Keywords
androgen insensitivity syndrome - androgens - ultrasound - magnetic resonance imaging
- primary amenorrhea - Mullerian structures - gonads - secondary sexual characteristics
Introduction
Androgen insensitivity syndrome (AIS) is a rare X-lined genetic disorder resulting
in impaired androgen receptor function in 46,XY individuals, which leads to varying
degrees of feminization of external genitalia. Depending on the degree of receptor
response to androgens and clinical features, AIS is categorized into three subtypes[1]
[2]:
-
(1) Complete AIS: Individuals with complete insensitivity to androgens. They have
female external genitalia with undescended testis as gonads.
-
(2) Partial AIS: Androgen receptor function is limited leading to an ambiguous external
genitalia and secondary sexual characteristics.
-
(3) Mild AIS: The least severe form, with an XY karyotype, male external genitalia,
normal male secondary sexual characteristics, and subtle androgen receptor abnormalities.
Radiological imaging, such as pelvic ultrasound (USG) and magnetic resonance imaging
(MRI), plays a crucial role in assessing the internal reproductive anatomy, localization,
and characterization of gonads, thereby aiding in the clinical evaluation of AIS patients.
Diagnosis is confirmed by karyotyping, which shows an XY pattern in a phenotypically
female pattern.
Case Presentation
This case report discusses two siblings, aged 18 (case 1) and 17 (case 2), highlighting
the role of imaging in the diagnosis and management of AIS. Both patients were referred
from the gynecology department for radiological evaluation of primary amenorrhea.
USG scanning was performed for both patients followed by an MRI, which revealed nonvisualization
of internal genital structures and the presence of bilateral inguinal testis in both
cases
Case 1
An 18-year-old female patient presented to the department of radiodiagnosis for evaluation
of primary amenorrhea. The patient's clinical details, laboratory investigations,
and USG findings are summarized in [Table 1]. Thelarche and pubarche were assessed using the Tanner staging system. There was
a similar family history of similar clinical complaints in one of the maternal aunt,
however, no records of genetic testing were available.
Table 1
Clinical features, laboratory, and imaging findings of both the siblings
|
Clinical and imaging features
|
Elder sister, age 18 y
|
Younger sister, age 17 y
|
|
Presentation
|
Primary amenorrhea
|
Primary amenorrhea
|
|
Secondary sexual characteristics
|
Normal breast development (Tanner stage III)
Sparse pubic hair (Tanner stage II)
Absent axillary hair (Tanner stage I)
|
Normal breast development (Tanner stage III)
Absent pubic and axillary hair (Tanner stage I)
|
|
Physical examination
|
Normal external genitalia
|
Normal external genitalia
|
|
Hormonal levels
|
|
Serum
testosterone
(ng/dL)
(normal: 8.4–48 ng/dL)
|
Raised (330 ng/dL)
|
Raised (370 ng/dL)
|
|
LH and FSH
(normal LH: 2.5–75 IU/L; FSH: 3.5–25 IU/L)
|
Normal (LH: 20 IU/L, FSH: 12 IU/L)
|
Normal (LH: 35 IU/L, FSH: 17 IU/L)
|
|
USG
|
|
Uterus
|
Not seen ([Fig 1A])
|
Not seen ([Fig 3A])
|
|
Cervix
|
Not seen
|
Not seen
|
|
Bilateral ovaries
|
Not seen
|
Not seen
|
|
Bilateral testis
|
Right
location: deep inguinal ring
Characteristics: heterogeneously hypoechoic ([Fig 1B])
|
Left
location: left inguinal canal
Characteristics: homogenous ([Fig 1B])
|
Right
location: right inguinal canal
Characteristics: homogenous in echotexture ([Fig 3B])
|
Left
location: superficial inguinal ring
Characteristics: heterogeneous in echotexture ([Fig 3B])
|
|
Karyotype
|
XY
|
XY
|
Abbreviations: FSH, follicle-stimulating hormone; LH, luteinizing hormone; USG, ultrasound.
MRI of the pelvis ([Fig 1C, D]) revealed nonvisualization of uterus and cervix in a retrovesical location with
the presence of a blind vaginal pouch of length 4 cm. Bilateral ovaries were not seen.
A well-defined, ovoid structure measuring 25 × 22 mm appearing hypointense on T1 and
heterogeneously hyperintense on T2 was noted in the right inguinal region ([Fig 1D, E]). Similar structure measuring 15 × 12 mm appearing hypointense on T1 and hyperintense
on T2 was observed in the left inguinal region ([Fig 1D, F]) as well, suggesting the possibility of bilateral undescended testis.
A diagnosis of complete AIS was given, corroborated by karyotyping and histopathology
([Fig 2A, B]).
The patient underwent laparoscopic gonadectomy and histopathology of the specimen
revealed testicular tissue with spermatogenesis arrest, vas deferens, and epididymis.
Case 2
A 17-year-old female patient (younger sibling of case 1) presented to the department
of radiodiagnosis for evaluation of primary amenorrhea. The patient's clinical details,
laboratory investigations, and USG findings are summarized in [Table 1]. Thelarche and pubarche were assessed using the Tanner staging system.
MRI of the pelvis ([Fig 3C, D]) revealed the absence of uterus and cervix with the presence of a small distal vaginal
pouch measuring 1.6 cm in length. Bilateral ovaries were absent, while distinct ovoid
structures, appearing T1 isointense and T2 hyperintense, resembling testis were seen
in the bilateral inguinal region measuring 14 × 8.5 mm on the right side and 24 × 14 mm
on the left side ([Fig 3E, F]).
A diagnosis of complete AIS was given which was then confirmed by karyotyping and
histopathology ([Fig 4A, B]).
The patient underwent laparoscopic gonadectomy and histopathology of the specimen
revealed testicular tissue with spermatogenesis arrest, vas deferens, and epididymis.
Discussion
Primary amenorrhea, characterized by the absence of menstruation by age 16 in the
presence of normal growth and secondary sexual characteristics, necessitates a thorough
diagnostic evaluation. Imaging modalities play a pivotal role in delineating structural
abnormalities of the reproductive organs and guiding targeted management strategies.
The imaging approach to primary amenorrhea involves a systematic and multimodal process
aimed at comprehensive assessment and characterization of pelvic anatomy. Initially,
ultrasonography emerges as the frontline imaging modality, offering versatility through
both transabdominal and transvaginal approaches. Transabdominal ultrasonography provides
an overview of pelvic structures, while transvaginal ultrasonography offers enhanced
resolution, particularly beneficial for visualizing the uterus, ovaries, and surrounding
soft tissues. This dual approach enables the identification of congenital anomalies
such as Mullerian duct abnormalities (e.g., Mayer-Rokitansky-Küster-Hauser [MRKH]
syndrome, septate uterus), ovarian cysts, or tumors.
Subsequently, MRI assumes a pivotal role, providing unparalleled soft tissue contrast
and multiplanar capabilities. MRI serves as a complementary tool to ultrasonography,
particularly in cases where USG findings are equivocal or further characterization
of complex pelvic anatomy is warranted. Notably, MRI plays a crucial role in evaluating
associated anomalies such as spinal dysraphism in patients with suspected Mullerian
duct anomalies, ensuring a comprehensive assessment of the entire genitourinary tract.
In the evaluation of primary amenorrhea, a thorough understanding of the diverse differentials
is essential for guiding the diagnostic workup and formulating appropriate management
strategies. These differentials encompass a wide range of conditions, including anatomical
anomalies, endocrine disorders, and chromosomal abnormalities.[1]
[3]
-
Mullerian duct anomalies: These congenital abnormalities involve malformations of
the Mullerian ducts, which give rise to the uterus, fallopian tubes, and upper two-thirds
of the vagina. MRKH syndrome is characterized by congenital absence or underdevelopment
of the uterus and upper two-thirds of the vagina, often associated with normal ovaries
and secondary sexual characteristics. There are various subtypes of Müllerian duct
anomalies, among which uterine aplasia/hypoplasia without functional endometrium most
commonly presents with primary amenorrhea.
-
Endocrine disorders:
-
Congenital adrenal hyperplasia (CAH): CAH results from enzymatic deficiencies in cortisol
biosynthesis, leading to excess androgen production. In females, this can manifest
as virilization of external genitalia and primary amenorrhea due to ovarian dysfunction.
-
Hypothalamic-pituitary axis dysfunction: Disorders affecting the hypothalamic-pituitary
axis, such as hypothalamic amenorrhea or pituitary adenomas, can disrupt the normal
hormonal regulation of menstruation, resulting in primary amenorrhea.
-
Disorders of sex development (DSD), which encompass congenital conditions characterized
by atypical development of chromosomal, gonadal, or anatomical sex, imaging assumes
a crucial role. The major categorizes include three main groups based on karyotype:
46,XX DSD, 46,XY DSD, and sex chromosome DSD.[4] Imaging serves as a cornerstone in the process of gender assignment and plays a
pivotal role in identifying gonads and Müllerian structures.
The phenotypic spectrum of AIS encompasses individuals with a complete female phenotype
with normal female external genitalia (as in complete AIS) to a male phenotype with
undervirilization depending on the residual androgen receptor activity. Clinical symptoms
vary based on the patient's age and receptor sensitivity. In infancy, they may present
with inguinal hernia or labial swelling in phenotypically female children.[2]
[5]
The majority of patients with complete AIS typically present with primary amenorrhea
during puberty, accompanied by some degree of thelarche and sparse to absent pubic
or axillary hair. These changes are often attributed to converting androgens to estrogen.[2] The development of Mullerian structures is suppressed due to the production of anti-Mullerian
hormones by the testis, inhibiting normal uterine development.
The diagnosis of AIS relies on clinical evaluation, hormonal profiling, and genetic
testing. Radiology plays an important role in the comprehensive assessment and management
of patients with AIS, providing valuable insights into the underlying anatomical abnormalities
and guiding treatment decisions.
USG is the first modality generally employed in females presenting with primary amenorrhea
to assess the uterus and ovaries and detect the presence of male gonads. It has the
advantages of being readily available, inexpensive, and rapid. The presence of ovarian/testicular
tissue on USG helps to differentiate Mullerian agenesis versus pure gonadal dysgenesis
as normal ovaries are seen in the former condition whereas testis are noted in the
latter. The location of the ectopic testis is variable as they can be found in the
inguinal canal, sublabial, or intra-abdominal.[5]
[6] USG has limited sensitivity in detecting gonads located above the inguinal canal.
MRI is a problem-solving tool, especially in the identification of streak gonads and
gonads located intra-abdominally. Due to its excellent soft tissue resolution and
multiplanar capability, it is the modality of choice to evaluate the Mullerian structures.
It can detect suspicious intratesticular nodules like Sertoli cell adenoma, which
are more common in the undescended testis in AIS patients and guide therapeutic procedures.
Paratesticular cysts have been commonly observed with the undescended testis.[1]
The presence of uterus on imaging favors the possibility of 46,XX DSD like CAH whereas
presence of testicular tissue or streak gonads on imaging suggest the possibility
of 46,XY DSD, which include conditions like pure gonadal dysgenesis, androgen insensitivity
syndrome, and sex chromosome DSD (including Klinefelter, Turner, and mixed gonadal
dysgenesis).
Each of these differential diagnoses requires specific diagnostic approaches for confirmation.
A comprehensive approach to patient management in AIS is essential considering both
the psychological and physical well-being of the patient. The management strategy
is tailored to their receptor sensitivity and can include medical as well as surgical
interventions. Gonadectomy is generally advised to mitigate the risk of underlying
malignancy.
