Biology of DSDs: Swyer Syndrome

Description

Swyer syndrome, also known as Complete Gonadal Dysgenesis, is a sex development condition which affects individuals with a 46,XY karyotype. Because there is no testicular tissue to produce anti-Mullerian hormone and testosterone, individuals with Swyer develop female reproductive structures.

If you want to help improve medical research and psychological support for individuals with these conditions, you can donate to DSDFamilies (https://dsdfamilies.org/donate).

Sources

[1] NIH. (2020). Swyer syndrome. Genetics Home Reference, National Library of Medicine.

[2] Jones, R., Lopez, K. (2014). Chapter 5: Sexual differentiation. Human Reproductive Biology, 4th edition. Elsevier. 95.

[3] LOCAH. (2018). The intersex masterpost. Medium.

[4] NIH. (2020). Swyer syndrome. Genetic and Rare Diseases Information Center.

[5] Azidah, AK. (2013). Swyer syndrome in a woman with 46,XY gonadal dysgenesis. Malaysian Family Physician, 8(2).

[6] Bagci, G., et al. (2011). Complete gonadal dysgenesis 46,XY (Swyer syndrome) in two sisters. Amer Soc Repro Med.

[7] Michala, L., et al. (2008). Swyer syndrome, presentation and outcomes. Journal of Obstetrics and Gynecology, 115(6).

[8] Nollman, J. (2013). An intersex story from X to Y. AIS DSD Support Group.

[9] Taneja, J., et al. (2016). Rare successful pregnancy in a patient with Swyer Syndrome.

AIS support group:

https://www.aisdsd.org

Transcript

Swyer syndrome, also known as Complete Gonadal Dysgenesis, is a sex development condition which affects individuals with a 46,XY karyotype. Because there is no testicular tissue to produce anti-Mullerian hormone and testosterone, individuals with Swyer develop female reproductive structures, such as a uterus, fallopian tubes, cervix, and vagina. Swyer syndrome is one of the rarest DSDs, affecting every 1 and 80,000 newborns--a rate of around 0.001% of births.

At conception, the chromosome set for Swyer begins with the typical 46,XY. Most cases are not inherited. Rather, Swyer is caused by random mutations in various transcription factors required for male sex development. For example, around 15 percent of cases involve a mutation in the SRY gene on the Y chromosome, the sex determining region Y protein which triggers gonadal differentiation into testes.

Without testes, female reproductive development proceeds. Around 18 percent of cases involve a mutation in the MAP3K1 gene on chromosome 5. MAP3K1 is involved in, among other things, regulating sex differentiation before birth.

According to the National Library of Medicine, the mutations in this gene that cause Swyer syndrome decrease signaling that leads to male sex differentiation and enhance signaling that leads to female sex differentiation. Other gene mutations have been implicated in Swyer, such as mutations in the DHH gene (located on chromosome 12) and the NR5A1 gene (located on chromosome 9), though these are less common. For this video, we'll explore Swyer syndrome resulting from SRY mutation.

Around the 8th week after conception, the 46,XY fetus undergoes gonadal differentiation. Because the SRY gene on the Y chromosome is non-functional, the bipotential gonads do not differentiate into testes. The lack of two X chromosomes means that the gonads cannot differentiate into ovaries either, resulting in undeveloped clumps of tissue called streak gonads. This phenomenon is called complete gonadal dysgenesis. With no testes present to produce the anti-Mullerian hormone and testosterone necessary for male reproductive development, the Wolffian structure (which would have formed the epididymis, vas deferens, and seminal vesicle) disintegrates, and the Mullerian structure (which forms the fallopian tubes, uterus, cervix, and upper part of the vagina) develops.

Thanks to the mutations in SRY, and no anti-Mullerian hormone, the fetus develops a Mullerian reproductive system and female external genitalia.

Swyer syndrome is usually not diagnosed at birth. Like MRKH, which results in underdeveloped Mullerian structures, the common indicator for Swyer is that affected young women never start their periods. Thus, most diagnoses occur between 15 and 18 years old.

The diagnostic process utilizes a pelvic ultrasound to see whether the uterus is present and an MRI to show more detailed imagery of the internal reproductive anatomy. During imaging, doctors will usually see that the patient has developed female reproductive anatomy but is missing developed ovaries. This is the opposite of MRKH, where patients usually have fully developed ovaries but an underdeveloped or absent uterus. Clinicians will utilize karyotype and hormone testing to narrow the diagnosis.

For Swyer, the karyotype will come back with 46,XY, rather than 46,XX, confirming the adolescent does not have MRKH. Once diagnosed, the doctors will refer the patient to a pediatric or adolescent gynecologist and other specialists for treatment.

The treatments for Swyer syndrome depend on the specific characteristics of the affected patient. Hormone replacement therapy (HRT) is the most common. HRT with estrogen and progesterone is typically needed to induce menstruation and the development of female secondary sex characteristics. HRT can also help mitigate the risk of reduced bone density later in life.

Because of the non-functioning gonads, women with Swyer are usually infertile. However, thanks to the development of the Mullerian structure, including the fallopian tubes, uterus, cervix, and vagina, many affected women can become pregnant and carry to term through egg donation and advanced reproductive technologies.

There are important psychological issues to address if one is diagnosed with Swyer syndrome. Like all other DSDs, it is critical that a diagnosis is not withheld from the patient. Doctors and parents have a moral obligation to inform the patient of the diagnosis as soon as possible. The method and timing of providing information depends upon the patient's age and cognitive development. If the DSD is diagnosed during adolescence, the parents and patient are usually told immediately.

Second, the most critical part of informing a patient with Swyer is that she understands she is a healthy woman like her XX counterparts. Thanks to the absence of testosterone and AMH and the presence of the Mullerian structure, her physical development is female.

In all, women with Swyer have a 46,XY karyotype with an inactive SRY gene or other inactive male coding genes, and therefore develop as females. With loving support from parents and peers, experts in psychology and counseling, and professional treatments with hormone replacement therapy and advanced reproductive technologies, women with Swyer can live healthy lives and be secure in their own bodies.

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© 2020 Zachary A. Elliott, All Rights Reserved.