Birth Defects

Question 1

Transplacental exposure to drugs

Answer 1

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

Question 2

Shift from descriptive and comparative approach to embryology and birth defects…

Answer 2

to a more experimental and systems biology approach

Question 3

Classification of anomalies

Answer 3

1. 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

Question 4

Syndromes

Answer 4

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.

Question 5

Sequences

Answer 5

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

Question 6

Features of DiGeorge syndrome (22q11.2 deletion)

Answer 6

a. Multiple genes involved, affecting neural crest cell migration and pharyngeal arch developmentb. CATCH-22Cardiac anomalies Abnormal faceThymic hypoplasia/aplasiaCleft palateHypocalcemia

Question 7

Hierarchies of gene expression in cardiac development

Answer 7

Cell migration, mitotic rate (cell division), interaction between tissue types, controlled cell death

Question 8

Isotretinoin exopsure is a phenocopy of 22q11.2 deletion

Answer 8

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

Question 9

22q11.2 del and isotretinoin both affect the TBX1 gene/pathway

Answer 9

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

Question 10

Developmental fields

Answer 10

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)

Question 11

VACTERL association

Answer 11

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

Question 12

Timing of exposures

Answer 12

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

Question 13

Timing of exposures - Rubella

Answer 13

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

Question 14

Neural tube defects

Answer 14

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.

Question 15

Neural tube defects are multifactorial

Answer 15

Causes1. Maternal folic acid deficiency- Dietary- Maternal MTHFR mutation- Maternal folate antagonists (methotrexate)2. Teratogens3. Single Gene Defects4. Chromosomal disorders5. Amniotic Bands

Question 16

Genetic and environmental interactionsLiability

Answer 16

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

Question 17

Liability/threshold model for NTDsNeural tube deffects

Answer 17

-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

Question 18

Prevention of birth defects

Answer 18

a. Prenatal vitamins -These are very high in Folateb. Reducing/eliminating harmful exposuresc. Early detection and interventiond. Fetal surgerye. Future – gene therapy?

Question 19

Summary

Answer 19

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

Question 20

Birth Defects

Answer 20

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.

Question 21

Birth defects have multiple etiologies:

Answer 21

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%

Question 22

Teratology – The study of birth defects and the mechanisms responsible for them.

Answer 22

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).

Question 23

Teratogens and Xenobiotics

Answer 23

Teratogens – exogenous agents (physical or chemical) that disrupt developmental pathways causing birth defects.Xenobiotics – compounds foreign to nature.

Question 24

Transplacental exposure:

Answer 24

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.

Question 25

fetal alcohol syndrome (FAS)

Answer 25

a. Effects of developmental toxicity are exemplified by fetal alcohol syndrome (FAS), although there are some pharmacologic effects. b. An important point is that FAS produces what is essentially a phenocopy of chromosomal disorders. c. Each results in growth retardation, dysmorphic, features and cognitive deficiencies. Dosage, again, is very important.

Question 26

Classification of anomalies:

Answer 26

Though we have moved away from descriptive approaches to birth defects, a broad mechanistic classification of anomalies can be useful. 1. Malformations: Morphologic or structural abnormalities due to an intrinsically abnormal developmental process (Ex. Polydactyly, syndactyly).2. Deformations: Morphologic or structural abnormalities due to a mechanical force, usually extrinsic (Ex. Arthrogryposis due to intrauterine compression).3. Disruptions: Morphologic or structural abnormalities due to destructions or normally developing tissue.4. Syndrome: A constellation of anomalies believed to be pathologically related (Ex. Down syndrome)5. Sequence: A cascade of anomalies triggered by one initiating aberration (Ex. Potter’s sequence).

Question 27

Tetralogy of Fallot

Answer 27

a. Mutations affecting the expression of genes in neural crest cells contributing to further development beyond the truncus arteriosus will contribute Tetralogy of Fallot (TOF). b. The most common genetic mutation associated with TOF is the deletion on chromosome 22, del 22q11, associated Shprintzen and diGeorge syndromes c. This deletion is associated with 40% of cases of TOF. d. Mutations in the gene associated with Alagille syndrome, JAG1 account for another 20%. e. The functions of the gene(s) missing from chromosome 22q11 responsible for abnormal neural crest cell migration are beginning to be understood. i. Three genes in chromosome 22q11.2 (TBX1, CRKL, and ERK2) have been identified whose haploinsufficiency (presence of only one allele) causes dysfunction of the neural crest cell and anterior heart field and anomalies of 22q11.2 deletion syndrome.

Question 28

Organogenesis involves hierarchies of gene expression:

Answer 28

Using the tools of molecular biology embryologists are now dissecting hierarchical pathways of development and developmental fields that determine organogenesis and mechanisms of birth defects.

Question 29

Cardiac developmental pathway:

Answer 29

a. Two of the large number of hierarchical pathways contributing to development of the heart. b. The pathway on the left depicts the hierarchy of genetic expression of genes regulating muscular differentiation and positioning of the heart. c. On the right is the pathway regulated by the expression of genes in neural crest cells that migrate into the developing aortic arches (truncus arteriosus).d. These hierarchies of gene expression involve the appropriate timing of activation and inhibition of genes involved in cell migration, mitotic rate (cell division), interaction between tissue types, and controlled cell death.

Question 30

All phenotypes are the result of interactions between environmental and genetic factors:

Answer 30

This leads to the production of phenocopies – Phenocopies are overlapping phenotypes of a genetic disease and a teratogenic effect due to a similar effect at molecular level or pathway. Theoretically, anything produced by genetic mutations can also be produced by environmental manipulations.

Question 31

Organs form within developmental fields:

Answer 31

a. Tissues sharing gene expression - e.g. Hedgehog signaling pathways b. Tissues related to each other through location – e.g. branchial arches c. Tissues sharing developmental timing – e.g. embryonic inner cell mass d. Tissues affected by interacting processes – e.g. cell proliferation and apoptosis

Question 32

Developmental field defect example: VACTERL association

Answer 32

a. Birth defects associating with each other more frequently than can be accounted for by chance alone. V = Vertebral anomalies A = Anal atresia C = Cardiac anomalies (primarily septal defects) TE = Esophageal atresia, tracheal esophageal fistula R = Renal L = Limb (Predominantly radial upper limb) anomaliesb. As yet not accounted for by chromosomal, monogenic, or environmental factors. i. Increased frequency in monozygotic twinning (discordant = one affected)c. Developmental field may include early events such as implantation and inner cell mass formation that are known to be affected by twinning.

Question 33

Genetic-Environmental Interactions:

Answer 33

a. Genetic and environmental interactions producing birth defects can be described by a threshold model that divides populations by genetic risks that are modified by the environment in a “dose” dependent fashion.b. Some congenital heart disease (e.g. ventricular septal defects) and neural tube closure abnormalities (anencephaly and spina bifida) are birth defects that comply with multifactorial threshold risk models. c. For neural tube defects, an environmentally determined threshold is associated with folic acid levels. The prevalence of spina bifida has been reduced to 1:2400 pregnancies (1/2 of the previous prevalence) by fortification of common foods with folic acid.d. Maternal folic acid deficiency increases risks for spina bifida, especially in areas such as western England and Northern Ireland, where genetic predisposition is high.

Question 34

Maternal folic acid deficiency increases risks

Answer 34

a. Maternal folic acid deficiency increases risks for spina bifida, especially in areas such as western England and Northern Ireland, where genetic predisposition is high. b. Understanding of environmental-genetic interactions creates opportunities for prevention. c. Folic acid supplementation with prenatal vitamins beginning when couples decide to conceive decreases the risk in the general population. d. With higher doses (1 mg/day) risks for recurrent neural tube defects are decreased in couples that have already had one affected pregnancy.

Question 35

TORCHES infections

Answer 35

Bacteria, viruses, and other organisms are able to be passed from mother to child. Several vertically transmitted infections are included in the TORCH complex, which stands for:T – Toxoplasmosis / Toxoplasma gondiiO – Other infections (see below)R – RubellaC – CytomegalovirusH – Herpes simplex virus-2 or neonatal herpes simplexThe “other agents” under O include:CoxsackievirusChickenpox (caused by varicella zoster virus)ChlamydiaHIVFurther information: HIV and pregnancyHuman T-lymphotropic virusSyphilisZika fever, caused by Zika virus, can cause microcephaly and other brain defects in the child

Question 36

Major causes of birth defectsCategegoris

Answer 36

1. InfectionRubellaToxoplasmosisSyphilisCytomegalovirusHIV2. Maternal Disease stateDiabetesPhenylketonuriaEndocrinopathies3. Drugs and ChemicalsAlcoholFolic acid antagonistsAndrogensPhenytoinThalidomideWarfarin13-cis-retinoic acidOthers

Question 37

DiGeorge syndrome

Answer 37

a. DiGeorge syndrome, also known as 22q11.2 deletion syndrome is a syndrome caused by the deletion of a small segment of chromosome 22. i. microdeletion syndrome characterized by low copy repeats and the deletion occurs near the middle of the chromosome at a location designated 22q11.2b. Salient features can be summarized using the mnemonic CATCH-22 to describe 22q11.2 deletion syndrome, with the 22 to remind one the chromosomal abnormality is found on the 22 chromosome, as below:Cardiac abnormality (commonly interrupted aortic arch, truncus arteriosus and tetralogy of Fallot)Abnormal faciesThymic aplasiaCleft palateHypocalcemia/Hypoparathyroidismc. Individuals with a 22q11.2 deletion can have many possible features, ranging in number of associated features and from the mild to the very serious. Symptoms shown to be common include:1. Congenital heart disease (40% of individuals), particularly conotruncal malformations (interrupted aortic arch (50%), persistent truncus arteriosus (34%), tetralogy of Fallot, and ventricular septal defect)2. Cyanosis (bluish skin due to poor circulation of oxygen-rich blood)3. Palatal abnormalities (50%), particularly velopharyngeal incompetence, submucosal cleft palate, and cleft palate4. Hypocalcemia (50%)(due to hypoparathyroidism)Significant feeding problems (30%)5. Renal anomalies (37%)6. Hearing loss (both conductive and sensorineural) (hearing loss with craniofacial syndromes)