complications of development Flashcards
what are the causes of mal-development and what proportion does each account for *
genetic - 30%
environmental - 15%
multifactorial - 55% - not single/small numebr of factors
prognosis for trisomy 18
weeks/months
what are different ways there can be changes in the number of conceptuses/fetuses that develop *
twins
triplets
chimera
describe identical twins *
one conceptus forms 2 inner cell masses to form 2 genetically identical individuals
ther fertilised egg splits during development
describve chimerism *
2 genetically distinct conceptuses combine to form 1 individual
happens early so there is no immunological reaction to the foreign DNA
have 2 different genetic patterns in 1 person
describe conjoined twins *
there is incomplete innermass separation - identical twins but the separation is partial
what is the effect of chromosomal abnormalities *
the distribution of cells and chromosomes can change development
changes to chromosomes can effect gene expression - can effect development
describe mosaicism *
this is non-disjunction - the chromosomes dont split as well as they should into individual cells early in development in mitotic divisions - some cells have different chromosomes to other cells
as number of affected cells increases the impact of the condition increases
what is the effect of abnormalities in the distribution between inner cells and trophectoderm (placenta) *
some cells in early blastocyst form bilayer of inner cells that forms the embryo, others form the outer layer of cells that forms the placenta
how the cells distribute depends on quality of cells - normal cells become the inner bilayer, abnormal cells form the placenta because it is easier to make the placenta than the baby
describe the control of eye colour
on human chromosome 15
brown is the most common colour world wide, other colours are more common in caucasians
differentiation of eyes occurs about day 22 post fertilisation
therefore event causing abnormal eye colour must occur before day 22
what can the problems with chromosomes be *
too many, too few, translocations
they all cause syndromes - interactions between genes is complex, there is cross-talk between systems - therefore there can be compensation between inputs in different systems altering the outcomes of the abnormalities
XY linked conditions where there are too many chromosomes *
klinefelter’s - XXY = decreased fertility
XXYY, XXXY, XXXYY = severe forms related to klinefelter’s
normally have X inactivation in females - klinefelters is in males - there is not complete inactivation = x chromosomes exert effects
XYY (XYYY) - very variable - super male - taller and have learning problems
XXX - limited effects, some mental changes
XXXX, XXXXX - more severe because more chromosomes are active and having an effect
X inactivation is targeted at 1 chromosome, rather than ensuring only have 1 x chromosome - otherwise these conditions wouldnt have severe effects
autosomal problems with too many chromosomes *
down’s - chromosome 21 - heart problems determine the survival, have widespaced eyes, flat face and are happy - can alter brain function but doesnt necessarily
edward’s - ch18 - most die before born, very few live-born, if they do, they live less than 2weeks
patau’s - ch13 - most die before birth, 80% of live-birth die in 1 year
other chromosome abnormalities of too many are not found in live birth - most are found in spontaneous preg loss tissues (miscarriage/stillborn) - except Ch1 - biggest ch, carries the most genes - therefore development stops immediately on fertilisation because it is so severe
what cases of too many chromosomes result in less severe effects than full trisomies *
mosaic/partial extra chromosome material
eg might get modest lip deformation rather than full cleft palate which would be seen in trisomy 13
depends on what the DNA is and where it is
describe chromosomal abnormalities where there are too few chromosomes *
XY linked are the only viable ones
- Turner’s - XO = female, short, infertile
- YO - not viable
autosomal
- no complete losses are viable
- partial loss syndromes are known - variable impact
describe chromosomal abnormalities with altered distributions *
translocation
XY linked - get XX male (there is some Y translocated onto x - enough to cause the male phenotype even though XX)
autosomal - linked with the development of tumours (lymphoma, leukaemia, sarcoma) - factors that are to do with growth on a different ch might not be switched off = uncontrolled growth
what is the overall effect of mutations *
they take away or add functions
receptors that mediate effects can be mutated
what is the effect of altered expression *
have more/less of a key regulator - impacts how the cell behaves
effect of loss of function of the KIT receptor *
effects skin colouration in midline - have pale heart shape on abdo, and white line on head
describe Halt-Oram syndrome *
atrial septal defects - the division between chambers doesnt happen therefore heart pumping is inefficient so it becomes enlarged
range of hand abnormalities - varies even between hands
phenotype due to mutation in TBX5 (TF) - this is required for both heart and hands to develop
describe achondroplasia *
there is a dramatic shortening of long bones (particularly in the arms/legs) - the rest of the body is in proportion
there is a gain in function of FGFR3 - it is permenantly on - disrupting development
achondroplasia technically means ‘lack of cartilage’ - in reality there is a defect in conversion of cartilage to bone = lack of bone growth
why have we got to be careful using models as insight for mal-development &
they have different numbers of genes - not related to size
microbiome is heavily involved in how our body works
different terms for birth defect *
congenital malformation - does not mean there is a genetic involvement
congenital abnormality
what is a birth defect *
change in the pattern of development
teratology/dysmorphology - something has affected how development has taken place
number of pregancies affected by birth defects
3% affected by major abnormalities (cause 25% of infant deaths)
15% pregnancies affected by minor abnormalities - little health impact
what is a teratogen *
any agent that can disturb the development of an embryo or fetus
infectious teratogens and the defects they can cause *
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
physical teratogens and the defects they can cause *
X-rays & other ionising radiation - Microcephaly, spina bifida, cleft palate, limb defects
chemical teratogens and the defects that they can cause *
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 - too much causes damage but 1 drink is unlikely to have significant effects - what is the line
chemicals cause variable damage
when do teratogens affect development *
when things are dividing most rapidly
teeth, palate and genitalia are vulnerable later
ears are vulnerable the whole time
there are variable effects
symptoms that can be affected in maldevelopment *
limbs and digits
urogenital
heart
CNS
face
lungs
describe polydactyly *
can be minor - if the digits themselves are normal the hand will be able to work in the normal way
forelimb bud development happens at day 27/8, hindlimb at day29
they grow out from lateral plate mesoderm rapidly under the control of special signalling regions
they are fully formed and patterned by day56
can pin down when the mistake happened, but not necessarily what caused it
what is wrong with this hand *
initially you think that the problem is that there is an extra digit in the middle - because the middle digits are not separated at the bottom
look closer and ‘little finger’ is actually like a thumb - so it is actually that the hand has been mirrored down the middle - there are 4 digits and 2 thumbs
describe the zone of polarising activity *
group of cells - controls the pattern of digit development but we dont know what it is
if transfer into opposite position of developing chick wing - you get the mirror image development of digits
the controlling factor of limb and digit development is called ‘sonic hedgehog’
describe cleft lip and palate *
rest of face is normal
happens because in development there is the frontonasal prominence - this is lost in a controlled way - the nose and eyes are on the sides of the head until 5th week PF, during this time the precursers of the nose, cheeks, lips, mouth and chin are formed
they move centrally across the face for 5wks , then the eyes move to the front through the face
during this development grooves are formed that are then filled in - this leads to sequential loss of the frontonasal prominence - if the grooves dont fill in properly = cleft
pair of grooves form in lip - filled in by 2 separate things - so can get just 1 side cleft
for palate - there are 2 bits of tissue that meet and fuse in the middle - so cleft palate is centrally placed
surgery good - healing process is rapid for children - baby heal well = enhanced QOL
describe spina bifida *
twin spine
protusion of tissue classically near the lower back, can happen in >1 place
the nerve directs the development of the bone 0 if nerve development is wrong it means that the bone development is also wrong
get buldge of tissue - maybe CSF (meningocele)/neural tissue (myelomeningocele), or just be a patch of hair over the damaged area (spina bifida occulata)
1-2/1000 pregnancies
surgery can help the anatomical (if tissue vulnerable to locking or damage, ie can cover the neural tissue with skin) but not the functional problems - there is neurological damage below the point of the spina bifida - usually effects the legs
describe why spina bifida occurs *
the spinal column forms as a tubular structure - then the neural tube is sealed
if sealing goes wrong you get a gap - this us a neuropore = spina bifida - if doesnt close at this point 21-28days it never will
this is failure to complete neurulation
how can we prevent spina bifida *
folic acid in diet decreases the incidence by 70%
the source of nutrition for the early embryo is the egg - takes 3 months for the egg to develop before it is released from the follicle, so need to be taking folic acid at least 3 months before you get pregnant
describe anacephaly *
defect in skull and brain development
1-8/10000 births
females affected more commonly
brain stem is intact, missing the major part of the brain
anterior neuropore closure incomplete
folic acid given at right time might show benefit
describe the effect of thalidamide *
10000 affected infants known, 50% initial survival rate
taken in the 1st trimester for morning sickness
limbs affected, deformed eyes, hearts, urinary and ailmentary tracts, blindness and deafness
impact is variable between people
damage done around day 28
is thalidamide used now *
yes - in some leprosy and cancer treatments
it is good because it is stable and doesnt have to be stored at cold temperatures
how does thalidamide effect limbs *
effects rapidly growing bv - effects can be generic - hence the range of things that are seen - all embryonic tissue relys on normal vascular tissue for the provision of nutrients
effects bv development in limb buds = cell death - therefore limbs cant bud in development
timing of thalidamide usage matches with limb development
(now used for cancer to cut off the blood supply - dont want to give it to women of reproductive age)
describe respiratory distress syndrome *
also called respiratory distress syndrome of the newborn, surfactant deficiency disorder (SDD); previously called hyaline membrane disease (HMD).
1% of all births
lungs wont expand because there is a high surface tension, because there is no surfactant
give injection of steroids in uteri 2-3 days before birth if possible
it is a functional, not a structural problem
lung surfactant increases in last trimester - so 100% babies born at 24wks gave RDS, 50% at 26-28wks, and 25% at 30-31wks
surfactant levels continue to increase after birth
describe the main events that contribute to human embryology *
start with implantation that leads immediately to preimplantation development of the conceptus
preimplantation development occurs in the fallopian tube over approx 6days - characterised by a series of cleavage divisions which double the number of cells in the conceptus to produce a ball of undifferentiated cells - the morula
the morula differentiates so inner cells differ from the outer - this develops into the blastocyst - which has an outer layer of trophectoderm, an inner cell mass and a fluid filled cavity
the blastocyst then hatches from the ZP at day 6 and implants in uterine lining - complete 10days PF
inner cell mass has become a bilayer disk composed of hyoblast and epiblast cells - gives rise to all cells of fetus
describe the conversion of the blastocyst to an embryo *
grastulation - bilayer is converted into a trilayer embryo containing ectoderm, mesoderm and endoderm days 14-18PF
- there is proliferation of the epiblast cells, then they differentiate to form mesoderm cells, they move into the space between the epiblast and the hyoblast
- the mesoderm cells are throught to differnetiate further to generate the endoderm, which replaces the hyoblast cells which are lost by apoptosis
before gastrulation is complete - neurulation has begun - differentiation of the epiblast (ectoderm) to generate the CNS under control of the notocord in the mesoderm of the developing embryo
at the same time; precursers of other tissues are developing and embryo is converted from flat structure to 3D
at the same time (14-21days) at least 2 groups of cells are present outside the embryuo proper - the primordal germ cells in the yolk sac endoderm at the caudal end of the embryo, and the cardiac and vascular progenitors in the primary heart field at the cranial end of the embryo
folding of the embryo occurs laterally which fuses the ventral midline (chest and abdomen) of the embryo, and the anterio-posterior direction, which folds the primordal germ cells into the hind gut, and the developing heart progenitors under the head of the embryo
these changes continue during the development of the urogenital system, which continue from weeks 3-4 of development
by the end of week 4 of development teh precursers of all internal tissues have been laid down, and many external features are also developing
development during weeks 5-8 involves elaboration of the tissues generated during the early weeks
urogenital, cardiac, facial and lung development all procede rapidly during the second month of development
limb development occurs over the same time frame, as the initial limb buds grow, and the terminal regions are converted to hand or foot plates that in tern develop digits
why is the formation of the 3 germ layers important *
they are the precursers to all the tissues in the body
ectoderm gives rise to skin and the CNS
mesoderm to the muscles, blood, skeleton, heart and kidney
endoderm to gut, lungs and liver
muscular and vascular tissue are generally of mesodermal origin so tissues are usually a mix of germ layer types
describe the development of the neuroplate *
happens in neurulation
develops as 2 folds which increase in size until they meet over the neural groove and fuse to form the neural tube
the fusion process continues over week 4 of development as the CNS becomes a sealed tube
the structure of the neural folds is much more complex at the cranial side of the embryo – brain development has started by this stage
illustrate the lateral folding of the embryo and time frames *
19, 20,21,24,28 days respectively
illustrate the development of weeks 5-8 PF and time *
illustrate the development of the limbs and time *
when does embryonic development end and why
8 weeks - it is clearly human so is now fetal development
at this point it is 1cm wide
size at end of trimester 1
7cm and 50g
what is oligodactyly
loss of digits
summarise the production of the limbs *
happens over many weeks - formation is integrated with the rotation of these structures
upper limb bud at 24 days, lower limb at 26
at 47days get fingers
at 52 days fingers can touch
at 56 limbs rotate to definitive orientation
describe the development of the kidney *
pronephros is the most immature kidnye
mesonephros, an intermediate phase
metanephros is the most developed kidney and persists as the definitive adult kidnye
describe the descent of the kidneys *
the ureters extend during the process - so that kidneys stay connected to the bladder
however, the kidneys form new connections with the developing arterial system as they move - renal arteries break down and reform
mal developments in the urogenital tract *
abnormalities in the development of the kidneys are common - the human body can function normally with 1 kidney - so the impact may be limited
intersex - neitheer 100% male or female nad may not match the chromosomes present in the cells of the individuals
maldevelopments in development of the kidney *
one kidney may be retained in the pelvis
retention of an extra artery may restrict the ureter, and cause enlargement of the renal pelvis
the kidneys may fuse to form a horseshoe kidney - the extra tissue makes it impossible to move so it will remain in the pelvis
describe gonadal development *
they arise from intermediate mesoderm within the urogenital ridges of the embryo
the genital ducts arise from paired mesonephric and paramesonephric ducts
gonads show no differentiation in development until week 7 PF
differential development of the male reporductive system is dependant on the activity of SRY protein, coded by SRY gene on Y chromosome
mesonephric ducts give rise to male genetial ducts, paramesonephric to female
within the mesonephrus the mesonephric and paramesonephric ducts develop - identifyable ta 5 weeks PF
at the same time the gonad precurser is developing from the mesonephric mesoderm and is covered by coelomic epithelial cells
describe the development of teh gametes *
happens at the same time as the developing reproductive tissues
the primordal germ cells give rise to gonads
they originate in the epiblast, then migrate to the caudal part of the yolk sac
when the main caudal structures of the embryo proper have developed, the PGCs migrate through the hindgut and dorsal mesentry to the mesonephros and to the gonads
by week 7 the embryo has an indifferent reproductive system
the SRY causes the development pattern in the next 3 weeks satrting from week 7-8, the female development starts later 8-9wks PF
the key regulator in male development is testosterone which is converted into dihydrotestosterone (supports development of the wolffian ducts whcih give rise to male circulation) - produced in testes leidig cells under stimulation opf hCG from the maternal circulation - male development starts when hCG is at its peak
sertoli cells produce anti-mullerian hormone (AMH) that causes regression of the paramesonephric ducts
abnormalities in the development of the reproductive system *
in male - inabiolity to create the correct hormones or the inability to respond to them
eg androgen insensitivity syndrome/testicular feminisation syndrome occurs in genetic males with mutant androgen receptor - no./limited virilisation, internally the woolffian ducts are rudimentary or lacking , testes structure is variable and they dont descend. AMH production is normal so there is regression of the mullerian ducts
in female - congenital adrenal hyperplasia - mutation in CYP 21A2 so cortisol production limited = no -ve feedback on ACTH = overstim of adrenals which make weak androgen - androstenedione = partial virilisation of the genitailia - the internal organs are female as no male testosterone/AMH
describe cardiac development *
complex - convert tube to 4 chambers
main events - folding of teh embryo and heart tube fusion, heart looping, septation
the cardiogenic cells develop in a U outside the mebryo proper, they form a pair of heart tubes which fuse to formn single heart tube by 21days PF - can pump blood unidirectionally
looping of the heart and septationngive rise to the 4 chambered structure of the normal hunan heart - the vascualr connections are made so that major veins are connected to the atria, and arteries to the ventricles, valves develop
the foramen ovale is between the atria -little blood flow to lungs is needed - allow blood to pass for R (high O2) to L atria - then to L vent - then through aorta
the pul artery is connected to aorta by the ductus arterosus - diverting blood that would normally go into lungs round rest of arterial system
at birth foramen ovale and ductus arterosus should close
describe cardiac abnormalities *
tetralogy of Fallot - pulmonary stenosis (thickened, narrow pul outflow tract - allow less blood to lungs), thickened right ventricle wall, ventricular septal defect (allow deox blood to R vent), aorta overrides septal defect
transposition of the great arteries - ie ox blood flows from L vent into pul artery to lungs, deox from R into aorta - baby is cyanotic on birth - treatment is prostaglandins to keep the ductus arteriosus open and open a link between the atria; definitive treatment would involve switching the 2 arteries to restore normal blood flow
describe lung development *
development begins in the 1st trimester but is not completed until after delivery
production of surfactant begins in the 3rd trimester and gradually increases
artificial surfactant can be given to preterm infants
summarise the events during the first 2 months of pregnancy *
week 1 - fertilisation to implantation
week 2 - bilaminar disk forms, trophoblast with lacunae, extraembryonic mesoderm develops, uteroplacental circulation begins
week 3 - laterality established, formation of germ layers, trilaminar embryonic disk, CNS induction, neural folds elevate
week 4 - neural tube closure, villus formation continues in the placenta, pharyngeal arches present, neurulation is complete
5 - arm and legs bud, developing face, gut, optic cup and lens placode develop, brachial arches and clefts develop
6 - physiological umbicilical hernia, developing face, muscel development, endodermal derivitives, auricular hillocks, atrial septum formed, digit formation
week 7 - limb cartiliges and digital rays, developing face, conotruncal and ventricular septa, external genitalia, facial prominences fused, digits present and eyelids form
