Swyer syndrome is a condition that affects sex development. Sex development usually follows a particular path based on an individual's chromosomes; however, in Swyer syndrome, sex development is not typical for the affected individual's chromosomal pattern.
People usually have 46 chromosomes in each cell. Two of the 46 chromosomes, known as X and Y, are called sex chromosomes because they help determine whether a person will develop male or female sex characteristics. Girls and women typically have two X chromosomes (46,XX karyotype), while boys and men typically have one X chromosome and one Y chromosome (46,XY karyotype). In Swyer syndrome, individuals have one X chromosome and one Y chromosome in each cell, which is the pattern typically found in boys and men; however, they have female reproductive structures.
People with Swyer syndrome have female external genitalia and some female internal genitalia; the uterus and fallopian tubes are normally-formed, but the gonads (ovaries or testes) are not functional. Instead, the gonads are small and underdeveloped and contain little gonadal tissue. These structures are called streak gonads. The streak gonadal tissue is at risk of developing hard-to-detect cancers, so it is usually removed surgically. Swyer syndrome is sometimes called 46,XY complete gonadal dysgenesis; the medical term “dysgenesis” indicates that development (in this condition, development of the gonads) is reduced and not typical.
People with Swyer syndrome are usually raised as girls and have a female gender identity. Swyer syndrome may be identified before birth, at birth, or later when a child does not go through puberty as usual. Because they do not have functional ovaries that produce hormones, affected individuals often begin hormone replacement therapy during adolescence to start puberty, causing the breasts and uterus to grow, and eventually leading to menstruation. Hormone replacement therapy also stimulates bone development and helps reduce the risk of abnormally low bone density (osteopenia and osteoporosis). Women with Swyer syndrome do not produce eggs (ova), but they may be able to become pregnant with a donated egg or embryo.
In most individuals with Swyer syndrome, the cause is unknown. However, variants (also known as mutations) in one of several genes have been found to cause the condition in some affected individuals.
Variants in the SRY gene have been found in approximately 15 percent of individuals with Swyer syndrome. The SRY gene, located on the Y chromosome, provides instructions for making the sex-determining region Y protein. This protein is a transcription factor, which means it attaches (binds) to specific regions of DNA and helps control the activity of particular genes. The sex-determining region Y protein starts processes that are involved in male-typical sex development. These processes cause a fetus to develop male gonads (testes) and prevent the development of female reproductive structures (uterus and fallopian tubes). SRY gene variants that cause Swyer syndrome prevent production of the sex-determining region Y protein or result in the production of a nonfunctioning protein. Without functional sex-determining region Y protein, a fetus will not develop testes but will develop a uterus and fallopian tubes, despite having an X and a Y chromosome.
Swyer syndrome can also be caused by variants in the MAP3K1 gene; research indicates that variants in this gene may account for up to 18 percent of cases. The MAP3K1 gene provides instructions for making a protein that helps regulate signaling pathways that control various processes in the body, including processes of determining sex characteristics before birth. The variants in the MAP3K1 gene that cause Swyer syndrome decrease signaling that leads to male-typical sex development and enhance signaling that leads to female-typical sex development. These changes in signaling prevent the development of testes and allow the development of a uterus and fallopian tubes.
Variants in the DHH and NR5A1 genes have also been identified in a small percentage of people with Swyer syndrome. The DHH gene provides instructions for making a protein that is important for early development of tissues in many parts of the body. The NR5A1 gene provides instructions for producing another transcription factor called the steroidogenic factor 1 (SF1). This protein helps control the activity of several genes related to sex development and the production of sex hormones. Variants in the DHH and NR5A1 genes disrupt the process of sex development, preventing affected individuals with a 46,XY karyotype from developing testes and causing them to develop a uterus and fallopian tubes.
Changes affecting other genes have also been identified in a few people with Swyer syndrome. Nongenetic factors, such as hormonal medications taken by the mother during pregnancy, have very rarely been associated with this condition.
Additional Information from NCBI Gene:
Swyer syndrome occurs in approximately 1 in 80,000 people.
Most cases of Swyer syndrome are not inherited; they occur in people with no history of the condition in their family. These cases often result from new (de novo) variants in a gene that occur during the formation of reproductive cells (eggs or sperm) or in early embryonic development. Noninherited cases can also result from nongenetic causes.
SRY-related Swyer syndrome is usually caused by a new variant. However, some individuals with Swyer syndrome inherit an altered SRY gene from an unaffected father who is mosaic for the variant. Mosaic means that an individual has the variant in some cells (which can include some reproductive cells) but not in others. In rare cases, a father may carry the variant in every cell of the body but also has other genetic variations that prevent him from being affected by the condition. Because the SRY gene is on the Y chromosome, Swyer syndrome caused by SRY gene variants is described as having a Y-linked inheritance pattern.
When Swyer syndrome is associated with an MAP3K1 or NR5A1 gene variant, the condition is also usually caused by a new variant. In the rare inherited cases, the variant may be inherited from either parent, since these genes are not on the Y chromosome. In these cases, the condition has an autosomal dominant pattern of inheritance, which means one copy of the altered gene in each cell is sufficient to cause the condition. However, the parent with the genetic variant typically does not have signs and symptoms.
Swyer syndrome caused by variants in the DHH gene is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have variants. The parents of an individual with an autosomal recessive condition each have one copy of the altered gene. Females with one DHH gene variant generally have typical sex development. Males with one DHH gene variant may also be unaffected, or they may have genital differences such as the urethra opening on the underside of the penis (hypospadias).