M1SDemb: Embryology

Embryological development can be divided into 3 main stages:

1. Early Development (1st to 3rd week): Fertilisation, Implantation, Gastrulation
2. Embryonic Period (4th to 8th week): Differentiation, Organogenesis
3. Fetal Period (9th week to 9th month): Growth and Specialisation of the fetus

1. Early development
Embryoblast
(Inner cell mass) Trophobla
Week 1 (Outer cell m
Once the ovum has been fertilized by the spermatozoon, a
zygote (single cell) is formed. This undergoes a rapid
succession of mitotic divisions (cleavage) without an
Blastocoele
increase in size, forming blastomeres, and eventually a A Blastocyst
(cavity)
morulla (12-32 blastomeres).
- A hollow cavity (blastocoele) forms at around day 3, marking the blastocyst stage.
- The centrally placed cells are called inner cell mass (embryonic pole, or embryonic stem cells)
and ultimately form tissues of the embryo (embryoblast).
- The outer cells, called the outer cell mass, form the trophoblast, which plays an important role
in the formation of the placenta and the embryonic membranes.

At around days 5-6, implantation of the blastocyst on the endometrial lining of the uterus occurs.

Ectopic Pregnancy
An ectopic pregnancy is a complication of pregnancy in which the fertilized ovum is implanted in any
other tissue other than the uterine wall. Most ectopic pregnancies occur in the Fallopian tubes
(tubal pregnancy), but implantation can also occur in the cervix (placenta praevia), ovaries, internal
os, or abdominal cavity. The fetus produces enzymes that allow it to implant in varied types of
tissues, and thus an embryo implanted elsewhere than the uterus can cause great tissue damage in
its efforts to reach a sufficient supply of blood.

Week 2

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DAY 8 Trophoblast cells surrounding the embryonic
cells proliferate and invade deeper into the uterine
Syncytiotrophoblast
lining. Epiblast

Differentiation of the cell masses occur: Amniotic cavity

- Embryoblast (ICM) differentiates to form the
epiblast and hypoblast. (bilaminar embryonic
disk) Primitive yolk sac
- Trophoblast cells (OCM) differentiates to form
the cytotrophoblast and syncytiotrophoblast.
Hypoblast
Movement of the hypoblast laterally and Cytotrophoblast
downwards forms the primitive yolk sac; and the
amniotic cavity, between the epiblast and amnioblast occurs.

- DAY 9 Growth of the cytotrophoblast and syncytiotrophoblast is much quicker than the
bilaminar embryonic disk (epiblast and hypoblast). Lacune begin to form in the
syncytiotrophoblast. As it carries on growing.

DAY 12 lacunar networks form and capillaries in the endothelium begin to expand to form maternal
sinusoids and enzymes digest the lining of these maternal sinusoids to allow blood to flow into the
lacunar network to create a uteroplacental circulation to allow gas and metabolite exchange.

Extra embryonic mesoderm forms and expands to create the chorionic cavity. A large portion of the
primitive yolk sac is pinched off and forms a secondary yolk sac.

Connecting stalk forms from the extraembryonic

mesoderm which has been growing throughout
week 2. This will make the future umbilical cord.

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Week 3

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Gastrulation occurs, in which distinct layers are formed from within embryo, which will later grow
into different organs. The epiblast (embryonic cells) flattens into a bilaminar embryonic germ disc,
composed of 2 germ layers: the upper ectoderm and the lower endoderm.

As growth proceeds, the embryonic disc becomes pear-

shaped, and a narrow streak appears on its dorsal surface
formed of ectoderm, called the primitive streak. The further
proliferation of the cells of the primitive streak forms a layer
of cells that will extend between the ectoderm and the
endoderm to form the mesoderm.

Further thickiening of the ectoderm gives rise to the neural

plate on the dorsal surface of the embryo. The plate sinkw
beneath the surface of the embryo to form the neural tube,
which ultimately gives rise to the CNS.

A notochord, derived from mesoderm, forms in the centre

of the embryonic disc and on the ventral surface of the
neural tube. This notochord will eventually be replaced the
vertebral column.

The primitive yolk sac becomes modified to become the secondary yolk sac, while a chorionic cavity
develops between the 2 layers of mesoderm. Eventually, the placenta develops.

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Embryonic Period
The initially flat embryonic disc develops into a “C-shaped” A
cylindrical structure. Cephalocaudal flexion (in the Yolk sac
Amniotic cavity
longitudinal direction) and lateral folding (in the
transversal folding) occur simultaneously, forming the A
abdominal wall, permitting a delimitation of the embryo.
This also leads to enclosure of mesoderm and endoderm
Y
by the ectoderm, which later forms the epidermis. Y A
Neurulation, development of the CNS, also occurs.

Derivatives of the Germ layers Y

Ectoderm Mesoderm Endoderm
Epidermis: Connective Tissue, Cartilage, Epithelium of Digestive tube:
Hair, Nails, Sebaceous Glands Bones and Joints Foregut, Midgut, Hindgut
CNS: Brain and Spinal Cord Walls of Heart Parenchyma of Digestive tube:
PNS Muscles: Tonsil, Thyroid, Parathyroids,
Smooth, Striated and Cardiac Thymus, Liver, Pancreas
Sensory epithelium of sense Urogenital System: Kidneys,
organs Gonads and their Ducts,
Inner ear Suprarenal Cortex Epithelium of Respiratory
Eye (lens) Mesothelium (Serous Tract:
membranes): Pleura, Lungs
Pituitary gland (hypophysis) Pericardium, Peritoneum Middle Ear (Tympanic Cavity
Teeth (enamel) and Eustachian tube)
Epithelium of some organs Blood and Lymph cells Part of Bladder and Urethra

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  Gastrulation begins with the formation of the primitive streak
on the surface of the epiblast.
 Initially, the streak is vaguely defined, but in a 15- to a 16-day
embryo, it is clearly visible as a narrow groove with slightly
bulging regions on either side.
 The cephalic end of the streak, the primitive node, consists of a
slightly elevated area surrounding the small primitive pit.
 Cells of the epiblast migrate toward the primitive streak.
 Upon arrival in the region of the streak, they become fl ask-
shaped, detach from the epiblast, and slip beneath it. This
inward movement is known as invagination.
 Once the cells have invaginated, some displace the hypoblast,
creating the embryonic endoderm, and others come to lie
between the epiblast and newly created endoderm to form
mesoderm.
 Cells remaining in the epiblast then form ectoderm.
 Thus, the epiblast, through the process of gastrulation, is the
source of all of the germ layers, and cells in these layers will
give rise to all of the tissues and organs in the embryo.
Each of the three germ layers (ectoderm, mesoderm, and endoderm)
gives rise to specific tissues and organs:
 Embryonic ectoderm gives rise to the epidermis, central and
peripheral nervous systems, eyes and internal ears, neural crest
cells, and many connective tissues of the head.
 Embryonic endoderm is the source of the epithelial linings of
the respiratory and alimentary (digestive) tracts, including the
glands opening into the gastrointestinal tract, and glandular
cells of associated organs such as the liver and pancreas.
 Embryonic mesoderm gives rise to all skeletal muscles, blood
cells, the lining of blood vessels, all visceral smooth muscular
coats, serosal linings of all body cavities, ducts and organs of
the reproductive and excretory systems, and most of the
cardiovascular system. In the body (trunk or torso), excluding
the head and limbs, it is the source of all connective tissues,
including cartilage, bones, tendons, ligaments, dermis, and
stroma (connective tissue) of internal organs.

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WEEK 4
 By the fourth week, the embryo divides into two layers; the
outer epiblast that forms the entire body of the baby and the
hypoblast, which is a temporary layer that forms a yolk sac for the
nourishment of the baby.
 Vasculogenesis (formation of the circulatory system), the formation of
limbs, beginning of digestive and respiratory system occurs with the
fourth week of pregnancy.
 The organs formed up to this week are prone to bodily defects in the
first trimester of the pregnancy.
 As the embryo divides, the placenta is formed which delivers
nutrients, oxygen, and water to the baby from the mother throughout
the pregnancy.
 By the end of the fourth week (one month), the size of the baby
reaches about 1/4th inch in length.

Neurulation

 Following gastrulation, the ectoderm gives rise to epithelial

and neural tissue, and the gastrula is now referred to as
the neurula.
 The neural plate that has formed as a thickened plate from the
ectoderm continues to broaden and its ends start to fold
upwards as neural folds.
 Neurulation refers to this folding process whereby the neural
plate is transformed into the neural tube, and this takes place
during the fourth week.
 They fold, along a shallow neural groove which has formed as a
dividing median line in the neural plate.

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  This deepens as the folds continue to gain height when they will
meet and close together at the neural crest.
 The cells that migrate through the most cranial part of the
primitive line from the paraxial mesoderm, which will give rise
to the somitomeres that in the process of somitogenesis will
differentiate into somites that will form the sclerotome, the
syndrome, the myotome, and the dermatome to form cartilage
and bone, tendons, dermis (skin), and muscle.
 The intermediate mesoderm gives rise to the urogenital
tract and consists of cells that migrate from the middle region
of the primitive line.
 Other cells migrate through the caudal part of the primitive line
and form the lateral mesoderm, and those cells migrating by
the most caudal part contribute to the extraembryonic
mesoderm.
 The embryonic disc begins flat and round but eventually
elongates to have a wider cephalic part and narrow-shaped
caudal end. Cranial and caudal neuropores become
progressively smaller until they close completely (by day 26)
forming the neural tube.


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Fetal Period
The foetal period (9th week to 9th month) is about continued differentiation of organs and tissues,
most importantly this period is about growth both in size and weight.

Organogenesis
- Early development: Any organ develops from a primordium (bud) derived from one or more
germ layers found in the germ disc during early development.
- Embryonic period: After folding is completed, the primordial of many organs become easily
recognizable as a simple shape. Primordium undergoes changes in shape, size and site to
become anatomically recognizable.
- Fetal period: Differentiation of cells in the developing organ into specific cell types help with
maturation whereby the organ becomes capable of normal function.

Development of the Lungs and Pleura

Germ layer:
- Lungs: Endoderm – Ventral wall of primitive foregut
- Pleura: Mesoderm surrounding diverticulum
Primordium: Laryngotracheal diverticulum

Embryonic Period
1. The diverticulum is partially partitioned off by the formation of the
tracheoesophagal septum from the tracheoesophagal ridges/grooves on
either side. This divides the foregut into the laryngotracheal tube (ventral)
and the esophagus (dorsal).
2. The partitioned portion of the laryngotracheal diverticulum separates off by
splitting along the septum from the esophagus. The caudal end enlarges to
form the lung bud, which is surrounded by splanchnic mesoderm.
3. Several generations of branching progressively increases the surface area
for gas exchange. This branching takes place mostly dichotomously except
after the formation of the primary when the R. divides into 3 and L. into 2. By the end of the
embryonic period, the lungs have the correct appearance but are still immature.

Fetal Period

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- Cells lining terminal sacs become progressively flattened (increase efficiency of gas exchange)
- Rich vasculature develops around the terminal sacs (increase perfusion of alveoli)
- Type 2 cells in terminal sacs secrete increasing amounts of surfactant (reduces surface tension
in the fluid in the sacs to facilitate easy expansion of lungs at birth. Hence premature birth
predisposes to respiratory distress syndrome)
- Endodermal cells differentiate into respiratory epithelium and glands
- Mesodermal cells give rise to cartilaginous plates, smooth muscles and connective tissue.
o Splanchnic mesoderm forms visceral pleura
o Somatic mesoderm forms parietal pleura

Esophageal atresia and Tracheoesophagal Fistula

Atresia is a condition where the laryngotracheal septum formed by fusion of the laryngotracheal
ridges are deviated posteriorly, resulting in a reduced lumen diameter; while a fistula results when
the margins of the laryngotracheal ridges fail to fuse adequately, resulting in an abnormal opening
left between the laryngotracheal tube and the esophagus. Newborn infants with these malfunctions
cough and choke during eating due to aspiration of food and saliva into lungs due to blocked
esophagus, and may result in pneumonia.
Development of the Diaphragm

Germ Layer: Mesoderm formed in neck by fusion of myotomes of 3rd, 4th and 5th cervical segments.
Hence, the diaphragm’s nerve supply is derived from the phrenic nerve (C3, C4, C5).
Primordium: Septum Transversum – An incomplete mesodermal partition on ventral aspect of
embryo caudal to developing heart. The incompleteness is due to 2 pleuroperitoneal canals dorsal
to it (one on each side) which allows communication between the pleural and peritoneal cavities.

The diaphragm is formed from:

1. Septum Transversum: Forms the muscle and central tendon
2. 2 Pleuroperitoneal membranes: Forms peripheral areas of diaphragmatic pleura and
peritoneum covering its upper and lower surfaces
3. Dorsal meso-esophagus: Forms crura

Development
1. Pleuroperitoneal folds develop from the dorsolateral body wall growing ventromedially to fuse
with the septum transversum and the dorsal meso-oesophagus, thereby forming the
pleuroperitoneal membranes. This effectively closes the pleuroperitoneal canals.
2. The developing lungs growing caudally (especially at the periphery) helps add the peripheral
portions of the diaphragm from the body wall, as well as create the dome shape. Hence, the
periphery of the diaphragm shares nerve supply with the thoracic nerves.
3. Progressive caudal migration of the diaphragm results in the phrenic nerve taking a course more
in line with the body axis.

Diaphragmatic Hernia
Congenital hernia can occur as the result of incomplete fusion of
the 3 components. Abdominal contents can then be pushed up
through the hiatus into the thoracic cavity. The herniae occur at the
following sites:
- Pleuroperitoneal canal (caused by incomplete fusion of
pleuroperitoneal folds with septum transversum)
- Opening between xiphoid and costal origins of the diaphragm
- Esophageal hiatus

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Development of the Cardiovascular System

Germ Layer: Mesoderm

Primordium: Endocardial Heart Tubes

Formation of the Heart Tube

Clusters of cells arise in the mesenchyme (mesoderm) at the
cephalic end of the embryonic disc, cephalic to the site of the
developing mouth and CNS. They form a plexus of endothelial
blood vessels that fuse to form the R. and L. endocardial tubes,
which soon fuse to form a single median endocardial tube. As the
head fold of the embryo develops, the endocardial tube and
pericardial cavity rotate on a transverse axis through almost 180⁰
to come ventral to the esophagus and caudal to the developing
mouth.
The heart tube starts to bulge into the pericardial cavity.
Meanwhile, the endocardial tube becomes surrounded by a thick
layer of mesenchyme, which will differentiate into
myocardium (cardiac muscle) and visceral layer of the serious
pericardium. The primitive heart has been established, and
the cephalic end is the arterial end and the caudal end is the
venous end. The arterial end is continuous beyond the
pericardium with a large vessel, the aortic sac.

Further development of the heart tube

The heart tube then undergoes differential expansion so that
several dilatations, separated by grooves result. From the
arterial to venous end, these dilatations are the bulbus cordis,
ventricle, atrium, and the R. and L. horns of the sinus
venosus. The bulbus cordis and ventricle elongate and bend,
finally forming a compound S-shape, such that the atrium lies
posterior to the ventricle. The passage between the atrium
and ventricle narrows to form the atrioventricular canal. A
gradual migration of the heart tube occurs so that the heart
passes from the neck to the thoracic region.

Development of the Atria

1. Atrioventricular canal becomes divided into R. and L.
halves by appearance of ventral and dorsal
atrioventricular cushions, which fuse to form the
septum intermedium

2. A septum primum develops from the roof of the

primitive atrium and grows down to fuse with the
septum intermedium. The opening between the lower
edge of the septum primum and the septum
intermedium is the foramen primum.

3. Before total obliteration of the foramen primum has

taken place, degenerative changes occur in the

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 central portion of the septum primum, such that a foramen secundum appears, so that the
atrial chambers can communicate again.

4. A thicker septum secundum grows down from the atrial roof on the R. side of the septum
primum. The lower edge of the septum secundum overlaps the foramen secundum in the
septum primum but does not reach the atrial floor and does not fuse with the septum
intermedium. The space between the free margin of the septum secundum and septum primum
is the foramen ovale.

5. Before birth, the foramen ovale allows oxygenated blood that has entered the R. atrium from
the IVC to pass into the L. atrium. At birth, however, owing to the raised BP in the R. atrium, the
septum primum is pressed against the septum secundum and fuses with it, and the foramen
ovale is closed, separating the atria. The lower edge of the
septum secundum seen in the R. atrium becomes the
annulus ovalis, and the depression below this is the fossa
ovalis. The R. and L. auricles later develop as small
diverticula from the R. and L. atria.

Development of the Ventricles

1. A muscular ventricular septum projects upward from the
floor of the primitive ventricle. The space bounded by the
upper edge of the septum and the septum intermedium is
the interventricular foramen.
2. Bulbar ridges (spiral endocardial thickenings) appear in the
distal part of the bulbus cordis grow and fuse to form a
spiral aorticopulmonary septum. The proliferation of
bulbar edges and septum intermedium results in the
closure of the interventricular foramen.
3. The aorticopulmonary septum grows down and fuses with
the upper edge of the muscular ventricular septum to form
the membranous part of the septum. This effectively shuts
off interventricular communication; while ensuring R.
ventricular communication with the pulmonary trunk and
L. ventricular communication with the aorta.

The truncus arteriosus (distal part of bulbus cordis) is divided by the spiral aorticopulmonary
septum to form the roots and proximal portions of the aorta and pulmonary trunk. The proximal
portion of the bulbus cordis becomes incorporated into the R. ventricle as the conus
arteriosus/infundibulum; and into the L. ventricle as the aortic vestibule. Two coronary arteries
arise just distal to the aortic valves.

Atrial Septal Defects

In 25% of hearts, the foramen ovale persists. Oxygenated blood from the L. atrium passes over the R.
atrium, decreasing the efficiency of circulation.

Ventricular Septal Defects

This occurs when the fusion between the membranous and muscular parts of the ventricular septum
is incomplete. Blood under high pressure passes through the defect from L. to R., causing
enlargement of the R. ventricle.

Tetralogy of Fallot

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This occurs when the bulbar ridges fail to fuse correctly to form the aorticopulmonary septum,
resulting in unequal division of the bulbus cordis, and consequent narrowing of the pulmonary trunk
resulting in interference with R. ventricular outflow. The anatomic abnormalities include large
ventricular septal defect; stenosis of pulmonary trunk; exit of aorta immediately above the
ventricular septal defect; and severe hypertrophy of the R. ventricle.

Embryonic Adult Structure

Dilatation
Sinus venosus Smooth part of right atrium (sinus venarum), coronary
sinus, oblique vein of left atrium
Primitive atrium Trabeculated parts of right and left atria
Primitive Trabeculated parts of right and left ventricles
ventricle
Bulbus cordis Smooth part of right ventricle (conus arteriosus),
smooth part of left ventricle (aortic vestibule)
Truncus Aorta, pulmonary trunk
arteriosus
Development of the GIT

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Most of the primitive have a dorsal mesentery (mesogastrium, mesentery, mesocolon). From the
dorsal aorta in the midline, 3 main branches of arteries (celiac, sup. mesenteric, inf. mesenteric) run
down the mesentery to supply the foregut, midgut and hindgut respectively. A ventral mesentery
mostly disappears soon after formation, except in relation to the stomach and liver.

Development of the Stomach

Germ layer:
- Stomach Walls: Endoderm of primitive foregut
- Greater momentum: Mesoderm – Dorsal and
Ventral Mesentery
Primordium: Fusiform swelling (dilatation in caudal
part of foregut, dorsal to septum transversum)

1. With growth of the foregut, the primitive

stomach grows caudally into the abdominal
cavity and acquires a ventral mesogastrium.
Insufficient movement may result in a hernia.

2. Besides showing increased growth over the

dorsal aspect, the stomach undergoes rotation through a longitudinal axis resulting in a change
of position of the closely related vagus nerves. Rotation through a ventrodorsal axis moves the
caudal end (pylorus) of the stomach to the right. The L. vagus nerve now lies on the anterior
surface of the stomach. Excessive development of muscle in the pylorus results in hypertrophic
pyloric stenosis where food is unable to leave the stomach, leading to projectile vomiting.

3. The dorsal mesogastrium grows and projects ‘sac-like’ towards the left-side and helps form the
lesser sac of the peritoneal cavity and the greater omentum in its caudal part.

4. Portions of the dorsal mesogastriun (cranial part)

depending on their connections are referred to as
the gastrosplenic and splenorenal ligaments.

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Development of Liver

Germ Layer: Endoderm of distal end of ventral foregut

Primordium: Liver Diverticulum (Hepatic bud)

1. The liver diverticulum appears on the ventral side of the foregut just caudal to the septum
transversum. It forms the gall bladder component (cystic) caudally and the liver (hepatic)
component cranially.
2. The hepatic part grows into the septum transversum and divides in a dichotomous fashion
repeatedly. The terminal (distal) parts of this branching system differentiate into the
hepatocytes, which secrete bile into the more proximal parts which will form the bile ducts.
3. As the liver becomes too large for the septum transversum, it grows out caudally into the
abdominal cavity and separates the ventral mesogastrium into the falciform ligament and the
lesser omentum.

Biliary Atresia
Failure of the bile ducts to canalize during development causes atresia (lack of a lumen). Jaundice
soon appears after birth; clay-coloured stools and very dark coloured urine is produced.

Development of the midgut

The duodenum (except 1st part), jejunum,
ileum, ascending colon and proximal ⅔ of
the transverse colon are developed from
the midgut. Destined to develop into the
longest segment of the gut, the midgut
undergoes rapid elongation during the
embryonic period.

1. Loop formation
2. Coiling (cranial segment)
3. Physiological Herniation with
associated 90⁰ counterclockwise
rotation. This occurs in the umbilical
cord which contains a space that is a
continuation of the primitive
peritoneal cavity.
4. Return to the abdominal cavity along
with a further 180⁰ counterclockwise
rotation. This results in the sup.
mesenteric artery occupying a position
between the duodenum and the
transverse colon.
5. Fixation: Parts of the original
mesentery (all midgut viscera except
transverse colon) become attached to
the posterior abdominal wall,
rendering these associated segments
retroperitoneal.
6. Vitellointestinal duct is obliterated.

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Potential Complications
1. Failure to return will result in hernia in the umbilical region
2. Incomplete rotation (e.g. during return will result in coon being on the left side). Abnormal
adhesions form, which run across the anterior surface of the duodenum and cause obstruction
in the second part.
3. Reverse rotation (i.e. clockwise) results in duodenum lying anterior to the transverse colon. Also
causes duodenal obstruction, leading to vomiting.
4. Inadequate fixation gives abnormal motility to the gut which could predispose to complications
like volvulus (a loop getting twisted around itself and getting strangulated)

Meckel’s Diverticulum
This represents a persistent portion of the vitellointestinal duct. It may possess a small area of
gastric mucosa, and bleeding may occur from a “gastric” ulcer in its mucous membrane. Moreover,
the pain from this ulcer may be confused with pain from appendicitis. Should a fibrous band connect
the diverticulum to the umbilicus, a loop of small bowel may become wrapped around it, causing
intestinal obstruction.

Development of the Pancreas

Germ layer: Endoderm of the caudal end of the dorsal and ventral foregut
Primordia: Dorsal and Ventral Diverticula
- The ventral diverticulum which appears immediately caudal to the liver diverticulum.
- The dorsal diverticulum is located slightly cranial to the ventral diverticulum.

1. Both diverticula grow and branch repeatedly to give rise to

glandular portions more distally and ducts more proximally to
the gut. The endocrine portions arise from the most peripheral
branches by budding off.
2. The ventral pancreas, with its duct and the common bile duct
associated with it, migrates around the right side of the
duodenal loop to a position on the concave aspect of the
duodenum just caudal to the dorsal pancreas. Hence, the duct
of the ventral pancreas opens into the duodenum just below
that of the dorsal pancreas.
3. The common bile duct is brought to the R. side of the duodenum by this migration. When the
duodenum turns to the right to become retroperitoneal, the common bile duct lies posterior to
the proximal part of the duodenum. This also explains why the ventral pancreas lies posterior
to the sup. mesenteric artery.
4. The ducts of the 2 glands become connected and the final main
pancreatic duct is derived from the proximal ventral and distal
dorsal pancreatic ducts and the connecting portion. The
proximal dorsal pancreatic duct remains as the accessory
pancreatic duct.

The duodenum develops from the caudal end of the foregut as well
as the cranial-most part of the midgut; hence its blood supply is from
both the celiac trunk (splenic artery and hepatic artery --- sup.
pancreaticoduodenal branch) and the sup. mesenteric artery (inf.
pancreaticoduodenal branch)

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Development of the Kidney

Germ layer: Intermediate mesoderm along posterior wall of abdominal cavity

Primordium: Metanephric diverticulum and metanephric mass

The kidney develops from 3 different, slightly overlapping systems (from

cranial to caudal):
- Pronephros: Rudimentary and non-functional. Consist of 7-10 solid cell
groups in the cervical region and forms nephrotomes (vestigial excretory units) at the beginning
of the 4th week. Earlier groups of cells regress before more caudal groups are formed. By the end
of the 4th week, the pronephros disappears.

- Mesonephros: Functions for a short time in early foetal life. The

mesonephros and mesonephric ducts are derived from the
upper thoracic to upper lumbar (L 3) segments. In the middle of
the 2nd month, the mesonephros forms a large ovoid organ on
each side of the midline (with the developing gonad lying on
the medial side).
o Mesonephric ducts: The first excretory tubules of
mesonephros appear early in the 4th week. The tubules
acquire a glomerular capillary tuft at the medial end
and enter the longitudinal mesonephric (Wolffian)
duct at the lateral end. Cranial tubules start
degenerating while caudal tubules are still
differentiating, but most of them disappear by the end
of the 2nd month.

- Metanephros: Forms the permanent kidney. It appears in the 5 th week and becomes functional
at the end of the 1st trimester. However, it is not responsible for excretion of waste products,
which is achieved by the placenta. Urine passed into the amniotic cavity mixes with the amniotic
fluid and is swallowed by the fetus to enter the intestinal tract and absorbed by the
bloodstream. The process then repeats.
o Nephrons (the excretory system) develop from the metanephric mesoderm in a similar
way as the mesonephric system. The mesodermal intermediate cell mass of the lower
lumbar and sacral regions develops into the metanephric tissue cap. Upon contact with
the elongating ureteric bud, it is induced to condense around the ureteric bud, forming
small renal vesicles, and becoming comma-shaped bodies, followed by S-shaped
bodies, and finally metanephric tubules.
 The proximal end forms the Bowman’s capsule, which is deeply indented by
glomerulus
 The distal end is in open connection with collecting tubules.
 As the nephron lengthens, the PCT, DCT, and LoH develops.

There is no increase in number of nephrons post-natally. The kidneys were lobulated at

birth, but the lobulation disappears with growth of nephrons.

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 o The collecting system develops from the ureteric bud, an outgrowth
of the mesonephric duct. The bud penetrates metanephric tissue,
dilating to form the renal pelvis and the branches repeatedly, into
the major and minor calyces and finally the collecting tubules.

Ascent of kidneys
The kidneys were initially located in the pelvic region and supplied by the pelvic
branch of the aorta. However, due to diminution of body curvature and growth
of body in the lumbar and sacral regions, the kidneys shift to a more cranial
position in the abdomen and becomes supplied by the arteries originating from
the abdominal aorta. The lower vessels then degenerate.

Renal Agenesis
This condition refers to the failure of development of one or both kidneys.
- Unilateral renal agenesis: Usually not of any major concern as long
as the other kidney is healthy. However, people with this condition
have considerably higher chances of hypertension.
- Bilateral renal agenesis: The absence of kidneys causes a deficiency
of amniotic fluid (oligohydramnios) in pregnant women. Normally,
the amniotic fluid acts as a cushion for the developing fetus.
Insufficient amniotic fluid may result in compression of the fetus,
resulting in further malformations. Most infants that are born alive
do not live beyond 4 hrs.

Ectopic/Pelvic Kidney
The kidney is arrested in some part of its normal ascent and usually
found at the pelvic brim. Such a kidney may present with no signs or symptoms and may function
normally. However, should it be inflamed, it may, because of its unusual position, give rise to a
mistaken diagnosis.

Horseshoe Kidney
This condition is the result of the fusion of the caudal ends of
both kidneys as they develop. Both kidneys commence to
ascend from the pelvis, but the interconnecting bridge becomes
trapped behind the inf. mesenteric artery so that the kidneys
come to rest in the low lumbar region. Both ureters are kinked
as they pass inferiorly over the bridge of renal tissue, producing
urinary stasis, which may result in infection and stone
formation. Surgical division of the bridge corrects the condition.

Duplications of urinary tract / Double Pelvis / Bifid ureter

Double pelvis of the ureter is usually unilateral. The upper pelvis is
small and drains the upper group of calyces; the larger lower pelvis
drains the middle and lower groups of calyces. This cause is a
premature division of the ureteric bud near its termination. In bifid
ureter, the ureters may join in the lower 3 rd of their course, may open
through a common orifice into the bladder, or may open
independently into the bladder. In the latter case, one ureter crosses
its fellow and may produce urinary obstruction.

Ectopic ureter

19
Instead of opening into the bladder, the ureter may open into the urethra, vagina or uterus. The
result is constant dribbling of urine (urinary incontinence).

Supernumerary Renal Arteries

These arteries represent persistent fetal renal
arteries, which grow in sequence from the aorta
to supply the kidney as it ascends from the pelvis.
They may cross the pelviureteral junction and
obstruct the outflow of urine, producing
dilatation of the calyces and the pelvis, known as
hydronephrosis.

Development of the Bladder and Urethra

A urorectal septum divides the cloaca into the anorectal canal and
urogenital sinus between the 4th and 7th weeks. The cloaca membrane is
divided into the urogenital membrane and the anal membrane.

The urogenital sinus has 3 portions:

- Vesical part: This is the largest part of the urogenital sinus and forms
the urinary bladder. It is initially continuous with the allantois, which
will eventually be obliterated to form a thick fibrous cord called the
urachus, which eventually forms the median umbilical ligament,
connecting the apex of the bladder with the umbilicus.
- Pelvic part: This is a narrow canal which forms the prostatic and
membranous parts of the urethra in males.
- Phalic / Definitive part: This part is flattened from side to side, and is
separated from the exterior by the urogenital membrane.

The caudal end of the

mesonephric duct is
absorbed into the
developing bladder
and forms the trigone
and part of the urethra
(in males, the prostatic
urethra). In the male, the cranial end of the mesonephric duct
is joined to the developing testis by the efferent ductules of
the testes, and so it becomes the duct of the epididymis, the
vas deferens and the ejaculatory duct. In the female, the mesonephric duct largely disappears. Only
small remnants persist as the ducts of the epoophoron and paroophoron.

The mucosa of the bladder is formed by incorporation of the mesonephric ducts and ureters in the
trigone region, and is hence of mesodermal origin. However, the mesodermal lining is replaced by
endodermal epithelium with time, and eventually, the entire bladder is lined by epithelium of
endodermal origin.

20
The urethra is of endodermal origin from the urogenital sinus. In males, the distal (penile) part is
derived from the urethral plate. The surrounding connective tissue and smooth muscle tissues are
derived from splanchnic mesoderm.

Development of the Reproductive Systems

Genetic sex is determined at fertilization. It is the Y chromosome which is

key to sexual dimorphism. In males, the SRY (sex-determining region on Y)
gene located on Yp11 encodes a testis-determining transcription factor
that initiates male sex determination. Females have an XX sex chromosome
complement, without a Y chromosome or testis-determining factor.

Indifferent Gonads (Common to both males and females)

Like the kidneys, the indifferent gonads develop from the intermediate
mesoderm along the posterior wall of the abdominal cavity. The gonads
appear initially as longitudinal gonadal ridge, medial to the urogenital ridge.

Primordial germ cells appear among endoderm cells in

the wall of the yolk sac close to the allantois. They
migrate along the dorsal mesentery of the hind gut to
arrive at the primitive gonads at the beginning of the
5th week, invading the gonadal ridges in the 6th week. If
germ cells are absent, gonads do not develop.

The epithelium proliferates and penetrates the

condensed mesenchyme (mesoderm) to form the
primitive sex cords, which are connected to the
surface epithelium.

----------------------------------------------------------------

Testis
Under the Y chromosome influence (SRY gene), the
primitive sex cords proliferate and penetrate deep into
the medulla to form the testis/medullary cords.

The testis cords develop and become horseshoe shaped in the 4 th month. They comprise primitive
germ cells and sustentacular/Sertoli cells derived from the gonadal surface epithelium. Meanwhile
the cords near the testis hilum break up to form the rete testis, a network of tiny cell strands. At
puberty, the solid testis cords acquire a lumen to form seminiferous tubules which connect to the
rete testis. The mesenchyme of the gonadal ridge develop shortly after the onset of testis cord
differentiation to form the interstitial Leydig cells which lie between the testis cords. These cells
produce testosterone from the 8th week onwards to influence differentiation of genital ducts and
external genitalia.

21
Ovary
The primitive sex cords dissociate into irregular
cell clusters containing groups of primitive germ
cells and occupy the medullary part of the
ovary. The medullary cords later disappear,
and are replaced by vascular stroma to form
the ovarian medulla.

The surface epithelium continues to proliferate

to give rise to secondary cortical cords at the
7th week. They penetrate the underlying
mesenchyme and split into isolated cell
clusters, each surrounding 1 or more primitive
germ cells. The germ cells develop into
oogonia; while the surrounding epithelial cells
form follicular cells.

-------------------------------------------------------

Descent of the testis

The gubernacula, which are folds of
mesenchymal tissue/peritoneum attached to
the caudal end of the testis, aid in the descent
of the testis. It extends to the inguinal region
between the internal and external oblique
muscles, and forms an extra-abdominal
portion extending towards the scrotal
swellings.

As the testis descends behind the peritoneum,

it drags along the fascia/muscles in its course:

Origin Structure
Processus Parietal and visceral
vaginalis layers of tunica vaginalis
Transversalis Internal spermatic fascia
fascia
Int. oblique Cremasteric fascia and
muscle
Ext. oblique External spermatic fascia
Transversus (does not cover path of
abdominis migration)

The processus vaginalis is an evagination of peritoneum into the ventral abdominal wall. It follows
the course of the gubernaculums into the scrotal swellings and forms the inguinal canal together
with the muscular and fascial layers of abdominal wall. Its connection with the peritoneal cavity is
obliterated at or shortly after birth.

The descent of the testis is controlled by the outgrowth or regression of the extra-abdominal portion
of the gubernaculums, increase in intra-abdominal pressure due to organ growth and hormonal
influences, e.g. androgens and Mullerian-inhibiting substances.

22
Congenital Inguinal Hernia
This occurs when the processus vaginalis is unobliterated, and intestinal loops descend into the
scrotum via the inguinal canal from the deep inguinal ring through the superficial ring. The remains
of the processus vaginalis form the hernial sac.

Hydrocele of testis and/or spermatic cord

The processus vaginalis may become very much narrowed but not completely obliterated; hence its
lumen remains in communication with the abdominal cavity. Peritoneal fluid accumulates in it
around the testis in the tunica vaginalis, forming a hydrocele. The hydrocele can be tapped to
remove the excess fluid by inserting a fine trocar and cannula through the scrotal skin.

Cryptorchidism
This refers to imperfect descent of the testis, which could be due to abnormal androgen
production. This results in inability to produce mature spermatozoa as the temperature within the
body retards spermatogenesis. The descent may be incomplete, and the testis fails to reach the floor
of the scrotum and may be found within the abdomen, within the inguinal canal at the superficial
inguinal ring, or high up in the scrotum. Maldescent, in which the testis travels down an abnormal
path, and may be found in the superficial fascia of the ant. abd. wall above the inguinal ligament, in
front of the pubis, in the perineum or in the thigh.

--------------------------------------------------------------------------------------------------------------------------------------

Descent of the ovaries

The gubernacula (genital ligament), attached to the caudal ends of the ovaries, aid in their descent,
which is much less than that in males. The ovaries are located just below the rim of the true pelvis.
- The cranial part of the gubernaculum, together with the ovarian artery and vein, forms the
suspensory ligament of the ovary, which suspends the ovary from the pelvic wall
- The caudal part of the gubernaculum forms the ligament of ovary proper and the round
ligament of the uterus, which supports the ovary and uterus in the pelvis.

-------------------------------------------------------------------------------------------------------------------------------------
Genital Ducts
2 pairs of indifferent genital ducts, the mesonephric/Wolffian and paramesonephric/Mullerian
ducts, are initially present in both males and females. Their development is influenced by hormones.

Male Female
Mesonephric / Testosterone, major androgen Absence of testosterone causes
Wolffian ducts produced by Leydig cells, causes regression of these ducts
virilisation of these ducts
Paramesonephric Mullerian-inhibiting substance Oestrogens (maternal, placental,
/ Mullerian ducts (MIS) / Anti-mullerian hormone foetal) and absence of MIS causes
(AMH) produced by Sertoli cells ducts to develop into uterine tubes,
causes regression of these ducts uterus, and upper part of the vagina

23
Male Genital Ducts
- Efferent ductules: Arise from mesonephric
excretory tubules. Connect to rete testis.
- Mesonephric duct: Main genital duct
o Elongate and become highly
convoluted near efferent ductules to
form epididymis
o Obtain thick muscular coat to form
vas deferens from tail of epididymis to seminal vesicles
o Forms the ejaculatory ducts beyond the seminal vesicles

-----------------------------------------------------------------------------------------------------------------------------------
Female Genital Ducts
Paramesonephric duct: Formed from a longitudinal invagination
of epithelium on the anterolateral surface of the urogenital ridge,
this duct forms the main female genital ductal system.
- Cranial vertical part: Opens into the abdominal cavity with
funnel-like structure with fimbriae.
- Horizontal part: Runs lateral to the mesonephric duct then
crosses ventrally in the caudomedial direction. Establishes
the broad ligament of the uterus, dividing the pelvic cavity
into uterovesical pouches and Pouch of Douglas
- Caudal vertical part: Comes into close contact with opposite
paramesonephric duct in the midline. The caudal tip projects
into the posterior wall of the urogenital sinus. Both parts are
initially separated by a septum, but later fuse to form the
uterus and cervix. The surrounding mesenchyme forms
myometrium; while the peritoneal covering forms the
perimetrium.

Vagina
The vagina is of dual origin:
- Sinovaginal bulbs: These are evaginations from the pelvic
part of the urogenital sinus which proliferate to form a solid
vaginal plate. By the 5th month, it will be completely
canalized to from the lower part of the vagina. The lumen
is separated from the urogenital sinus by the hymen.
- Vaginal fornices: These wing-like expansions of the upper
part of the vagina form around the end of the uterus.
These are of paramesonephric origin.

24
Agenesis of the Uterus
This is a rare condition where the uterus is absent as the result of a failure of the paramesonephric
ducts to develop.

Infantile Uterus
This is a condition in which the uterus is much smaller than normal and resembles that present
before puberty. Amenorrhea is present, but the vagina and ovaries may be normal.

Failure of Fusion of the paramesonephric ducts

Failure of the paramesonephric ducts to fuse may cause a variety of uterine defects:
- Uterus may be duplicated with 2 bodies and 2 cervices
- There may be a complete septum through the uterus, making 2 uterine cavities
and 2 cervices
- There may be 2 separate uterine bodies with one cervix
- One paramesonephric duct may fail to develop, leaving one uterine tube and
half of the body of the uterus.

----------------------------------------------

Indifferent External Genitalia

The indifferent external genitalia
comprises of:
- Cloacal folds: Slightly elevated regions around the cloacal
membrane formed by migration of mesenchymal cells from the
primitive streak (ectoderm) during the 3rd week of
development.
o Cranial to cloacal membrane: Folds unite to form
genital tubercle (phallus)
o Caudal to cloacal membrane: Divided into the urethral
folds and anal folds when the cloacal membrane is
subdivided into urogenital and anal membranes at the
6th week
- Genital swellings (Labioscrotal folds): Pair of elevation
on either side of urethral folds.

25
 Male Female
Development Influenced by androgens Stimulated by oestrogens
Genital - Initially located in inguinal region Enlarge to form the labia majora
swellings - Move caudally and fuse, each
making up half the scrotum
- Halves separated by scrotal septum
Genital - Rapidly elongates, pulling urethral Elongates slightly to form the clitoris
tubercle folds forward to form urethral
groove
Urogenital - Extends along the caudal aspect of Remains open to form vestibule
groove the elongated genital tubercle
- Lined by endodermal cells to form a
urethral plate
Urethral folds - Fuse over urethral plate to form Do not fuse; Forms the labia minora
penile urethra at end of 3rd month.
- The canal does not extend to the tip
of the phallus
- Ectodermal cells from the tip of the
glans penetrate inward to form
epithelial cord at the 4th month
- Canalizes to form the external
urethral meatus.

26
27
Embryological development begins with fertilization, the joining of a male and female gamete
during sexual reproduction, to produce a single cell containing a unique set of genetic
information. The combination of genes produced by this association helps to determine the
growth, appearance, and function of an individual.

Development is usually categorized into a number of periods, which are characterized by the
anatomical changes that occur. Embryological development occurs during the first eight weeks
after fertilization, fetal development from week nine to birth of the infant, and postnatal
development from birth, continuing into maturity.

The stages of embryological and fetal development are often referred to as the prenatal period.
The normal gestation period of a fetus is from 38-42 weeks. As such, the prenatal period is often
divided into three intervals of approximately 13 weeks: the first trimester, second trimester, and
third trimester.

Time-line
During prenatal development, limbs, organs, and systems need to be established in a time-
dependent sequence to ensure normal growth.

Day 1: Fertilization The union of the haploid gametes, a spermatozoon and a secondary oocyte,
creates a diploid zygote.

Days 1.5-3: First cleavage (approx. after 30 hours) The zygote divides to form two identical cells.
The cells from each division are referred to as blastomeres. Cells continue to divide to the 16-cell
stage.

Day 3: Morula Mitotic cell division continues and at the 16-cell stage, a morula forms.

Days 5-6: Blastocyst A single cavity forms within the morula creating a blastocyst. The blastocyst
hatches from the surrounding zona pellucida and the implantation process begins.

Days 7-12: Implantation The blastocyst fully implants in the uterine wall. Only if wall has been
successfully prepared by hormone.

Day 8: Bilaminar germ disc The inner cell mass, or embryoblast, differentiates into two layers: the
epiblast and hypoblast. Together, these form the bilaminar germ disc.

Day 13: Uteroplacental circulation The blood supply between mother and fetus begins to form.

Day 16: Gastrulation Start of the formation of the gastrula, or trilaminar germ disc, which
establish the three primary germ layers: the ectoderm, mesoderm, and endoderm. These three
layers eventually form all of the tissues and organs.
Day 16: Notochord The notochordal process begins to form during the gastrulation process. The
notochord gives rise to the primitive axis of the embryo.

Day 18: Neural tube The neurulation process begins. Between days 19 and 25, the neural plate
differentiates into the neural groove and then the neural tube, the precursor to the central
nervous system. During the closure of the neural tube, a population of cells called the neural
crest form. These cells contribute to the formation of the peripheral nervous system, including the
formation of neurons and glial cells of the sympathetic, parasympathetic, and sensory nervous
systems.

Day 20: Somites Somite development commences. These balls of mesoderm are formed from
masses of paraxial mesoderm either side of the notochord. They give rise to a number of organs
including the major muscles of the neck, trunk, limbs, connective tissue, ribs, and vertebrae.

28
Day 21: Embryonic folding Formation of the three-dimensional body plan begins. Extensive
folding of the embryo begins around day 21 in two planes, the horizontal plane, and the median
sagittal plane simultaneously to create a more life-like human shape.

Day 22: Organogenesis Start of organogenesis: as embryonic folding occurs, specific tissues
and organs arise from each of the three germ layers. The result of this process is the creation of
the major organ systems.

29
30
Primordial Germ Cells (PGCs) and Teratomas

Teratomas are tumors of disputed origin that often contain a variety of tissues, such as bone, hair, muscle, gut
epithelia, and others. It is thought that these tumors arise from a pluripotent stem cell that can differentiate into
any of the three germ layers or their derivatives

Birth Defects and Spontaneous Abortions: Chromosomal and Genetic Factors

Chromosomal abnormalities, which may be numerical or structural, are important causes of birth defects
and spontaneous abortions. It is estimated that 50% of conceptions end in spontaneous abortion and that 50% of
these abortuses have major chromosomal abnormalities. Thus approximately 25% of conceptuses have a major
chromosomal defect. The most common chro- mosomal abnormalities in abortuses are 45,X (Turner syndrome),
triploidy, and trisomy 16. Chromosomal abnormalities account for 7% of major birth defects, and gene
mutations account for an additional 8%.

Numerical Abnormalities

The normal human somatic cell contains 46 chromosomes; the normal ga- mete contains 23. Normal somatic
cells are diploid, or 2n; normal gametes are haploid, or n. Euploid refers to any exact multiple of n, e.g.,
diploid or triploid. Aneuploid refers to any chromosome number that is not euploid; it is usually applied when
an extra chromosome is present (trisomy) or when one is missing (monosomy). Abnormalities in chromosome
number may origi- nate during meiotic or mitotic divisions. In meiosis, two members of a pair of homologous
chromosomes normally separate during the first meiotic divi- sion so that each daughter cell receives one
member of each pair (Fig. 1.5A). Sometimes, however, separation does not occur (nondisjunction), and both
members of a pair move into one cell (Fig. 1.5, B and C ). As a result of nondisjunction of the chromosomes,
one cell receives 24 chromosomes, and the other receives 22 instead of the normal 23. When, at fertiliza- tion, a
gamete having 23 chromosomes fuses with a gamete having 24 or 22 chromosomes, the result is an individual
with either 47 chromosomes (trisomy) or 45 chromosomes (monosomy). Nondisjunction, which occurs during
either the first or the second meiotic division of the germ cells, may involve the autosomes or sex chromosomes.
In women, the incidence of chromosomal abnormalities, including nondisjunction, increases with age, especially
at 35 years and older.

Occasionally nondisjunction occurs during mitosis (mitotic nondisjunc- tion) in an embryonic cell during the
earliest cell divisions. Such conditions produce mosaicism, with some cells having an abnormal chromosome
num- ber and others being normal. Affected individuals may exhibit few or many of the characteristics of a
particular syndrome, depending on the number of cells involved and their distribution.

Sometimes chromosomes break, and pieces of one chromosome attach to another. Such translocations may be
balanced, in which case breakage and reunion occur between two chromosomes but no critical genetic material
is lost and individuals are normal; or they may be unbalanced, in which case part of one chromosome is lost
and an altered phenotype is produced. For example, unbalanced translocations between the long arms of
chromosomes 14 and 21 during meiosis I or II produce gametes with an extra copy of chro- mosome 21, one of
the causes of Down syndrome (Fig. 1.6). Translocations are particularly common between chromosomes 13, 14,
15, 21, and 22 be- cause they cluster during meiosis.

TRISOMY 21 (DOWN SYNDROME)

Down syndrome is usually caused by an extra copy of chromosome 21 (tri- somy 21, Fig. 1.7). Features of
children with Down syndrome include growth retardation; varying degrees of mental retardation; craniofacial
abnormalities, including upward slanting eyes, epicanthal folds (extra skin folds at the medial corners of the
eyes), flat facies, and small ears; cardiac defects; and hypotonia (Fig. 1.8). These individuals also have relatively
high incidences of leukemia, infections, thyroid dysfunction, and premature aging. Furthermore, nearly all
develop signs of Alzheimer’s disease after age 35. In 95% of cases, the syndrome is caused by trisomy 21
resulting from meiotic nondisjunction, and in 75% of these instances, nondisjunction occurs during oocyte
formation. The incidence of Down syndrome is approximately 1 in 2000 conceptuses for women under age 25.
This risk increases with maternal age to 1 in 300 at age 35 and 1 in 100 at age 40.

31
In approximately 4% of cases of Down syndrome, there is an unbal- anced translocation between chromosome
21 and chromosome 13, 14, or 15 (Fig. 1.6). The final 1% are caused by mosaicism resulting from mitotic
nondisjunction. These individuals have some cells with a normal chromo- some number and some that are
aneuploid. They may exhibit few or many of the characteristics of Down syndrome.

TRISOMY 18

Patients with trisomy 18 show the following features: mental retardation, con- genital heart defects, low-set
ears, and flexion of fingers and hands (Fig. 1.9). In addition, patients frequently show micrognathia, renal
anomalies, syndactyly, and malformations of the skeletal system. The incidence of this condition is
approximately 1 in 5000 newborns. Eighty-five percent are lost between 10 weeks of gestation and term,
whereas those born alive usually die by age 2 months.

TRISOMY 13

The main abnormalities of trisomy 13 are mental retardation, holo- prosencephaly, congenital heart defects,
deafness, cleft lip and palate, and eye defects, such as microphthalmia, anophthalmia, and coloboma (Fig. 1.10).
The incidence of this abnormality is approximately 1 in 20,000 live births, and over 90% of the infants die in the
first month after birth.

KLINEFELTER SYNDROME

The clinical features of Klinefelter syndrome, found only in males and usually detected at puberty, are sterility,
testicular atrophy, hyalinization of the semi- niferous tubules, and usually gynecomastia. The cells have 47
chromosomes with a sex chromosomal complement of the XXY type, and a sex chromatin body (Barr body:
formed by condensation of an inactivated sex chromo- some; a Barr body is also present in normal females) is
found in 80% of cases (Fig. 1.11). The incidence is approximately 1 in 500 males. Nondisjunction of the XX
homologues is the most common causative event. Occasionally, pa- tients with Klinefelter syndrome have 48
chromosomes: 44 autosomes and four sex chromosomes (XXXY). Although mental retardation is not generally
part of the syndrome, the more X chromosomes there are, the more likely there will be some degree of mental
impairment.

TURNER SYNDROME

Turner syndrome, with a 45,X karyotype, is the only monosomy compat- ible with life. Even then, 98% of all
fetuses with the syndrome are sponta- neously aborted. The few that survive are unmistakably female in
appearance (Fig. 1.12) and are characterized by the absence of ovaries (gonadal dysgen- esis) and short stature.
Other common associated abnormalities are webbed neck, lymphedema of the extremities, skeletal deformities,
and a broad chest with widely spaced nipples. Approximately 55% of affected women are mono- somic for the
X and chromatin body negative because of nondisjunction. In 80% of these women, nondisjunction in the male
gamete is the cause. In the remainder of women, structural abnormalities of the X chromosome or mitotic
nondisjunction resulting in mosaicism are the cause.

TRIPLE X SYNDROME

Patients with triple X syndrome are infantite, with scanty menses and some degree of mental retardation. They
have two sex chromatin bodies in their cells.

Structural Abnormalities

Structural chromosome abnormalities, which involve one or more chro- mosomes, usually result from
chromosome breakage. Breaks are caused by environmental factors, such as viruses, radiation, and drugs. The
result of breakage depends on what happens to the broken pieces. In some cases, the broken piece of a
chromosome is lost, and the infant with partial deletion of a chromosome is abnormal. A well-known syndrome,
caused by partial dele- tion of the short arm of chromosome 5, is the cri-du-chat syndrome. Such children have
a catlike cry, microcephaly, mental retardation, and congenital heart disease. Many other relatively rare
syndromes are known to result from a partial chromosome loss.

32
Microdeletions, spanning only a few contiguous genes, may result in microdeletion syndrome or contiguous
gene syndrome. Sites where these deletions occur, called contiguous gene complexes, can be identified by
high-resolution chromosome banding. An example of a microdeletion occurs on the long arm of chromosome
15 (15q11–15q13). Inheriting the deletion on the maternal chromosome results in Angelman syndrome, and the
children are mentally retarded, cannot speak, exhibit poor motor devel- opment, and are prone to unprovoked
and prolonged periods of laughter (Fig. 1.13). If the defect is inherited on the paternal chromosome, Prader-
Willi syndrome is produced; affected individuals are characterized by hypotonia, obesity, mental retardation,
hypogonadism, and cryptorchidism (Fig. 1.14). Characteristics that are differentially expressed depending upon
whether the genetic material is inherited from the mother or the father are examples of genomic imprinting.
Other contiguous gene syndromes may be inherited from either parent, including Miller-Dieker syndrome
(lissencephaly, devel- opmental delay, seizures, and cardiac and facial abnormalities resulting from a deletion at
17p13) and most cases of velocardiofacial (Shprintzen) syndrome (palatal defects, conotruncal heart defects,
speech delay, learning disorders, and schizophrenia-like disorder resulting from a deletion in 22q11).

Fragile sites are regions of chromosomes that demonstrate a propensity to separate or break under certain cell
manipulations. For example, fragile sites can be revealed by culturing lymphocytes in folate-deficient medium.
Although numerous fragile sites have been defined and consist of CGG re- peats, only the site on the long arm
of the X chromosome (Xq27) has been correlated with an altered phenotype and is called the fragile X
syndrome. Fragile X syndrome is characterized by mental retardation, large ears, promi- nent jaw, and pale blue
irides. Males are affected more often than females (1/1000 versus 1/2000), which may account for the
preponderance of males among the mentally retarded. Fragile X syndrome is second only to Down syndrome as
a cause of mental retardation because of chromosomal abnor- malities.

Gene Mutations

Many congenital formations in humans are inherited, and some show a clear mendelian pattern of inheritance.
Many birth defects are directly attributable to a change in the structure or function of a single gene, hence the
name single gene mutation. This type of defect is estimated to account for approximately 8% of all human
malformations. With the exception of the X and Y chromosomes in the male, genes exist as pairs, or alleles, so
that there are two doses for each genetic determinant, one from the mother and one from the father. If a mutant
gene produces an abnormality in a single dose, despite the presence of a normal allele, it is a dominant
mutation. If both alleles must be abnormal (double dose) or if the mutation is X-linked in the male, it is a
recessive mutation. Gradations in the effects of mutant genes may be a result of modifying factors.

The application of molecular biological techniques has increased our knowledge of genes responsible for normal
development. In turn, genetic analysis of human syndromes has shown that mutations in many of these same
genes are responsible for some congenital abnormalities and childhood diseases. Thus, the link between key
genes in development and their role in clinical syndromes is becoming clearer.

In addition to causing congenital malformations, mutations can result in inborn errors of metabolism. These
diseases, among which phenylketonuria, homocystinuria, and galactosemia are the best known, are frequently
accom- panied by or cause various degrees of mental retardation.

Diagnostic Techniques for Identifying Genetic Abnormalities

Cytogenetic analysis is used to assess chromosome number and integrity. The technique requires dividing cells,
which usually means establishing cell cultures that are arrested in metaphase by chemical treatment.
Chromosomes are stained with Giemsa stain to reveal light and dark banding patterns (G-bands; Fig. 1.6)
unique for each chromosome. Each band represents 5 to 10 × 106 base pairs of DNA, which may include a few
to several hundred genes. Recently, high resolution metaphase banding techniques have been devel- oped
that demonstrate greater numbers of bands representing even smaller pieces of DNA, thereby facilitating
diagnosis of small deletions.

New molecular techniques, such as fluorescence in situ hybridization (FISH), use specific DNA probes to
identify ploidy for a few selected chro- mosomes. Fluorescent probes are hybridized to chromosomes or genetic
loci using cells on a slide, and the results are visualized with a fluorescence microscope (Fig.1.15). Spectral
karyotype analysis is a technique in which every chromosome is hybridized to a unique fluorescent probe of a
different color. Results are then analyzed by a computer.

33
ABNORMAL GAMETES

In humans and in most mammals, one ovarian follicle occasionally contains two or three clearly distinguishable
primary oocytes (Fig. 1.26A). Although these oocytes may give rise to twins or triplets, they usually degenerate
before reaching maturity. In rare cases, one primary oocyte contains two or even three nuclei (Fig. 1.26B). Such
binucleated or trinucleated oocytes die before reaching maturity.

In contrast to atypical oocytes, abnormal spermatozoa are seen fre- quently, and up to 10% of all spermatozoa
have observable defects. The head or the tail may be abnormal; spermatozoa may be giants or dwarfs; and
sometimes they are joined (Fig. 1.26C ). Sperm with morphologic abnor- malities lack normal motility and
probably do not fertilize oocytes.

Ovulation

During ovulation, some women feel a slight pain, known as middle pain because it normally occurs near the
middle of the menstrual cycle. Ovulation is also generally accompanied by a rise in basal temperature, which
can be monitored to aid in determining when release of the oocyte occurs. Some women fail to ovulate because
of a low concentration of gonadotropins. In these cases, administration of an agent to stimulate gonadotropin
release and hence ovulation can be employed. Although such drugs are effective, they often produce multiple
ovulations, so that the risk of multiple pregnancies is 10 times higher in these women than in the general
population.

Contraceptive Methods

Barrier techniques of contraception include the male condom, made of latex and often containing chemical
spermicides, which fits over the penis; and the female condom, made of polyurethane, which lines the vagina.
Other barriers placed in the vagina include the diaphragm, the cervical cap, and the contraceptive sponge.

The contraceptive pill is a combination of estrogen and the progesterone analogue progestin, which together
inhibit ovulation but permit menstruation.

Chapter 2: First Week of Development: Ovulation to Implantation 41

Both hormones act at the level of FSH and LH, preventing their release from the pituitary. The pills are taken
for 21 days and then stopped to allow men- struation, after which the cycle is repeated.

Depo-Provera is a progestin compound that can be implanted subder- mally or injected intramuscularly to
prevent ovulation for up to 5 years or 23 months, respectively.

A male “pill” has been developed and tested in clinical trials. It contains a synthetic androgen that prevents
both LH and FSH secretion and either stops sperm production (70–90% of men) or reduces it to a level of
infertility.

The intrauterine device (IUD) is placed in the uterine cavity. Its mech- anism for preventing pregnancy is not
clear but may entail direct effects on sperm and oocytes or inhibition of preimplantation stages of development.

The drug RU-486 (mifepristone) causes abortion if it is administered within 8 weeks of the previous menses. It
initiates menstruation, possibly through its action as an antiprogesterone agent.

Vasectomy and tubal ligation are effective means of contraception, and both procedures are reversible,
although not in every case.

Infertility

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Infertility is a problem for 15% to 30% of couples. Male infertility may be a result of insufficient numbers of
sperm and/or poor motility. Normally, the ejaculate has a volume of 3 to 4 ml, with approximately 100 million
sperm per ml. Males with 20 million sperm per ml or 50 million sperm per total ejaculate are usually fertile.
Infertility in a woman may be due to a number of causes, including occluded oviducts (most commonly caused
by pelvic inflam- matory disease), hostile cervical mucus, immunity to spermatozoa, absence of ovulation, and
others.

In vitro fertilization (IVF) of human ova and embryo transfer is a frequent practice conducted by laboratories
throughout the world. Follicle growth in the ovary is stimulated by administration of gonadotropins. Oocytes
are recovered by laparoscopy from ovarian follicles with an aspirator just before ovulation when the oocyte is in
the late stages of the first meiotic division. The egg is placed in a simple culture medium and sperm are added
immediately. Fertil- ized eggs are monitored to the eight-cell stage and then placed in the uterus to develop to
term. Fortunately, because preimplantation-stage embryos are resistant to teratogenic insult, the risk of
producing malformed offspring by in vitro procedures is low.

A disadvantage of IVF is its low success rate; only 20% of fertilized ova implant and develop to term.
Therefore, to increase chances of a successful pregnancy, four or five ova are collected, fertilized, and placed in
the uterus. This approach sometimes leads to multiple births.

Another technique, gamete intrafallopian transfer (GIFT), introduces oocytes and sperm into the ampulla of
the fallopian (uterine) tube, where fertilization takes place. Development then proceeds in a normal fashion. In a
similar approach, zygote intrafallopian transfer (ZIFT), fertilized oocytes are placed in the ampullary region.
Both of these methods require patent uterine tubes.

Severe male infertility, in which the ejaculate contains very few live sperm (oligozoospermia) or even no live
sperm (azoospermia), can be overcome using intracytoplasmic sperm injection (ICSI). With this technique,
a single sperm, which may be obtained from any point in the male reproductive tract, is injected into the
cytoplasm of the egg to cause fertilization. This approach offers couples an alternative to using donor sperm for
IVF. The technique carries an increased risk for fetuses to have Y chromosome deletions but no other
chromosomal abnormalities.

Abnormal Zygotes

The exact number of abnormal zygotes formed is unknown because they are usually lost within 2 to 3 weeks
of fertilization, before the woman re- alizes she is pregnant, and therefore are not detected. Estimates are that as
many as 50% of pregnancies end in spontaneous abortion and that

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Chapter 2: First Week of Development: Ovulation to Implantation 45

half of these losses are a result of chromosomal abnormalities. These abortions are a natural means of screening
embryos for defects, reducing the incidence of congenital malformations. Without this phenomenon,
approximately 12% instead of 2% to 3% of infants would have birth defects.

With the use of a combination of IVF and polymerase chain reaction (PCR), molecular screening of embryos
for genetic defects is being conducted. Single blastomeres from early-stage embryos can be removed and their
DNA amplified for analysis. As the Human Genome Project provides more sequenc- ing information and as
specific genes are linked to various syndromes, such procedures will become more commonplace.

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