Are you more of a visual learner? Check out our online video lectures and start your genetics course now for free!


Image: “X Y chromosome” by Janice Y Ahn, Jeannie T Lee. License: CC BY 2.0

Overview of Swyer Syndrome

Image by Lecturio

Swyer syndrome is a disorder of sex development that is characterized by complete testicular dysgenesis. Disorders of sex development comprise a group of conditions that are characterized by abnormal sex chromosomes, gonadal dysgenesis, or atypical anatomical sex characteristics. Swyer syndrome is a condition that presents with complete dysgenesis of the testicles in a phenotypical woman who has a 46,XY karyotype. The condition also is known as pure or complete gonadal dysgenesis.

Epidemiology of Swyer Syndrome

Disorders of sex development are rather common, with an estimated incidence of 1 per 4,500 live births. However, Swyer syndrome has an incidence of 1 per 80,000 live births. The condition is not inherited. Most patients with Swyer syndrome do not have a family history.

The condition itself is relatively benign, but several morbidities have been associated with the syndrome. For example, gonadoblastoma and dysgerminoma are more common in patients with Swyer syndrome compared to the general population.

Pregnancy in patients with Swyer syndrome is not possible without ova donation. Even with ova donation procedures, the potential for a successful pregnancy is quite low and similar to those with ovarian failure due to other causes. Patients with Swyer syndrome are phenotypically women, but they have poor development of secondary sexual characteristics without the administration of sex hormones.

Pathogenesis of Swyer Syndrome

In normally developing fetuses, common gonadal primordial cells develop and later evolve into either testes or ovaries, depending on the presence of male-specific or female-specific molecular ligands. The timing, dose, and expression of the sex-determining genes are essential for normal development of the gonads and normal sex development of the fetus. Swyer syndrome is caused by sex-determining region Y (SRY) gene mutation.

Problems in the timing, dose, or expression of those genes are responsible for most cases of disorders of sex development, including Swyer syndrome.

Development of the testes

The expression of the SRY gene on the Y chromosome is responsible for the development of the testes from the primordial gonad. The secretion of anti-Müllerian hormone induces the regression of the Müllerian ducts, whereas secretion of testosterone from Leydig cells promotes differentiation of the seminal vesicles, epididymis, and vas deferens. These structures arise from the Wolffian ducts, which start to form only in the presence of testosterone from the developing testes.

Genes involved in Swyer syndrome


Swyer syndrome results from a mutation in the SRY gene in about 20% of cases. The most common type of mutation is a small deletion in the DNA-binding region of the SRY gene. The second most common gene to be involved in complete gonadal dysgenesis in an XY woman is NR5A1, which encodes for the steroidogenic factor-1 nuclear receptor. Mutations in this gene are responsible for about 9% of the cases of Swyer syndrome.

The first target of the activation of the SRY gene is the activation of the transcription of the SOX9 gene. A faulty SOX9 gene will render the SRY gene ineffective in determining the sex of the fetus and will cause Swyer syndrome.


Mutations in the MAPK pathway are responsible for the reduction of the expression of SOX9 and SRY genes and the activation of the expression of female-specific genes such as WNT, beta-catenin, and FOXL2. The endpoint is again a female phenotype in an individual with an XY karyotype. MAPK mutations are responsible for about 18% of Swyer syndrome cases.

In summary, most cases of Swyer syndrome result from the defective expression of the SRY gene, the downregulation of the SRY gene and its targets, or the defective expression of one of the SRY gene targets.

Clinical Characteristics of an Individual with Swyer Syndrome

Individuals with Swyer syndrome are phenotypically women. The Müllerian structures are usually normal at birth. The gonads in patients with Swyer syndrome do not produce any sex hormones; therefore, primary amenorrhea is universal.

Individuals with Swyer syndrome typically show normal prepubertal development; hence, diagnosis usually is made during diagnostic workup for primary amenorrhea.

Individuals with Swyer syndrome are usually taller than those who are age- and sex-matched. Women with Swyer syndrome are an average of 10–12 cm taller than those without Swyer syndrome. This could be related to the delayed closure of the epiphyseal plates due to the low serum levels of sex hormones.


Image: SRY Gene pathway. By Silverthorn, Dee, License: Public Domain

Diagnostic Workup for Individuals with Primary Amenorrhea

Breast examination

Individuals with primary amenorrhea should undergo breast examination to assess stage of breast development. Women with Swyer syndrome typically show delayed or no breast development. In such cases, a follicle-stimulating hormone serum level test should be performed. Patients with Swyer syndrome have gonadal dysgenesis; therefore, follicle-stimulating hormone serum levels are expected to be high.

Karyotype test


Image: Human karyotype (259 35) Karyotype Human 46,XY (man). By Doc. RNDr. Josef Reischig, CSc., License: CC BY-SA 3.0

The next step in an individual with gonadal dysgenesis would be a karyotype test.

  • Patients with Swyer syndrome have a 46,XY karyotype.
  • Patients with primary ovarian failure have a 46,XX karyotype.
  • Turner syndrome presents with a 45,X karyotype.

Tumor markers

Once a diagnosis of gonadal dysgenesis is made, tumor markers should be checked because of the increased risk of tumor formation in the abnormal gonads.

The main tumor markers to be checked in an individual with Swyer syndrome are as follows:

  1. Alpha-fetoprotein
  2. Beta-human chorionic gonadotropin
  3. Lactate dehydrogenase
  4. Placental alkaline phosphatase

Genetic testing and sequencing to identify the specific causative defective gene are not indicated in patients with Swyer syndrome because identification of the mutated gene will not affect the treatment plan.

Transabdominal pelvic ultrasonography

Transabdominal pelvic ultrasonography is indicated in all patients with primary amenorrhea to evaluate the status of the Müllerian structures and the ovaries. Patients with Swyer syndrome have streak gonads and normal Müllerian structures.

When transabdominal pelvic ultrasonography is not sufficient to confirm a radiological picture of gonadal dysgenesis, a magnetic resonance imaging study of the pelvic structures is indicated.

The median time from a patient’s presentation to the clinic until the diagnosis of Swyer syndrome is 1.5 years.

Treatment of Swyer Syndrome

Hormone-replacement therapy

The risk of neoplasia in abnormal streak gonads is very high; therefore, once a diagnosis is made, gonadectomy is indicated in all individuals with Swyer syndrome. The second step in the management of Swyer syndrome is the induction of normal female puberty and the induction of the development of normal secondary sexual characteristics. This is achieved by the administration of estrogen, followed by cyclical estrogen- and progestin-replacement therapy until the age of 50 years.

Early hormone-replacement therapy is the only available option for the normal development of breasts. If hormone-replacement therapy is not initiated early enough, and good breast development is not achieved after the administration of estrogen, breast-augmentation surgery should be discussed.

Early initiation of hormone-replacement therapy in individuals with Swyer syndrome is essential for the prevention of osteoporosis and for the adequate development of bone mass during adolescence.

Note: The major concern in the treatment of patients with XY GD is the risk of gonadoblastoma, a mixed germ-cell, sex-cord tumor.

Image by Lecturio


Individuals with Swyer syndrome benefit from group psychotherapy, where they can meet and discuss their issues with other individuals who have similar conditions and with people with disorders of sex development in general.


The only option for pregnancy in individuals with Swyer syndrome is the use of donor ova. The rate of successful pregnancies is similar to that observed in patients with 46,XX ovarian failure. Patients with Swyer syndrome have a hypotrophic uterus; therefore, the elective Cesarean section at 36 weeks is advised to avoid any possible complications such as uterine rupture during labor.

Do you want to learn even more?
Start now with 1,000+ free video lectures
given by award-winning educators!
Yes, let's get started!
No, thanks!

Leave a Reply

Register to leave a comment and get access to everything Lecturio offers!

Free accounts include:

  • 1,000+ free medical videos
  • 2,000+ free recall questions
  • iOS/Android App
  • Much more

Already registered? Login.

Leave a Reply

Your email address will not be published. Required fields are marked *