complications of development

Question 1

what are the causes of mal-development and what proportion does each account for *

Answer 1

genetic - 30%

environmental - 15%

multifactorial - 55% - not single/small numebr of factors

Question 2

prognosis for trisomy 18

Answer 2

weeks/months

Question 3

what are different ways there can be changes in the number of conceptuses/fetuses that develop *

Answer 3

twins

triplets

chimera

Question 4

describe identical twins *

Answer 4

one conceptus forms 2 inner cell masses to form 2 genetically identical individuals

ther fertilised egg splits during development

Question 5

describve chimerism *

Answer 5

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

Question 6

describe conjoined twins *

Answer 6

there is incomplete innermass separation - identical twins but the separation is partial

Question 7

what is the effect of chromosomal abnormalities *

Answer 7

the distribution of cells and chromosomes can change development

changes to chromosomes can effect gene expression - can effect development

Question 8

describe mosaicism *

Answer 8

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

Question 9

what is the effect of abnormalities in the distribution between inner cells and trophectoderm (placenta) *

Answer 9

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

Question 10

describe the control of eye colour

Answer 10

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

Question 11

what can the problems with chromosomes be *

Answer 11

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

Question 12

XY linked conditions where there are too many chromosomes *

Answer 12

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

Question 13

autosomal problems with too many chromosomes *

Answer 13

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

Question 14

what cases of too many chromosomes result in less severe effects than full trisomies *

Answer 14

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

Question 15

describe chromosomal abnormalities where there are too few chromosomes *

Answer 15

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

Question 16

describe chromosomal abnormalities with altered distributions *

Answer 16

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

Question 17

what is the overall effect of mutations *

Answer 17

they take away or add functions

receptors that mediate effects can be mutated

Question 18

what is the effect of altered expression *

Answer 18

have more/less of a key regulator - impacts how the cell behaves

Question 19

effect of loss of function of the KIT receptor *

Answer 19

effects skin colouration in midline - have pale heart shape on abdo, and white line on head

Question 20

describe Halt-Oram syndrome *

Answer 20

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

Question 21

describe achondroplasia *

Answer 21

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

Question 22

why have we got to be careful using models as insight for mal-development &

Answer 22

they have different numbers of genes - not related to size

microbiome is heavily involved in how our body works

Question 23

different terms for birth defect *

Answer 23

congenital malformation - does not mean there is a genetic involvement

congenital abnormality

Question 24

what is a birth defect *

Answer 24

change in the pattern of development

teratology/dysmorphology - something has affected how development has taken place

Question 25

number of pregancies affected by birth defects

Answer 25

3% affected by major abnormalities (cause 25% of infant deaths)

15% pregnancies affected by minor abnormalities - little health impact

Question 26

what is a teratogen *

Answer 26

any agent that can disturb the development of an embryo or fetus

Question 27

infectious teratogens and the defects they can cause *

Answer 27

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

Question 28

physical teratogens and the defects they can cause *

Answer 28

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

Question 29

chemical teratogens and the defects that they can cause *

Answer 29

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

Question 30

when do teratogens affect development *

Answer 30

when things are dividing most rapidly

teeth, palate and genitalia are vulnerable later

ears are vulnerable the whole time

there are variable effects

Question 31

symptoms that can be affected in maldevelopment *

Answer 31

limbs and digits

urogenital

heart

CNS

face

lungs

Question 32

describe polydactyly *

Answer 32

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

Question 33

what is wrong with this hand *

Answer 33

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

Question 34

describe the zone of polarising activity *

Answer 34

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’

Question 35

describe cleft lip and palate *

Answer 35

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

Question 36

describe spina bifida *

Answer 36

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

Question 37

describe why spina bifida occurs *

Answer 37

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

Question 38

how can we prevent spina bifida *

Answer 38

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

Question 39

describe anacephaly *

Answer 39

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

Question 40

describe the effect of thalidamide *

Answer 40

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

Question 41

is thalidamide used now *

Answer 41

yes - in some leprosy and cancer treatments

it is good because it is stable and doesnt have to be stored at cold temperatures

Question 42

how does thalidamide effect limbs *

Answer 42

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)

Question 43

describe respiratory distress syndrome *

Answer 43

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

Question 44

describe the main events that contribute to human embryology *

Answer 44

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

Question 45

describe the conversion of the blastocyst to an embryo *

Answer 45

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

Question 46

why is the formation of the 3 germ layers important *

Answer 46

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

Question 47

describe the development of the neuroplate *

Answer 47

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

Question 48

illustrate the lateral folding of the embryo and time frames *

Answer 48

19, 20,21,24,28 days respectively

Question 49

illustrate the development of weeks 5-8 PF and time *

Answer 49

Question 50

illustrate the development of the limbs and time *

Answer 50

Question 51

when does embryonic development end and why

Answer 51

8 weeks - it is clearly human so is now fetal development

at this point it is 1cm wide

Question 52

size at end of trimester 1

Answer 52

7cm and 50g

Question 53

what is oligodactyly

Answer 53

loss of digits

Question 54

summarise the production of the limbs *

Answer 54

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

Question 55

describe the development of the kidney *

Answer 55

pronephros is the most immature kidnye

mesonephros, an intermediate phase

metanephros is the most developed kidney and persists as the definitive adult kidnye

Question 56

describe the descent of the kidneys *

Answer 56

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

Question 57

mal developments in the urogenital tract *

Answer 57

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

Question 58

maldevelopments in development of the kidney *

Answer 58

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

Question 59

describe gonadal development *

Answer 59

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

Question 60

describe the development of teh gametes *

Answer 60

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

Question 61

abnormalities in the development of the reproductive system *

Answer 61

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

Question 62

describe cardiac development *

Answer 62

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

Question 63

describe cardiac abnormalities *

Answer 63

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

Question 64

describe lung development *

Answer 64

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

Question 65

summarise the events during the first 2 months of pregnancy *

Answer 65

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