Embryology and Defects Flashcards
how does gestational timing differ with embryological timing?
Embryological timings are usually about 2 weeks less than the gestational time frames
GA uses LMP (2 weeks ahead/greater)
embryological age is the true foetal age
when does gestational timing starts from?
last menstrual period
which trimester has the most rapid weight gain in the foetus?
1st
what system is used to measure development of the embryo?
Carnegie stages
what is a blastocyst?
consists of a bilayer of epiblast and hypoblast
present at ~9-10 days
0.1 cm wide
give rise to all the tissues of the foetus
what is an embryo?
small developing conceptus present at ~5-6 weeks and is around 1cm wide.
what is a foetus?
after 8 weeks of development the conceptus can be referred to as the foetus (recognisable human)
developing conceptus
what is a conceptus?
anything derived from a fertilised egg
where are red blood cells produced in the embryo?
liver
what 4 process allow cells to reach embryological development?
o Proliferate
– in response to GF, receptor expression, cell survival
– all via para- or autocrine signalling.
o Move
– chemoattractants, cognate receptors, facilitated (via remodelling and proteases)
o Differentiate
– paracrine regulation, receptor expression, loss of proliferation.
o Cell loss
– PCD controlled by mainly paracrine factors.
what do the different signalling methods mean?
- paracrine
- autocrine
(- endocrine)
o Paracrine – to adjacent cells.
o Autocrine – to oneself.
- endocrine over long distances via vasculature but this does not occur in embryo development due to a lack vasculature
what is meant by concentration signalling?
the strongest signals are received by cells located closest to the source of the signalling molecules.
what is meant by a bud in development e.g limb bud?
If the source cells are at the tip, the highest levels of proliferation will remain at the tip and thus a “bud” will form towards the apex
With +ve stimuli and –ve stimuli, asymmetrical development
how does the formation of embryological structures depend on factors (to achieve their shapes etc)?
gradients of factors, combinations of factors, temporal changes in factors or responses to them.
what animal models are used to make sense of the complexity of the multiple influences driving embryology?
o Chick – limbs, mainly with wings.
o Fish – eyes.
o Mouse – knock-out or knock-in with tissue specificity.
our genes are similar to these animals
what are HOX genes?
group of related genes that specify regions of the body plan of an embryo along the head-tail axis of animals (AP) e.g. differences in the vertebrae, CNS divisions, patterns in the limbs.
what is HOX activation controlled by?
Activation of HOX is controlled by retinoic acid, a derivative of vitamin A.
HOX genes provide body plan of embryo
what does the conceptus start off as?
bilaminar disc inside a blastocyst
– comprised of an epiblast and a hypoblast layer
what is the result of gastrulation of the conceptus (day 14-18)?
3 layers created:
- ectoderm
- mesoderm
- endoderm
gastrulation is one of many complexes series of changes that occur to the blastocyst bilayer
where does gastrulation take place?
what happens in it?
occurs down the primitive streak
a. Epiblast cells migrate towards the centre.
b. Epiblasts then differentiate into the mesoderm cells and move down into the new mesoderm layer (between epi- and hypoblast)
c. The hypoblast cells apoptose and are replaced by endoderm cells (which has differentiated from mesoderm cells)
gastrulation is the process by which the blastula cells migrate and divide to form the 3 primary germ layers of the gastrula
(neurulation refers to the folding of the neural plate into the neural tube)
what does the endoderm develop into?
- lining of the organs
- becomes gut, liver, pancreas and lungs.
what does the mesoderm develop into?
muscles, kidneys, heart, blood and skeleton
MK-HBS
what does the ectoderm develop into?
skin and the CNS
what does the ectoderm proliferate into after gastrulation?
proliferates to form the neural plate i.e. CNS
(with no proliferation at the neural groove due to negative stimulation of notochord)
and the neural fold’s fold over and form the neural canal.
what happens at day 28?
the yolk sac is pinched off into the umbilical cord (allantois)
what starts to develop in the 2nd month of development?
o Limbs develop – days 28-56.
o Face develops.
o Internal tissues develop
– heart, lungs and gut.
by which day will the conceptus look human?
day 56
what is left open when the embryo tissues fuse down the midline at day 22-23?
the anterior and posterior neuropore
what day should the neuropores have closed by?
day 25-28
what is the consequence of incomplete closure of the posterior neuropore?
Spina bifida
incomplete neurulation
what are the types of spine bifida?
o Myelomeningocele
– neural tissue in bulge. The spinal cord is therefore affected
o Meningocele
– no neural tissue in bulge, may have CSF instead
- the membrane bulges out, the meninges is stuck in the vertebrae
o Spina bifida occulta
– hair growth over area affected, no growth.
there is no formation of vertebrae at the bulge suggesting that bone growth is dependent on neural tissue growth
what is consequence of incomplete closure of the anterior neuropore?
anencephaly
how can incomplete spina bifida be treated and prevented in the first place?
o Surgery can help anatomical but not functional problems
o Folic acid can prevent but must be taken VERY early
as the problem manifests 4 weeks PF so must be taken early (take 3 months earlier)
what is anencephaly?
due to failed closure of anterior/rostral neuropore
literally means “lack of head” but is reduced brain development.
females affected more than males
how can anencephaly and spina bifida be prevented?
early intake of folic acid
- 3 months before conception
(70% of SB cases due to lack)
how does the heart develop from day 20- week 8 to make the primitive heart?
- The two endocardial tubes fuse into a primitive heart tube (21).
a. Endocardial tubes develop in the mesoderm and come together as the body cavity closes around day 21.
b. The primitive heart tube is joined at the cranial end in like a horseshoe (McDonald’s arc shape) which is then split to form the muscular tube (snap at the apex)
- The heart then undergoes a turning action (anti-clockwise) to form the primitive heart (23-28) and the 4 chambers form.
what day does blood flow through the heart begin?
day 22
when does the ductus arterioles and foramen oval close?
at birth when the heart shifts from single cycle flow in the foetus to a figure of eight loop flow
what is the role of the ductus arteriosus and patent foramen oval?
The ductus arteriosus and patent foramen ovale act as shunts to the blood supply (so that the blood avoids the pulmonary system)
when does the forelimb bud appear?
day 27-28
when does the hindlimb bud appear?
day 29
when do the limbs fully form by?
day 56
what is budding of the limbs?
Budding is growth from the lateral plate mesoderm which is done rapidly under control of special signalling regions.
what causes achondroplasia? what does this affect?
FGFR3 (fibroblast growth factor receptor 3) gain of function mutation:
stops the conversion of cartilage to bone resulting in too much cartilage
–> Affects the elongation of limbs rather the detail (i.e. primary formation is not affected)
what was thalidomide originally used for?
to treat morning sickness
what did thalidomide affect in developing babies?
Mainly affected limbs but also eyes, heart, alimentary/urinary tracts, blindness and deafness
o Amelia – “prolonged exposure” to thalidomide.
o Phocomelia – “short exposure” to thalidomide.
what is thalidomide currently used for?
used to treat leprosy and some cancers.
how did thalidomide affect limb development?
it damages developing vessels and therefore deprived adjacent cells of nutrients and prevented proper growth
particularly in the limbs so leads cell death in the developing limb bud
why may thalidomide be used for cancers?
it affects vessel development therefore may affect angiogenesis for tumour survival
what molecules are involved the regulation of limb development?
o Shh
– Sonic Hedgehog protein – zone of polarising activity.
o FGF8
– Fibroblast-like Growth Factor-8
– apical ectodermal ridge.
name another condition affecting limb development
polydactyly
what are the development stages of the foetal kidney?
1) Pronephros (no excretory function)
- the most immature form
2) Mesonephros (limited excretory function)
- intermediate phase
3) Metanephros (definitive kidney)
- most developed
what happens when the mesonephros has developed?
o Metanephric ducts grow out of the cloaca and begin to form the kidneys.
o Mesonephric ducts begin to differentiate into gonads (testes)
– ducts mainly apoptose in females.
what are some kidney developmental errors?
o Renal agenesis
– degeneration of ureteric bud:
Unilateral – L>R.
Bilateral – “Potter’s syndrome” Oligohydramnios.
o Abnormal shaped kidneys.
o Abnormal ureter
– bifid ureter, double kidneys, supernumerary kidney (extra kidney).
o Pelvic or horseshoe-shaped kidney
– kidney doesn’t ascend or kidneys fuse caudally to horseshoe shape.
o Bladder exstrophy.
what forms the bladder?
endoderm
what is the purpose of the trigone (mesodermal origin)?
Signals bladder filling
what does the male ductal system originate from?
Mesonephric duct aka Wolffian duct
mesonephric tube becomes the testes.
what does the female ductal system originate from?
Paramesonephric duct aka Mullerian ducts
where do gametes come from and how do they end up in the embryo?
Primordial germs cells (PGC) give rise to eggs and sperm and are found outside the embryo in the yolk sac
They move into the embryo and then move into the developing genital ridges (the gonads are “indifferent” before the PGCs move in and they are identical in males and females to begin with).
at what week do the ductal systems develop around?
week 7
they gonads show no differentiation in development until about week 7
under what influence does the male ductal system begin to form?
Under influence of SRY gene
(Sex-determining Region Y) of Y chromosome
in its absence the female ductal system develops
what early tissue do gonads arise from?
intermediate mesoderm within urogenital ridges
what are the precursors of gametes?
primordial germ cells
until which week are the organs sexually indifferent?
week 7
what is the influence of the SRY gene on sexual differentiation?
SRY +ve –> development proceeds along male path (~7th week onwards).
SRY –ve –> development proceeds along female path (~9th week onwards).
what will the testis contain?
spermatogonia, Leydig cells, Sertoli cells
what do Leydig cells produce? what effect does this product have?
testosterone
supports growth of mesonephric ducts (thus, without testosterone, the mesonephric ducts will regress).
what is testosterone converted in to and what does this lead to?
DHT is produced to support the development of prostate, penis and scrotum
how do the testis make sure that the paramesonephric ducts regress (female ducts)?
Sertoli cells will produce produce AMH (Anti-Mullerian Hormone)/MIS (Mullerian Inhibiting Substance) which induces the paramesonephric duct regression
in the absence of these hormones, the female ducts precursor will be persist
what is the precursor to the ureter?
what is the precursor to the kidney?
ureteric bud
metanephric blastema
kidney ascends during development
ureter extends in length
what are the male components the mesonephric ducts will differentiate into?
rete testes, efferent ducts, epididymis, vas deferens, seminal vesicle, trigone of bladder
i.e. everything testes and trigone
what will the urogenital sinus differentiate into?
bladder (w/o trigone)
prostate gland
bulbourethral gland
urethra
how do the testes descend?
- Arise in lumbar region and descend into pelvic cavity via inguinal canal.
- Descent is due to tethering of testes to anterior body wall by the gubernaculum.
- Growth and elongation of embryo coupled with shortening of gubernaculum pulls testes through body wall.
what do the ovaries contain when they differentiate?
oogonia and stromal cells
what causes the mesonephric (male) ducts to regress in the female and the paramesonephric ducts to persist?
the absence of testosterone cause male duct regression
the absence of AMH/MIS cause female duct persistence
[AMH is also Mullerian Inhibiting Substance]
what do the mesonephric duct differentiate into in the female?
bladder
what female components will the paramesonephric duct differentiate into?
oviducts
uterus
upper 1/3rd of vagina
what will the urogenital sinus give rise to in the female?
bulbourethral glands
lower 2/3rd of vagina
what is needed to drive testosterone production in the developing embryo?
hCG
which peaks 8 weeks LMP, however, testosterone is needed 8 weeks PF
what are the risk associated with undescended testes?
increased risk of cancer
do not function normally.
what is hypospadias?
fusion of urethral folds’ incomplete
– urethra exits penis early
what causes two uteruses to be formed?
abnormal fusion of ducts
what is Persistent Mullerian Duct Syndrome?
- affects males
- mutations in AMH/MIS or receptor
- no inhibitory function so the paramesonephric duct persists
- testis either sit by ovaries or one/both can descend
- DHT can be produced (from testosterone) so the external genitalia is present
what is Androgen Insensitivity (“Testicular Feminisation”) Syndrome? what are the features?
- affects males (XY)
- mutations in the androgen receptor
- normal external genitalia but undescended testes
- mesonephric ducts rudimentary due to loss of testosterone
- however MIS is produced so causes Mullerian duct regression so no oviducts, uterus or upper 1/3rd of vagina.
what are the syndromes and the essential hormones they affect when it comes to male and female reproductive system development?
Persistent Mullerian duct syndrome (males)–> MIS/AMH
Androgen Insensitivity (“Testicular Feminisation”) Syndrome (males)–> testo, androgens
Congenital adrenal hyperplasia (females) –>cortisol
what is Congenital adrenal hyperplasia?
- the female analogue to androgen insensitivity
- genetic females (XX) have no 21-OH enzyme (no cortisol)
- this causes overproduction of ACTH and overactive adrenal glands
what is the effect of overactive adrenal glands in the developing female reproductive system? what remains unaffected?
Leads to increased weak androgen production (DHEAS) –> weak virilisation (masculinisation)
Enlarged clitoris, partial or complete labia majora fusion.
however, all internal genetalia are all female:
- testes absent (no SRY)
- no mesonephric ducts as no testosterone
- Mullerian ducts persist as no MIS/AMH
what are the signs that the face has not correctly formed?
cleft lip and palate
how does the face form? [week 5-10 ]
- the eyes and ears are very lateral on the head
- the mesenchyme in between must apoptose i.e. disappear so the eyes and nostrils come towards the midline
- grooves are produced for the inward “pulling” of the structures. These are filled with tissue
how many primary bronchi are the in the embryo?
There are 3 right and 2 left primary bronchi
when is lung surfactant produced?
produced from week 25 PF
what are the stages of development of the lungs?
1) embryonic (W3-4)
2) pseudoglandular (W5-16)
- here the blood capillaries migrate closer to the bronchioles into canalicular phase
3) canalicular (W16 -26)
4) saccular (W26-birth)
5) alveolar (M8-childhood).
what is the consequence of low physiological surfactant levels?
RDS
– Respiratory Distress Syndrome
what is the composition of lung surfactant?
lipids, proteins and glycoproteins, trace cholesterol and other components
how can in utero production of lung surfactant be increased ?
injection of glucocorticoids
what cells produce lung surfactant?
type 2 pneumocytes
what is the function of lung surfactant?
induce low surface tension in the alveoli
wha is the development of detailed structures called? what dysregulates this process?
process of patterning
teratogens are factors that dysregulate patterning
What are some examples of teratogens?
during which trimester do they cause the most major effects?
drugs, radiation, infections
drug e.g. thalidomide
infection e.g rubella, HSV, HIV
radiation e.g. X-ray and ionising radiation
Most exert their main effects in the 1st trimester of pregnancy. Major defects occur if they are present early in development
what is neurulation?
differentiation of the ectoderm (epiblast) to CNS under the control of the notochord in the mesoderm
folding of the neural plate to neural tube
what develops rapidly in the second month (week 8) of development?
urogenital cardiac facial lung limbs
new tissues have been formed, they just need development at foetal stage of development
(increase size and remodelling)
this is the key process of trimester 2 and 3
what is the gain and loss of digits called?
limb maldevelopment
polydactyly (more common)
oligodactyly respectively
describe thalidomide
- used for morning sickness initially
- maldevelopment of upper limb in utero
- found to have been useful in some cancers and leprosy
- administration at 8 weeks where morning sickness can be severe eclipses the start of limb development
- upper limbs were particularly sensitive to thalidomide
summary of kidney development errors
- one retained kidney in the pelvis (not ascended)
- retention of extra artery may obstruct ureter causing renal pelvis enlargement
- kidneys formed separately fuse to form horseshoe kidney (also remains in kidney due to shape)
One functional adult kidney may suffice
where do the male and female ducts arise from?
mesonephric and paramesonephric ducts which come from within the mesonephros (intermediate kidney)
mesonephric duct–> ductus deferens and epidydimis
paramesonephric duct–> fallopian tubes, cervix, uterus, upper third of vagina
what gives rise to gametes in the gonads?
primordial germ cells
which hormone is the key regulator of male gonadal development? how is this produced?
what does this tell about the timing of development?
testosterone/DHT
produced by Leydig cells under stimulation of hCG in maternal circulation
male development starts at around 9-10 GA when maternal hCG are close to peak
what are the most common causes of mal-developments in male embryo reproductive systems?
as a result of:
1) inability to produce hormones like testosterone and anti-Mullerian hormone
2) inability to target tissues to respond to hormones (defects in receptors)
MALES: what causes Androgen Insensitivity Syndrome (Testicular Feminisation Syndrome) ?
what are the features:
mutant androgen receptor
features:
- no/limited virilisation of external genitalia
- mesonephric ducts are rudimentary/lacking
- varied testis structure, do not descend
- however AMH is produced to cause female duct regression
FEMALES: what causes Congenital Adrenal Hyperplasia?
what effect does this have on the genitalia development?
mutation in 21-hydroxylase (a cytochrome p450 enzyme)
partial virilisation of female genitalia:
- cortisol production from foetal adrenal is limited
- no -ve FB on pituitary ACTH
- high ACTH and overstimulation of adrenals
- production of weak androgens which cause partial virilisation of external genitalia
- internal systems are female tho with no male ducts (no testosterone, no AMH as no Sertoli cells are present)
where is AMH produced?
Sertoli cells
molecule related to inhibin
simple: Spina bifida
Fusion of the spinal cord should be complete by week 4 but in spina bifida, the posterior neuropore doesn’t close properly.
what is a cleft palate?
A defect posterior to the incisive foramen.
- Failure of tissue migration to complete fill the midline grooves.
- Masses of tissue migrate from the lateral side of the face in towards the midline to fill in these grooves
- Failure to fill these grooves leads to cleft palate or lip
- The upper lip consists of two grooves so the defect tends to be asymmetric
what is the tetralogy of Fallot?
Classically 4 defects
1) Pulmonary stenosis
2) thickening of right ventricle
3) ventricular septal defect
4) malpositioned aorta
what is an atrial septal defect?
caused by patent foramen ovale
Blood flows between both atria.
what is achondroplasia?
- mutation
- effect
normal sized torso and short limbs
- Gain of function mutation in FGFR3
- Achondroplasia means “lack of cartilage”
- Defect is in conversion of cartilage to bone & lack of bone growth
FGFR3 (Fibroblast Growth Factor Receptor 3)
what is Holt Oram Syndrome?
Affecting the heart and hands:
- Atrial septal defect
- range of hand deformaties e.g. absent radial bone, abnormal wrist bone
Phenotype due to mutation in TBX5 (transcription factor) – required as both structures develop.
what is the cause of polydactyly?
Thought to be associated with ZPA (zone of polarising activity)–> gives rise to digits.
- So in polydactyly you may end up with more ZPAs giving rise to many digits
- Expresses sonic hedgehog (Shh)- a protein which stimulates limb development
where is sonic hedgehog expressed?
polydactyly
name chemical agents (teratogens) and the defects they may cause:
- thalidomide
- lithium
- amphetamines
- cocaine
- alcohol
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
what is the Ebstein anomaly?
rare heart defect: tricuspid valve is not formed properly
As a result, blood leaks back through the valve and into the right atrium.
what is the Triad of Congenital Rubella Syndrome?
1) Sensorineural deafness
2) Eye abnormalities
—especiallyretinopathy,cataract,glaucoma, andmicrophthalmia
3) Congenital heart disease
—especiallypulmonary artery stenosisandpatent ductus arteriosus
which end of the neural tube is the origin of the heart in development?
the rostral end (head)
simple cardiac embryology stages
- endocardial tubes with unidirectional blood flow
- they fuse into primitive heart
- single tube created (primitive ventricle and primitive atrium below)
- looping and septation gives rise to the 4 chambers of the heart whilst vascular connections are maintained
- valves develop
how does oxygen delivery to the foetus differ to that post delivery?
lungs in utero are in little need of blood flow so are by passed in the atria via the foramen ovale
blood that is is returning with high oxygen can be shunted from the right atrium to the left atrium to the body
what is the difference in pulmonary circulation in utero and post delivery?
the right ventricle does not need to go the lungs but goes straight to the aorta in order to bypass the lungs
blood that reaches the right ventricle reaches the aorta directly via the ductus arteriosus
what happens to the heart structures post delivery?
foramen ovale and ductus arteriosus should be closed off and the lung should become involved
what is an example of cardiac development abnormality?
Tetralogy of Fallot
- pulmonary stenosis
- thickened right ventricle
- ventricular septal defect
- aorta overrides septal defect
what effect does the septal defect have on circulation in the heart?
deoxygenated blood from the right ventricle enters the left ventricle
what is “baby blue syndrome”?
TRANSPOSITION of the Great Arteries: if the great vessels are positioned incorrectly
i. e.
- the aorta is connected to the RIGHT ventricle
- the pulmonary artery is connected to the LEFT ventricle
- -> two separated blood flows are established on each side of the heart
- this is not problematic in utero due to the presence of the foramen ovale and ductus arteriosus
- but once the baby is delivered and these close off the blood flows are completely separated
- ->this causes a cyanotic baby
–> prostaglandins given to keep ductus arteriosus open
what enables facial structures to reach their correct positions during development?
the repeated formation of clefts and the following filling up of the clefts leads to the loss of tissue from the centre of the face so the tissues can move to their correct places
what is the development basis for cleft in the lip and palate?
the facial structures form from two separate sides of the head
what is the difference in appearance in the cleft lip and cleft palate?
cleft lip is asymmetric
cleft palate is symmetric as both side fail to fuse correctly in the middle
what are the stages of lung development?
- embryonic
- pseudoglandular
- canalicular
- saccular
- alveolar (overlaps into birth)
at what stage of lung development does surfactant start to be produced?
saccular (early 3rd trimester)
increases from here
what results from low lung surfactant in infants?
Respiratory Distress Syndrome
how can surfactant production be enhanced in a potential pre term baby?
the birth is delayed by glucocorticoids:
- this means there is more time to develop surfactant
- glucocorticoids enhance surfactant production in the lungs
artificial surfactant maybe given
