Practical Approach to Imaging Children with Ambiguous Genitalia

Practical Approach To Imaging Children With Ambiguous Genitalia
Govind B. Chavhan MD, Dimitri Parra MD, Kamaldine Oudjhane MD, Stephen Miller MD, Paul Babyn MD
Department of Diagnostic Imaging, The Hospital For Sick Children, University of Toronto, Canada
INTRODUCTION
IMAGING OF AMBIGUOUS GENITALIA
Correct and appropriate gender assignment in patients with ambiguous genitalia is necessary for the child’s healthy physical and
psychological development. Workup of these patients is best accomplished via a coordinated approach by pediatric endocrinologist,
geneticist, urologist and radiologist to arrive at timely diagnosis and proper management. Imaging has an important role to play in
accurately demonstrating anatomy and possible effects on other organs (1).
In this review we discuss currently used classifications of confusing conditions causing ambiguous genitalia, and the role of imaging
modalities like ultrasound, genitogram and MRI. Finally we provide a simplified approach towards workup and discuss risk of
development of cancer in these children.
Mixed gonadal dysgenesis
ULTRASOUND:
Ü Primary modality, quick, and should include inguinal, perineal, renal and adrenal regions
Ü Establishes presence or absence of gonads and Mullerian derivatives
Ü Easy to find uterus and ovaries in neonatal period as they are prominent under influence of maternal hormones
Ü Identification of only one ovary in 40% and neither ovary in 16% cases has been seen in normal patients (5)
Female pseudohermaphrodite:
EMBRYOLOGY
a
The embryology of sexual differentiation is quite complex. Even though the chromosomal basis for sex is determined at conception,
internal structures are undifferentiated up to six weeks of gestational age. Three important precursor components of genital system are
germ cells, genital ridge and two sets of internal sex ducts: the Mullerian/paramesonephric ducts and Wolffian/mesonephric ducts (2). At
approximately six week fetal age, the genital ridge becomes either gonad: ovary or testis. Germ cells populate undifferentiated gonads.
Testicular development is guided by testes determining factor/substance (TDF/TDS), which is encoded by SRY located on short arm of
Y-chromosome. Under influence of TDF germ cells in the genital ridge differentiate into Sertoli cells (which secrete Mullerian inhibiting
substance/factor (MIS/MIF)) and Leydig cells (which produce testosterone). MIF causes complete regression of Mullerian ducts while
testosterone promotes maturation of spermatogonia and regulates development of the male phenotype by paracrine and endocrine
actions. By paracrine action, the Wolffian duct develops into epidydimis, vas deferens, ejaculatory duct and seminal vesicles.
In the absence of the Y chromosome gonads differentiate into ovaries at around 11-13 weeks. Ovarian hormones are thought to play no
role in female phenotype differentiation. Absence of MIF leads to persistence of Mullerian structures, which develop into Fallopian tubes,
uterus, cervix and upper vagina. Due to absence of testosterone, Wolffian ducts involute.
Undifferentiated external genital structures consist of the urogenital tubercle, urogenital swelling and urogenital folds. These structures
develop into the glans penis, scrotum and the shaft of penis in male respectively. In female they develop into the clitoris, labia majora and
minora respectively (2).
Overview of normal reproductive system development
Chart I:
Reproductive system precursors
In absence of
Y-chromosome
TDF from
Y-chromosome
Ova
Sertoli cells Leydig cells
Testes
Ovary
TDF
MIS
a
b
Mullerian
ducts
Wolffian ducts
Uterus
Fallopian tubes
Upper vagina
Epidydimis
Vas deferens
Seminal vesicles
Ejaculatory duct
Ü
Ü
Ü
Enlarged adrenal glands showing normal corticomedullary differentiation with measurement of single limb length >20mm and width
>4mm is suggestive of congenital adrenal hyperplasia (1)
Normal sized adrenal glands does not exclude the diagnosis of CAH (6, 7)
‘Cerebriform appearance’ is reportedly specific for CAH (8)
The conditions causing ambiguous genitalia can be classified on pathophysiological basis as disorders of chromosomal, gonadal
and phenotypic sex origin. On the basis of gonadal histology the disorders can be classified broadly into four groups- female
pseudohermaphrodite, male pseudohermaphrodite, true hermaphrodite and gonadal dysgenesis (1). The salient features are discussed in
Table 1 and important imaging features are highlighted.
1. Genotype/ Karyotype
2. Gonads
46XX, SRY/TDF gene
negative
Ovary only
3. Phenotype
Ambiguous, from mild clitoral
enlargement to complete
virilization
4. Causes
1. Congenital adrenal
hyperplasia.
2. Transplacental androgen
exposure
5. Types
6. Diagnostic Features
7. Usual
Gender assignment
8.Others features
Six types of CAH. First 4 are
virilizing
Presence of virilised external
genitalia, non-palpable gonads
and presence of Mullerian
structures on imaging and
raised 17-OH -Progesterone
Female
60-70% of neonatal cases of
ambiguous genitalia
Data from references- 1, 3, and 4
46XY
Testes only
46XX (60-70%), 46XY,
46XX/XY- mosaic
Both ovarian and testicular
tissues, Ovary+testes,
Ovary+ovotestes, Bilat
ovotestes, Ovostestes+ testes.
Uterus is almost always present
Variable. Female with
clitoromegaly to male with
hypospadias, bifid scrotum
Variable degree of
feminization, Ambiguous
genitalia, small phallus,
variable labio-scrotal fusion
1.Inborn error of testosterone
Genetic
biosynthesis
2. Leydig cell aplasia/
hypoplasia
3. 5 alpha- reductase deficiency
4. Androgen insensitivity
syndrome(AIS)
5. Isolated MIF activity
deficiency
AIH can be
-1. complete (Morris),
2. incomplete (Reifenstein) or
3. mild (Kennedy)
Normal/raised testosterone,
good testosterone response to
HCG injection and absence
of mullerian structures on
imaging
Complete AIS- female
Incomplete AIS- depending
on degree of virilisation but
usually female
Most diverse and difficult to
diagnose group
Presence of both ovarian and
testicular tissue
Pure
45XY 45XO Mosaic
Variable 46XX, 46XY 45XO
Testes + streak gonad (Testes
with Sertoli and Leydig cells,
No germinal cells)
Bilateral streak gonads
Variable Ambiguous or female
Female. Sexual infantilism
and primary amenorrhoea at
puberty
Genetic
Genetic
--
1. 46XX, 46XY presents with
primary amenorrhoea and
delayed secondary sexual
characters
2. 45XO with with typical
Turner syndrome appearance
Testes one side & streak gonad Streak gonads with
on other with ambiguous
underdeveloped mullerian
genitalia
derivatives
Rare accounting for less than
10% cases
High cancer risk
Figure 4: Mixed Gonadal Dysgenesis. This child presented with ambiguous genitalia with perineal hypospadias and labial fusion. Normal infantile
uterus was seen (A). Morphologically appearing testis was seen anterolateral to the urinary bladder on the right side (B). Morphologically appearing
ovary with cystic areas was seen on left side (C). There was another gonadal tissue on the left side anterolateral to the urinary bladder (D). This tissue
had a cystic area within it. There was a long phallus buried under the skin (E). Genitogram (F) showed normal vagina with uterus (arrow) on top of it.
Biopsy of the right gonad revealed testicular tissue, left sided morphologically ovarian gonad showed fallopian tube and epidydimis without any
ovarian tissue, and left gonadal tissue anterolateral to the bladder showed dysgenetic gonads with primitive sex cord components.
impression
Ü Is important to examine all perineal orifices and insert catheter for short distance into orifice to preserve morphological
appearance
Ü Presence of hydrocolpos/hydrometrocolpos with ambiguous genitalia with two perineal orifices (one of which is anus)
confirm presence of a urogenital sinus malformation as a consequence of virilisation of the fetus (1)
b
c
Figure 2: Male Pseudohermaphrodite. This teenage phenotypic female presented with amenorrhoea and prominent labioscrotal folds giving some
degree of genital ambiguity. Uterus and ovaries were not present in the pelvis (A). Right (B) and left (C) testes were seen in the inguinal canals.
Genotype was 46XY. This was a case of incomplete androgen insensitivity (Reifenstein syndrome) with some degree of ambiguity to genitals.
Complete androgen insensitivity is called Morris syndrome where child has female external genitals from birth.
No sexual ambiguity
neonatally.
Female
High cancer risk
Figure 5: Genitogram in complex urogenital sinus anomaly. This child had genital
ambiguity. Contrast injection through an orifice just below the phallus opacified a
tract (arrows), presumably urethra and a triangular pouch. Contrast then refluxed into
urethra and bladder anteriorly and vagina posteriorly from the triangular pouch. There
was another tract coming from the triangular area superior to the cannulated one and
opening at the tip of phallus (arrowheads).
Chart II:
True Hermaphrodite:
b
c
d
Palpable Gonads
No palpable Gonad
Confirmed on US
as Testes
No Uterus / Ovaries
Testes seen Intrabdominally
Uterus seen
No ovary or other
gonad
Uterus & Ovaries
seen
Extra gonad seen
Male pseudohermaphrodite
Streak Gonad
Persistent Mullerian
duct Syndrome
No Testicular Tissue
Ovary or
Ovotestes
Female
Pseudohermaphordite
Mixed Gonadal
Dysgenesis
Only uterus seen
Search for gonads by
MR, Venography,
Laparoscopy &
confirmed by biopsy
Ovaries
Streak Gonads
True Hermaphrodite
Uterus +
streak gonads
Pure Gonadal Dysgenesis
* Structure sonographically appearing like testes or ovary on imaging may be dysgenetic. Structure appearing like ovary
may represent Fallopian tube, epidydimis or combination of both. Biopsy confirmation may be required.
Ü As 20-30% of children with XY pure gonadal dysgenesis and 15-20% with mixed gonadal dysgenesis develop a gonadal
MRI
Ü Multiplanar capability and superior tissue characterization by means of T1 and T2-weighted sequences can provide
detailed anatomical information, however, not widely used yet
Ü MRI useful in evaluation of ambiguous genitalia, with MR depiction of uterus possible in 93%, vagina in 95%, penis in
100%, testes in 88%, and ovary in 74% cases (11)
Ü For evaluation of intrapelvic structures, MR and US are considered equally sensitive. For evaluation of gonads, MR is more
sensitive than US (12)
Ü Ectopic gonads, both testes and non-cystic immature ovaries, display medium signal intensity on T1-weighted and high
signal intensity with an outer rim of medium signal on T2-weighted images (13)
Ü Streak gonads are difficult to find and are seen as low-signal-intensity stripes on T2-weighted images (14)
Ü High signal intensity in streak gonads could represent neoplastic change (13)
Ü Hypertrophied clitoris can be differentiated from penis on MRI by absent or poorly developed supporting structures of
penis such as bulbospongiosus and posteriorly located transverse perinei muscles in the female pseudohermaphrodite
(15)
Ü Renal and adrenal evaluation can be performed in same MR examination with extended field of view
Figure 3: True Hermaphrodite. This child had ambiguous external genitals. Normal uterus was seen in the pelvis on US (A). A gonadal tissue was seen
in the right inguinal canal (B) that was sonographically appeared a testis. Another gonad was seen in the left iliac fossa (C) that also morphologically
appeared to be a testis. No follicles were seen in either of these gonads. Genitogram (D) shows normal vagina with reflux of contrast in the cervix
(arrow). Urethral configuration was that of unusual female type or severe hypospadias.
Biopsy of the right gonad showed immature testicular tissue and that of left gonad showed ovotestes. Cytogenetic analysis in this child showed
genotype of 46XY in both gonads.
Ü Ovotestis is seen as a structure with some testicular echotexture as well as follicles. Gonads with normal ovarian and testicular
appearance may prove ovotestes on histology.
a
Pure gonadal dysgenesis
Ü Confused with Congenital Androgen Insensitivity Syndrome (CAIS) as they present at puberty with failure of menarche in a normal
female phenotype. They usually will have normal or hypoplastic Mullerian derivatives while in CAIS there are no Mullerian derivatives.
Ambiguous Genitalia
RISK OF NEOPLASM
Ü If not seen on US, testicular tissue should be searched for by MRI and testicular venography in view of increased risk of malignancy
Ü Abnormality in MIF production in otherwise normal testes results in male phenotype/genotype with persistent Mullerian structures.
This is called ‘persistent Mullerian duct syndrome’ (9).
a
Female
f
Gonadal dysgenesis
According to anatomical
findings and genetic make up
Contradictory gonad removed
e
Ü Demonstrates male or female type of urethral configuration, any fistulous communication with vagina or rectum
Ü Shows presence or absence of vagina, its relationship with urethra and specially the level of external sphincter, cervical
Table 1.
Mixed
d
The aims of evaluating a child with ambiguous genitalia are: 1. establish genetic sex, 2. determine the hormonal profile,
3. evaluate the anatomy of internal and external genitalia and gonads, and 4. in older children, assess the phenotypic and
psychological sex (17).
Chart II displays a simplified approach for understanding concepts. Actual workup may turn complex and tedious, requiring
multiple tests such as hormonal assay, chromosomal study, laparoscopy and biopsy, and genitogram.
FLUOROSCOPY/GENITOGRAM:
Male pseudohermaphrodite:
Testosterone
True
Hermaphrodite
Figure 7: Normal right ovary and uterus on axial T2-weighted image (A) and normal uterus on sagittal T2-weighted image (B). Another axial T2-w
image (C) shows ectopic ovaries (arrows) over ileopsoas muscles bilaterally in this case of mullerian agenesis
Ü At least a rudimentary uterus and Fallopian tube can be seen on the side of streak gonad.
Ü On the side of testes local MIF diffusion prevents development of Fallopian tube (10)
CLASSIFICATION
Male
Pseudohermaphrodite
c
c
Figure 1: Female Pseudohermaphrodite. This infant had ambiguous genitalia. Genotype was 46XX. Normal uterus and both ovaries were seen in the
pelvis. Longitudinal (A) and transverse (B) images of right adrenal gland show enlargement of the gland, however, corticomedullary differentiation
is maintained. Similarly left gland (C) is also enlarged. There is also ‘cerebriform appearance’ to the glands. This was a case of congenital adrenal
hyperplasia resulting into virilization of external genitalia. 17-OH-Progesterone was elevated.
a
Female
Pseudohermaphrodite
b
c
DIAGNOSTIC APROACH
Sex ducts
Germ cells
Genital ridge
a
b
b
Figure 6: Normal testes (arrows) are seen as hyperintense oval structures with hypointense rim around it on T2-weighted images (A) and displays
isointense signal on T1-weighted images. T2-weighted axial image of the pelvis (B) shows normal two corpora cavernosa (arrows) sorrounding
corpus spongiosus (arrowheads).
Ü
Ü
Ü
Ü
Ü
Ü
Ü
neoplasm within the first or second decade, streak gonads should be removed (16)
Presence of the H-Y antigen, a gene product of Y-chromosome, is implicated for development of neoplasms
Gonadoblastomas are the most commonly seen tumors and arise commonly from dysgenetic intra-abdominal gonads
Presence of an echogenic focus associated with pelvic organs or in ectopic gonadal tissue in inguinal canals or labioscrotal
folds, should be regarded with suspicion as gonadoblastomas often calcify
Other germ cell tumors seen are dysgerminomas, teratomas, teratocarcinoma, yolk sac tumor, embryonal carcinoma and
choriocarcinoma (1)
Increased risk of developing Wilm’s tumor, particularly when XYgonadal dysgenesis is associated with glomerulopathy in
Drash syndrome
Average age of development of Wilms tumor in Drash syndrome is 3 years
Screening in the form of annual renal US is indicated in children with dysgenetic gonads up to school age for Wilms tumor
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