birth defects mechanisms Flashcards
- Describe the principal causes of human birth defects and their relative distribution.
Unknown- 40%, Multifactorial- 25%, Environmental- 10%, Chromosomal- 15%, Monogenic -10%
Teratology
The study of birth defects and the mechanisms responsible for them
describe hierarchical pathways involved in development of cardiac chambers
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)
describe hierarchical pathways involved in development of cardiac aorta/pulmonary development
cardiac neural crest cells > conotruncus, aortic arches > aorticopulmonary septation and arch development (PAX3, RARgamma, ET1, HAND)
What are developmental fields
tissues share gene expression pathways, location, developmental timing, or interacting processes.
list birth defects that are cmmonly associated with eachother
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
possible etiology of VACTERL associations
early embryonic organization
phenocopies
similar birth defects resulting from predominantly genetic or predominantly environmental factors. Theoretically, anything produced by genetic mutations can also be produced by environmental manipulations
birth defects that comply with multifactorial threshold risk models
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
Tetralogy of Fallot
Supravalvular pulmonic stenosis, Overriding aorta, Ventricular septal defect, Right ventricular hypertrophy
tetralog of Fallot mechanism of birth defect
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%.
Isotretinoin exposure in utero
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.
Which genes play a role in 22q11.2 deletion syndromes
TBX1, CRKL, and ERK2- haploinsufficiency causes dysfunction of neural crest cells and anterior heart field
Teratogens
exogenous agents (physical or chemical) that disrupt developmental pathways causing birth defects
Xenobiotics
compounds foreign to nature
how do teratogens gain access to embryo
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
List common teratogens
thalidomide, Vitamin A analogues, cholesterol synthesis inhibitors, anticonvulsants, ethyl alcohol
Mechanisms of drug/xenobiotic induced birth defects
deleterious interactions with surface and intracellular signaling proteins and cytotoxicity that “kills” cells, usually by inducing apoptosis
fetal alcohol syndrome
Produces what is essentially a phenocopy of chromosomal disorders. Each results in growth retardation, dysmorphic, features and cognitive deficiencies. Dosage is very important.
Classifications of birth defects
malformation, disruption, deformation, dysplasia
what type of birth defect is tetralogy of fallot
malformation (JAG mutation on chrom 22) or disruption (isotretinoin exposure)
example of deformation birth defect
Pulmonary hypoplasia results when physical restraint, as caused by oligohydramnios (diminished amniotic fluid) or a diaphragmatic hernia, prevents alveolar expansion.
example of dysplasia birth defect
Point mutations of Fibroblast Growth Factor Receptor genes lead to skeletal dysplasias (abnormal formation of bone) such as achondroplasia
isolated vs syndromic birth defects
isolated: usually multifactorial. Syndromic: chromosomal, monogenic or teratogenic
DiGeorge syndrome vs Velo-cardio-facial syndrome
Both are deletions on chrom22q11. Digeorge: congenital heart disease, hypoparathyroidism, thymic aplasia. Velo-cardio-facial: cleft palate, septal defects, Shprintzen syndrome
