Swyer syndrome is characterized by complete gonadal dysgenesis in a phenotypically female who has a 46, XY karyotype. The presentation of Swyer syndrome is that of a tall female, with primary amenorrhea. The follicle-stimulating hormone levels are elevated and there is usually poor secondary sexual characteristics’ development. Karyotyping is indicated. Once the diagnosis is made, treatment consists of bilateral gonadectomy, hormone replacement therapy, and psychotherapy. The only option for fertility is the use of donor ova.

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

Overview of Swyer Syndrome

Swyer syndrome is one form of the disorders 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 phenotypically female patient who has a 46, XY karyotype. The condition is also known as pure or complete gonadal dysgenesis.

Epidemiology of Swyer Syndrome

Disorders of sex development, in general, are quite common with an estimated incidence of 1 per 4500 live births. On the other hand, pure gonadal dysgenesis or Swyer syndrome has an incidence of 1 in 80,000 live births. The condition is not inherited. Most of the cases do not have a family history. Inheritance is very rare.

The condition itself is relatively benign; however, several morbidities have been previously associated with the syndrome. Gonadoblastoma or dysgerminoma are more common in patients with Swyer syndrome compared to the general population.

Pregnancy in patients with Swyer syndrome is not possible without an ova donation procedure. Even with ova donation-based 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 females, but with poor secondary sexual characteristics’ development. Without the administration of sex hormones, the development of secondary sexual characteristics is poor.

Pathogenesis of Swyer Syndrome

In the normally developing fetus, a common gonadal primordial develops that later evolves into either a testis or an ovary depending on the presence of male-specific or female-specific molecular ligands. The timing, dose, and expression of these sex-determining genes are essential for the normal development of the gonads and for the 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 these genes are responsible for the majority of the cases of disorders of sex development including Swyer syndrome.

The development of the testis

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

Genes involved in Swyer syndrome


Swyer syndrome results from a mutation in the SRY gene in about 20% of the 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 female is the 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 or 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.

Therefore, 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 Mullerian 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, the diagnosis is usually made during the diagnostic workup for primary amenorrhea.
Individuals with Swyer syndrome are usually taller than those who are age and sex matched. Females with Swyer syndrome are in average 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 a breast examination to assess the stage of breast development. Females with Swyer syndrome typically show delayed or no breast development. In that case, a follicle-stimulating hormone serum level test is performed. Patients with Swyer syndrome have gonadal dysgenesis; therefore, the follicle-stimulating hormone serum level is 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 would be a karyotype test to assess the karyotype in the individual of gonadal dysgenesis.

  • 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.

Checking tumor markers

Once the 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:

  1. Alpha-fetoprotein
  2. Beta-human chorionic gonadotrophin
  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 the 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 Mullerian structures and the ovaries. Patients with Swyer syndrome have streak gonads and normal Mullerian structures.

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

The median time from the presentation to the clinic until the diagnosis of Swyer syndrome is made is 1.5 years.

Treatment of Swyer Syndrome

Hormone replacement therapy

The risk of neoplasia in the abnormal streak gonads is very high; therefore, once the 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 was not achieved after the administration of estrogen, breast augmentation surgery should be discussed.

The 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.

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


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


The only option for pregnancy in an individual 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, an elective cesarean section at 36 weeks is advised to avoid any possible complications such as uterine rupture during labor.

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