1.1 46, XY DSD Characterized by Abnormal Gonadal Development

Gonadal dysgenesis can be caused by mutations in testes determining factors on the Y chromosome. In approximately 10%–20% of cases, a mutation is found in the sex-determining region Y (SRY) gene [2]. A number of patients with 46, XY gonadal dysgenesis have been reported with a duplication of the Xp21.2 → p22.11 region of the X chromosome, which contains the DAX1 gene [3]. Inheritance patterns that have been reported include sporadic cases (de novo variants), autosomal dominant, autosomal recessive, X-linked recessive, and Y-linked. Individuals with pure 46, XY gonadal dysgenesis typically present normal external female genitalia. The gonads are streak gonads without hormone production, so Müllerian structures are present, but no development of secondary female characteristics during puberty is typically observed [2]. Adrenarche is usually normal. The completely undeveloped streak gonads are associated with a 15%–30% increased risk of abdominal tumors, most commonly dysgerminoma [1, 4]. Elevated gonadotropin levels and low testosterone and dihydrotestosterone levels are typically observed in these individuals [5].

1.2 46, XY DSD Characterized by Androgen Insensitivity

AIS stems from X-linked androgen receptor mutations, which hamper androgen-dependent male sexual differentiation to varying extents. Clinically, individuals with complete AIS exhibit female external genitalia. Although the gonads have differentiated into testes, they can be found in different locations such as the intra-abdominal region, inguinal canals, or within the labia. The regression of Müllerian structures (i.e., the upper part of the vagina, uterus, and Fallopian tubes) occurs due to the normal production of anti-Müllerian hormone in the fetus. During puberty, breast development occurs as a result of the aromatization of excess androgens into estrogens, although pubic and axillary hair are usually scarce or absent. In contrast, individuals with partial AIS exhibit varying degrees of virilization at birth. Consequently, these patients may be raised as either females or males. Elevated gonadotropin levels and normal or elevated testosterone levels are common in these patients [2, 5].

46, XY females are an uncommon occurrence, with limited data available on their incidence. Estimates of the prevalence of AIS and gonadal dysgenesis range widely, from 1 to 5 per 100,000 births [6] and 1 per 80,000 births [7], respectively. AIS is considered to be the most common cause of 46, XY DSD, followed by gonadal dysgenesis.

Ultrasound is generally recommended as the first imaging method for clinical evaluation because of its accessibility and the lack of necessity for sedation or contrast agents. Nevertheless, the quality of information provided by ultrasound relies on the expertise of the evaluator and the device utilized. Magnetic resonance imaging (MRI) is better suited for visualizing gonads, even though streak gonads can be difficult to detect using MRI. Laparoscopy is the gold standard for evaluating these intra-abdominal tissues [5].

2.1 Case History/Examination

A 19-year-old woman presented to the outpatient clinic in January 2024 with a failure to attain menarche. Her developmental milestones were attained at appropriate ages, and she had been developing phenotypically. She had not commenced sexual activity. She was the second child of four children (two males and two females), her younger sister being 10 years old, and developing well so far. Her mother who often accompanied her to the clinic was tall (179 cm), had attained menarche at the age of 14 years, and looked phenotypically normal. There was no family history of genital ambiguity. The patient was tall (height 177 cm), weighed 53 kg, and had an upper-to-lower segment ratio of 1:1. Her waist circumference was 88 cm, hip circumference was 103 cm and had a feminine voice with sparse axillary hair. The patient had palpable breasts (Tanner stage 3) and pubic hairs (Tanner stage 4). Her external genitalia appeared normal, although the vaginal length was not determined because her mother declined consent.

2.2 Investigations

Hormonal profile tests revealed hypergonadotropic hypogonadism and normal 17-hydroxyprogesterone and testosterone levels (Table 1). Anti-Mullerian hormone level was not measured. An ultrasound scan of the abdomen and pelvis revealed a normal, anteflexed uterus with a normal endometrial stripe and no evidence of ovarian pathology. However, the sonographic findings were inconsistent with the hormonal profile. She was advised to undergo an MRI scan of the pelvis, which revealed a hypoplastic uterus with absent ovaries. She subsequently underwent karyotyping, which revealed karyotype 46, XY.

2.3 Differential Diagnosis

A diagnosis of primary amenorrhea secondary to 46, XY (complete gonadal agenesis) was made, and the patient and her mother were educated about the medical condition, its prognosis, and fertility prospects in the future.

2.4 Treatment

She was started on a combined contraceptive pill (Femiplan) which contains 0.03 mg of ethinylestradiol and 0.15 mg of levonorgestrel and experienced withdrawal bleeding in the third cycle.

2.5 Follow-Up

She has been counseled on exploratory laparoscopic gonadectomy but has not yet consented.