, chemical agents and maternal conditions such as autoimmune disease or diabetes, maternal obesity
• alcohol, cortison, heroin, lead, tetracycline, warfarin
• ionizing radiation, hyperthermia

Question 13

Susceptibility to teratogens

Answer 13

• genotype of the embryo (or mom); gene-environment interactions. The maternal genome is also important in determining drug metabolism, resistance to infection and potentially other influences
• developmental stage at the time of exposure (most sensitive weeks 3-8)
• birth defect severity can depend on the dose and duration of exposure

Question 14

Fetal Alcohol Syndrome

Answer 14

• FASD refers to all alcohol-related defects
• alcohol is the leading cause of congenital mental retardation
• not clear how much alcohol is necessary to cause defects, but there is probably no safe level
• amount of alcohol, timing and genetics all contribute to FASD severity
• effects: learning and remembering, understanding and following directions, controlling emotions, communicating and socializing, daily life skills such as feeding and bathing
• fetal alcohol syndrome is the most serious type of FASD and includes structural defects, growth deficiency and intellectual disability
• FAS is characterized by small head size (microcephaly),indistinct philtrum, narrow upper lip, low nose bridge and flat midface

Question 15

How does alcohol interfere with embryo development

Answer 15

• interfere with cell migration, proliferation, adhesion, survival and signaling
• several genes are misregulated in the embryo following maternal alcohol exposure

Question 16

Congenital heart defects-

Answer 16

• malformation of the heart is the most common birth defect found in 1% of live births and an estimated 10% of all fetuses
• heart defects have a broad range of severity
• heart development can be altered by teratogens and chromosomal abnormalities, but most cases are thought to be due to multifactorial causes
• the same malformation can result from disrupting several different developmental events

Question 17

Septal defects

Answer 17

• hole in the heart
• atrial septal defect is an opening in the wall that serparates the left and right atria, oxygen rich blood is pumped back into the lungs
• ventricular septal defect- separates the ventricles, O2 rich blood to flow from the left to right ventricle instead of the aorta, 20% of defects

Question 18

Dextrocardia

Answer 18

• the heart is positioned on the right side of the thorax instead of the left
• reversal of heart laterality is often caused by defects in establishing the left-right body axis during embryongenesis
• heterotaxy can result in several congenital heart malformations including septal defects, double outlet right ventricle and transposition of the great arteries

Question 19

Identification of congenital heart defects

Answer 19

• rapid breathing
• cyanosis
• fatigue
• poor blood circulation

Question 20

Heart defects in 22q11.2 deletion syndrome

Answer 20

• heterogeneous multisystem syndrome
• 3 million base pair deletion on chromosome 22 (30-40 genes)
• 5-10% of cases are inherited (autosomal dominant)
• congenital heart disease in 80% of patients
• heart malformations include tetralogy of Fallot and truncus arteriosus

Question 21

Rise of the great arteries

Answer 21

• the outflow tract of the embryonic heart gives rise to the greater arteries
• during heart development the outflow tract remodels to form the aorta and pulmonary artery

Question 22

Truncus arteriosus

Answer 22

• persistent truncus arteriosus
• single common blood vessel comes out the heart, instead of the usual two vessels (the main pulmonary artery and aorta)
• it occurs when the blood vessel coming out of the heart in the developing baby fails to separate completely during development, leaving a conection between the aorta and pulmonary artery
• O2 poor and O2 rich blood are mixed together as blood flows to the lungs and the rest of the body
• truncal valve is often abnormal, the valve can be thickened and narrowed which can block the blood as it leaves the heart

Question 23

Tetralogy of Fallot

Answer 23

• ventricular septal defect
• pulmonary stenosis (narrowing of pulmonary valve and artery)
• overriding aorta *increases flow)
• ventricular hypertrophy

Question 24

Cardiac Neural Crest Cells

Answer 24

• cardiac neural crest cells migrating from the dorsal neural tube into the arterial pole participate in separation of the outflow tract
• genes located in the 22q11.2 deletion region (specifically TBX1) are thought to regulate cardiac neural crest cell development