Abnormalities of human development

Question 1

Summarise the different causes of Mal-development

Answer 1

Genetic – 30%

Environmental – 15%

Multifactorial – 55%

Question 2

Describe the formation of twins

Answer 2

Identical twins / triplets: one conceptus forms 2 / 3 inner cells masses to form 2 / 3 genetically identical individuals
occurs early on in pregnancy

Question 3

Describe chimerism

Answer 3

Chimerism: 2 genetically distinct conceptuses combine to form one individual
Occurs early on- such that the two conceptuses don’t have the capacity to reject each other.

Question 4

Describe conjoined twins

Answer 4

Incomplete inner cell mass separation

Were going to form identical twins- but split partially- may be conjoined at the limbs or midline

Question 5

What can chimerism result in

Answer 5

Skin with different pigmentation- as it reacts to that from the different conceptus

Question 6

Describe how cells and chromosomes can affect development

Answer 6

The distribution of cells and chromosomes can change development.

Changes to chromosomes can affect gene expression.

Question 7

Describe the impact of cellular distributions on development

Answer 7

Mosaicism (non disjunction) – differences between cells within one individual

Distribution of cells between inner cell mass & trophectoderm (placenta)- ‘faulty’ cells form trophoblast and placenta, more functional cells form embryo, as placenta is easier to develop.

Chimerism - fused multiple zygotes
Non-identical zygotes

Question 8

Summarise the control of eye colour

Answer 8

Human chromosome 15.

Brown most common colour; others mostly in Caucasians.

Differentiation of eyes begins about Day 22 PF.

Event must predate Day 22.

Question 9

Summarise the impact of chromosomal problems

Answer 9

Too many, too few, translocations.

ALL give rise to syndromes- variable phenotype due to different severity of defects and multiple regulatory pathways involved

Cross-talk between systems

Question 10

Describe the issue with too many sex chromosomes

Answer 10

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
XXXX, XXXXX. More severe effects
Showed that only one X chromosome is inactivated- why severity of multiple X syndrome increases with more Xs

Question 11

Describe the issue with too many autosomes

Answer 11

Too many
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- occurs at fertilisation- Ch1 so big- they have too many genes such that without it- development cannot take place.

Question 12

Summarise mosaic or partial extra chromosomal material

Answer 12

Too many

Mosaic or partial extra chromosomal material

Less severe symptoms than in complete trisomies.

Question 13

Summarise the issues with two few chromosomes

Answer 13

Too few
XY linked
Turner’s syndrome - X0. Female, short stature, infertile
Y0 not viable- Y chromosomes are small and contain fewer genes
Autosomal
No complete losses are viable
Partial chromosome loss syndromes known and characterised

Question 14

Describe the chromosomal issues associated with altered distribution of chromosomes

Answer 14

Altered distribution - translocations
XY linked
“XX male” – XY translocation
Autosomal 
Linked with development of tumours; lymphoma; leukaemia; sarcoma- genes not found where they normally are - so they lose their normal regulation- may lead to inappropriate activation of receptors or signalling molecules.

Question 15

Describe two factors that can alter the function of a gene product

Answer 15

Mutations

Altered expression- translated chromosome

Question 16

Appreciate how many genes are found in both humans and animals

Answer 16

Piebaldism in mouse and boy caused by a mild mutation of the KIT receptor.
Leads to altered pigmentation in skin in the middle of stomach and forehead

Question 17

Describe Holtt-Oram syndrome

Answer 17

Holt-Oram syndrome - heart/hand defects
Atrial septation defects- don’t form the four chambers- big baggy heart- can have surgery to get rid of excessive connective tissue
Phenotype due to mutation in TBX5 (transcription factor) – required as both structures develop.
Range of hand abnormalities- no opposable thumb- may Development into digit- vary in same patient- one ahdn may be normal, the other not

Question 18

Describe achondroplasia

Answer 18

Gain of function mutation in FGFR3
Achondroplasia means “lack of cartilage”
Defect is in conversion of cartilage to bone & lack of bone growth
Long bones of limbs affected- trunk growth is normal.

Question 19

Summarise the issues with applying animal models to humans

Answer 19

We do not always know the details of causes and effects in humans

Models can give insight but
Microbiome has an important effect in humans
Fruitflies contain many more genes than us
Different pregnancy spans
A lot we don’t know about the role of our own genome.

Question 20

Summarise embryogenesis

Answer 20

It provides an overview of what happens during the eight weeks after fertilisation of a human oocyte, developing into a very small, recognisably human infant.

After 8 weeks of development, the conceptus is referred to as a fetus (being recognisable as human), and the later stages of pregnancy are concerned mostly with growth and elaboration of the structures that develop during the first two months.

Question 21

When is embryological development considered to start

Answer 21

Embryological development is usually considered to start with Fertilisation (Session 2.4, summarised in Figure 5.2.1), which leads immediately into Preimplantation Development of the conceptus

Question 22

Where does fertilisation normally take place

Answer 22

In the Ampulla of the Fallopian tube

Question 23

Summarise the formation of the blastocyst

Answer 23

Preimplantation development normally occurs within the Fallopian tube (oviduct) over a period of ~6 days, and is characterised by a series of cleavage divisions, which sequentially double the number of cells in the conceptus (2, 4, 8, 16 cells) to produce a ball of undifferentiated cells (the Morula). The Morula differentiates so that the inner cells differ from those on the outside (Figure 5.2.3). 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 24

Describe hatching of the blastocyst

Answer 24

The Blastocyst then hatches from the Zona Pellucida (within which it has developed up to this time, about day 6 after fertilisation), and begins to implant in the uterine lining (Session 3.3), a process which is complete about 10 days post-fertilisation. By this time the inner cell mass, which was a group of undifferentiated cells (Figure 5.2.3), has become a bilayer disk, composed of hypoblast and epiblast cells (Figure 5.2.4). This bilayer disk gives rise to all the tissues of the human fetus, through a complex series of changes.

Question 25

Describe the process of gastrulation

Answer 25

The first of these is gastrulation, which 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 postfertilisation.

This process is summarised in Figure 5.2.5., showing the proliferation (P) of epiblast cells, which then differentiate (D) to form mesoderm cells; these move (M) 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 (A).

Question 26

Describe the formation of the primitive streak in gastrulation

Answer 26

5) Gastrulation: Primitive streak forms medially along the bilaminar embryonic disc, indicating site where epiblast cells begin to migrate between the two layers - proliferating before differentiating to mesoderm cells and migrating under the epiblast - forming three layers of germ cells
Epiblasts become the ectoderm
Middle layer is the mesoderm
Hypoblasts become the endoderm

Question 27

Summarise the formation of the three germ layers

Answer 27

Formation of the three germ layers is a key stage in embryology, as they are the precursors to all the tissues in the body. Ectoderm gives rise to skin and the central nervous system; mesoderm to muscles, blood, skeleton, heart and kidney; endoderm to gut, lungs and liver. 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 28

Summarise neurulation

Answer 28

Before Gastrulation is complete, Neurulation has been initiated (Figure 5.2.6). Neurulation is the differentiation of the Ectoderm (Epiblast) to generate the central nervous system (Brain and Spinal cord), under the control of the notocord in the mesoderm of the developing embryo.
The early stages are shown in Figure 5.2.6, with 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 (Figure 5.2.7).

This fusion process continues during week 4 of development (Figure 5.2.7), as the central nervous system becomes a sealed tube. Note that the structure of the neural folds is much more complex at the upper (cranial) end of the embryo; brain development has started by this stage.
The ectoderm proliferates to form the neural plates

Question 29

Describe the role of the notochord in neurulation

Answer 29

§ After gastrulation has formed 3 layers, the ectoderm proliferates to form the neural plate (with NO proliferation at the neural groove – negative stimulation of notochord) and the neural fold’s fold over and form the neural canal.

Question 30

Describe the roles of the different germ layers

Answer 30

Endoderm: forms the GI tract, liver, pancreas and lungs
Mesoderm: form inner layers of skin, muscles, heart and bone - wraps around the yolk sac entirely to form the visceral/parietal mesoderm (peritoneum) and the mesentery
Ectoderm: form the outer layers of skin, hair, glands and nervous system - wraps around the rest of the embryo on folding to form skin

Question 31

Describe the timeline of neurulation

Answer 31

Development of neural plate from the ectoderm
this develops into two folds (day 20) which increases in size and meets over the neural groove
They fuse to form the neural tube (anterior neuropore closes 25, posterior neuropore- day 28)
The fusion process continues during week 4 of development

Failure of neurulation can lead to:
spinal bidifa (posterior neuropore)
anencephaly (anterior neuropore)
Oropharangeal membrane- anterior- also known as the prechordal plate 
cloacal membrane- posterior

Question 32

By week 3, what extra-embryonic tissues exist

Answer 32

In parallel with neurulation, the precursors of other tissues are developing within the embryo, and it is being converted from a flattened structure into a 3-dimensional embryo (Figure 5.2.8).

In addition to structures developing within the embryo during this third week of development (days 14-21), at least two groups of cells are present outside the embryo proper; the primordial germ cells (PGC) 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 (Sessions 5.3 and 5.4).

Question 33

Describe the two different types of embryonic foldings

Answer 33

Folding of the embryo occurs both laterally, which fuses the ventral midline (chest and abdomen) of the embryo (Figure 5.2.8), and in the anterio-posterior direction, which folds the PGCs into the hind gut, and the developing heart progenitors under the head of the embryo
Lateral folding- forms gut tube and the main body cavities

Question 34

Summarise the process made by week 4 of development

Answer 34

These changes continue during development of the urogenital system (Chapter 5.4) and heart (Chapter 5.5), which continue from weeks 3-4 of development.

By the end of week 4 of development, the precursors of all internal tissues have been laid down, and many external structures are also developing. Development during weeks 5-8 involves mostly the elaboration of the tissues generated during the early weeks

Question 35

Summarise the development of structures in the second month of development

Answer 35

Urogenital, cardiac, facial and lung development all proceed rapidly during the second month of development. In addition to these structures, limb development occurs over this same time-frame (Figure 5.2.10), as the initial limb buds grow, and the terminal regions are converted to hand or foot plates that in turn develop digits.

Question 36

Describe the formation of the amniotic sac

Answer 36

Amniotic sac: folds around the embryo, so that the layer of trophoblasts above the lateral plates, where the ectoderm was present surrounds the embryo, containing the foetus until term

Question 37

What is meant by embryonic folding

Answer 37

7) Embryonic folding: transition of trilaminar disc to cylinder due to both lateral and cranial-caudal folding, this pinches the yolk sac, so that the primitive gut forms, and the yolk sac protrudes from the base of the embryo, attached by the yolk stalk (which becomes umbilical cord)
§ After day 21, the body cavity then closes by day 28 and pinches off the yolk sac into the umbilical cord (allantois).

Question 38

Summarise fertilisation, cleavage and compaction

Answer 38

1) Fertilisation: sperm penetrates the zona pellucida, and pronuclei of sperm and egg cell both enter ovum, leading to completion of meiosis 2 and expulsion of second polar body
2) Cleavage: after fertilisation cell divides to form two identical cells, then keeps dividing to 32 cells - when a morula is formed (ball of undifferentiated cells)

3) Compaction: cells within the morula become closer, and the outer cell layer differentiate to trophoblasts, whereby the inner cell mass become embryoblasts
Morula formed at day 4

Question 39

Technically, when does embryonic development cease

Answer 39

Technically, embryonic development ceases after 8 weeks post-fertilisation, as the conceptus is now clearly human, and is therefore classified as a fetus – so fetal development would be the correct terminology. It is clear that this is more semantic than real, as development of the face (Session 5.7), urinary and reproductive systems (Session 5.4), and lungs (Session 5.8) all continue beyond the end of week 8.

Question 40

Describe the main purposes of terms 2 and 3

Answer 40

As noted earlier (Session 3), trimesters two and three of human pregnancy are more about growth and maturation of structures, than the development of tissues. This means that tissues will need to undergo changes (increased size and remodelling) as the fetus increases in size from ~7 cm and 50g at the end of the first trimester to ~30cm and 3500g at term

Question 41

What is meant by a birth defect

Answer 41

Birth defect = congenital malformation = congenital abnormality

Question 42

Describe what is meant by teratology or dysmorphology

Answer 42

Changes in the PATTERN of development

Teratology or dysmorphology

Question 43

Describe how imperfect pregnancies often are

Answer 43

Major abnormalities ~3% of pregnancies (cause 25% of infant deaths.
Minor abnormalities ~15% (little health impact)

Question 44

Define what is meant by a teratogen

Answer 44

Teratogen: Any agent that can disturb the development of an embryo or fetus

Question 45

Describe some of the defects caused by infectious agents

Answer 45

Infectious agents
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 46

Describe some of the defects caused by physical agents

Answer 46

Physical agents

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

Question 47

Describe some defects caused by chemical agents

Answer 47

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 48

When do major congenital abnormalities occur in pregnancy

Answer 48

o Major defects occur if teratogens are present earlier in development.
Tissues that develop faster therefore more likely to be affected
CNS
Heart
eyes
Upper limbs
Ear

Tissues that develop at a later stage, more likely to be affected by minor abnormalities and functional defects:
teeth
palate
external genitalia.

Question 49

Summarise the consequences of changes in limb development

Answer 49

They vary greatly in severity, from the partial or complete loss of one or more limbs, to the loss or gain of a digit that has little functional impact on the person concerned.

The gross defects are rare with a general incidence of ~0.5/1000 births, but this can be increased by teratogens such as thalidomide. Less severe complications such as polydactylyl (more than 5 digits per hand or foot) are more common (1-10/1000 births), and the causes are not well understood. Loss of digits (oligodactylyl) is much less common.

Question 50

Summarise limb development

Answer 50

• 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.

Question 51

Describe the key processes of limb development

Answer 51

Limb bud- hand/foot plate- digits
Proliferation -apoptosis- differentiation
Upper limbs develop before lower limbs

Question 52

Describe the role of zonal polarising activity patterning the A/P axis

Answer 52

ZPA- sonics the hedgehog protein- should only be present posteriorly
Sonic Hedgehog (shh) is the polarizing factor for limb development
If present anteriorly too- can get mirror image of digits- giving polydactyly,

Question 53

Summarise defects in facial development

Answer 53

Facial development is one of the most complex processes within embryology, so this session will be about an overview of the process, rather than detailed consideration of the many tissues that are found within the developing human face.
Clefting of the upper lip, palate, or both, are the most common developmental defects, with an incidence of ~1/1000 births

Question 54

Outline the formation of the structures on the face

Answer 54

The primary structures of the face form on the sides of the head – for example the eye can readily be seen in Figure 5.1.1, and this pattern persists until at least 5 weeks post-fertilisation. The precursors of the nose, cheeks, lips, mouth and chin are also formed during this time period. As summarised in Figure 5.7.1., these structures then move over a period of about 5 weeks until the reach the expected positions, with the nose centrally placed, and the eyes facing forwards on the face (Figure 5.7.1). This requires the movement of pre-existing structures (e.g. eyes) through the tissues of the developing face, a process that is not fully understood.

Question 55

Describe how the structures of the face move to their expected positions

Answer 55

While the process may not be understood, the events that occur can be described, and are summarised in Figure 5.7.2. It seems that repeated formation of clefts in the face, and then filling in of the clefts, leads to sequential loss of tissue from the centre of the face, and the movement of tissues to the correct places.

You get rid of the frontonasal prominence- form clefts- two either side of the midline- then fill in these clefts and fuse the remaining tissue

Failure to fill in the lateral clefts = cleft lip
Failure to fuse the tissue from the two clefts = cleft palate

Question 56

Describe how the arrangement of the face differs throughout the animal kingdom

Answer 56

The development of the facial tissues on the separate sides of the head is common in vertebrate development; most fish and birds retain this arrangement, with the eyes remaining on the side of the head into adult life. There are exceptions – birds that hunt for moving prey (e.g. raptors and owls) have varying degrees of binocular vision.

Question 57

Describe the formation of cleft lips and palate

Answer 57

One result of this need to form the face from two separated halves is that the process may not function completely, which can give rise to clefts in the lip (usually upper lip, Figure 5.7.3. left) or in the palate. Clefting in both lip and palate may also be found. Note that cleft lip is often asymmetric, as only one of the two clefts shown in Figure 5.7.2. does not function correctly, whereas cleft palate is usually symmetric as the halves of the palate do not meet and fuse correctly.

These structural defects can be modified by surgery, and as shown in Figure 5.7.4, the results can be excellent. The infant had a bilateral cleft lip originally, but there is little or no evidence of this after healing from the surgery. The turnover of cells in infants is normally very rapid, and healing often occurs with little or no scarring, so surgical outcomes can be very impressive.

Can affect breathing and feeding.

Question 58

Describe the epidemiology of spina bifida

Answer 58

The incidence of spina bifida is 1-2 per 1000 pregnancies, with variation between study populations. This makes it one of the most common developmental defects

Question 59

Describe the treatment for spina bifida

Answer 59

Surgery can be use to address anatomical problems; rather than have an exposed spinal cord, skin can be placed to protect the neural tissue. This will not address any functional problems; defects in the spinal cord often lead to damage to the nerves supplying associated tissues, and a range of linked complications eg inability to walk.

Question 60

Describe the different types of Spina bifida

Answer 60

§ Types of Spina bifida – TOP = bad prognosis à good prognosis = BOTTOM:

o Myelomeningocele – neural tissue in bulge.

o Meningocele – no neural tissue in bulge.

o Spina bifida occulta – hair growth over area affected, no growth.

§ The fact that there is no formation of vertebrae at the bulge suggests that bone growth is dependent on neural tissue growth.

Question 61

Summarise CNS development

Answer 61

§ From day 22-23, the tissues will fuse down the midline leaving just 2 openings at the anterior neuropore and the posterior neuropore.

§ During days 25-28, the neuropores SHOULD close.

§ Spina bifida – “Twin spines”:

o Occurs when the fusion doesn’t fuse completely.

§ “Failure to complete neurulation”.

o Can occur towards the top of bottom of the spine.

o Can result in faulty neurology in lower body.

Defect not necessarily at the bottom of the spine

Question 62

When should folic acid be given in pregnancy

Answer 62

The most effective treatment is folic acid; if the maternal diet is low in folate, then the risks of spina bifida increase. It has been calculate that about 70% of cases of spina bifida are due to low maternal folate, so this does not explain all of this developmental abnormality. The timing of spinal development is early, so folate needs to be given before conception, preferably about 3 months beforehand

Remember- takes egg 3 months to mature before being released- pre-banks all its nutrients at this stage

Question 63

Summarise spina bifida

Answer 63

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

Question 64

Describe the epidemiology of anencephaly

Answer 64

Defect in skull and brain development

Incidence: 1 – 8 per 10,000 births
Female babies affected more commonly than male

Question 65

Describe the different causes of anencephaly

Answer 65

Folic acid (given at the right time) may show benefit

Implies similar causes to spina bifida

Anterior neuropore closure incomplete

Question 66

When does lower limb rotation take place

Answer 66

Week 7

Limbs rotate to give definitive position, resulting in helical pattern of lower-extremity dermatomes.

Question 67

Why is it hard to determine the impact of folic acid treatment for anencephaly

Answer 67

Some studies have suggested that folic acid can also decrease the incidence of anencephaly, although the smaller numbers make it difficult to determine the scale of the benefit.

Question 68

What is thalidomide

Answer 68

~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.

Question 69

Which structures does thalidomide most commonly affect

Answer 69

Effects on upper limbs generally most common, but lower limbs and internal organs can also be affected

Question 70

Describe how thalidomide interferes with the regulation of limb development

Answer 70

§ Areas:

o Shh – Sonic Hedgehog protein – zone of polarising activity.

o FGF8 – Fibroblast-like Growth Factor-8 – apical ectodermal ridge.

§ Thalidomide:

o Interferes with the blood vessel development which led to apoptosis and death of developing cells.

o Amelia – “prolonged exposure” to thalidomide -widespread death and all signalling/cells lost

o Phocomelia – “short exposure” to thalidomide.- leading to uniform cell death and only partial loss of AER signalling which recovers.

Question 71

Summarise the defects with the urogenital system

Answer 71

This topic therefore considers both processes, and also identifies the main mal-developments that may occur. Abnormalities in the development of kidneys are relatively common (~1/1000 births); in many cases, the human body can function normally with one kidney, so the impact may be limited.
‘Intersex’ is a preferred terminology to describe sexual development that is neither 100% female or 100% male, and may not match the chromosomes present in the cells of the individuals. It is estimated to occur in ~0.5/1000 births. This is a complex and controversial topic, so the focus will be on describing what can be observed.

Question 72

Summarise the developmental phases of the kidney

Answer 72

The development of the kidney proceeds through a series of successive phases, each marked by the development of a more advanced kidney:

Pronephros is the most immature form of kidney
Mesonephros, an intermediate phase
Metanephros is most developed and persists as the definitive adult kidney

Question 73

Which tissue gives rise to the kidney

Answer 73

§ Pronephros – develops first, precursor tissue that leads to…

o As Mesonephros forms, the Pronephros is degenerating.

o Has NO excretory function, solely developmental.

§ Mesonephros – connects to cloaca, limited excretory function.

o Both pro- and meso-nephros have small tubules that stick out.

§ Metanephros – definitive kidney.

Question 74

What happens to the mesonephros

Answer 74

§ After the mesonephros has formed, two things happen:

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.

Question 75

Describe the ascent of the kidneys

Answer 75

§ Vascular buds initially grow from the kidney and invade the common iliac arteries.

§ As the kidneys ascent cranially, the kidneys DON’T drag the blood supply (like testes decent) but form new vessels and then induce regression of old vessels.

§ Bladder (from cloaca) development:

o Endoderm à bladder – except for the trigone (mesodermal) which develops from mesonephric duct.

o Trigone signals filling of the bladder.

Cranially from lower in the pelvis to just below the adrenal glands.

Question 76

Outline the key stages in kidney development

Answer 76

Urogenital ridge forms
Nephric duct develops
Joins with neprhogenic cords to form pronephros, mesonephros and metenephros
Mesonephros temporarily functions as the kidney
Metanephros ( uteric bud) form the ureters, calyces, renal pelvis and collecting ducts
Metanpheric mesenchyme forms the rest of the kidney
kidney migrates cranially

Question 77

What does the metanephros do

Answer 77

Uteric bud is the last to develop and induces mesoderm mesenchyme differentiation to form metanephric blastema, and eventually the kidneys.

Question 78

What happens to the ureters during renal development

Answer 78

Note that the ureters, which connect the kidneys to the bladder, extent in length during this process, retaining the kidney-bladder connections; in contrast the kidneys form new connections with the developing arterial system as they move, so that renal arteries break down and re-form during this process.

Question 79

Summarise the main events of gonadal development

Answer 79

The gonads 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 about Week 7 post fertilisation
Differential development of the male reproductive system is dependent on the activity of sex-determining region Y (SRY) protein, coded for by the SRY gene on the Y chromosome.

The mesonephric ducts give rise to MALE genital ducts
The paramesonephric ducts give rise to FEMALE genital ducts

Question 80

Outline the key stages in gonadal and reproductive tract development

Answer 80

The gonads arise from intermediate mesoderm within the urogenital ridges of the embryo
The genital ducts arise from paired mesonephric and paramesonephric ducts
The mesonephric ducts give rise to MALE genital ducts (Wolffian system)
The paramesonephric ducts give rise to FEMALE genital ducts (Mullerian system)
The gonads and reproductive tracts are indifferent up until 7 weeks of development; differentiation is influenced largely by the presence or absence or SRY (on the Y chromosome)
If SRY+, then development proceeds along the male path
If SRY-, then development proceeds along the female path
Within the mesonephros, the mesonephric and paramesonephric ducts develop, and are readily identifiable by week 5 post fertilisation (Figure 5.5.4). At the same time, the gonad precursor is developing from the mesonephric mesoderm, and is covered by coelomic epithelial cells.

Question 81

Describe the development of the primordial germ cells

Answer 81

In parallel with the developing reproductive tissues, the primordial germ cells (PGC) are following a separate developmental pathway. PGC will give rise to the gametes within the gonads, and seem to have a very different development compared with most cells in an embryo. They originate in the epiblast, but then migrate to the caudal part of the yolk sac (Figure 5.4.5A). Once the main caudal structures of the embryo proper have developed, the PGC migrate through the hind-gut and dorsal mesentery to the mesonephros and thence to the developing gonads. By week 7 of development, the embryo has an indifferent reproductive system (Figure 5.4.6), which can differentiate to form either female or male structures.

Question 82

Ultimately, what regulates the development of the male or the female

Answer 82

In the human, development of the male system depends on the expression of Sex-determining Region Y (SRY) from the Y chromosome, which causes the conversion of the indifferent system to the male tract, gonadal and genital pattern during the next 3 weeks.

In the absence of SRY, the female tract, gonads and genital pattern develops; this starts a little later (weeks 8-9 post fertilisation).

Question 83

Describe the key hormones involved in the development of the male and female tracts

Answer 83

The key regulators in male development are testosterone, which is produced from the testis Leydig cells, under the stimulation of hCG from the maternal circulation. Male development starts in weeks 7-8 (weeks 9-10 gestational age), which is when maternal hCG levels are close to their peak. Testis Sertoli cells produce anti-Mullerian hormone (AMH), which causes the regression of the Mullerian (paramesonephric) ducts. Testosterone support development of the Wolffian ducts, which give rise to the male reproductive tract.

The indifferent genitalia of the early embryo can be converted into the male or female structures, as shown in Figure 5.4.7. The key regulator seems to be dihydrotestosterone (DHT), a potent androgen that is produced from testosterone originating in the Leydig cells of the testis

Question 84

Outline the development of the male reproductive tract

Answer 84

Male reproductive tracts (SRY +ve):

o Gonads develop into a testis containing – spermatogonia, Leydig cells, Sertoli cells.

§ Leydig cells produce testosterone – supports growth of mesonephric ducts (thus, without testosterone, the mesonephric ducts will regress).

· Some testosterone à DHT- supports development of prostate, penis and scrotum.

§ Sertoli cells produce AMH (Anti-Mullerian Hormone)/MIS (Mullerian Inhibiting Substance) – this induces regression of paramesonephric ducts (again, absence of MIS/AMH, ducts will persist).

o Summary:

§ Ureteric bud à ureter.

§ Mesonephric ducts à rete testes, efferent ducts, epididymis, vas deferens, seminal vesicle, trigone of bladder – ANYTHING IN TESTES AND TRIGONE.

§ Urogenital sinus à bladder (- trigone), prostate gland, bulbourethral gland, urethra.

Question 85

Describe the decent of the testes

Answer 85

Descent of the testes:

§ 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.

Question 86

Describe the development of the female reproductive system

Answer 86

§ Female reproductive tracts (SRY -ve):

o Gonads develop into an ovary – containing oogonia and stromal cells.

o No testosterone is produced so mesonephric tubes (Wolffian tubes) regress.

o No AMH/MIS so Mullerian (paramesonephric) ducts persist.

o Summary:

§ Ureteric bud – ureter.

§ Mesonephric ducts – trigone of bladder.

§ Paramesonephric ducts (Mullerian) give rise to – oviducts, uterus, upper 1/3rd of vagina. - fuse in the middle to form uterus and vagina

§ Urogenital sinus gives rise to – bulbourethral glands, lower 2/3rd of vagina.

Question 87

Describe some issues with kidney development

Answer 87

One kidney may be retained in the pelvis (Figure 5.4.3A), rather than moving to the usual abdominal position immediately under an adrenal gland. Retention of an extra artery (or another problem) may obstruct (partly or fully) the ureter, and cause enlargement of the renal pelvis (Figure 5.4.3C). The kidneys form separately, but may fuse to form a horseshoe kidney (Figure 5.4.3B); the extra tissue makes it impossible for it to move, so it will remain in the pelvis as shown. All these abnormalities may compromise kidney function. In an adult, one functional kidney may suffice, but this may not always apply during development.
§ Kidney developmental errors:

o Renal agenesis – degeneration of ureteric bud:

§ Unilateral – 1: 1000, 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.

Question 88

Summarise the problems that can occur in embryonic development

Answer 88

In male embryos, the most common mal-developments are the result of either (a) the inability to produce the appropriate hormones (testosterone and anti-Mullerian hormone (AMH) or (b) the inability of target tissues to respond to these hormones, normally the result of defects in the cognate receptors.

Question 89

Describe androgen insensitivity syndrome

Answer 89

§ Androgen Insensitivity (“Testicular Feminisation”) Syndrome (males):

o Occurs in genetic (XY) males with mutations in the androgen receptor.

o Lack of virilisation (androgens have no effect on receptor).

§ Normal female external genetalia but undescended testes.

§ Mesonephric ducts rudimentary due to loss of testosterone.

§ Normal production of MIS from Sertoli cells causes Mullerian duct regression so not oviducts, uterus or upper 1/3rd of vagina.

Question 90

Describe congenial adrenal hyperplasia

Answer 90

§ Congenital adrenal hyperplasia (female analogue to AIS):

o Occurs in genetic females with no 21-OH enzyme (no cortisol).

§ Causes overproduction of ACTH and overactive adrenal glands.

o Leads to increased weak androgen production (DHEAS) à weak virilisation.

§ Enlarged clitoris, partial or complete labia majora fusion.

o Internal genetalia are all female – testes absent (no SRY), no mesonephric ducts as no testosterone to support, no AMH/MIS so Mullerian ducts persist.

Question 91

Describe some other abnormalities in gonadal development

Answer 91

§ Hypospadias – fusion of urethral folds’ incomplete – urethra exits penis early.

§ Mullerian duct anomalies (abnormal fusion of ducts) – e.g. two uteruses.

§ Persistent Mullerian duct syndrome (males):

o Occurs in males with mutations in AMH/MIS or receptor.

§ No inhibition so paramesonephric ducts persist.

§ Testis either sit by ovaries or one/both can descend.

o Testosterone/DHT is produced so normal external genetalia/ducts.

§ Testosterone is needed about 8 weeks PF (post-fertilisation) but the hCG peak is 8 weeks after LMP (last menstrual period). hCG drives the testosterone production.

§ Undescended testes – increased risk of cancer, do not function normally

Question 92

Summarise the key events in cardiac development

Answer 92

Folding of embryo and heart tube fusion
Heart looping
Septation

Question 93

Describe the formation of the single heart tube

Answer 93

In brief the cardiogenic cells develop in a U (or horseshoe) pattern outside the embryo proper. These form a pair of heart tubes, which fuse to form a single heart tube by ~21 days post-fertilisation. This tube is already able to pump blood unidirectionally.

Lateral folding of the cariogenic cells causes them to separate in half and each form endocardial tubes

Form the mesoderm

Question 94

Describe the formation of the heart

Answer 94

1. 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 (MacDonald’s arc shape) which is them split to form the muscular tube.
2. The heart then undergoes a turning action (anti-clockwise) to form the primitive heart (23-28) and the 4 chambers form.

§ This is the primary and secondary heart field forming into the primitive heart tube by fusing and then breaking the arch at the apex.

§ Blood flow begins around day 22.
§ The primitive heart tube undergoes an anti-clockwise turning motion which results in the ventricles being at the bottom with the atria at the apex.

§ The atria rotate BEHIND the arteries.

§ From day 17-28, the head-tail folding is also occurring which aids rotation of the heart and the movement of the heart more internally.

§ The folding of the head and tail is what turns the heart in the anti-clockwise motion as seen on the left.

o Pressure of the folding head pushes the heart to the centre of the body which squishes the atria (less muscular than ventricles).

o The squished atria then spring out and straighten.

o The final twisted form then resembles…

Question 95

Summarise lopping of the heart and septation

Answer 95

Looping of the heart and septation give rise to the 4-chambered structure of the normal human heart (Figure 5.5.2). During this process the vascular connections are maintained, so that the major veins are connected to the atria, and major arteries to the ventricles. Valves develop, to ensure that blood flows unidirectionally within the heart.

Question 96

Describe septum formation

Answer 96

Between atria and ventricles, endocardial cushions, from either side, form and fuse
Septum premium forms and joins endocardial cushion
Septum secundum forms above and below septum premium
Muscular intraventricular septum forms from below.

Question 97

Describe foramen formation in the heart

Answer 97

Foramen primum is left from the incompletely fused septum primum
new foramen is called foramen secundum, forms within the septum primum
septum secundum grows to partially cover foramen secundum to form foramen ovale

Question 98

Summarise the fetal circulation

Answer 98

The provision of oxygen to the embryo and fetus from the placenta is linked to the main structural difference between the heart in utero, and after delivery. As little blood flow to the lungs is needed, there is a gap between the atria, the foramen ovale (Figure 5.5.2). This allows blood returning to the heart (which is relatively high in oxygen) to pass from the right atrium to the left atrium, thence to left ventricle, from where it is pumped through the aorta to the body. The other major difference is that the main artery from the right ventricle is connected to the aorta by the ductus arteriosus (Figure 5.5.2), diverting blood that would normally go to the lungs into the rest of the arterial system.

Question 99

Describe the changes that occur to the fetal circulation at birth

Answer 99

The ductus arterius constricts, allowing all blood leaving the right ventricle to travel to the lungs via the pulmonary arteries.
The foramen ovale closes, leaving a small depression called the fossa ovalis. this isolates oxygenated blood and deoxygenated blood within the heart.

Question 100

Summarise maldevelopment of the heart

Answer 100

Maldevelopment of the heart is relatively common, and can have a severe impact on the infant. As most abnormalities are structural, surgical procedures have been developed to correct some abnormalities. As these complications may become clinically significant at the time of birth (as the blood flow needs to be changed to include the lungs), surgery may need to be done shortly after delivery.

Question 101

Describe tetralogy of Fallot

Answer 101

Tetralogy of Fallot: pulmonary stenosis (decreased flow to lungs), thickened right ventricular wall, ventricular septal defect (mixing of blood and pressure problems) and aorta overriding septal defect

Perhaps the most important aspects are the septal defect between the ventricles (which tends to allow deoxygenated blood into the left ventricle, and the stenosis of the pulmonary artery (decreasing blood flow to the lungs).

Question 102

Describe the transposition of vessels

Answer 102

There are many variants involving the transposition of blood vessels; transposition of the great arteries (Figure 5.5.5) is one of the easier ones to understand. The aorta is connected to the right ventricle, and the pulmonary artery to the left ventricle. This generates two separate blood flows; oxygenated blood is cycled through the left side of the heart via the lungs; de-oxygenated blood through the right side of the heart to the rest of the body. Before birth, this does not matter, as the foreman ovale and ductus arteriosus allow mixing of the blood flows sufficiently to sustain fetal growth and development. The closure of these connections after delivery separates the blood flows, so the infant becomes cyanotic (‘blue baby syndrome’). Immediate treatment may involve administering prostaglandins to keep the ductus arteriosus open, and perhaps opening of a link between the atria. Definitive treatment would usually involve the switching of the two arteries, to restore the normal blood flows.

The precise pattern of vascular changes can be very variable, so the best treatment can vary considerably between individual patients.

Question 103

Summarise the different type of heart malformations

Answer 103

Hypoplasia- underdevelopment
Obstruction defects:
valve, artery, vein, narrowing or block
Aortic/Pulmonary stenosis, coarctation of the aorta

Septal Defects:
Ventricular septal defect - most common
atrial septal defect - patent forman ovale

Cyanotic defects:
Results in cyanosis
Transposition of vessels
Tetralogy of Fallot.

Question 104

Summarise lung development

Answer 104

§ There are 3 right and 2 left primary bronchi.

§ Surfactant is produced from week 25 PF.

§ Stages of development are – embryonic (W3-4), pseudoglandular (W5-16), canalicular (W16 -26), saccular (W26-birth) and alveolar (M8-childhood).

o From PG à canalicular, blood capillaries migrate closer to the bronchioles.

Last organ to fully develop

Question 105

Describe the different zones of lung organogenesis

Answer 105

Conducting zone = 16 generations

Segmental bronchi are continued by several generations of
Intersegmental bronchi (up to ca. 1 mm diameter). After these follow the
Bronchioli (< 1mm diameter) that after several divisions go over into
Terminal bronchioli (ca. 0.4 mm diameter). They subdivide numerous times and represent the end stretch of the purely conductive respiratory tract. The measurements come from histological findings.

Respiratory zone = 7 generations

Out of the terminal bronchioli several generation of
Respiratory bronchioli (= 3 generations) proceed. From them follow several generations of
Alveolar ducts (= 3 generations) that in
Alveolar sacculi (last generation = 23rd generation) end

Conducting zone:
Embryonic- psueoglandular

Respiratory zone:
Canalicular —

Question 106

Describe the production of surfactant

Answer 106

The production of surfactant begins early in the third trimester of pregnancy (Figure 5.8.1) and gradually increases. Adequate production of surfactant is necessary for normal lung function at birth. Prodction starts at a bout week 26
o Composition – lipids, proteins and glycoproteins.

§ ~40-45% DP-PC.

§ ~40-45% other phospholipids.

§ ~5% other proteins. Trace cholesterol and other components.

o In utero production can be increased by an injection of glucocorticoids (2-3 days).

o Half-life = 5-10 hours.

o Produced by T2 pneumocytes.

o Function – induce low surface tension in the alveoli.

Question 107

Describe respiratory distress syndrome

Answer 107

Respiratory distress syndrome (RDS), respiratory distress syndrome of newborn (RDSN), surfactant deficiency disorder (SDD); previously called hyaline membrane disease (HMD).
Overall incidence ~1% of all births

~100% at GA 24 weeks
~50% at GA 26-28 weeks
~25% at GA 30-31 weeks

Question 108

What should be done in RDS

Answer 108

Preterm infants often suffer from lung complications due to low levels of surfactant (Respiratory Distress Syndrome, RDS). Delaying the birth of a preterm infant may give more time for surfactant to be produced, and this can be accelerated by an injection of glucocorticoid to the mother, which also increases surfactant production in the infant’s lungs. Optimal timings are not fully established, although 24-48 hours between administration and delivery of the infant or infants is often the aim.

Artificial surfactant has also been developed, and this can be administered to preterm infants while their lungs develop sufficiently to produce enough surfactant to allow normal function.