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Daniel EMBRYOLOGY OF GUT MALFORMATIONS 2023.pptx
1. Embryology of GUS
malformations
Daniel Bizuwork Y-1 General surgery resident
Moderator - Dr. Addisu M.D, Assistant Professor of Pediatric
Surgery
Aug 30, 2023
2. Presentation outline
Objectives
Introduction
Embryology of the urinary system
Common urinary system malformations
Embryology of the genital system
Common genital system malformations
Summary
References
2
3. Objectives
• To understand the embyologic origin of the urinary system
• To understand the embryologic origin of the genital
system
• To be familiar with important urogenital malformations
• To comprehend the embryologic basis of common
urogenital malformations
3
5. Embryology of the urinary system
Kidney Systems
Pronephros
• 4th week
• 7-10 solid cell groups
Mesonephros
• Intermediate mesoderm of upper thoracic & upper lumbar L3
• Appear at 4th week, Disappear at 8th week
Metanephros
• Definitive Kidney, appear at 5th week
• excretory unit from metanephric mesoderm
5
6. Embryology of the urinary system
• Pronephros
• Appears in week 4 as a cluster
of a tubule and a few cells
(nephrotomes)
• Develops in nephrogenic
cords in the cervical region
• Rudimentary and
nonfunctional
• Degenerates by the end of
week 4
6
7. Embryology of the urinary system
• Mesonephros
• Week 5, regresses by week 10.
• Consists of:
• A longitudinal mesonephric duct
(also called the wolffian duct)
• A series of tubules coming off that
main duct, growing anteriorly
toward the aorta
• Mesonephric tubules ->Bowman
capsules
• Blood flows down the aorta →
glomerular capillaries
• Filtered through Bowman capsule
• Filtrate travels down the
mesonephric tubule →
mesonephric duct → cloaca →
allantois
• Mesonephros is present only from
weeks 5–10
• The mesonephric ducts persist in
males -> male reproductive system.
7
9. Embryology of the urinary system
• Metanephros
• The permanent kidney, 5th week
• Metanephric blastema -> nephrons
• Releases GFs that stimulate the
development the ureteric buds
• Reciprocal induction
• Ureteric buds grow toward and
invade the metanephric blastema
• Elongating stalk of the ureteric bud
develops into the ureter
• Within the metanephric blastema,
the ureteric buds undergo a series
of branchings to form the:
• Renal pelvis
• Major calyces
• Minor calyces
• Collecting tubules
9
10. Embryology of the urinary system
• Metanephric mesodermal cap - Mesoderm from the metanephric blastema
sitting “on top of” the developing collecting ducts
• Bowman capsule: forms off of the growing end of the metanephric tubule
• Glomerular capillaries: Develop from the common iliac arteries and become
associated with Bowman capsule at the end of the metanephric tubules →
begin creating “urine”
• Nephrons are formed until birth.
• Nephron maturation continues after birth.
10
11. Embryology of the urinary system
• Position of the kidney and changes in vascularization
• The kidneys are initially located in the pelvic region.
Diminution of body curvature and
Growth of the body in the lumbar and sacral regions
• As the kidneys ascend, the original blood supply degenerates.
• New vessels (higher up) develop off the aorta and invade the kidneys,
becoming the mature renal arteries.
• If the original vessels fail to regress, they may persist as additional renal
arteries or veins.
11
13. Embryology of the urinary system cont’d
Bladder and Urethra
• During 4 to 7 weeks of development cloaca divides by urorectal septum into
anal canal posteriorly & urogenital sinus anteriorly
Vesical part
– Forms most of the bladder and is continuous with the allantois
Pelvic part - gives rise to
– Male - prostatic and membranous urethra.
– Female - urethral and paraurethral glands.
Phallic part
– It is flattened from side to side, and as the genital tubercle grows, this
part pulled ventrally.
13
18. Anomalies of
number
• Renal agenesis
• Renal
hypoplasia
• Supernumerary
kidneys
Renal cystic
diseases
• Renal dysplasia
and multicystic
kidney - ADPKD
& ARPKD
• MCDK
• Simple (solitary)
renal cyst
Anomalies of
form and fusion
• Horseshoe
kidney
• Crossed fused
renal ectopia
Congenital Renal Anomalies 18
Anomalies of ascent
• Renal fusion and renal ectopia
Anomalies of renal rotation
• Ventral , ventromedial, dorsal,
lateral
Anomalies of renal vasculature
• Aberrant, accessory or multiple
vessels, RAA, Renal AVF
Renal collecting system anomalies
• Bifid pelvis,Calyceal diverticulum,
Hydrocalycosis, Megacalycosis,
infundibulopelvic stenosis
19. Renal agenesis
URA
• 1 in 1000, M>F, Lt>Rt
• Compensatory hypertrophy
Embryologic cause
• Failure of the UB to develop from the
WD , Failure of reciprocal induction
• VACTERL
• Prenatal u/s or incidental
BRA- incidence - rare?? , M>F
• Potter syndrome BRA+ oligohydramnios
• Pulmonary hypoplasia
• incompatible with life
Associated malformations
• Absent ureter - 60% in URA
• UPJO,UVJO, UV reflux - 11,7,30 %
Genital abnormalities
• UDT(43%), Penile agenesis,
hypospadia
• Clitoral hypertrophy,uterine &
vaginal hypoplasia/agenesis
• inguinal hernia repair - Vas
Prognosis
• Poor - 40% - stillbirth
19
20. Multicystic Dysplastic Kidney
• Nonheritable
• Multiple cysts of varying sizes
• No identifiable normal renal
parenchyma.
• the 2nd most common cause of an
abdominal mass in a newborn,
after hydronephrosis
• 2 types - Infundibulopelvic &
hydronephrotic
• Etiology
• Obstructive theory
• Ureteric bud theory
• Dx - Prenatal u/s
• Incidence - 1 in 1k-4k live births
• Contralateral UPJO 3-12%,VUR 18-43%
• Benign - 40% spontaneously involute
• No significant association with
hypertension and malignancy
• Dx - U/S - randomly distributed cysts,
Abnormal echogenicity of r. parenchyma
• VCUG - To look for VUR - 15%-30%
• Rx - Follow up u/s q6mo for 1st 18-24
mo
• Nephrectomy - htn, cyst rupture
20
22. Duplication of the ureter 22
• It is the most common ureteral abnormality
• Congenital condition in which the ureteric bud splits (or arises
twice), resulting in two ureters.
• Occurring in 1 % of the population, M:F -1:2
23. Duplication of the ureter cont’d
• 2 types
• Partial - The two ureters drain into
the bladder via a single common
ureter.
– Rarely clinically significant.
• Complete - Ureteric bud arises twice
rather than splitting
– The two ureters drain separately
one ureter opening normally into
the bladder
• Other being ectopic, ending in the
vagina, the urethra or the vulval
vestibule.
• Ureteral triplication, quadriplication
- rare
• Incontinence, infection,
obstruction
• Associated with ureteral
ectopia and ureterocele
23
24. Obstruction of the UPJ
• Common congenital abnormality of
the ureter.
• More common in boys
• Most cases are unilateral and on
the left
• Partial obstruction at the junction
of the renal pelvis and upper
ureter.
• Failure to recanalize adequately -
intrinsic UPJ obstructions.
• Extrinsic - Fibrosis, Defective
innervation, interruption of smooth
muscle continuity
• Secondary - VUR - 14%
24
25. Obstruction of the UPJ cont’d
• Increased hydrostatic pressure
• In 20–30% of patients, the ureter is
draped over a lower-pole vessel
– producing an extrinsic UPJ
obstruction.
• Abdominal mass, UTI
• Associated anomaly-VACTERL
• Antenatal Dx - confirm 14 days
postnatal
• Ix - U/S, VCUG, MRU, Diuretic
isotope renogram
25
26. Posterior urethral valve
• PUVs are the most common cause of
BOO in boys
• incidence- 1 in 5,000 to 8,000 male births
• Etiology - Unknown
• Abnormal integration of the
mesonephric duct into the cloaca
• Clinical features
• delayed voiding or a reduced urinary
stream,respiratory distress
• Failure to thrive, lethargy, poor feeding,
urinary tract infection (UTI), and
hydronephrosis
• a palpable walnut-sized bladder
• Unilateral VUR is present in
25% and bilateral VUR in 25%
of infants with PUV
• Dx - Prenatal U/S, Definitive Dx
is by VCUG
• Rx - Surgery- cutaneous
vesicostomy (Temporary
urinary diversion), Valve
ablation (Endoscopic)
26
27. Hypospadia
• a urethral meatus that opens onto the ventral surface of the penis
• Anterior(65-70%) - distal most common, middle(10-15%), posterior(20%)
• Incidence - 0.8 and 8.2 per 1,000 live male births
• Etiology
• A defect in the androgen stimulation of the developing penis
• diminished response to hCG & delayed maturation of the HPA
• Clinical significance
• Ventral location of the meatus - difficult urination
• Associated with chordee, meatal stenosis, inguinal hernia and cryptorchidism
• Ventral curvature with chordee - Painful erection - Psychosexual issues
• Rx - Urethral reconstruction, Hormonal therapy
• NO Circumcision!
27
29. Embryology of the genital system
• Chromosomal sex → determines gonadal sex → determines phenotypic sex
• Up until 6 weeks of gestation, sex development is identical and nonbinary;
developing structures include:
• Nonbinary, bipotent, undifferentiated gonads
• Mesonephric ducts (also known as wolffian ducts)
• Paramesonephric ducts (also known as müllerian ducts)
• Urogenital sinus
• The genital tubercle, genital swellings, and genital folds
• In general, female organs and structures are the “default” phenotype if
specific genes and hormones are not present to stimulate male differentiation
29
30. Embryology of the genital system
• Primitive sex cords.
– Indifferent gonad.
– Some of the PGCs are surrounded by cells of the primitive sex cords.
– Primordial germ cells form the testis or medullary cords.
• The cords break up to give rise to tubules of the rete testis.
• Interstitial Leydig cells,
– Derived from the original mesenchyme of the gonadal ridge
– Begin production of testosterone by 8th week
– Able to influence sexual differentiation.
30
32. Embryology of the genital system
• Genital Ducts -Indifferent Stage
Initially
• Both male and female embryos
have two pairs of genital ducts:
• Mesonephric (Wolffian) ducts
– The mesonephric ducts open
into the urogenital sinus on
either side of the sinus tubercle.
– Genital ducts in the male Genital
ducts are stimulated to develop
by testosterone
.
• Paramesonephric (mullerian) ducts
– longitudinal invagination of the
epithelium on the anterolateral
surface of the urogenital ridge .
– In the midline, it comes in close
contact with the
paramesonephric duct from the
opposite side.
– The caudal tip of the combined
ducts projects into the posterior
wall of the urogenital sinus.
– Where it causes a small
swelling, the sinus tubercle.
32
33. Embryologic development of the bipotent gonads
• A portion of the intermediate
mesoderm covering the anterior
portion of the nephrogenic cords →
known as the gonadal ridge
• Epithelial cells in the gonadal ridge:
• Proliferate and condense
• Penetrate into the mesenchyme to
form the primitive sex cords
• These cells will become the stromal
cells:
• Sertoli and Leydig cells in males
• Granulosa and theca cells in females
• Primordial germ cells:
• Will differentiate into spermatozoa
or oocytes
• Originate in the epiblast
• Migrate to the yolk sac → through
the allantois (umbilical cord) →
along the dorsal mesentery of the
hindgut → genital ridges
• Germ cells invade the gonadal
ridges by approximately 6 weeks
• Developing sex cords associate
with migrating primordial germ cells
to form gonads.
33
35. Descent of the Testes
• Passage through the abdominal
wall is via the inguinal canal..
• Entry - deep (internal) inguinal ring.
• Exit - superficial (external) ring near
the pubic tubercle
• 2 structures- Gubernaculum & CSL
• 2 hormones- Testosterone & INSL-
3
• others - MIF, CGRP,EGF,Descendin
• the gubernaculum undergoes two
phases: INSL3 - outgrowth and
regression
• Normally
– Testes reach the inguinal region by
12 wks
– Migrate through the inguinal canal
by 28 wks
– Reach the scrotum by 33 weeks.
• Blood supply retained from the aorta
• Processus vaginalis, muscular and
fascial layers - form the inguinal canal.
• The canal is obliterated at birth or
shortly thereafter
35
37. Male External Genitalia
• Under the influence of androgens
• Characterized by rapid elongation of the genital tubercle-
phallus.
• During this elongation lateral walls of the urethral groove.
– Extends along the ventral aspect of the elongated phallus
– But does not reach the most distal part, the glans.
– With further development, they move caudally, and each
swelling then makes up half of the scrotum.
– The two are separated by the scrotal septum.
37
38. Female External Genitalia
• Estrogen stimulate development of the external genitalia of the
female.
• The genital tubercle elongates only slightly and forms the clitoris.
• Urethral folds do not fuse, as in the male, but develop into the
labia minora.
• Genital swellings enlarge and form the labia majora.
• The urogenital groove is open and forms the vestibule.
38
40. Common reproductive system malformations
• Gartner duct cysts:
• benign cysts that can be seen on either side of female reproductive
organs (typically the upper vagina). These cysts represent remnants of
the mesonephric ducts and are usually asymptomatic.
• Müllerian anomalies:
• abnormal fusion of the müllerian/paramesonephric ducts can result in a
variety of uterine, cervical, and vaginal anomalies. Individuals are often
asymptomatic, though they may present with infertility or issues related to
menstruation.
40
41. Disorders of sexual development (DSDs)
• Congenital adrenal hyperplasia (CAH) 46XX karyoype
• Increased formation of male sexual hormones (androgens) with virilization
of the external female genitals. Characterized by low levels of cortisol,
high levels of ACTH, and adrenal hyperplasia.
• Type I - IV
• Androgen insensitivity syndrome (AIS)
• Mutations in the androgen receptors cause partial or complete resistance
to testosterone
• 46,XY karyotype , Testis persent internally
• Elevated testosterone, some converted to Estrogen peripherally
• no sexual hair and have normal-appearing external female genitalia
• assigned female gender at birth and will present at puberty with
amenorrhea
41
42. Disorders of sexual development (DSDs)
• Aromatase deficiency: inability to convert testosterone to
estrogen, primarily causing virilization
• 5α-reductase deficiency: autosomal recessive disorder that
impairs conversion of testosterone to DHT
• Pure gonadal dysgenesis: nonfunctional gonads.
• Klinefelter syndrome: 47,XXY or 48,XXXY
• Turner syndrome: 45,X0
• Ovotesticular disorder of sex development (formerly called
"true hermaphroditism") 46XX, SRY translocation ,4XY
42
43. References
1. Langman’s Medical Embryologly-13th edition
2. Ashcrafts Pediatric Surgery 6th edition, 2014
3. Campbell and walsh urology 11th edition
4. Netter's atlas of human embryology
5. Uptodate
6. Pictures from Pinterest
43
Purpose unclear, though may be a “scaffold” off which the next structure (the mesonephros) develops
Mesonephros - Develops lower, in the thoracolumbar region
Connects with the cloaca at the caudal end of the primitive gut tube
Small glomerular vessels grow posteriorly off the aorta toward the mesonephric tubules, forming primitive renal corpuscles:
Mesonephric tubules grow around the glomerular capillaries, forming Bowman capsules (though these will ultimately regress).
Mesonephros -> Primitive urinary system
Cells in the intermediate mesoderm in the pelvic region begin to differentiate into a structure called the metanephric blastema, which ultimately becomes the cells making up the nephrons
Ureteric bud- an outpouching off the caudal portion of the mesonephric duct
Elongates, forming the tubular system of the nephrons → becomes known as the metanephric tubule, The metanephric tubule fuses with the collecting tubule, creating 1 continuous system.
Become associated with Bowman capsule at the end of the metanephric tubules → begin creating “urine” (Note: True waste products from the fetus are removed via the placenta.
(Note: True waste products from the fetus are removed via the placenta.
Metanephric tissue cap covers each collecting tubule
Under the inductive influence of the tubule the renal vesicles give rise to small S-shaped tubules.
Capillaries grow into the pocket at one end of the S and differentiate into glomeruli.
As the caudal portion of the body grows downward, the relative location of the kidneys “ascends” into the upper quadrants of the abdomen
This ascent of the kidney is caused by:-
Diminution of body curvature and
Growth of the body in the lumbar and sacral regions
The kidney and the renal pelvis normally rotate 90 degrees ventromedially during ascent so that the calyces face laterally and the pelvis points medially.
Malrotation is frequently associated with turner syndrome.
URA 1 in 1k, common boys>girls, Left kidney often absent - compensaory hypertrophy
, Absence of a hemitrigone implies the ub failed to form properly. A normal trigone with some evidence of a ureter suggests involution of a MCDK
Zinner’s syndrome - 1st case report from Eth. triad of URA+Ipsilateral seminal vesicle cyst+ Ipsilatoral ejaculatory duct obstruction.
These kidneys have no function by definition, and usually the contralateral kidney is normal and exhibits compensatory hypertrophy. Only unilateral involvement is compatible with life. The kidney often does not have a reniform appearance, and it typically associated with an atretic ureter with no connection between glomerulus and calyces. Typically, the kidney has the appearance of a bunch of grapes, with little stroma between the cysts. Renal size is highly variable, ranging from a small nubbin of tissue to a big mass that fills the abdomen
Ureteric bud theory - abnormal interaction between the ureteric bud and metanephric mesenchyme. Mutations in genes
such as EYA1, SIX1, WNT, WT-1, GNF, AT2, and PAX2. Mackie GG, Stephens FD. Duplex kidneys: a correlation of renal dysplasia
with position of the ureteral orifice. J Urol 1975;114:274
Histopathology- low cuboidal epithelium, surrounded by collars of spindle cells & filled with proteinaceous fluid
Normally the lumen of the ureteral bud solidifies with ureteral lengthening and later recanalization.
At 5 to 6 weeks’ gestation, the orifice of the mesonephric duct migrates from an anterolateral position in the cloaca to Müller’s tubercle on the posterior wall of the urogeni_x0002_tal sinus, occurring simultaneously with division of the cloaca.
When the insertion of the mesonephric ducts into the cloaca is too anterior, normal migration of the ducts is impeded, and the ducts fuse anteriorly, resulting in abnormal ridges, which become the PUV.
Remnants of the mesonephric duct normally remain as small distinct, paired lateral folds termed the inferior urethral crest and plicae colliculi.
respiratory distress secondary to pulmonary hypoplasia may be the primary manifestation of PUV
a palpable walnut-sized bladder, secondary to the hypertrophic detrusor muscle
This defect can occur from deficient androgen production by the testes and placenta, from failure
of testosterone to convert to dihydrotestosterone by the
5α-reductase enzyme, or from deficient androgen recep_x0002_tors in the penis.
Sex differentiation from the mesonephric (wolffian) and paramesonephric (müllerian) ducts:
In females, the mesonephric ducts regress while the paramesonephric ducts persist. The paramesonephric ducts remain open to the intraembryonic coelom (the eventual peritoneal cavity) near the gonads, and the inferior/medial ends fuse into a common body in the midline, forming the uterus and upper vagina.
In males, the mesonephric ducts are closely associated with the gonads; they enter the urogenital sinus separately on each side becoming parts of the ejaculatory system, while the urogenital sinus becomes the bladder and prostate.
Male development starts as a result of the presence of the sex-determining region of the Y chromosome gene (SRY gene):
Produces SRY protein (also known as testis-determining factor [TDF])
SRY/TDF stimulates the differentiation of the bipotent gonad into testes by stimulating stromal cells to differentiate into:
Leydig cells → secrete testosterone
Sertoli cells → secrete müllerian inhibitory factor (MIF) (also called antimüllerian hormone (AMH))
Seminiferous tubules
Testosterone:
Stimulates differentiation of the wolffian/mesonephric ducts into:
Epididymis
Vas deferens
Seminal vesicles
Ejaculatory ducts
Is converted to dihydrotestosterone (DHT) by 5α-reductase → stimulates development of:
The prostate from the urogenital sinus
External male genitalia
MIF → causes regression of the müllerian/paramesonephric ducts (which develop into internal female structures)
Primordial germ cells differentiate into sperm.
The process of differentiation is largely completed by 12 weeks of gestation.
The testes develop retro peritoneally in the abdominal region
Must move caudally and pass through the abdominal wall to reach the scrotum.
Processus vaginalis - The peritoneum of the abdominal cavity forms an evagination-
DSDs are a group of conditions characterized by atypical sexual development in an individual, which may involve abnormalities in the structure and/or function of the internal reproductive organs and/or external genitalia.
1 21hydroxylase deficiency - 21 OHD gene - on short arm of chr-6
Type 1 Nonsalt wasting, 2 -saltwasting/classic type 3- chr-8 4- severe salt wasting, ONLY on e to be found in both genders.
