birth defects mechanisms

Question 1

1. Describe the principal causes of human birth defects and their relative distribution.

Answer 1

Unknown- 40%, Multifactorial- 25%, Environmental- 10%, Chromosomal- 15%, Monogenic -10%

Question 2

Teratology

Answer 2

The study of birth defects and the mechanisms responsible for them

Question 3

describe hierarchical pathways involved in development of cardiac chambers

Answer 3

Anterior lateral mesoderm > cardiac tube (under influence of MEF2 and TIN-like genes) > rightward bend (Shh activates Nodal) > looped cardiac tube ( Nkx activate HAND) > chamber maturation (RXRalpha, neuregulin, NF-1)

Question 4

describe hierarchical pathways involved in development of cardiac aorta/pulmonary development

Answer 4

cardiac neural crest cells > conotruncus, aortic arches > aorticopulmonary septation and arch development (PAX3, RARgamma, ET1, HAND)

Question 5

What are developmental fields

Answer 5

tissues share gene expression pathways, location, developmental timing, or interacting processes.

Question 6

list birth defects that are cmmonly associated with eachother

Answer 6

VACTERL: vertebral anomalies, anal atresia, cardiac anomalies (septal defects), Tracheal esophageal fistula, esophageal atresia, renal, limb anomlies (radial upper limb). As yet not accounted for by chromosomal, monogenic, or environmental factors. Increased frequency in monozygotic twinning

Question 7

possible etiology of VACTERL associations

Answer 7

early embryonic organization

Question 8

phenocopies

Answer 8

similar birth defects resulting from predominantly genetic or predominantly environmental factors. Theoretically, anything produced by genetic mutations can also be produced by environmental manipulations

Question 9

birth defects that comply with multifactorial threshold risk models

Answer 9

Congenital heart disease and neural tube closure abnormalities (anencephaly and spina bifida) - genetic risks are modified by the environment in a dose dependent fashion. Ie. for neural tube defects, folic acid intake is environmental

Question 10

Tetralogy of Fallot

Answer 10

Supravalvular pulmonic stenosis, Overriding aorta, Ventricular septal defect, Right ventricular hypertrophy

Question 11

tetralog of Fallot mechanism of birth defect

Answer 11

Genetic mutations affecting expression of genes in neural crest cells- 1. deletion on chromosome 22, del 22q11, associated Shprintzen and diGeorge syndromes. 2. Mutations in the gene associated with Alagille syndrome, JAG1 account for another 20%.

Question 12

Isotretinoin exposure in utero

Answer 12

Produces a phenocopy of diGeorge syndrome, including tetralogy of Fallot. Vitamin A is a morphogen (a factor that stimulates the development of a structure) that regulates migration of neural crest cells in the region of the developing branchial crests and arches.

Question 13

Which genes play a role in 22q11.2 deletion syndromes

Answer 13

TBX1, CRKL, and ERK2- haploinsufficiency causes dysfunction of neural crest cells and anterior heart field

Question 14

Teratogens

Answer 14

exogenous agents (physical or chemical) that disrupt developmental pathways causing birth defects

Question 15

Xenobiotics

Answer 15

compounds foreign to nature

Question 16

how do teratogens gain access to embryo

Answer 16

Teratogens gain access to the embryo/fetus across the placenta because the chemical properties (i.e. size, lipid solubility, pH, etc) that allow them to be absorbed into the maternal circulation also allow them to cross the placenta (hemomonochorionic anatomy). The placenta has drug metabolizing enzymes that are protective against low dose environmental toxins such as polycyclic aromatic hydrocarbons, but these systems are not active against most drugs

Question 17

List common teratogens

Answer 17

thalidomide, Vitamin A analogues, cholesterol synthesis inhibitors, anticonvulsants, ethyl alcohol

Question 18

Mechanisms of drug/xenobiotic induced birth defects

Answer 18

deleterious interactions with surface and intracellular signaling proteins and cytotoxicity that “kills” cells, usually by inducing apoptosis

Question 19

fetal alcohol syndrome

Answer 19

Produces what is essentially a phenocopy of chromosomal disorders. Each results in growth retardation, dysmorphic, features and cognitive deficiencies. Dosage is very important.

Question 20

Classifications of birth defects

Answer 20

malformation, disruption, deformation, dysplasia

Question 21

what type of birth defect is tetralogy of fallot

Answer 21

malformation (JAG mutation on chrom 22) or disruption (isotretinoin exposure)

Question 22

example of deformation birth defect

Answer 22

Pulmonary hypoplasia results when physical restraint, as caused by oligohydramnios (diminished amniotic fluid) or a diaphragmatic hernia, prevents alveolar expansion.

Question 23

example of dysplasia birth defect

Answer 23

Point mutations of Fibroblast Growth Factor Receptor genes lead to skeletal dysplasias (abnormal formation of bone) such as achondroplasia

Question 24

isolated vs syndromic birth defects

Answer 24

isolated: usually multifactorial. Syndromic: chromosomal, monogenic or teratogenic

Question 25

DiGeorge syndrome vs Velo-cardio-facial syndrome

Answer 25

Both are deletions on chrom22q11. Digeorge: congenital heart disease, hypoparathyroidism, thymic aplasia. Velo-cardio-facial: cleft palate, septal defects, Shprintzen syndrome