Development (21.02.2020)

Question 1

What are the causes of Mal-development?

Answer 1

Genetic – 30%

Environmental – 15%

Multifactorial – 55%

Question 2

What are some ‘common’ Mal-developments?

Answer 2

• trisomy 13 (patau)
• trisomy 18 (Edward)
• cleft lip
• eye mosaic (heterochromia)
• chimerism
• additional finger
• thalidomide?

Question 3

Multiple pregnancies - what are the different types?

Answer 3

• Identical twins / triplets: one conceptus forms 2 / 3 inner cells masses to form 2 / 3 genetically identical individuals
• Chimerism: 2 genetically distinct conceptuses combine to form one individual
• Changes in the numbers of conceptuses or fetuses that develop (very early in development)
• Twins
• Triplets
• Chimaera (2 genetically different patterns in one human)
• conjoined twins (incomplete inner cell mass separation) - the extent of conjointment determines future

=> very gross changes in development

Question 4

Conjoined twins

Answer 4

• incomplete inner cell mass separation

- the extent of conjointment and how much shared tissue there is and what the tissue is determines survival

Question 5

Cells and chromosomes + cellular distributions

Answer 5

• The distribution of cells and chromosomes can change development.
• Changes to chromosomes can affect gene expression.
• Mosaicism (non disjunction) – differences between cells within one individual (e.g. different eye colours)
• Distribution of cells between inner cell mass & trophectoderm (placenta)
• Chimerism - fused multiple zygotes
  Non-identical zygotes

Question 6

Mocaisism

Answer 6

(non disjunction) – differences between cells within one individual

Question 7

Eye colour

Answer 7

• Human chromosome 15.
• Brown most common colour; others mostly in Caucasians.
• Differentiation of eyes begins about Day 22 PF.
• Event that changes something must predate Day 22.

Question 8

What is the most common eye colour?

Answer 8

brown

Question 9

What are the possible chromosomal problems?

Answer 9

• Too many, too few, translocations.
• ALL give rise to syndromes
• Cross-talk between systems

Question 10

changes in chromosome numbers - too many

Answer 10

• XY linked
• Kleinfelter’s syndrome (XXY). Decreased fertility
• XXYY, XXXY, XXXYY, etc – severe forms related to KS
• XYY (XYYY) – very variable (taller, learning problems)
• XXX. Limited effects, some mental changes -> this has something to do with X-inactivation (a single X chromosome is inactivated)
• XXXX, XXXXX. More severe effects
• in females one X chromosomes is inactivated, in males the other X chromosomes may still have effects

Autosomal

• Down’s syndrome (ch21) (1 / 1000 live births)
  - Heart problems determine survival.
• Edward’s syndrome (ch18) (1 / 6000 live births)
  • Most die before birth, very few live-born, live ≤2 weeks.

Patau’s syndrome (ch13) (1 / 15,000 live births)
- Most die before birth, 80% live-born die within 1 year.

• Others not found in live birth, most detected in some spontaneous pregnancy loss tissues.
• Ch1 trisomy not found in pregnancy loss tissues, lost pretty much immediately after fertilisation in trisomy.
• Mosaic or partial extra chromosomal material
• Less severe symptoms than in complete trisomies.

Question 11

Chromosomal problems - too few

Answer 11

XY linked

• Turner’s syndrome - X0. Female, short stature, infertile
• Y0 not viable!!!

Autosomal

• No complete losses are viable
• Partial chromosome loss syndromes known and characterised

Question 12

Chromosomal problems - altered distributions / translocations

Answer 12

XY linked
- “XX male” – XY translocation

Autosomal
- Linked with development of tumours; lymphoma; leukaemia; sarcoma

Question 13

Function of gene product problems

Answer 13

• Mutations
• Altered expression
• Many genes are found in both animals and humans.
• some gene problems can have very limited effects.Others can have a range of problems (e.g. holt-oram syndrome causing hand and heart defects)/

Question 14

Holt-Oram syndrome - heart/hand defects

Answer 14

• Phenotype due to mutation in TBX5 (transcription factor) – required as both structures develop.
• Atrial septation defects
• Range of hand abnormalities

Question 15

Achondroplasia

Answer 15

• Gain of function mutation in FGFR3
• constantly active in achondroplasia?
• Achondroplasia means “lack of cartilage”
• Defect is in conversion of cartilage to bone & lack of bone growth

Question 16

What are birth defects?

Answer 16

• Birth defect = congenital malformation = congenital abnormality
• Changes in the PATTERN of development
• Teratology or dysmorphology
• Major abnormalities ~3% of pregnancies (cause 25% of infant deaths.
• Minor abnormalities ~15% (little health impact)

Question 17

What are teratogens?

Answer 17

Any agent that can disturb the development of an embryo or foetus

• most vulnerable in the 1st trimester when tissues are dividing fast
• some tissues are vulnerable for longer or at a later stage

Question 18

What are teratogen classes?

Answer 18

Infectious agents
physical agents
chemical agents

Question 19

List some infectious agents that are teratogens.

Answer 19

Rubella virus - Cataracts, glaucoma, heart defects, deafness, teeth
Herpes simplex virus - Microphthalmia, microcephaly, retinal dysplasia
HIV - Microcephaly, growth restriction
Syphilis - Mental retardation, deafness
Zika virus – microcephaly

flu?

Question 20

List some physical agents that are teratogens.

Answer 20

X-rays & other ionising radiation - Microcephaly, spina bifida, cleft palate, limb defects

Question 21

List some chemical agents that are teratogens.

Answer 21

Thalidomide - Limb defects, heart malformations
Lithium - Heart malformations
Amphetamines - Cleft lip and palate, heart defects
Cocaine - Growth restriction, microcephaly, behavioral abnormalities
Alcohol - Fetal alcohol syndrome, maxillary hypoplasia, heart defects

Question 22

Systems to consider in development

Answer 22

Limbs and digits (e.g. polydactyly)
Urogenital
Heart
Central nervous system (spine and head) (e.g. spina bifida)
Face (e.g. cleft lip)
Lungs

Question 23

Limb development

Answer 23

• Forelimb bud appears at d27/8
• Hindlimb bud at d29
• Grow out from lateral plate mesoderm rapidly under control of special signalling regions
• Fully formed and patterned by d56.
• day 35 hand plate is formed
• day 44 5 digital rays

possible mal-developlent: polydactyly

sonic hedgehog (shh) controls the limb development

Rotation in limb development

Question 24

Development of the face

Answer 24

• We start with our eyes on the side (like birds and fish)
• there is controlled breakdown of tissue in the middle
• gradual formation of face
• If the clefts are not filled properly you get cleft palate.
• surgical repair heals very well if done early, very good repair

Question 25

Spina bifida

Answer 25

- can be due to folate deficiency - cause early in pregnancy, sealing up of the tube imperfect around days 22-28 gives rise to spina bifida (there is a neuropore) - 1-2 per 1000 pregnancies - usually occurs at the base of the spine, can also be in multiple places - bulge of tissue - it may just be CSF but it may also contain neural tissue Neural tissue controls the development of the vertebrae above the spinal cord - Surgery can help anatomical, but not functional Summary - It is variable, but can be severely disabling - The primary problem is failure to complete neurulation (posterior neuropore) - The problem is present within 4 weeks of fertilisation problems

Question 26

When should folate be given?

Answer 26

- around 3 months before conception or more (because the early conceptus has nutrients and energy supplies from the egg) - however it would be good to have sufficient folate in your daily diet

Question 27

Anencephaly

Answer 27

- Defect in skull and brain development - Incidence: 1 – 8 per 10,000 births - Female babies affected more commonly than male - usually brainstem is okay - top of the spine has not closed (anterior neuropore has not closed) - Folic acid (given at the right time) may show benefit - Implies similar causes to spina bifida - Anterior neuropore closure incomplete

Question 28

Thalidomide

Answer 28

- drug for morning sickness - taken by women in 1st trimester of pregnancy in the 1960s - ~10,000 affected infants known, ~50% initial survival rate. Limbs affected. - In addition, deformed eyes and hearts, deformed alimentary and urinary tracts, blindness and deafness. - Used in some leprosy and cancer treatments at present. - interferes with BV development in the developing limb. - prolonged exposure leading to widespread cell death and all signalling cells are lost - phocomelia: shoer exposure leading to uniform cell death and only partial loss of AER signalling which recovers - Thalidomide – affects rapidly developing blood vessels, notably those of upper limbs - variable impact - Blood vessel affects can be generic, hence the range of effects observed. -> cancer treatment

Question 29

Respiratory distress syndrome

Answer 29

``` - Overall incidence ~1% of all births ~100% at GA 24 weeks ~50% at GA 26-28 weeks ~25% at GA 30-31 weeks - high surface tension, lungs won't expand properly (because not enough surfactant) - inject steroids ```

Question 30

What is pre-implantation development?

Answer 30

- normally occurs within the Fallopian tube (oviduct) over a period of ~6 days - characterised by a series of cleavage divisions, which to produce a ball of undifferentiated cells (the Morula). - The Morula differentiates so that the inner cells differ from those on the outside - This then develops into the Blastocyst, a structure that has an outer layer of trophectoderm, an inner cell mass, and a fluid-filled cavity.

Question 31

Implantation

Answer 31

- after preimplantation the Blastocyst hatches from the Zona Pellucida (within which it has developed up to this time, about day 6 PF), - begins to implant in the uterine lining, a process which is complete about 10 days PF. - By this time the inner cell mass, which was a group of undifferentiated cells has become a bilayer disk, composed of hypoblast and epiblast cells - This bilayer disk gives rise to all the tissues of the human fetus, through a complex series of changes (i.e. gastrulation

Question 32

Gastrulation

Answer 32

- converts the bilayer of hypoblast and epiblast cells into a trilaminar embryo - containing the three layers of Germ Cells (Ectoderm, Mesoderm and Endoderm) - occurring during days 14-18 PF - proliferation of epiblast cells, which then differentiate to form mesoderm cells; - these move into the space between the epiblast and hypoblast. - These mesoderm cells are thought to differentiate further to generate the endoderm, which replaces the hypoblast cells which are lost by apoptosis.

Question 33

When does gastrulation occur?

Answer 33

during days 14-18 PF

Question 34

What are the 3 layers of germ cells? What do they differentiate into?

Answer 34

- Ectoderm (skin and CNS) - Mesoderm (muscles, blood, skeleton, heart, kidney) - Endoderm (gut, liver, lungs) - Muscular and vascular tissue are generally of mesodermal origin, so tissues are normally a mixture of germ layer types (e.g. muscle in the skin and gut).

Question 35

Neurulation

Answer 35

- Neurulation has been initiated before gastrulation is complete. - Neurulation is the differentiation of the Ectoderm (Epiblast) to generate the CNS (Brain and Spinal cord), under the control of the notocord in the mesoderm of the developing embryo. - The early stages: development of the neural plate; this develops two folds, which increase in size until the meet over the neural groove and fuse to form the neural tube

Question 36

What is more common, excess digits or too few digits?

Answer 36

- excess digits are more common - oligodactylyl = too few - polycactylyl = too many