Swyer Syndrome · What Is It, Causes, Diagnosis, Treatment, and More

Swyer syndrome, also known as complete gonadal dysgenesis (CGD), is a rare congenital disorder of sex development (DSD). These conditions, also referred to as differences in sex development, occur when individuals present inconsistencies among their genetic sex (i.e., XX or XY chromosomes), reproductive organs, and external genitalia. The previous terminology for DSDs includes terms like hermaphrodite or intersex. However, these terms can be considered derogatory, so they are no longer in common use. 

In Swyer syndrome, individuals have a 46, XY karyotype, so they are genetically considered male, but they develop female external genitalia and reproductive structures and have nonfunctional gonads instead of ovaries or testes. 

Swyer syndrome results from mutations in genes that are involved in sex development. Normally, during the first trimester of fetal life, the gonads develop into either testes or ovaries depending on whether a person has an XY or XX karyotype. In males, a gene on the Y chromosome called the sex-determining region Y or SRY gene, helps the fetal gonads turn into testes. Once developed, the testes start producing androgens like testosterone, which are mainly responsible for development of male external genitalia. Internally, there’s a set of ducts called Wolffian and Mullerian ducts. Testosterone also causes the Wolffian ducts to differentiate into the male reproductive system. At the same time, the testes also produce a hormone called anti-Müllerian hormone, which prevents the Müllerian ducts from developing into the female reproductive system and instead makes them degenerate. In females, since there is no Y chromosome, the SRY gene is absent. As a result, the ovaries develop from the internal gonads, and androgen levels remain relatively low, so they develop female external genitalia. 

Between 15–20% of individuals with Swyer syndrome have mutations in the SRY gene. When the SRY gene is mutated or nonfunctional, testes fail to develop, and the fetus follows the default pathway of female sexual development, despite having an XY karyotype. 

In many other cases, the SRY gene is unaffected and mutations in other genes involved in the sex-determining pathways are often implicated (e.g., SOX9, NR5A1, MAP3K1, DHH).  

Swyer syndrome is most often sporadic, meaning it arises from a new, or de novo, mutation, with no previous family history. Rarely, mutations in the SRY gene can be inherited from the father, who may have a mosaic Y chromosome or have a partial form of gonadal dysgenesis. Because the mutation lies on the Y chromosome, it can only be passed from father to an XY child. Other genes involved in Swyer syndrome can follow autosomal dominant, autosomal recessive, or X-linked inheritance, depending on the specific mutation. 

Even when a person is the first in their family with Swyer syndrome, genetic testing can help identify if the condition might be inherited. If parental mosaicism is suspected (e.g., a parent carries a mutation in only some of their cells), genetic counseling is also recommended as there may be a risk of recurrence in their descendants.  

Although individuals with Swyer syndrome develop a vagina, uterus, and female external genitalia, they do not have functional ovaries. Instead, they have what is known as streak gonads, in which the incomplete development of the ovaries leads to their replacement by functionless tissue that does not secrete sex hormones.  

Due to the lack of ovaries, individuals with Swyer syndrome cannot conceive naturally. However, with the help of donated eggs and assistive reproductive techniques (e.g., in-vitro fertilization), individuals with Swyer syndrome can still carry to term and give birth.  

In addition, individuals with Swyer syndrome typically do not undergo puberty due to low levels of  estrogen and progesterone, which are required for the development of secondary sex characteristics like breast enlargement. Swyer syndrome also increases the risk of developing gonadal tumors in late adulthood, which can progress to invasive carcinomas of the streak gonads. If left untreated, tumors of the gonads can affect the reproductive system by increasing in size or by spreading cancerous cells to other abdominal organs.  

The diagnosis of Swyer syndrome is made based upon a thorough medical history, clinical evaluation, identification of characteristic findings (e.g. no menstruation, streak gonads), and a variety of tests. Although affected individuals are born with Swyer syndrome, diagnosis rarely occurs at birth. Most cases are diagnosed in their teens, when tested for delayed puberty or primary amenorrhea.   

Oftentimes, imaging is suggested to identify the internal reproductive organs. Initially, an ultrasound is usually performed, followed by MRI if the ultrasound findings are concerning or unclear. For further investigation, diagnostic laparoscopy can be performed, which is a minimally invasive surgical procedure that provides a clear view of the abdominal organs through a few small incisions. 

Chromosomal analysis is often performed to confirm the diagnosis of Swyer syndrome. A specific procedure that requires the identification of each chromosome, called fluorescent in situ hybridization (FISH) can be used to determine their 46XY karyotype. Additional genetic analysis may be performed to identify the specific mutation leading to Swyer syndrome. 

Treatment for Swyer syndrome focuses on supporting healthy development, preventing complications, and affirming identity. 

In most cases, treatment involves hormonal replacement therapy, including the replacement of estrogen and progesterone, the two main hormones that are produced by the ovaries. When possible, this therapy usually begins at the ages associated with puberty, in order to induce menstruation and the development of secondary XX-related characteristics, such as breast enlargement, and body hair. Hormone replacement therapy can also help prevent bone loss (i.e. osteoporosis) later in life, as estrogens play an important role in the growth and maturation of the bones. 

In order to mitigate the risk of cancer, streak gonads are often removed surgically to avoid a gonadal malignancy. 

Finally, it is important to remember that receiving a diagnosis of Swyer syndrome can be emotionally complex, especially if it happens during adolescence or adulthood. Once a diagnosis is established, psychosocial and emotional support are an essential part of care.