Swyer Syndrome

Swyer syndrome is a disorder of sex development caused by a defect in the SRY gene on chromosome Y. The syndrome is characterized by complete testicular dysgenesis in an individual who has a 46,XY karyotype and is phenotypically female. The presentation of Swyer syndrome is that of a tall female with a normal childhood and development until puberty, which is characterized by primary amenorrhea and no development of secondary sexual characteristics. Management includes hormone replacement therapy and gonadectomy.

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Epidemiology and Etiology


  • 46,XY complete gonadal dysgenesis (CGD)
  • Gonadal dysgenesis, XY female type


  • 1 in 80,000100,000 live births
  • Patients have a higher risk of developing gonadoblastoma or dysgerminoma compared with the general population.


The karyotype of an individual with Swyer syndrome is 46 XY.

Swyer syndrome can be caused by various genetic abnormalities:

  • Sex-determining region Y (SRY) gene mutation 
    • Occurs in 20% of cases
    • SRY gene plays a vital role in male sex determination by triggering the transformation of gonadal tissue into testes.
    • The mutation is most often a small deletion in the DNA-binding region of the SRY gene on the Y chromosome.
  • Map3K1 gene mutation
    • Occurs in 18% of cases
    • Encodes a protein that aids in determining sexual characteristics during gestation
    • Mutations reduce the expression of SOX9 and SRY genes and activate the expression of female-specific genes (WNT, beta-catenin, and FOXL2).
  • NR5A1 gene mutation
    • Occurs in 9% of cases
    • Encodes for the steroidogenic factor-1 nuclear receptor, a protein important for the production of sexual hormones/differentiation
  • SOX9 gene mutation
    • Usually inhibits the creation of the female reproductive system, allowing for the development of male reproductive organs

Pathophysiology and Clinical Presentation


  • Normal development until eighth week of gestation
  • SRY gene mutation occurs → primordial gonads do not develop into testes → anti-Müllerian hormone (AMH) and testosterone are not secreted → undeveloped male genitalia + development of uterus and vagina
Types of hypersensitivity - Swyer syndrome

Image displaying the importance of SRY in normal male genital development

Image by Lecturio.

Clinical presentation

  • Phenotypically female
  • Normal prepubertal development
  • Tall stature (10–12 cm taller than those without Swyer syndrome [age and sex matched])
  • Cognition/intelligence: normal
  • Behavioral phenotype: normal
  • Sex development/ fertility: 
    • Primary amenorrhea
    • Infertility due to non-functioning ovaries (pregnancy is possible with ova donation)
    • ↓ Estrogen due to non-functional ovaries (streak gonads)
  • Associations: ↑ risk of tumor formation in the abnormal gonads (gonadoblastoma or dysgerminoma)

Diagnosis and Management


  • Mainly clinical, based on lack of puberty and secondary sexual characteristics
    • Delayed or no breast development
    • Lack of pubic hair
    • Amenorrhea 
  • Confirmed via karyotype testing:
    • 46,XY: Swyer syndrome
    • 46,XX: primary ovarian failure
    • 45,XO: Turner syndrome
  • Laboratory studies
    • Elevated follicle-stimulating (FSH) and luteinizing (LH) hormone levels 
    • Tumor markers should be tested to identify gonadoblastoma or dysgerminoma: alpha-fetoprotein, beta-human chorionic gonadotropin, lactate dehydrogenase, and placental alkaline phosphatase.
  • Adjunct studies
    • Genetic testing and sequencing to determine defective gene (does not affect treatment plan)
    • Transabdominal pelvic ultrasound
      • Evaluates status of Müllerian structures and ovaries
      • Shows streak gonads and normal Müllerian structures


  • Hormone replacement therapy (to induce normal female puberty and the development of normal secondary sexual characteristics):
    • Estrogen-based therapy
    • Cyclical estrogen and progestin replacement therapy (for 50 years)
  • Gonadectomy: indicated in all patients with Swyer syndrome due to risk of neoplasia in abnormal streak gonads
  • Psychotherapy
  • Fertility treatment
    • Only option for pregnancy is the use of donor ova
    • Since most patients with Swyer syndrome have a hypotrophic uterus, they will require an elective cesarean section at 36 weeks to avoid uterine rupture during labor.

Differential Diagnosis

The following conditions are differential diagnoses for Swyer syndrome:

  • Congenital adrenal hyperplasia: a group of rare autosomal recessive diseases characterized by defects in enzymes of the adrenal glands involved in cortisol, androgen, and aldosterone synthesis. Patients may present with a wide range of symptoms, including virilization in females, salt-wasting leading to hypotension and other electrolyte abnormalities, and premature completion of growth resulting in short stature.
  • Complete androgen insensitivity syndrome: an X-linked recessive condition in which a genetic mutation causes a complete resistance to testosterone. As a result, individuals with this disorder are genotypically a male with 46,XY karyotype, but without masculinization of external genitalia or virilization. It does not significantly impair female genital or sexual development.
  • Hypergonadotropic ovarian dysgenesis: also known as 46,XX ovarian dysgenesis, a primary defect of the development of the ovary that leads to premature ovarian failure in a woman with a normal karyotype (46,XX). The failure of gonadal development is caused by resistance to gonadotrophin stimulation.


  1. Harry Ostrer, MD. Swyer syndrome. NORD. Retrieved August 13, 2020, from https://rarediseases.org/rare-diseases/swyer-syndrome/
  2. Michala, L., Goswami, D., Creighton, S. M., & Conway, G. S. (2008). Swyer syndrome: Presentation and outcomes. BJOG: An International Journal of Obstetrics and Gynaecology, 115(6), 737–741. https://doi.org/10.1111/j.1471-0528.2008.01703.x
  3. Mohnach L, Fechner PY, Keegan CE. (2008 [Updated 2016 Jun 2]). Nonsyndromic Disorders of Testicular Development. GeneReviews®. https://www.ncbi.nlm.nih.gov/books/NBK1547/
  4. Swyer Syndrome. (2020). NIH, Genetics Home Reference. https://ghr.nlm.nih.gov/condition/swyer-syndrome#statistics
  5. Agarwal, A, Agarwal, S. (2017). Swyer Syndrome With Gonadoblastoma: A Clinicoradiological Approach. PubMed Central (PMC). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5405651/

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