Birth Defect

Question 1

birth defects

Answer 1

• congenital malformation
• structural, functional, behavioral disorder present at birth
• structural malformations occur in 3% of live births
• caused by twinning (1%), genetics (28%), environmental factors (3-4%), genes (20-25%) and environment, and other unknown reasons (40-45%)

Question 2

genetics of birth defects

Answer 2

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

Question 3

chromosome defects

Answer 3

• alter embryonic development
• aneuploidy or structural defects
• 1/150 born with a defect caused by errors in number or structure

Question 4

mutations in single genes

Answer 4

• can alter development of multiple systems
• axenfeld-rieger
• primarily an eye disorder, can affect teeth, other parts of body
• wide spaced eyes, flattened mid face, flat nasal bridge, prominent forehead
• small teeth, folds of skin around belly button
• 1/200,000, AD
• PITX2 and FOXC1
• TFs in developing eye and other places

Question 5

gene-gene vs gene-environment

Answer 5

• interactions determine disease severity
• mendelian or complex
• mendelian-disease gene + modifying gene + environment give clinical phenotype
• complex-many genes + environment gives clinical phenotype

Question 6

holoprosencephaly

Answer 6

• multiple causes
• chromosome abnormalities
• environmental conditions-maternal diabetes
• single gene mutations
• 1/250 embryos and 1/10,000 live born
• failed forebrain division in 3rd-4th week
• 25-50% have chromosomal abnormality
• duplications 13q, del18p, del 7q36, dup3p24-pter, del2p21, dep21q22.3
• 18-25% mutation in a single gene
• SHH, PTCH1, GLI2, DISP1
• heterozygous deletions, nonsense, frameshift, missense

Question 7

infectious agents

Answer 7

• can also cause birth defects
• rubella viral infections during pregnancy linked to microcephaly, PDA, and cataracts
• congenital rubella syndrome
• coxsackie virus (B-inc in spontaneous abortion)
• cytomegalovirus
• herpes simplex
• parvovirus
• rubella
• toxoplasma
• treponema
• hyperthermia can interfere with neurulation and cause neural tube defects

Question 8

thalidomide

Answer 8

• widely used in 50s and 60s to treat nausea in pregnant women
• 10,000 babies born in 46 countries had limb malformations that were associated with thalidomide
• taken off market in 61
• mechanism of action unclear
• oxidative stress or disrupting angiogenesis
• 35th-37th day-absence of ears and deafness
• 39th-41st day- absence of arms
• 43-44 -phocomelia with three fingers
• 46-48- thumbs with three joints

Question 9

teratology

Answer 9

• study of birth defects
• teratogen is an agent that causes it
• drugs can enter placenta and affect baby
• alcohol, gentamycin, bromine, PTU, heroin, lead, tetracycline
• radiation
• metabolic conditions

Question 10

susceptibility to teratogens

Answer 10

• depends on several factors
• genotype of embryo, gene/environment interactions
• developmental stage at time of exposure
• dose and duration of exposure
• 3-8 weeks most sensitive- all organs have critical periods then

Question 11

fetal alcohol spectrum disorder

Answer 11

• severe form is fetal alcohol syndrome
• FASD refers to all alcohol related risks
• alcohol is leading cause of congenital mental retardation
• not clear how much alcohol is necessary to cause defects, but there is probably no safe level
• amt, timing, and genetics all contribute to FASD severity

Question 12

FAS

Answer 12

• small head
• epicanthal folds
• flat midface
• smooth philtrum
• low nasal bridge
• small eye openings
• short nose
• thin upper lip
• small brain with defects in neuronal migration
• interferes with cell migration and adhesion, cell proliferation and survival, cell signaling and gene expression

Question 13

congenital heart defects

Answer 13

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

Question 14

septal defects

Answer 14

• hole in heart
• ASD allows oxygen rich blood from LA back to RA
• VSD- oxygen blood from LV to RV 2-6 of every 1000 live births and more than 20% of all congenital heart diseases

Question 15

dextrocardia

Answer 15

• heart positioned on right side of thorax

- defects in L/R axis during embryogenesis

Question 16

heterotaxy

Answer 16

• can lead to septal defects
• double outlet right ventricle
• transposition of great arteries
• DORV always includes VSD
• TGA- aorta and pulm artery switched- often have septal defects too

Question 17

identification of congenital heart defects

Answer 17

• rapid breathing
• cyanosis
• fatigue
• poor blood circulation
• FTT

Question 18

22q11.2 deletion syndrome

Answer 18

• heterogeneous multisystem syndrome
• 3 million bp deletion on 22- 30-40 genes
• 5-10% of cases inherited AD
• congenital heart disease in 80% of patients
• tetralogy of Fallot and truncus arteriosus- outflow tract defects
• defects in palate, mental retardation, mild differences in facial features, recurrent infections
• 1/4,000 people

Question 19

outflow tract

Answer 19

• great arteries
• truncus arteriosus -persistant or common truncus
• single common BV out of heart, usually VSD

Question 20

tetralogy of fallot

Answer 20

• VSD
• pulm stenosis
• overriding aorta
• ventricular hypertrophy

Question 21

cardiac NCC

Answer 21

• contribute to outflow tract
• TBX1 are thought to regulate CNCC
• TBX1 is 22q11.2