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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_32_библиотеки_им_акад_М_И_Перельмана
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2 Embryology
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Figure 1.1 Key stages between fertilisation and
implantation of the blastocyst at 5–6 days.
As a result of the meiotic divisions during gametogenesis, the nuclei of the denitive
oocyte and spermatozoon contain a single copy
of each of the 22 autosomes and 1 sex chromosome. Fusion of the nuclear DNA of the two gametes during fertilisation creates a zygote whose
nucleus contains 46 chromosomes – with one
copy of each pair of autosomes and one of the two
sex chromosome derived from each parent. On
its journey along fallopian tube, the newly fertilised zygote undergoes a series of mitotic divisions
(termed cleavage) to form a mass of cells termed
the blastocyst (Figure 1.1).
Major chromosomal abnormalities can arise
either during gametogenesis or fertilisation or
the early mitotic divisions of the zygote. Most
chromosomal abnormalities of this severity
lead to spontaneous abortion of the embryo but
trisomy 21 (Down syndrome), trisomy 13 (Patau
syndrome) and trisomy 18 (Edward syndrome)
are compatible with survival. Of these, however,
only trisomy 21 is compatible with longer term
survival into adult life.
Trisomies can occur as a result of non-
disjunction (in which a pair of chromosomes
fail to separate during gametogenesis) or trans-
location (in which a chromosome, or piece of a
chromosome, becomes attached to another chromosome during meiotic division).
e corollary of non-disjunction and translocation is the formation of a gamete which
lacks one copy of that particular chromosome. is results in the formation of a zygote
whose nucleus contains only a single (unpaired)
copy of the particular chromosome. is is
termed monosomy. Absence of an entire autosome (complete monosomy) invariably leads to
spontaneous abortion of the embryo whereas
some partial monosomic states are compatible
with survival. By contrast to the abnormalities
aecting autosomes, major structural abnormalities of the sex chromosomes are not only
consistent with survival but are relatively common. Examples include Klinefelter syndrome
(47XXY) and Turner syndrome. Approximately
50% cases of Turner syndrome exist as complete
monosomy (45X) whilst 30% of cases occur in
mosaic form 45X/46XX) and 20% result from
a structural deletion of genetic material on one
of the X chromosomes. 45X/46XY mosaicism is
known as mixed gonadal dysgenesis. Mosaicism
is dened as the presence of two genetically distinct cell lines derived from the same zygote.
Abnormalities of the sex chromosomes oen
occur in mosaic form.
Genetic mutations occurring at the level of
individual genes can be studied using techniques such as polymerase chain reaction (PCR)
and uorescence in situ hybridisation (FISH).
A number of inherited conditions aecting the
genitourinary tract can be ascribed to identiable
mutations, e.g. autosomal recessive polycystic
kidney disease (ARPKD), autosomal dominant
polycystic kidney disease (ADPKD), X-linked
Kallmann’s syndrome and renal coloboma syndrome. However, attempts to identify specic
mutations in common urological conditions with
a strong familial tendency such as vesico ureteric
reux, upper tract duplication and hypospadias
have been unrewarding. e occurrence of these
disorders in members of the same family is more
likely to result from the interaction of multiple
genes than the eect of a single gene mutation.
e possible role of environmental factors in
modifying gene expression during embryological
development of the genitourinary tract is poorly
understood.
EMBRYOGENESIS
Human gestation spans a period of 38 weeks,
from fertilisation to birth. e formation of
Upper urinary tract 3
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Figure 1.3 Precursors of the upper urinary tract,
metanephros and ureteric bud.
Figure 1.2 Embryonic disc at 16 days with
inpouring of cells into the primitive streak to
create intraembryonic mesoderm.
organs and systems occurs mainly between the
third and tenth weeks with subsequent development being characterised mainly by dierentiation, branching, maturation and growth.
By the time the blastocyst implants into the
primed endometrium (approximately 6 days
aer fertilisation) it has undergone organisation
to form an outer trophoblastic layer and inner
cell mass. Over the ensuing 10 days, the amniotic cavity and the yolk sac develop within the
blastocyst – with the embryonic disc forming in
the interface between them. Ectodermal tissue
originates from cells on the amniotic surface of
the embryonic disc whereas endodermal tissues
are derived from cells adjacent to the yolk sac.
Inpouring of cells into the embryonic disc from
the amniotic surface via the primitive streak
creates a third layer – the intraembryonic mesoderm (Figure 1.2). It is from the intraembryonic
mesoderm that much of the genitourinary tract
is ultimately derived.
UPPER URINARY TRACT
(FIGURE 1.3)
By the fourth week, two blocks of mesoderm
have appeared on each side of the midline.
Sequential dierentiation within this mesoderm gives rise to the pronephros in the most
cephalad region, the mesonephros in the midzone and the metanephros in the most caudal
region. e pronephros regresses rapidly and
serves no function in the human embryo. At
around the same time, condensations of mesenchyme lying lateral to the mesonephros undergo
canalisation to form the mesonephric ducts,
which advance in a caudal direction to merge
with the cloaca. Tubular structures within the
mesonephros establish a communication with
the mesonephric duct to full a transient excretory role until around 10 weeks. ese tubules
then regress in the female but in the male they
persist as precursors of the eerent tubules of
the testis.
At around 28 days, the ureteric bud develops as a protrusion from the mesonephric
duct. e ureteric bud then advances towards
the metanephros to penetrate the metanephric mesenchyme at around 32 days. e formation of nephrons by interaction between
the ureteric bud and metanephros occurs by a
process of reciprocal interaction between the
two tissues – a phenomenon which occurs in
the embryological development of a number of
systems. Sequential budding and branching of
the ureteric bud gives rise to the renal pelvis,
the major calices, the minor calices and the collecting ducts whilst the glomeruli, convoluted
tubules and loop of Henle are derived from
the metanephric mesenchyme (Figure 1.4). e
cortex and medulla are discernible by 15 weeks
and new generations of nephrons continue to
be added to the cortex up until 36 weeks. In
humans, the process of nephrogenesis ceases
at 36 weeks and the total number of nephrons
remains xed thereaer at approximately 1 million per kidney. Nephron numbers are reduced
in the kidneys of preterm and low-birth-weight
infants. Almost 3000 dierent genes have been
identied as being involved in ureteric bud
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Figure 1.4 Embryonic urinary tract at 6–8 weeks.
formation and nephrogenesis. e roles played
by many of these genes have been studied in
transgenic mice and in clinical genetic studies.
Of these, the gene encoding for glial cell linederived neurotophic factor (GDNF), Wilms
tumour suppressor gene (WT1) and RET protooncogene have been shown to play key roles.
Abnormalities of Renal Ascent
and Fusion
ese anomalies date from the sixth to tenth
weeks of gestation, when the embryonic kidney is ascending in its relative position on the
posterior abdominal wall before adopting its
denitive position. Examples include, horseshoe
kidney (Figure 1.5), pelvic kidney (Figure 1.6)
and crossed fused renal ectopia (Figure 1.7).
Fetal Renal Function
Although the kidneys excrete urine into the amniotic cavity from around the ninth week onwards,
the homeostatic role which is normally played by
the kidneys is fullled by the placenta – which
eectively “dialyses” the fetus until birth. e
kidneys nevertheless serve an important function
by producing urine – which is a major constituent of the amniotic uid surrounding the fetus. In
addition to providing a protective environment
for the fetus, amniotic uid also promotes normal lung development. Reduced amniotic uid
Renal Dysplasia
Although “dysplastic” is oen used loosely to
refer to any congenitally small kidney, the term
“dysplasia” refers more accurately to kidneys
demonstrating certain characteristic histological features. ese include disordered renal
architecture, immature “primitive” undierentiated tubules, small cysts and the inappropriate
(metaplastic) presence of cartilage and bromuscular tissue. Renal dysplasia can arise from
faulty interaction between the ureteric bud and
metanephric tissue or the eects of insults to the
developing kidney – notably severe obstructive
uropathy.
A hypoplastic kidney is one which is reduced
in size but retains normal internal architecture –
although with fewer nephrons.
Cystic Anomalies
e patterns of cystic renal disease and their aetiology are considered in Chapter 10.
Figure 1.5 Abnormality of ascent and fusion-
horseshoe kidney.
Figure 1.6 Abnormality of ascent-pelvic kidney.
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Lower urinary tract / Clinical Considerations 5
volume (oligohydramnios) is associated with pulmonary hypoplasia as well as “moulding deformities” of the fetus such as “Potter’s facies” and
limb deformities.
LOWER URINARY TRACT
(FIGURE 1.8)
e lower urinary tract is derived from the cloaca,
a single cavity comprising the primitive hindgut
and allantois. Between the fourth and seventh
weeks the cloaca subdivides to form the urogenital sinus anteriorly and anorectal canal posteriorly. Historically, this subdivision was ascribed to
a process of active descent of the urorectal septum (Tourneux fold) aided by lateral ingrowth
of (Rathke) folds from the side walls of the cloaca. However, this explanation has been largely
refuted by more recent studies which have demonstrated that subdivision of the cloaca occurs as
a predominantly “passive” process resulting from
spatial realignment, dierential dorsoventral
growth of the cloaca and unfolding of the caudal
body axis.
As the bladder develops, the mesonephric
ducts migrate caudally to merge with the upper
urethra, whereas the ureters retain a more xed
position in relation to the bladder (Figure 1.9).
Figure 1.7 Abnormality of ascent and fusion-
crossed fused renal ectopia.
Clinical Considerations
Persistent cloacal malformations represent the
female equivalent of high anorectal malformations in males and are characterised by conuence of the urethra, vagina and rectum to form
a common channel with a single opening on the
perineum. Cloacal malformations originate from
abnormalities occurring during subdivision of
the cloaca between 4 and 7 weeks. e origins of
bladder exstrophy and epispadias are less clear.
Complete upper tract duplication occurs when
two (rather than one) ureteric buds develop on
the mesonephric duct. A bid ureteric bud gives
rise to incomplete ureteric duplication.
e Meyer-Weigart law describes the paradoxical anatomy of the ureters observed in cases
of complete duplication whereby the upper pole
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Figure 1.8 Subdivision of the cloaca into the urogenital compartment and anorectum at 4–7 weeks.
ureter enters the urinary tract in a more caudal
position than the lower pole ureter. is phenomenon is explained by the pattern of early development in which the mesonephric duct descends
towards the developing posterior urethra taking
the upper pole ureter with it whilst the lower pole
ureter remains anchored on the trigonal region of
the bladder.
GENITAL TRACTS
Dierentiation and development of the gonads
and genital tracts is initiated by the migration of
primordial germ cells from the yolk sac, across the
coelomic cavity and into primitive mesenchyme
on the posterior wall of the embryo. e genital
ridge is formed by reciprocal induction between
the germ cells and surrounding mesenchyme. e
paramesonephric ducts develop as condensations
of coelomic epithelium lying lateral to the mesonephric ducts. At 6 weeks the structures which
represent the precursors of the reproductive
tract are identical in males and females. With the
exception of the gonads these structures are destined to dierentiate passively down a “default”
female pathway unless actively switched down a
male pathway by the genetic information carried
by the testis-determining gene (SRY).
Figure 1.9 Changing anatomical conguration of
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the ureters and mesonephric duct derivatives.
Genital tracts / Internal Genitalia 7
Internal Genitalia
Female (Figure 1.10)
Within the genital ridge, primordial germ cells
and mesenchymal support cells interact to form
ovarian follicles within the developing ovary.
Because they are not exposed to testosterone,
the mesonephric ducts regress spontaneously, to
leave only vestigial remnants (epioophoron, paroophoron and Gartner’s cysts). In the absence of
exposure to anti-Müllerian hormone (AMH), the
paramesonephric ducts in females persist to give
rise to the fallopian tubes and lower genital tract.
It has become apparent that dierentiation
and development of the ovary is not a purely
passive (“default”) process determined solely by
the absence of the SRY gene. e Dax1 ovarian
promoting factor gene encoded on the X chromosome has been shown to act in conjunction with
other genes to actively promote ovarian development and inhibit expression of the SRY gene. At
around the tenth week, the caudal extremities
of the paramesonephric ducts fuse and attach
to the urogenital sinus. Over the ensuing weeks
the uterus forms from the fused paramesonephric ducts. In the conventional account of the
development of the vagina, the fused paramesonephric ducts attach to the urogenital sinus to
create a condensation of tissue (sinu vaginal bulb)
which advances downwards to the perineum as
a solid vaginal plate which then canalises to create the vaginal lumen. e upper two-thirds of
the vagina have been conventionally described as
being of paramesonephric origin with the lower
Figure 1.10 The undifferentiated genital tract is genetically programmed down a pathway of
female differentiation unless directed down a male pathway by the presence of the SRY gene.
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third of the vagina and introitus being derived
from urogenital sinus and ectoderm, respectively
(Figure 1.11). However, recent studies have cast
doubt on this model and it has become apparent that the development of the human vagina is
more complex than was previously thought.
Male (Figure 1.12)
Dierentiation of the male genital tract is ultimately
dependent on the presence of the testis-determining
gene (SRY) located on the short arm of the Y chromosome. However, the role of the SRY gene is mediated by a cascade of other downstream genes. e
testis determining factor encoded by the SRY gene is
a transcription factor which promotes upregulation
of SOX9 and other transcription factors.
Anti-Müllerian Hormone (AMH), also termed
Müllerian Inhibitory Substance (MIS) substance, is
secreted by the Sertoli cells of the testis from the
seventh week onwards.
●
AMH is responsible for causing regression of
the paramesonephric ducts (with the excep-
tion of vestigial remnants such as the testicu-
lar appendage and utriculus).
●
AMH stimulates the Leydig cells of the fetal
testis to secrete testosterone from the ninth
week onwards.
●
AMH promotes the rst stage of testicular
descent.
Under the inuence of testosterone the mesonephric ducts dierentiate to form the epididymis, rete testis, vas deferens, ejaculatory ducts
and seminal vesicles. Development of the prostate
gland between 12 and 19 weeks commences with
the emergence of buds from the urogenital sinus.
Figure 1.12 Differentiation of the male genital tract in response to anti-Müllerian hormone and
testosterone.
Figure 1.11 Development of the female lower
genital tract between 10 and 12 weeks.
Genital tracts / External Genitalia 9
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ese undergo branching morphogenesis to form
the ducts and glandular acini of the prostate
gland whilst the capsule and stroma are derived
from surrounding mesenchyme. Development of
the prostate relies on reciprocal inductive signalling between urothelium and mesenchyme and is
highly dependent on androgenic stimulation.
External Genitalia (Figure 1.13)
Unless they are exposed to androgens, the external genitalia of both males and females are destined to dierentiate passively down a female
pathway.
Female
e external genitalia dierentiate passively to
create the normal female genital phenotype. e
genital tubercle gives rise to the clitoris and the
urogenital sinus contributes to the vestibule of
the vagina. e urogenital folds persist as the
labia minora and the labio scrotal folds form the
labia majora.
Male
Until 12 weeks the male external genitalia share
the same undifferentiated morphology as the
female (Figure 1.14). Thereafter, the urethral
plate in the male advances further onto the
genital tubercle, expands in width and opens
out to create the urethral groove. Formation of
penile urethra has been likened to the action
of a zip, with the “closing zipper” drawing the
lateral margins of the urethral groove together
in the midline in a proximal to distal direction. Formation of the penile urethra is complete by 15 weeks, with the terminal portion
being formed by in-growth of ectoderm from
the tip of the glans. Virilisation of the male
genitalia is highly dependent on exposure to
androgens and the presence of the appropriate androgen receptors within the target tissues. The enzyme 5-alpha reductase plays a
key role in promoting virilisation by converting testosterone to its more potent derivative,
dihydrotestosterone.
Figure 1.13 Differentiation of external genitalia determined by androgenic stimulation in the male.
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Figure 1.14 Diverging pathways of differentiation from 12 weeks onwards. (Reproduced by kind
permission of Lawrence Baskin.)
Testicular Descent
Anti-Müllerian Hormone initiates the rst stage
of testicular descent by stimulating contraction
of the gubernaculum and anchoring the testis in
the inguinal region. e second stage is testosterone dependent and occurs around 25–30 weeks
when the gubernaculum draws the testis down
the inguinal canal into its nal scrotal position.
Descent of the testis is preceded by a protrusion
of the peritoneum (processus vaginalis). is normally closes spontaneously before birth or in the
rst few weeks of life but may persist to give rise
to a communicating hydrocele or inguinal hernia.
Figure 1.15 Fusion defect – bicornuate uterus.
Clinical Considerations
Female
Abnormalities originating from defective development of the paramesonephric ducts include:
absence of a Fallopian tube and hemiuterus,
absence (agenesis) of the upper vagina
(Rokitanskysyndrome) septate vagina and bicornuate uterus (Figure 1.15). Virilisation of the
external genitalia occurs in females with congenital adrenal hyperplasia who are exposed to
high levels of circulating androgens in utero. By
contrast to the external genitalia, the ovaries and
internal reproductive tract develop normally.
Male
Persistent Müllerian duct syndrome is characterised by bilateral undescended testes and the
presence of persistent paramesonephric duct
structures. Proximal and mid-sha forms of
hypospadias arise from incomplete closure of the
urethral groove and proximal hypospadias may
be accompanied by other features of inadequate
virilisation such as cryptorchidism and a persistent Müllerian utriculus. Virilisation defects can
result from a number of dierent mechanisms;
defects in androgen synthesis pathways, 5-alpha
reductase deciency and insensitivity of the genital tissues to androgens due to receptor and post
Genital tracts / Clinical Considerations 11
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receptor defects. Intrauterine exposure to environmental “endocrine disruptors” has also been
suggested as a possible factor but the evidence is
still largely lacking.
KEY POINTS
●
e genitourinary tract is commonly
aected in children with chromosomal
abnormalities.
●
e ureteric bud plays a pivotal role in
nephrogenesis and the embryological
development of the upper tract.
●
With the exception of the gonads, the
genital tracts of both sexes dierentiate
passively down a female pathway unless
actively switched down a male pathway
by the testis-determining gene (SRY).
●
Single-gene mutations have been identied in some inherited conditions of
the urogenital systems. However, the
conditions most commonly encountered in paediatric urology are sporadic or result from the interaction of
multiple genes.
FURTHER READING
Baskin L. Basic science of the genitalia
(Chapter). In: Docimo SG, Canning D, Khoury
A, Pippi Salle JL (eds), Textbook of Clinical
Paediatric Urology, 6th Edition. Boca Raton,
FL: Taylor & Francis, 2019: 1141–1149.
Baskin L, Shen J, Sinclair A, Cao M, Liu X, Liu
G, Isaacson D, Overland M, Li Y, Cunha GR.
Development of the human penis and clitoris. Differentiation. 2018 Sep–Oct;103:74–85.
Schoenwolf GC, Bleyl SB, Brauer PR, Francis-
West PH. Larsens Human Embryology.
Philadelphia: Elsevier Saunders, 2015:
375–428.
Thomas DFM. Embryology of cloaca and
genitourinary sinus malformations. Asian J
Androl. 2020 Mar–Apr;22(2);124–128.
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