Syntax Literate: Jurnal Ilmiah Indonesia p–ISSN: 2541-0849
e-ISSN: 2548-1398
Vol. 8, No. 12, December 2023
CONGENITAL
ADRENAL HYPERPLASIA WITH CONCOMITANT MULLERIAN AGENESIS: A RARE OCCURRENCE IN
46 XX DISORDERS OF SEXUAL DEVELOPMENT
Wahyuni Z1*, Yuad H2, Margareta Sari Y3
1Resident of Obstetrics and Gynecology
Specialist Program, Andalas University, Indonesia
2Reproductive Endocrinology and Infertility
Department of Dr. M. Djamil Hospital, Indonesia
3Urology and Reconstructive Surgery Department
of Dr. M. Djamil Hospital, Indonesia
Email: [email protected]*
Abstract
The most common cause of 46 XX DSD is due to congenital adrenal hyperplasia with varying degrees of virilization. Females with CAH do not produce an anti-mullerian hormone (AMH), therefore the internal genitalia, which are Mullerian derivatives, develop normally. We report a unique case of CAH with aplasia of the uterus and upper vagina. The clinical, laboratory, and imaging findings of the patient are presented with a review of the literature. We report an ongoing case of a 20-year-old patient with ambiguous genitalia and primary amenorrhea. On physical examination, we found that she had an underdeveloped breast and clitoral virilization with separate urethral and vaginal openings. We performed a G-banded chromosome analysis, with 46 XX results. Laboratory test showed her 17-hydroxyprogesterone level was immensely elevated, while her FSH, LH, and estradiol level was below normal. Ultrasound imaging revealed the absence of uterus and cervix. Nevertheless, we found a diminutive uterine remnant during diagnostic laparoscopy with normal ovaries and fallopian tubes. On vaginoscopy examination, we found her vagina to be 5 cm long with blind end. In the presence of primary amenorrhea in patients with CAH, it is important to investigate for possible associated mullerian anomalies.
Keywords: Congenital, Adrenal
Hyperplasia, Concomitant Mullerian Agenesis
Introduction
Ambiguous genitalia is a sex
development disorder that is chromosomal, gonadal, and anatomically atypical
which is generally characterized by the presence of external genital organs
that are not male or female or have features of both sexes (Krishnan & Wisniewski,
2014);(Rajuddin & Fauzan,
2018);(Mehmood & Rentea, 2023). Terminology, such as hermaphrodite,
pseudo-hermaphrodite, and intersex have now been replaced by Disorders of
Sexual Development (DSD) (Crouch, 2022). The most common cause is congenital adrenal
hyperplasia, which is responsible for 90-95% of these cases (Mampilly, Ananthamurthy,
Mohanty, & Das, 2022);(Mehmood & Rentea, 2023).
Congenital Adrenal Hyperplasia (CAH)
is the term used to describe a group of genetically determined disorders of
defective steroidogenesis resulting in variable deficiencies of cortisol and/or
aldosterone end products that simultaneously lead to the accumulation of
androgens and their virilizing effects (New et al., 2000). Mayer-Rokitansky-Syndrome Küster-Hauser
(MRKH), also referred to as Müllerian aplasia, is a congenital disorder
characterized by aplasia of the uterus and upper vagina in women with normal
secondary sex characteristics and a normal female karyotype (46XX) (Patnaik, Brazile, Dandolu,
Ryan, & Liao, 2015);(Herlin, Petersen, &
Brännström, 2020).
In this case, we present patients
with ambiguous genitalia with 46XX karyotyping results, increased levels of
17-hydroxyprogesterone, and aplasia of the uterus and upper vagina. A
20-year-old patient, self-identified as female, came to Reproductive
Endocrinology and Infertility Polyclinic at RSUP Dr. M. Djamil Padang with a
chief complaint of primary amenorrhea. She denied having cyclical lower
abdominal pain. The patient admitted that her breasts did not grow while her
pubic hair started to grow when she was 12 years old.
The patient was raised as a woman,
feels like a woman, and has sexual attraction towards men. The patient urinates
from the opening at the bottom of her genitalia. There are no complaints of
urination or defecation. The patient is the 3rd child of 4 siblings, born
spontaneously after a term pregnancy. There was no history of maternal exposure
to androgens (testosterone, progesterone, aldosterone, glucocorticoids) or
pesticides (dichlorodiphenyltrichloroethane, DDT), which cause endocrine
disruption or virilization during pregnancy. Moreover, there was no history of
hospitalization or vomiting in childhood. There was no history of similar
complaints or unexplained infant deaths in the family.
On physical examination we found her
height was 152 cm, weight 42 kg and vital signs are in normal range. She had
excessive facial hair. According to the modified Ferriman-Gallwey scoring
system, her hirsutism score was 10 (moderate level) (Ilagan, Paz-Pacheco,
Totesora, Clemente-Chua, & Jalique, 2019). She also had moderate nodulocystic acne and
untreated cleft palate. No neck enlargement and skeletal abnormalities were
found.
The patient's breast was
underdeveloped (Tanner stage M2) (Fig 1A), while the pubic hair growth seemed
normal (Tanner stage P4) (Fig 1B). A structure resembling a penis was found ± 4
cm in size. There were no palpable testes (Fig 1B). There is no labial fusion.
The external urethral orifice is 0.5 cm below the "penis". A separate
pinpoint vaginal introitus was seen 0,5 cm below the urethral orifice (Fig 1C)
[Prader stage 4].
Fig 1. Physical examination findings
Ultrasonographic investigations did
not reveal a clear image of the uterus, fallopian tubes, and cervix (Fig2A-2D).
Fig 2.
Ultrasonographic
findings: unclear image of the uterus, fallopian tubes, and cervix
Subsequently,
karyotyping of peripheral blood was performed and revealed a 46XX karyotype. On
laboratory examination, the 17-hydroxyprogesterone (17-0HP) level was
significantly increased to 176.93 ng/mL (normal female, ≤ 2.85 ng/mL). The LH,
FSH, and estradiol level was low: 2.21 mlU/mL, 3.06 mlU/Ml, and 18.0 pg/mL,
respectively. The cortisol level in this patient was normal (5,1 ug/dl).
Complete blood count, renal function test, lipid profile, and electrolyte
status were all within normal limits. We have not conducted tests for androgens
and progesterone levels (not covered by the insurance).
We later
performed a diagnostic pelvic laparoscopy. Both ovaries and fallopian tubes
appeared normal in size and shape. There was a band-shaped uterine remnant the
size of a peanut (Fig 3A, 3B). On cystoscopy examination, we found the urethra,
bladder, and ureteral orifice appeared normal (Fig 4A, 4B). On vaginoscopy, we
found the vagina to be 5 cm long with a blind end. We could not identify the
cervical portion (Fig 5A, 5B).
Fig 3. Pelvic laparoscopy findings
Fig 4.
Cystoscopy
findings
Fig 5. Vaginoscopy findings
Based on the history
taking, physical examination, and investigations performed on this patient, a
diagnosis of simple virilizing congenital adrenal hyperplasia with aplasia of
the uterus (suspected MRKH syndrome) was established. The patient was treated
with oral dexamethasone 0,25 mg once daily and also combined oral contraceptive
pill (containing ethinylestradiol 0,03 mg and levonorgestrel 0,15 mg) once
daily. She had clitoral hood reduction surgery for the clitoromegaly.
Research
Methods
The research design used in this research is
qualitative descriptive with a case study strategy. In the case study of a
20-year-old patient with ambiguous genitalia and primary amenorrhea, a
systematic approach was taken to investigate the possible causes and associated
conditions. The following methods and tests were employed:
1) Physical Examination: A thorough examination was conducted to
assess the patient's external and internal genitalia, including the breasts,
clitoris, urethra, and vagina.
2) G-banded Chromosome Analysis: A chromosomal analysis was performed
to determine the patient's karyotype and identify any chromosomal abnormalities
that may be associated with the patient's condition.
3) Laboratory Tests: The patient's hormonal levels were measured,
including 17-hydroxyprogesterone, follicle-stimulating hormone (FSH),
luteinizing hormone (LH), and estradiol. These tests helped to identify any
hormonal imbalances that may be contributing to the patient's condition.
4) Ultrasound Imaging: Ultrasound imaging was used to assess the patient's
internal reproductive organs, including the uterus, cervix, ovaries, and
fallopian tubes.
5) Diagnostic Laparoscopy: A diagnostic laparoscopy was performed to
further examine the patient's internal reproductive organs and identify any
abnormalities.
6) Vaginoscopy: A vaginoscopy examination was conducted to assess the
patient's vagina for any abnormalities or anomalies.
By employing this systematic approach, the
healthcare professionals were able to identify the patient's condition as
congenital adrenal hyperplasia (CAH) with aplasia of the uterus and upper
vagina. This methodical approach allowed for a comprehensive understanding of
the patient's condition and aided in the diagnosis and treatment process.
Results and Discussion
Disorders
of sex devolvement (DSD), formerly known as ambiguous genitalia or intersex
disorders, represent a spectrum of inherited conditions in which chromosomal,
gonadal sex or anatomy is atypical (Mampilly et al., 2022);(Mehmood & Rentea, 2023). In this case, a
karyotyping examination was carried out as a diagnostic first step according to
a diagnostic algorithm for patients with ambiguous genitalia, in this patient
the result was 46XX. The next examination was the 17-OHP hormone
(17-hydroxyprogesterone) which was highly increased.
Elevated
levels suggest congenital adrenal hyperplasia as a cause of virilization in
this patient. CAH is 95% caused by mutations in the CYP21A2 gene, which codes
for the adrenal steroid 21-hydroxylase. The salt-losing type is regarded as the
classic and most severe form of 21-hydroxylase deficiency, in which cortisol
production is virtually absent, and the aldosterone production is diminished
leading to salt wasting, failure to thrive, and potentially fatal hypovolemia
and shock (Twayana et al., 2022). Based on the overall health and
cortisol level in this patient, we concluded that the patient had a less severe
form of the disease (simple virilizing type).
In contrast to the
virilization of the external genitalia, internal female genitalia, the uterus,
fallopian tubes, and ovaries, develop normally. Females with CAH do not produce
anti-Müllerian hormone (AMH), which is produced by the testicular Sertoli
cells. Internal female structures are Müllerian derivatives and are not
androgen-responsive. Therefore, the affected female is born with virilized
external genitalia but normal female internal genitalia has the possibility of
normal fertility (New
et al., 2000).
Fig 6. Diagnostic Algorithm for patients with ambiguous
genitalia with karyotype 46, XX7
CAH is known to alter
the function of the hypothalamic–pituitary–ovarian axis. Potential aetiologies
for the alterations to the hypothalamic–pituitary–ovarian axis include elevated
androgens, elevated progesterone, expression of 5α-reductase in the ovary, or
even a direct glucocorticoid effect. Initial observations suggested that excess
androgens are aromatized to estrogen, which could suppress gonadotropin
secretion. Elevated androgen levels were also thought to inhibit
folliculogenesis, albeit in rat models.
However, recent
evidence has indicated that androgen excess impairs hypothalamic sensitivity to
progesterone. This causes increased gonadotropin-releasing hormone pulse
frequency, resulting in a preferential secretion of luteinizing hormone (LH).
The hypersecretion of LH increases ovarian androgen production, which further
potentiates and intensifies the effects of adrenal androgens. HPO axis
suppression can occur which causes primary amenorrhea and failure of the
patient's secondary sex development (Tanner mammary stage 2) (Mikhael,
Punjala-Patel, & Gavrilova-Jordan, 2019);(Pereira
& Lin-Su, 2018).
Patients with primary
amenorrhea should undergo a pelvic ultrasound to confirm the internal anatomy.
Furthermore, if the results are inconclusive it is necessary to conduct a
Magnetic Resonance Imaging (MRI) examination or diagnostic laparoscopy. We did
not perform an MRI scan on this patient due to the unavailability of a clinical
pathway for this specific case (hence could not be covered by the insurance).
Laparoscopic findings
suggest aplasia of the uterus, which is in line with MRKH syndrome diagnosis.
Once an MRKH syndrome is diagnosed, it is important to have a comprehensive
examination of various organ systems (especially the kidneys, vertebrae, and
heart) considering that there is a possibility that the patient has MRKH
syndrome with MURCS association (Morcel,
Camborieux, fr, & Guerrier, 2007).
For patients with
ovarian insufficiency, timely estrogen should be restarted, for secondary
sexual characteristic development, to minimize bone loss and to achieve
adequate uterine size for future fertility (Singh,
Agarwal, Sinha, SINGH Sr, & SINHA, 2022). The optimal pubertal induction
in women contains both estrogens and progesterone regimens. Different
therapeutic options have been described over the years in the literature, but
larger randomized trials are required to define the ideal approach.
The latest
acquisitions in the field seem to propose that transdermal 17β-estradiol and
micronized progesterone present the most physiological formulations available
for this purpose. Since such preparations were not available in our center, we
decided to use combined oral contraceptive pills once daily. On follow-up, after
30 days of steroid and hormonal therapy, menarche has still not occurred in
this patient. We plan to continue the treatment for 6 months, with monthly
laboratory and ultrasound examinations (Voutsadaki,
Matalliotakis, & Ladomenou, 2022).
Conclusion
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Margareta Sari Y (2023) |
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