Development (21.02.2020) Flashcards
What are the causes of Mal-development?
Genetic – 30%
Environmental – 15%
Multifactorial – 55%
What are some ‘common’ Mal-developments?
- trisomy 13 (patau)
- trisomy 18 (Edward)
- cleft lip
- eye mosaic (heterochromia)
- chimerism
- additional finger
- thalidomide?
Multiple pregnancies - what are the different types?
- 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
Conjoined twins
- incomplete inner cell mass separation
- the extent of conjointment and how much shared tissue there is and what the tissue is determines survival
Cells and chromosomes + cellular distributions
- 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
Mocaisism
(non disjunction) – differences between cells within one individual
Eye colour
- 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.
What is the most common eye colour?
brown
What are the possible chromosomal problems?
- Too many, too few, translocations.
- ALL give rise to syndromes
- Cross-talk between systems
changes in chromosome numbers - too many
- 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.
Chromosomal problems - too few
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
Chromosomal problems - altered distributions / translocations
XY linked
- “XX male” – XY translocation
Autosomal
- Linked with development of tumours; lymphoma; leukaemia; sarcoma
Function of gene product problems
- 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)/
Holt-Oram syndrome - heart/hand defects
- Phenotype due to mutation in TBX5 (transcription factor) – required as both structures develop.
- Atrial septation defects
- Range of hand abnormalities
Achondroplasia
- 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
What are birth defects?
- 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)
What are teratogens?
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
What are teratogen classes?
Infectious agents
physical agents
chemical agents
List some infectious agents that are teratogens.
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?
List some physical agents that are teratogens.
X-rays & other ionising radiation - Microcephaly, spina bifida, cleft palate, limb defects
List some chemical agents that are teratogens.
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
Systems to consider in development
Limbs and digits (e.g. polydactyly) Urogenital Heart Central nervous system (spine and head) (e.g. spina bifida) Face (e.g. cleft lip) Lungs
Limb development
- 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
Development of the face
- 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
Spina bifida
- 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
When should folate be given?
- 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
Anencephaly
- 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
Thalidomide
- 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
Respiratory distress syndrome
- 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 steroidsWhat is pre-implantation development?
- 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.
Implantation
- 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
Gastrulation
- 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.
When does gastrulation occur?
during days 14-18 PF
What are the 3 layers of germ cells? What do they differentiate into?
- 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).
Neurulation
- 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
What is more common, excess digits or too few digits?
- excess digits are more common
- oligodactylyl = too few
- polycactylyl = too many
