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CONGENITAL ANOMALIES
Mllerian duct anomalies (MDAs)
Anomalies of the External Genitalia
Ambiguous genitalia/intersex anomalies
Chromosome: Why is
it important?
INTERMEDIATE MESODERM
BIPOTENTIAL GONAD
SRY
testis
sertoli
leydig
AMH
(-) MD
(-) uterus
ovary
granulosa
theca
(-) AMH
(-) T
DHT
follicles
MD
Estrogen
progesterone
Internal
Genitalia
Wolffian
Duct
Internal
Genitalia
External
Genitalia
Schematic diagram of testosterone biosynthesis in the Leydig cell of the testis and of th
mechanism of androgen action within target cells.
17HSD3, 17- hydroxysteroid dehydrogenase 3; 5aR2, 5a-reductase 2.
Indifferent Embryo
Genotype of embryo 46XX or 46XY is
established at fertilization
Weeks 1-6 sexually indifferent or
undifferentiated stage; that is genetically
female and male embryos are phenotypically
indistinguishable
Week 7 begins phenotypic sexual
differentiation
Week 12 female or male characteristics of
external genitalia can be recognized
Week 20 phenotypic differentiation is
complete.
Indifferent Embryo
Components which form the adult
female and male reproductive systems
are:
1. Gonads
ovaries or testes
2. Genital Duct Systems
Paramesonephric and Mesonephric
Ducts
3. External Genitalia
Summary of differentiation
In females, the mllerian ducts give rise
to the fallopian tubes, uterus, and
upper vagina, and the wolffian ducts
persist in vestigial form.
In males, the wolffian ducts give rise
to the epididymides, vasa deferentia,
seminal vesicles, and ejaculatory ducts,
and the mllerian ducts regress.
EMBRYOLOGIC DEVELOPMENT
OF THE UTERUS AND VAGINA
Wk 4
PronephrosDisappears
Wk 2-4
Mesonephros
Mesonephric duct forms at caudal end of
mesonephric tubule
Wk 5
WK 6
Embryology of Vagina
Derived paramesonephric ducts vs.
mesonephric ducts vs. urogenital sinus, or a
combination.
Most accepted, superior part derived fusion
paramesonephric , while inferior part arises
from urogenital sinus, BUT assumes the
inductor function of the mesonephric ducts
stimulate adequate
mullerian/paramesonephric development.
phallus
penis or
Male
Female
Genital
Tubercle
Urogenital
Sinus
Penile urethra
Vestibule of
vagina
Urethral fold
Penis
Labia Minora
Labioscrotal
fold
Scrotum
Labia Major
Role of Dihydrotestosterone
Differentiation depends indirectly on gonadal
secretion in male fetus.
Testosterone acts locally on the tubules but
not directly on the external genitalia.
Hormonal action is exerted by
dihydotestsoterone (DHT) formed from
testosterone by the 5 alpha reductase
enzyme.
DHT causes external genitalia to become a
penis and scrotum and induces development
of prostate
EMBRYOLOGIC DEVELOPMENT
OF THE UTERUS AND VAGINA
1. MDs (red area) fuse on the midline to form the
uterus
proximal part - duct gives rise to fallopian tube
wolffian ducts (green areas) regress
distal remnant of wolffian duct forms Gartner duct
mllerian ducts
wolffian ducts
EMBRYOLOGIC DEVELOPMENT
OF THE UTERUS AND VAGINA
2.
UVC
UGS
Embryology
mllerian ducts
wolffian ducts
Vertical fusion
fusion of the ascending
sinovaginal bulb with the
descending mllerian
system
fusion of the lower one third
and upper two thirds of the
vagina
Complete vertical fusion
forms a normal patent
vagina
incomplete vertical fusion
results in an imperforate
hymen.
Congenital abnormalities
Abnormalities of Mullerian duct
development:Absence/ incomplete
development of both
Abnormalities of Mullerian duct
development:Absence/ incomplete
development of one
Imperfect fusion
Prevalence
Population - 5%
Infertile women - 3%
Recurrent miscarriages - 5-10%
Late abortions/ immature deliveries 25%
Prevalence
Race: No racial predilection
Age: Anomalies may be diagnosed in infancy,
adolescence, or young adulthood.
Infants: Obstructed mllerian system
(mucocolpos);
Adolescents: Primary amenorrhea, mass
(hematocolpos), or delayed onset of
menarche;
Adults: Fertility problems and/or carrying
pregnancy to term
Pathophysiology
2 paired MDs ~ female reproductive tract. fallopian
tubes, uterus, cervix, and upper 2/3 of vagina.
ovaries and lower 1/3 of vagina~separate embryologic origins
not derived from mllerian system.
Pathophysiology
Ovaries & lower vagina-not derived
from mllerian system
Ovaries - germ cells
lower vagina - arises from sinovaginal bulb
Morbidity / Mortality
MDA - not associated w/ significantly
increased mortality
Increased morbidity - obstructed or partially
obstructed mllerian systems: hematosalpinx,
hematocolpos, retrograde menses, &
endometriosis
Fairly high association - MDAs & renal
anomalies such as unilateral agenesis.
Anomalies are found only when dedicated
renal imaging is performed after the mllerian
abnormality is discovered; most commonly
seek medical attention because of infertility &
repeated pregnancy loss.
Complications
Menstruation: spasmodic
dysmenorrhoea, Menorrhagia
Coital: dyspareunia
Infertility: 1/4 reproductive problems
Obstetrical: abortions, preterm labour,
malpresentation, obstructed labour,
contractions poor
Anatomy
MDAs
PREVIOUSLY: categorized most commonly
into 7 classes according to the American
Fertility Society (AFS) Classification
Scheme (1988) as follows:
Normal Uterus
Class I (hypoplasia/agenesis)
Class II (Unicornuate uterus)
Class III (Didelphys uterus)
Class IV (Bicornuate uterus)
Class V (Septate uterus)
Class VI (Arcuate uterus)
Class VII (Diethylstilberol associated
anomalies)
Based on similar
Classification into 3 groups:
embryonic development defects and clinical presentation
1. Agenesis of uterus/vagina:
Rokitansky-Kuster-Hauser Syndrome.
2. Defects in Vertical Fusion
(obstructive or non-obstructive)
3. Lateral Fusion defects (obstructive or
non-obstructive).
HYPOPLASIA/AGENESIS
includes entities - uterine/cervical agenesis or
hypoplasia
most common form: Mayer-RokitanskyKuster-Hauser syndrome (combined
agenesis of the uterus, cervix, and upper
portion of the vagina)
Vaginal anomalies-Cloaca malform, UG
sinus, Atresia
no reproductive potential
15% of primary
amenorrhea
Normal secondary
development & external
female genitalia
Karyotype 46-XX
Vaginal atresia
b, Congenital
cervical atresia
with complete
vaginal
agenesis
Hymen
originates from the embryonic vagina buds
from the urogenital sinus
a composite of vaginal epithelium and
epithelium of the urogenital sinus interposed
by mesoderm.
becomes perforated or forms a central
canal establishing a communication between
the upper vaginal tract and the vestibule of
the vagina
Imperforate Hymen:
The hymen represents the junction of the sinovaginal bulbs with the urogenital
sinus; hence it is formed form the endoderm of the urogenital sinus epithelium
Clinically:
Vertical fusion
fusion of the ascending
sinovaginal bulb with the
descending mllerian
system
fusion of the lower one third
and upper two thirds of the
vagina
Complete vertical fusion
forms a normal patent
vagina
incomplete vertical fusion
results in an imperforate
hymen.
Imperforate hymen
solid membrane interposed between the
proximal uterovaginal tract and the
introitus
vertical fusion defect
most frequent cause of vaginal outflow
obstruction
0.1% of infant girls
Clinical Presentations
asymptomatic patient (incidental finding)
primary amenorrhea
Abdominal pain
back pain.
Physical Exam
Abdomen
Flat
soft
(+) hypogastric pain on deep palpation
Physical Exam
Pelvic Exam
no vaginal opening
Rectal exam
good sphincteric tone
empty rectal vault
uterus cannot be
assessed due to
voluntary guarding
Imperforate Hymen
Hymenotomy
Procedure
Y shape incision
2, 10 and 6 oclock
position
Menstrual blood
suctioned
500ml reddish brown
blood
Packing with
vaselinized OS
Clinical Presentation
primary amenorrhea
cyclical lower abdominal or pelvic pain
back pain
urinary retention (37-60% of patients)
constipation
Palpable lower abdominal mass
Pelvic mass on bimanual rectal exam
distended, bluish membrane on introitus
Differential diagnosis
transverse vaginal septum
Rokitansky-Kster-Maier-Hauser syndrome
Diagnostics
Ultrasonography
reliable
Rapidly diagnose hematocolpos or
hematometrocolpos
Transrectal ultrasonography
Delineates complex anatomy
MRI
If a complex mass is suspected
Diagnostics
Other Tests:
Laparoscopy
recommended to evacuate pelvic and intraabdominal endometrial material generated
because of retrograde menstruation.
speculated to reduce the potential for
secondary endometriosis.
Diagnostic Procedures:
Complications
recurrent obstruction
ascending pelvic infection
Endometritis
Salpingitis
Tuboovarian abscess
2ndary endometriosis from retrograde
menstruation
advocate irrigation of the peritoneal cavity by
using a laparoscopic technique
Clinical Presentation
Neonate
bulging membrane between the
labia
membrane may be white distended
from trapped mucoid material
(maternal estrogen)
Severe cases, distention in the distal
vaginal tract extends proximally into
the uterus
A lower abdominal midline mass
Mucocolpos (collection of
secretion behind the hymen) lead to
UTI or bladder obstruction
A. Normal uterus
Unicornuate
uterus
Septate uterus
Bicornuate
uterus
Arcuate uterus
UNICORNUATE UTERUS
complete, or almost complete,
arrest of development of 1
mllerian duct
If the arrest is incomplete, as in
90% of patients, a rudimentary
horn with or without functioning
endometrium is present.
If the rudimentary horn is
obstructed, it may come to
surgical attention when presenting
as an enlarging pelvic mass.
If the contralateral healthy horn is
almost fully developed, a full-term
pregnancy is believed to be
possible (see didelphys uterus).
DIDELPHYS UTERUS
BICORNUATE UTERUS
partial nonfusion of the
mllerian ducts
The central myometrium
extends to level of
internal os (bicornuate
unicollis) or external os
(bicornuate bicollis).
Distinguished from
didelphys uterus
because of some
degree of fusion b/w the
two horns-horns of
bicornuate uteri not fully
developed; typically,
smaller than those of
didelphys uteri.
Some patients are
surgical candidates for
metroplasty.
excluding
septate uterus from differential diagnosis. This image is of
bicornuate bicollis 2 cervices are present. Bicornuate
uterus is distinguished from didelphys uterus because
some degree of fusion has occurred b/w lower uterine
segments (ie, they are fused, but cavities are not
communicating).
BICORNUATE W/ pregnancy
SEPTATE UTERUS
Muscular
Fibrous
Septate:
Normal external surface,
need laparoscopy to dx
Defect in canalization or
resorption of midline
septum between mullerian
ducts.
Septum can cause
infertility, recurrent
midtrimester loss
Tx: resection of septum
hysteroscopically or
hysteroscopic metroplasty
Septate Uteri
Bicornuate Uterus
ARCUATE UTERUS
Several million
Treated with diethylstilbestrol (DES; an estrogen
analog used to prevent miscarriage) 1945-1971
The uterine anomaly in offspring of as many as
15% of exposed to DES during pregnancy
fetuses - variety of abnormal findings
uterine hypoplasia and a T-shaped uterine cavity
abnormal transverse ridges, hoods, stenoses of the
cervix, and adenosis of the vagina
risk of vaginal clear cell carcinoma
Imaging findings are pathognomonic for this anomaly
T-SHAPED UTERUS
Classic configuration of the uterine cavity in a typical
diethylstilbestrol-exposed uterus
Uteri are typically hypoplastic.
Treatment
Vaginal septum
Uterine septum
Rudimentary uterine horn
Bicornuate uterus
Very troubling
parents
unconscious emotional
significance
impact of deformities on future
generations
Labial Adhesion
children
chronic inflammation - vulva
usually asymptomatic but
when introitus sealed
completely- Complications
Treatment topical 1%
estrogen cream (tid x 2 wk)
rare anomaly
homologous to ectopic scrotum
reported w/ renal agenesis or dysplasia
and the VATER (vertebral defects, anal
atresia, tracheoesophageal fistula,
esophageal atresia)
Clitoral duplication usually seen in
bladder exstrophy/epispadias complex
in
Clitoral hypertrophy
fetal exposure to androgens
result of congenital deficiencies of
adrenal enzymes -cortisol synthesis;
more rarely, idiopathic virilization or
exposure to progestational agents in
utero.
Although rare, by neurofibromas of the
clitoral corpora
TREATMENT:
degree of masculinization, Spence-Allen
technique- better results than technique
by Pelleren
Pelleren plication complicated by painful
engorgement of recessed corpora at
puberty
Interlabial masses
Urethral prolapse
Prolapsed ectopic ureterocele
Hydrocolpos or hydrometrocolpos
Sarcoma botryoides or rhabdomyosarcoma
Periurethral cyst
Interlabial masses
Vaginal Polyp
Hymenal Polyp
compatible w/ life
Mx: one of the greatest challenges of
pediatric surgery & urology
Devt of lower urinary tract, genital &
anorectal systems is correlated closely in
Consequently, abnormal embryological devt
can involve all 3 systems.
Intersex Conditions
Ambiguous genitalia
External appearance
Diagnosis
History- Familial Hx detailed
Physical Examination- Very meticulous
Lab Studies:
Logical workup in infants w/ambiguous
genitalia includes the ff:
Chromosomal analysis
Endocrine screening
Serum chemistries/electrolyte tests
Androgen-receptor levels
5-alpha reductase type II levels
Physical Examination
External genitalia examination
size & degree of differentiation of structures
position of urethral meatus
Labioscrotal folds may be separated or folds may be fused
at the midline-giving scrotum-like appearance
Rugose scrotal or labioscrotal folds w/ pigmentation
possible corticotropin levels as part of adrenogenital
syndrome.
Gonadal examination
Palpation of gonads is important
inguinal gonads palpable, diagnoses is gonadal , Turner
syndrome, & pure gonadal dysgenesis can be eliminated.
Impalpable gonads possibility of a severely virilized
pseudohermaphrodite w/ CAH.
Rectal examination
Rectal examination ~ internal mllerian structures.
The uterus
Diagnosis
Imaging Studies:
Renal/bladder ultrasound: bedside in NICU
UTZ; visualization of a neonate's adrenal
glands, may be enlarged in infants w/ CAH;
low sensitivity
adrenal glands in CAH- glands cribriform
appearance
help identify mllerian structures
In a neonate, findings of ambiguous genitalia,
enlarged adrenal glands, and evidence of a
uterus are virtually pathognomonic for
CAH.
Diagnosis
Genitography: ductal anatomy
catheter inserted into distal urogenital sinus
(urethra)
Contrast outlines internal ductal anatomy.
Findings indicate N urethral anatomy, an
enlarged utricle, a mllerian remnant in , a
common urogenital sinus, or an area of
vaginal & urethral confluence in neonates.
CT scan & MRI-usually not indicated
may help identify internal anatomy
Diagnosis
Procedure
s:
1. EL/gonadal biopsy-many advocate
laparoscopy
2. Diagnostic laparoscopy/gonadal
biopsy: rapid identification and
delineation -Biopsy-gonads w/
additional trocars
3. Histologic Findings: Analysis - biopsy
specimens identify ovarian tissue,
testicular tissue, ovotestes, or streak
gonads
TYPE I
Pseudohermaphrodite
phenotypic
TYPE I
Pseudohermaphrodite
Overall, CAH - most frequent cause in newborn~ 60% of intersex
cases
TYPE I
Pseudohermaphrodite
21-Hydroxylase deficiency
(CYP21)
21-hydroxylase deficiency
Mild virilization 46 XX
female
Despite the mild
Severe virilization 46 XX
female
This patient also has salt
wasting
Maternal androgens
TYPE II
Pseudohermaphrodite
heterogeneous group
characterized by intrauterine state of relative functional
androgen deficiency, an apparently normal 46 XY
karyotype
and either identifiable testes or evidence that testes were
present during fetal development
Ext genitalia usually female or ambiguous
in certain categories (e.g. testicular regression syndrome)
may appear as phenotypically male
The defect may be in
1. the gonad-leading to deficiency in androgens, MIS, or
both
2. end-organ -tissues unresponsive to androgens or MIS
lead to abnormal phenotype
Tumors, if they occur, are sometimes malignant
TYPE II
Pseudohermaphrodite
5-alpha-reductase deficiency
5-alpha-reductase deficiency
TYPE IV
True hermaphrodite
Background: Ovotestis-both ovarian follicles
and testicular tubular elements
found exclusively in - true hermaphroditism
usually compartmentalized-connective tissue
separating the ovarian from testicular
components
rarely intermixture of elements occur
This diagnostic nomenclature is applied
regardless of the peripheral karyotype
TYPE IV
True hermaphrodite
TYPE IV
True hermaphrodite
true hermaphroditism-ambiguous
genitalia at birth
s - as
majority affected have been reared
However, because of functioning N ovarian
tissue, most people w/ true hermaphroditism
experience breast devt at puberty, & 40% w/
a 46,XX peripheral karyotype menstruate
TYPE III
TYPE III
Mixed gonadal dysgenesis
Term~ dysgenetic pseudohermaphroditism
(DMP) to describe - bilaterally dysgenetic testes &
incomplete virilization of the internal sex ducts
& external genitalia
Federman - similarities in karyotype, gonadal histology,
& phenotype that this group shares w/ pxs w/ MGD & w/ true
hermaphroditism
.
these 2 groups of patients - defect in sex chromosomes
that causes AbN testicular differentiation thus incomplete
virilization - ambiguous genitalia.
Precisely defined, DMP is an intersex state - bilaterally
dysgenetic testes w/ persistent internal MD structures,
cryptorchidism, & incomplete external virilization.
A dysgenetic testis histologically demonstrates
immature and hypoplastic testicular tubules in a
stroma characteristic of ovarian tissue but that lacks
oocytes.
This stroma similar to streak gonads - helps explain the
similarities of these syndromes
TYPE III
Mixed gonadal dysgenesis
TYPE III
Mixed Gonadal Dysgenesis
major feature shared by MGD and DMP is the risk of gonadal
malignancy when a Y chromosome is present in the karyotype.
~ 25% of gonads, including streak gonads malignant change, most
common gonadoblastoma, - gonadectomy before adulthood. Early
gonadectomy appears wise (1st decade)
seminomas and embryonal cell carcinomas
Gender assignment under debate
Glassberg, - no case reported of a tumor developing in fully descended
testis in MGD or DMP assign gender if sufficiently virilized
TYPE III
Pure gonadal dysgenesis
TYPE III
Pure gonadal dysgenesis
Workup &Treatment
Lab Studies:
Logical workup in infants with ambiguous
genitalia includes the following:
Chromosomal analysis
Endocrine screening
Serum chemistries/electrolyte tests
Androgen-receptor levels
5-alpha reductase type II levels
17-OHP levels
Summary definitions
True hermaphrodite: ovarian/testicular
tissue and ext. genitalia not normal
Male Pseudohermaphrodite: testes,ext.
genitalia female
Female Pseudohermaphrodite: ovaries,
ext. genitalia masculine characteristics
Male Pseudohermaphrodite
Androgen insensitivity syndrome
5 Alpha reductase deficiency
Testosterone biosynthesis defects
Female Pseudohermaphrodite
Congenital adrenal hyperplasia
Elevated androgens- circulation: drugs,
tumor
Clinical approach
Medical emergency
Congenital adrenal hyperplasia:
Electrolytes, 17OH progesterone
Team of experts
Assign sex
Phallus length
Psychological support
Imaging Studies:
Renal/bladder ultrasound
Genitography
CT scanning and MRI are usually not
indicated but may help identify internal
anatomy.
Procedures:
Exploratory laparotomy/gonadal biopsy
Diagnostic laparoscopy/gonadal biopsy
Histologic Findings: Histologic
analysis of gonadal biopsy specimens
may identify ovarian tissue, testicular
tissue, ovotestes, or streak gonads.
Treatment
Medical Care: depends on etiology & indicated for
conditions associated w/ ambiguous genitalia, including
CAH
Supplemental hormone therapy may be implemented if
gonadal function is compromised.
Surgical Care:
In virilized , surgical procedure - feminizing
genitoplasty & includes vaginoplasty and clitoroplasty
Medications
Glucocorticoids -- anti-inflammatory
properties , cause profound and varied
metabolic effects
modify immune response
Children w/ CAH require
corticosteroid replacement for
survival Replacement also reduces
the production of corticotropin &,
therefore, the overproduction of
androgens.
Drug Name
Adult Dose
Pediatric Dose
Contraindications
Interactions
Pregnancy
Precaution
s
Treatment
Consultations:
Geneticist/genetic counselor
Endocrinologist
Surgeon
Obstetrician/urologist
Psychologist
Medical/Legal Pitfalls:
Treatment for intersex states is
controversial.
Moratorium: on gender reassignment &
genital surgery until studies have been
completed on the long-term effects of
such surgery.