Swyer syndrome in a Syrian female: A rare case report

Abstract

Swyer syndrome, a form of complete gonadal dysgenesis, is a rare genetic condition in which phenotypic females exhibit a 46,XY karyotype. A 15-year-old girl presented with underdeveloped secondary sexual characteristics and amenorrhea. Laboratory investigations revealed elevated follicle-stimulating hormone levels and low estradiol levels, while imaging identified a small uterus and gonads. Chromosomal analysis confirmed a 46,XY karyotype. The patient was treated with hormone replacement therapy, resulting in significant pubertal development, reaching Tanner stage 3 within 8 months. This case highlights the importance of early recognition, chromosomal analysis, and tailored management in Swyer syndrome. Multidisciplinary approaches based on hormonal therapy, fertility counseling, and psychological support are crucial to improving patient outcomes. As the first case report of Swyer syndrome in Syria, this study underscores the need for heightened clinical awareness of this rare condition and widens the differential diagnosis for primary amenorrhea.

Introduction

Swyer syndrome, also known as 46,XY complete gonadal dysgenesis, is a rare genetic condition marked by a discrepancy between the chromosomal sex and phenotypic sex. Individuals with this condition possess a 46,XY karyotype but develop as phenotypic females. ¹ This mismatch arises due to incomplete or absent gonadal development, resulting in streak gonads that fail to produce sex hormones. Typically, the initiation of gonadal development is driven by the sex-determining region Y (SRY) gene. ² However, this process is impaired in Swyer syndrome. Affected individuals exhibit a normal female phenotype, including female external genitalia and a uterus. However, the gonads do not differentiate into functional ovaries and instead remain as streak gonads, ³ resulting in the absence of estrogen and other sex hormones. This hormonal deficiency prevents the development of secondary sexual characteristics and results in infertility. Swyer syndrome was first described by Gim Swyer in 1955; the condition has an estimated incidence of 1 in 80,000 to 100,000 births. ⁴

The significantly elevated risk of malignancy in individuals with Swyer syndrome is of particular concern; the likelihood of developing gonadoblastoma ranges from 15% to 45% among patients without a familial history. ⁵ Here, we present the case of an adolescent girl with Swyer syndrome characterized by amenorrhea and the absence of secondary sexual characteristics. To the best of our knowledge, this is the first documented case of Swyer syndrome in Syria.

Presentation

A 15-year-old girl was admitted to Homs University Hospital on 2 February 2025. Her aunt had brought her to the hospital owing to concerns about delayed development of secondary sexual characteristics. The patient had not yet experienced menarche as opposed to her peers. Physical examination confirmed Tanner stage 1. Other physical characteristics were unremarkable. Her height was 153.5 cm, and her weight was 39 kg; her calculated body mass index was 16.5, as per which she was classified in the underweight category. Her family history was significant for secondary hypogonadism in her sister. However, no documented medical history was available for her parents owing to the disruptions caused by war. Additionally, the patient did not express any psychological distress or social discomfort related to the absence of pubertal development.

Workup

Laboratory test results showed a serum estradiol level of 7.22 pg/mL and a follicle-stimulating hormone level of 117 mIU/mL. Ultrasound echocardiography revealed a clearly defined uterus with no masses or cysts. The uterus was normal in shape and position; the dimensions of the uterus were 17 × 13 × 10 mm. The endometrial cavity had collapsed, and no endometrial lining was present. The gonads were small, with no free fluid observed in the Douglas pouch (Figure 1).

Figure 1.

Ultrasound findings: the uterus had well-defined borders and a homogeneous texture, with no visible masses or cysts and a thin endometrial lining. The gonads were normal in appearance and small in size, measuring 12 × 2.5 mm.

Infantile uterus and adnexa were observed on magnetic resonance imaging; her uterus was small, measuring 35 mm in length, 20 mm in width, and 11 mm in thickness. The endometrium was thin and regular. The gonads were slightly thin, consistent with a dysgenetic gonad structure, measuring 24 mm in length and 6 mm in thickness. They contained small follicular exchanges with a diameter <4 mm.

No pathological masses, cysts, or fluids were observed in the pelvic region (Figure 2). Karyotyping analysis showed a 46,XY chromosomal pattern, establishing the diagnosis of Swyer syndrome.

Figure 2.

Magnetic resonance imaging (MRI) findings: the uterus was located on the midline, and the endometrial lining was thin and regular. The gonads were slightly thin in appearance, with small follicular changes distinguishable within them. No masses or cysts were detected.

Treatment

Treatment was initiated with oral conjugated estrogen in the form of tablets at a dosage of 0.625 mg daily for 6 months. Subsequently, the dosage was increased to 1.25 mg daily for 6 months. Gonadectomy was not discussed with the patient at this time.

Follow-up

Twelve months post-treatment, the patient exhibited significant development of secondary sexual characteristics, reaching Tanner stage 3. However, no visible changes occurred with respect to menarche, and the patient exhibited no changes in her voice. She did not report any acne. She was initiated on a cyclic regimen of oral conjugated estrogen in the form of tablets (2.5 mg daily for 20 days), followed by a 10-day drug-free period.

Discussion

Swyer syndrome is a rare genetic disorder characterized by complete gonadal dysgenesis, resulting in individuals with a normal female phenotype despite a 46,XY karyotype. Previous studies have shown that the absence of testicular development may be triggered by mutations in SRY, NR5A1, DHH, or other testis-determining genes as well as by duplication mutations in DAX1 or WNT4 or gain-of-function mutations in MAP3K1, all of which impair normal sex differentiation. ¹

Swyer syndrome commonly remains asymptomatic or undiagnosed until adolescence or early adulthood because most patients present with delayed puberty and primary amenorrhea. Primary amenorrhea is defined as the absence of menstruation in females aged ≥14 years who have not developed secondary sexual characteristics or in those who have not experienced menarche by the age of 15 years despite the presence of secondary sexual characteristics, similar to our patient, whose presentation was consistent with Swyer syndrome. Despite having normal external genitalia, she had a small, underdeveloped uterus and bilateral streak-shaped gonads. Due to estrogen deficiency, she did not exhibit any secondary sexual characteristics. However, she had scant pubic and axillary hair, which can be explained by the fact that adrenal glands remain functional and continue to produce androgens. ³

Interestingly, the patient’s sister also had secondary hypogonadism, which, upon evaluation, could not be directly linked to her sister’s condition of Swyer syndrome. However, owing to limited access to genetic testing, the underlying cause of secondary hypogonadism in the sibling remained uncertain. The absence of genetic studies in both cases limits our ability to further investigate potential genetic or familial links between the two conditions.

Many cases of Swyer syndrome have been well-documented in medical literature; this condition has been described as a rare genetic cause of impaired sexual differentiation, with primary amenorrhea being the most common presenting symptom. A previous case report described a 16-year-old girl with a similar presentation as our patient; however, she also had inguinal calcified nodules suspected to be calcified atrophic testes. She underwent gonadectomy due to the increased risk of gonadal malignancy. ⁶

Furthermore, the clinical presentation of Swyer syndrome can vary. In some cases, affected individuals may not display symptoms initially, leading to a delayed diagnosis. Some patients are diagnosed incidentally during evaluations for unrelated conditions. For instance, a previous case report of a patient who presented with lower abdominal pain, leading to the accidental diagnosis of Swyer syndrome after pelvic ultrasound, revealed a hypoplastic uterus and absent ovaries. ⁷ Given this variability, differential diagnoses should always be considered, including androgen insensitivity syndrome (AIS), where individuals with 46,XY karyotype are resistant to androgens, resulting in a female external phenotype and undescended testes; congenital adrenal hyperplasia due to 21-α hydroxylase deficiency, which can affect both 46,XY and 46,XX individuals, potentially leading to ambiguous genitalia or virilization in genetic females; ⁴ mixed gonadal dysgenesis, characterized by asymmetrical gonadal development, often with monosomy or mosaicism, leading to ambiguous genitalia; Mayer–Rokitansky–Küster–Hauser syndrome, a condition affecting 46,XX individuals with normal ovaries exhibiting absent or underdeveloped uterus and upper vagina, resulting in primary amenorrhea; and early testicular regression syndrome, wherein there is complete failure of testicular development, leading to the loss of testicular tissue, impaired fertility, and compromised hormone production, resulting in male pseudohermaphroditism. Chromosomal analysis remains the gold standard for diagnosing Swyer syndrome. In our case, the chromosomal study revealed a 46,XY karyotype, confirming the diagnosis of Swyer syndrome. The absence of testicular tissue suggests underlying genetic mutations in genes such as SRY or SOX9, which affect testicular development or maintenance.^2,8 Management primarily involves hormone replacement therapy (HRT), beginning with the administration of conjugated estrogen to induce pubertal growth spurt and secondary sexual characteristics. Our patient was started on an oral conjugated estrogen with a gradual increase in doses over 6 months, following which she showed progression from Tanner stage 1 to Tanner stage 3, along with a growth spurt and weight gain; she is expected to experience menarche soon. It is important to mention that fertility counseling is very crucial because individuals with Swyer syndrome have a functional uterus and may conceive through oocyte donation and assisted reproductive technologies. Patients should be reassured that the presence of an XY karyotype does not affect normal uterine and endometrial responses. ⁹ Cases of successful full-term pregnancy following fertility treatment in patients with Swyer syndrome have been reported. ¹⁰ There are fewer than 13 live births reported in patients with Swyer syndrome in medical literature; thus, the pregnancy course remains unclear. In most of these reported pregnancies, delivery was performed via cesarean section for different indications, one of which was a hypoplastic uterus. Thus, more reports are needed to understand the potential pregnancy outcomes in patients with this rare condition. Another critical aspect to consider is the high risk of gonadal malignancy because the incidence of gonadoblastoma in these patients ranges from 15% to 35% and increases with age. ¹¹ Therefore, prophylactic gonadectomy is often recommended in early childhood to prevent any malignant transformation. ¹²

Additionally, the most significant long-term complication in individuals with Swyer syndrome is osteoporosis because streak gonads (undeveloped ovaries) do not produce hormones such as estrogen and progesterone. Estrogen plays a crucial role in bone health and growth, and the lack of estrogen in patients with Swyer syndrome can lead to reduced bone density (osteopenia) and an increased risk of fractures, resulting in a condition known as osteoporosis. To prevent this, HRT is typically started during adolescence to help induce puberty, including breast development and menstruation, as well as prevent bone loss and osteoporosis.

Finally, living with Swyer syndrome can present psychological and emotional challenges that impact self-confidence and sexual identity. Providing psychiatric counseling and access to support groups is essential to address any associated emotional or psychological concerns, including gender identity and sexual orientation. ¹³ The reporting of this study conforms to the Case Report (CARE) guidelines. ¹⁴

Conclusion

This case highlights the importance of considering Swyer syndrome in the differential diagnosis of patients with primary amenorrhea and underdeveloped secondary sexual characteristics. A comprehensive management plan, including hormonal therapy and psychological support, is essential for the patient’s overall well-being. We emphasize the value of a multidisciplinary approach, highlighting the need for early diagnosis, proactive treatment, and complete patient care to ensure the best possible outcomes for patients with this rare condition.