- a form of cell division - 4 cells are formed with half the number of normal chromosomes - all 4 cells are genetically unique - only occurs in germ cells, those that give rise to gametes (sex cells)

- any agent that causes an abnormality following foetal exposure during pregnancy - medications are a common form of this

Congenital abnormalities and teratology Flashcards by David Houghton

What is meiosis?

a form of cell division
4 cells are formed with half the number of normal chromosomes
all 4 cells are genetically unique
only occurs in germ cells, those that give rise to gametes (sex cells)

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Following meiosis how many chromosomes do the spermatozoa and oocyte have?

23 chromosomes, not a pair though so they are haploid
possess half the normal 46 chromosomes (2 pairs of 23 chromosomes)
normal genotype contains 45X in female and 45Y in males

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What does teratology mean?

teratology comes from greek for monster
relates to birth defects
teratogens can cause birth defects

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What does congenital abnormalities, also called birth defects, congenital disorders, congenital anomalies and congenital malformations mean?

structural or functional anomalies that occur during intrauterine life
congenital disorders, or congenital malformations, these conditions develop prenatally and may be identified before or at birth, or later in life

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What are teratogens?

any agent that causes an abnormality following foetal exposure during pregnancy
medications are a common form of this

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There are 4 types of birth defects:

1 - malformation
2 - disruption
3 - deformation
4 - dysplasia

What does malformation mean?

abnormal development of organs or body regions (intrinsic through the embryo process)
heart and neural defects

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There are 4 types of birth defects:

1 - malformation
2 - disruption
3 - deformation
4 - dysplasia

What does disruption mean?

interference of the normal development of organs or body regions – external factors such as a teratogens

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There are 4 types of birth defects:

1 - malformation
2 - disruption
3 - deformation
4 - dysplasia

What does deformation mean?

abnormal form, shape or position of a body part (cleft lip)

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There are 4 types of birth defects:

1 - malformation
2 - disruption
3 - deformation
4 - dysplasia

What does dysplasia mean?

morphologic outcome of abnormal cellular organisation in tissues

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Any disturbance that may cause birth defects in development during embryology can change and be weighted differently depending on what?

1 - stage of embryonic development
2 -ethnicity
3 - gender
4 - if it occurs in meioses or mitosis

1 - stage of embryonic development

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What % of all neonatal deaths are due to congenital abnormalities?

1 - 5%
2 - 12.5%
3 - 25%
4 - 30%

2 - 12.5%

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The average gestational period is around 38 weeks. This 38 week period can be split into 3 clinical periods where a disturbance in foetal development will have a weighting on how much the disturbance would impact upon the embryo and/or foetus. What are the 3 time points on the figure below?

1 - 0-12, 13-26, >27 weeks
2 - 0-3, 13-26, >27 weeks
3 - 0-3, 3-8, >27 weeks
4 - 0-3, 3-8, >8 weeks

4 - 0-3, 3-8, >8 weeks

1st period in black = 0-3 weeks
2nd period in pink = 3-8 weeks
3rd period in purple = 8-38 weeks

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1 - teratogens, genetic, environmental
2 - epigenetic, genetic, environmental
3 - teratogens, epigenetic, environmental
4 - lifestyle, genetic, environmental

1 - teratogens, genetic, environmental

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1 - teratogens
2 - genetic
3 - environmental

If there are any disturbances between weeks 0-3 are likely to result in what?

death of embryo or have no effect at all

- ONE OR THE OTHER

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1 - teratogens
2 - genetic
3 - environmental

If there are any disturbances between weeks 3-8 are likely to result in what?

congenital malformations and/or deformation

- most sensitive time-point for major changes

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1 - teratogens
2 - genetic
3 - environmental

If there are any disturbances between weeks 8-38 are likely to result in what?

growth and maturation

- can lead to congenital abnormalities

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1 - teratogens
2 - genetic
3 - environmental

Of the 3 time points in the figure below what is the critical period that can have the largest effect on the embryo and foetal development should there be any disturbances?

weeks 3-8

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What are the 3 main causes of congenital abnormalities?

1 - genetics (chromosomal, non-disjunction, mutations)
2 - viral
3 - teratogens (environmental, chemicals, drugs/medications, alcohol)

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What is non-disjunction in meiosis?

failure of the chromosomes to separate during anaphase of meiosis
produces daughter cells with abnormal numbers of chromosomes

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What does aneuploidy mean?

1 - more than 2 sets of chromosomes
2 - missing or having one or more extra chromosome
3 - missing or having one or more autosomal chromosome
4 - missing or having one or more sex chromosome

2 - missing or having one or more extra chromosome
missing = hypodiploid (45 chromosomes)
extra = hyperdiploid (47 chromosomes)

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Monosomy and trisomy can both be caused by chromosome non-disjunction during meiosis. What does monosomy and trisomy mean?

monosomy = missing one chromosome = 44X or 44Y

- trisomy = an extra chromosome is present = 47X or 47Y

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Monosomy and trisomy can both be caused by chromosome non-disjunction during meiosis. Is monosomy (1 less chromosome) or trisomy (an extra chromosome) more lethal?

monosomy

- no genetic information is very dangerous

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Chromosomal non-disjunction can cause aneuploidy, missing or having one or more extra chromosome and polyploidy. What is polyploidy?

1 - more than 2 sets of chromosomes
2 - missing or having one or more extra chromosome
3 - missing or having one or more autosomal chromosome
4 - missing or having one or more sex chromosome

1 - more than 2 sets of chromosomes

can be triploidy = 3 sets of chromosomes in a cell (69 in total)
can be tetraploidy = 4 sets of chromosomes in a cell (92 in total)

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Chromosomal non-disjunction can cause aneuploidy, missing or having one or more extra chromosome and polyploidy, which is when one cell contains more than 2 sets of chromosomes, causing:

can be triploidy = 3 sets of chromosomes in a cell (69 in total)
can be tetraploidy = 4 sets of chromosomes in a cell (92 in total)

Is this dangerous?

yes either can cause miscarriage

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In addition to chromosome non-disconjunction, gaining (trisomy) or losing a chromosome (monosomy), chromosomes can also be re-arranged. Robertsonian translocation is the most common form of chromosomal translocation. What happens in this situation? 1 - X and Y chromosomes joint together 2 - autosomal chromosomes joint together 3 - two chromosomes join together in an abnormal way

3 - two chromosomes join together in an abnormal way | - short arms of the chromosome are generally lost

In addition to chromosome non-disconjunction, gaining (trisomy) or losing a chromosome (monosomy), chromosomes can also be re-arranged. Robertsonian translocation is the most common form of chromosomal translocation, where two chromosomes join together in an abnormal way. Generally the short arms of the chromosome are lost. Which chromosomes are most affected by this? 1 - 1 and 6 2 - 13 and 18 3 - 14 and 21 4 - 18 and 21

3 - 14 and 21 translocation increases the risk of down syndrome

What is an autosomal chromosome?

- non sex chromosome

What is Turners syndrome? 1 - genetic defect affecting men with one less Y chromosome 2 - genetic defect affecting men with one less X chromosome 3 - genetic defect affecting women with one less/partially missing X chromosome 4 - genetic defect affecting women with one less/partially missing Y chromosome

3 - genetic defect affecting women with one less/partially missing X chromosome - can cause short height, infertility, cognitive deficits and heart defects

Turners syndrome is a condition affecting only females that can cause short height, failure of the ovaries to develop and heart defects. Is this a monosomy or trisomy condition?

- monosomy as 1 or part of X chromosome is missing | - women normally have 45X, but instead will have 44X

There are 3 main types of trisomy that can affect the sex chromosome, what are they?

1 - 47 XXX = normal and fertile and maybe mental deficiencies 2 - 47 XXY = Klinefelter syndrome (long limbs, mental retardation, infertility) 3 - 47 XYY = normal appearance, but behaviour is affected

Klinefelter syndrome is a form of trisomy that can affect the sex chromosome, causing 47 XXY. What is Klinefelter syndrome? 1 - genetic defect affecting men with one extra Y chromosome 2 - genetic defect affecting men with one extra X chromosome 3 - genetic defect affecting women with one less/partially missing X chromosome 4 - genetic defect affecting women with one less/partially missing Y chromosome

2 - genetic defect affecting men with one extra X chromosome - males normally have 44 the and X and a Y chromosome = 46 chromosomes - causes long limbs, mental retardation, causes staining of seminiferous and aspermatogenesis (impaired production of spermatozoa so infertility

If a woman has trisomy sex chromosome resulting in 47 XXX, where she has gained an additional X chromosome, are they affected?

- healthy women generally use one X chromosome and the 2nd is inactivated - suspected that have 2 XX chromosomes are inactivated in this incidence so no major affect on the woman

What is mosaicism? 1 - 2 or more genetically different cells in their body following cleavage 2 - all cells in the body have slightly different genetics following cleavage 3 - all cells in the body are genetically the same following cleavage 4 - 2 or more cells are genetically altered in the body following cleavage

1 - 2 or more genetically different cells in their body - following fertilisation there is rapid cell proliferation called cleavage - if one of these cells is mutated all daughter cells will be mutated - earlier this occurs the more severe the effects are

Mosaicism can occur at the cleavage stage of embryonic development, that then goes on to develop the blastocyst. If non-disjunction occurs at the cleavage stage what can happen to the cells that have divided?

- some cells will have 46 chromosomes - some cells will have altered chromosome numbers - can involve autosomal or sex chromosomes but is less severe

What do gene mutations do to protein function that they generally provide the instructions for making?

- loss of protein structure and function

Genes provide the instructions for making proteins, but gene mutations cause the loss of protein structure and function, which accounts for aprox 7-8% of birth defects. What can these type of gene mutations have on the foetus?

- can be lethal or no real affect

Achondroplasia is due to a genetic mutation in the FGFR3 gene which influences cartilage structure and function. Achondroplasia literally means - a = not - chondro = cartilage - plasia = growth Essentially cartilage is the precursor for the majority of bone formation, so without this bones do not develop properly. This can present as short limbs. What is a more common name for Achondroplasia?

- dwarfism

Achondroplasia, more commonly known as dwarfism literally means - a = not - chondrp = cartilage - plasia = growth Essentially cartilage is the precursor for the majority of bone formation, so without this bones do not develop properly. What gene mutation generally causes this? 1 - fibroblast growth factor receptor 3 (FGFR-3) gene 2 - receptor activator of nuclear factor kappa beta (NFkB ligand) gene (RANK-L) 3 - fragile X Mental Retardation 1 gene 4 - Vascular endothelial growth factor (VEGF) gene

1 - fibroblast growth factor receptor 3 (FGFR-3) gene | - gene provides instructions for making cartilage

What is fragile x syndrome?

- genetic condition that causes a range of developmental problems including learning disabilities and cognitive impairment such as autism and ADHD

Fragile x syndrome is a genetic condition that causes a range of developmental problems including learning disabilities and cognitive impairment such as autism and ADHD. What gene mutation has been identified to play a key role in this syndrome? 1 - fibroblast growth factor receptor 3 (FGFR-3) gene 2 - receptor activator of nuclear factor kappa beta (NFkB ligand) gene 3 - fragile X Mental Retardation 1 gene (FMR1) 4 - Vascular endothelial growth factor (VEGF) gene

3 - FMR1 gene in X chromosome provides code for creating a protein - essential for normal cognitive development and female reproductive function

What are dominant genes?

- everybody has 2 copies of a gene (1 from mum and 1 from dad) - dominant gene is the one that causes traits even if only one copy of the gene is present

What are recessive genes?

- everybody has 2 copies of a gene (1 from mum and 1 from dad) - recessive genes only show traits if there are 2 copies of the recessive gene

What is gene imprinting?

- form of epigenetic - DNA or histones are methylated - methylation can turn on or off genes and affect protein production

Gene imprinting is a form of epigenetic, where DNA or histones are methylated. This methylation can turn on or off genes and affect protein production. What are the 2 common syndromes that we need to know about that are caused by gene imprinting?

- angelman syndrome (cognitive defects, seizures and ataxia (lose co-ordination) - prader-willi syndrome (short, cognitive defects, overeating, hypogonadism) - both affect chromosome 15

Gene imprinting is a form of epigenetic, where DNA or histones are methylated. This methylation can turn on or off genes and affect protein production. The 2 common syndromes that we need to know about that are caused by gene imprinting are: - angelman syndrome (cognitive defects, seizures and ataxia (lose co-ordination) - prader-willi syndrome (short, cognitive defects, overeating, hypogonadism) - both affect chromosome 15 Which of these is paternal and maternal?

- angelman syndrome = maternal | - prader-willi syndrome = paternal

There are a number of infections that can lead to birth defects or even miscarriage. What effect can the congenital rubella virus have? 1 - affects 1st trimester causing eye, cardiac, deafness and cognitive issues 2 - affects 1st and 2nd trimester causing muscle atrophy, limb hyperplasia, brain damage 3 - affects 1st trimester causing miscarriage 4 - causes microcephaly (top of head and/or brain is missing) caused by mosquitos

1 - affects 1st trimester causing eye, cardiac, deafness and cognitive issues

There are a number of infections that can lead to birth defects or even miscarriage. What can the varicella infection lead to? 1 - affects 1st trimester causing eye, cardiac, deafness and cognitive issues 2 - affects 1st and 2nd trimester causing muscle atrophy, limb hyperplasia, brain damage 3 - affects 1st trimester causing miscarriage 4 - causes microcephaly (top of head and/or brain is missing) caused by mosquitos

2 - affects 1st and 2nd trimester causing muscle atrophy, limb hyperplasia, brain damage

There are a number of infections that can lead to birth defects or even miscarriage. What effects does the herpes virus? 1 - affects 1st trimester causing eye, cardiac, deafness and cognitive issues 2 - affects 1st and 2nd trimester causing muscle atrophy, limb hyperplasia, brain damage 3 - affects 1st trimester causing miscarriage 4 - causes microcephaly (top of head and/or brain is missing) caused by mosquitos

3 - affects 1st trimester causing miscarriage

There are a number of infections that can lead to birth defects or even miscarriage. What effects does the Zika virus have, which is transmitted by mosquitos? 1 - affects 1st trimester causing eye, cardiac, deafness and cognitive issues 2 - affects 1st and 2nd trimester causing muscle atrophy, limb hyperplasia, brain damage 3 - affects 1st trimester causing miscarriage 4 - causes microcephaly (top of head and/or brain is missing) caused by mosquitos

4 - causes microcephaly (top of head and/or brain is missing) caused by mosquitos

There are a number of infections that can lead to birth defects or even miscarriage. What is Toxoplasmosis?

- disease resulting from infection with the toxoplasma gondii parasite - transmitted through undercooked contaminated meat, exposure from infected cat faeces, or mother-to-child transmission during - can cause miscarriage or severe development defects

There are a number of infections that can lead to birth defects or even miscarriage. What is congenital syphilis?

- syphilis is an infection transmitted by sexual contact - mother passed it onto child during pregnancy - can cause stillbirths, deafness, cognitive dysfunction and facial malformations

Thalidomide is a drug that was developed as a sedative, tranquilliser or nausea. This was classed as a teratogen, why? 1 - babies were born with nausea 2 - babies born with abnormal limb development, facial and systemic defects 3 - babies born with short limbs 4 - babies born with long limbs, poor muscle tone and cleft pallate

2 - babies born with abnormal limb development, facial and systemic defects

What are some of the most common environmental teratogens?

- smoking (reduces blood flow and hypoxia) - alcohol (growth and mental retardation) - mercury (consumed in fish) - chemical in water - lead - ionising radiation

The maternal health can also have a significant impact on foetal health. What are 2 common conditions that can cause birth defects?

- diabetes mellitus (brain, heart, vascular and limb defects) - thyroid disease (arrested physical and mental development)

Which chromosomes are the 3 most common forms of trisomy?

- 13, 18 and 21

The 3 most common chromosomes affected causing trisomy are 13, 18 and 21. What syndrome are each of these chromosomes commonly linked with, using PED to help guide?

- P = 13 = Patau syndrome (rarely survive >1 year) - E = 18 = Edwards syndrome (rarely survive >1 year) - D = 21 = Down syndrome

Do foetus that have trisomy always survive full gestation?

- no | - 50% have a miscarriage or stillbirth

What are multifactorial defects?

- inherited disorder that are caused by defects in multiple genes

Multifactorial defects are inherited disorder that are caused by defects in multiple genes. What are 2 common forms of multifactorial defects? 1 - cleft lip/palate and short limbs 2 - long limbs and poor muscle tone 3 - cleft lip/palate and neural tube defects causing spina bifida 4 - short limbs and cognitive impairment

3 - cleft lip/palate and neural tube defects causing spina bifida

In an attempt to detect if there are going to be birth defects or genetic abnormalities, what imaging modality is commonly used?

- ultrasound - generally 10-12 weeks = limb development and anencephaly (brain and skill defect) - generally 20 weeks = neural tubes and heart defects, trisomy syndromes and growth of foetus

In an attempt to detect if there are going to be birth defects or genetic abnormalities, what 3 blood tests can be used?

1 - human chorionic gonadotrophin (hCG) 2 - Pregnancy Associated Plasma Protein-A (PAPP-A) 3 - alpha-fetoprotein (AFP) produced by liver of foetus

In an attempt to detect if there are going to be birth defects or genetic abnormalities, amniocentesis can be performed. What is this?

- a sample of the amniotic fluid is taken and tested | - BUT CAN CAUSE MISCARRIAGE

In an attempt to detect if there are going to be birth defects or genetic abnormalities, chorionic villus sampling can be performed. What is this?

- sample of the chorionic villi which form the placenta is taken - BUT CAN CAUSE MISCARRIAGE

In an attempt to detect if there are going to be birth defects or genetic abnormalities. Are the tests that are performed 100 sensitive?

- no | - can still miss congenital abnormalities

Although congenital abnormalities cannot be prevented, we can try to minimise the risk. What are some common preventative strategies?

- folic acid: essential in neural tube closure - vaccination - infection treatment - dietary advice - alcohol and smoking avoidance - prenatal care - clean water - reduction of environmental pollution - support during pregnancy