Birth Defects Flashcards
Transplacental exposure to drugs
a. Dose dependentb. Passive vs. protein transport i. Size <500 Da (needs to be small enough) ii. pH iii. Lipid solubilityc. Receptors in placentad. Bioconversion of molecules (protective vs. harmful) i. some molecules are converted in the plasma by their unique enzymes ii. some conversions are protective, while others are harmful -caffeine not suggested during pregnancy
Shift from descriptive and comparative approach to embryology and birth defects…
to a more experimental and systems biology approach
Classification of anomalies
- Malformations–> Morphologic or structural abnormalities due to an intrinsically abnormal developmental process i. the most common ii. Example: Polydactyly and syndactyly2. Deformations–>Morphologic or structural abnormalities due to a mechanical force, extrinsic or intrinsic i. Example: Arthrogryposis and club feet secondary to oligohydramnios ii. often due to compressing of baby (extrinsic force) 3. Disruptions–> Morphologic or structural abnormalities due to destruction of normally developing tissue i. Example: Amniotic bands
Syndromes
A syndrome is a set of medical signs and symptoms that are correlated with each other.In some instances a syndrome is so closely correlated with a pathogenesis or etiology that the words syndrome, disease, and disorder end up being used interchangeably for them. This is especially true of inherited syndromes For example, Down syndrome, Wolf–Hirschhorn syndrome, and Andersen syndrome are disorders with known pathogeneses, so each is more than just a set of signs and symptoms, despite the syndrome nomenclature. In other instances, a syndrome is not specific to only one disease. For example, toxic shock syndrome can be caused by various toxins; premotor syndrome can be caused by various brain lesions; and premenstrual syndrome is not a disease but simply a set of symptoms.
Sequences
a. In medicine, a sequence is a series of ordered consequences due to a single cause. i. One initiating event that leads to cascadeb. It differs from a syndrome in that seriality is more predictable: if A causes B, and B causes C, and C causes D, then D would not be seen if C is not seen. i. However, in less formal contexts, the term “syndrome” is sometimes used instead of sequence.c. Examples include: i. oligohydramnios sequence(also known as Potter sequence)Pierre Robin sequencePoland sequence
Features of DiGeorge syndrome (22q11.2 deletion)
a. Multiple genes involved, affecting neural crest cell migration and pharyngeal arch developmentb. CATCH-22Cardiac anomalies Abnormal faceThymic hypoplasia/aplasiaCleft palateHypocalcemia
Hierarchies of gene expression in cardiac development
Cell migration, mitotic rate (cell division), interaction between tissue types, controlled cell death
Isotretinoin exopsure is a phenocopy of 22q11.2 deletion
a. Phenocopies – similar birth defect phenotype resulting from different genetic and environmental factors i. situation similar to genetic defect, however the Isotretinoin is an environmental cause b. Significant overlap with 22q11.2 deletion i. Craniofacial abnormalities ii. Cleft palate iii. Thymic aplasia iv. Cardiac anomalies (tetralogy of Fallot) v. Neural tube defects vi. Small, abnormal ears
22q11.2 del and isotretinoin both affect the TBX1 gene/pathway
a. Both will affect the TBX1 pathway b. isotretinoin will inhibit the TBX1 gene pathway, leading the deffects seenc. DiGeorge will instead lead to a deletion of this genetic pathway
Developmental fields
Developmental field – groups of embryonic structures that respond as a single developmental unit1. Tissues sharing gene expression (Hedgehog signaling pathway)2. Tissues related to each other through location (branchial arches)3. Tissues sharing developmental timing (embryonic inner cell mass)4. Tissues affected by interacting processes (cell proliferation and apoptosis)
VACTERL association
VACTERL association1. Verterbral anomalies2. Anal atresia3. Cardiac anomalies4. Tracheal/Esophageal anomalies5. Renal anomalies6. Limb anomalies*Likely a developmental field defect i. Defect of blastogenesis? ii. Common timing for critical development
Timing of exposures
a. Timing is very important when exposed to teratogens b. Each organ has a critical time when exposed to teratogens c. Early the exposure, typically the worst effect i. due to the organs developing in the first 9 weeks
Timing of exposures - Rubella
a. Exposure to same teratogen at different times during gestation can cause different effectsb. Congenital rubella syndrome: 1) Earlier effects are the WORST–> Congenital heart deffects, Deafness, neuro deffects, Cataracts 2) Later exposure–> inflammatory effects -not as terrible as the organs are already devloped
Neural tube defects
a. Neural tube defects (NTDs) are a group of conditions in which an opening in the spinal cord or brain remains from early in human development.b. In the 3rd week of pregnancy called gastrulation, specialized cells on the dorsal side of the embryo begin to change shape and form the neural tube. When the neural tube does not close completely, an NTD develops.c. Specific types include: spina bifida which affects the spine, anencephaly which results in little to no brain, encephalocele which affects the skull, and iniencephaly which results in severe neck problemsd. There are two types of NTDs: open, which are more common, and closed. i. Open NTDs occur when the brain and/or spinal cord are exposed at birth through a defect in the skull or vertebrae (back bones). Examples of open NTDs are anencephaly, encephaloceles, hydranencephaly, iniencephaly, schizencephaly, and spina bifida. Rarer types of NTDs are called closed NTDs. Closed NTDs occur when the spinal defect is covered by skin.
Neural tube defects are multifactorial
Causes1. Maternal folic acid deficiency- Dietary- Maternal MTHFR mutation- Maternal folate antagonists (methotrexate)2. Teratogens3. Single Gene Defects4. Chromosomal disorders5. Amniotic Bands
Genetic and environmental interactionsLiability
Liability = all genetic and environmental factors that influence the development of a multifactorial disordera. Liability is a term used to collectively describe all the genetic and environmental factors that contribute to the development of a multifactorial disorder. b. Although it is impossible to directly measure the liability of a certain individual, the liability for a group of people can be estimated based on the number of affected individuals within that group. c. Liability is best represented as a standard distribution curve as most individual who are unaffected will posses some degree of liability with only a small portion of a population having a liability that is very low or that exceed the threshold level
Liability/threshold model for NTDsNeural tube deffects
-Genetic predisposition-Sporadic genetic causes-Decreased maternal folate-Mechanical disruptionA relative of an affected person has a higher liability at the same thresholdShift threshold to the right with folic acid supplementation
Prevention of birth defects
a. Prenatal vitamins -These are very high in Folateb. Reducing/eliminating harmful exposuresc. Early detection and interventiond. Fetal surgerye. Future – gene therapy?
Summary
a. In the past, teratology focused on phenotypic descriptions and timing i. Continue to move to descriptions based on gene/protein interactionsb. Discussed examples of different causes of birth defects and how and why their phenotypes may overlap i. Hierarchies of gene expression ii. Phenocopies iii. Developmental fields iv. Timing of exposure to teratogens v. Gene/environment interactions
Birth Defects
a. Birth Defects: A birth defect is an abnormality of structure, function or metabolism (body chemistry) present at birth that results in physical or mental disabilities or death. (March of Dimes) b. Birth defects can be found in 5-7% of the total population (children → adults), though many are of no particular consequence. c. About 2% of infants are born with potentially life threatening birth defects.d. Birth defects are the leading cause of death outside of prematurity in the first year of life.
Birth defects have multiple etiologies:
Causes of birth defects:Chromosomal 10-15%Mendelian 2-10%Maternal/placental infections 2-3%Maternal disease states 6-8%Drugs and chemicals 1%Irradiations 1%Multifactorial 20-25%Unknown 40-60%
Teratology – The study of birth defects and the mechanisms responsible for them.
a. Clinical teratology in the past has largely been a descriptive exercise focusing on the timing of birth defects and so called critical periods of developmental susceptibility. b. This approach was based on experimental observations in animals and the epidemiology of Thalidomide, a potent teratogen that caused a specific pattern of limb defects called phocomelia. c. It was clear that exposure to the agent after 5 weeks was no longer associated with phocomelia (though other, less immediately evident problems also occurred). d. Some teratogens have different effects depending on the timing of exposure (Ex. Congenital rubella).
Teratogens and Xenobiotics
Teratogens – exogenous agents (physical or chemical) that disrupt developmental pathways causing birth defects.Xenobiotics – compounds foreign to nature.
Transplacental exposure:
a. 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). b. 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. i. Also, some drugs are converted to harmful intermediate forms by these same enzymes (caffeine).c. Many teratogens have been associated with recurring patterns of birth defects. d. Mechanisms of drug/xenobiotic induced birth defects include deleterious interactions with surface and intracellular signaling proteins and cytotoxicity that “kills” cells, usually by inducing apoptosis (programmed cell death). i. Both mechanisms produce recognizable syndromes Note: dosage is very important. Levels of exposures need to be high enough to induce biological effects. So far, most environmental exposures are low dose.
