Swyer syndrome

Alternate names

46, XY CGD; 46, XY complete gonadal dysgenesis; 46, XY pure gonadal dysgenesis; Gonadal dysgenesis, XY female type

Summary

Swyer syndrome is a genetic condition affecting sexual organ development, classified as a disorder of sex development (DSD). (SWY-er SIN-drome) A rare genetic condition in which people who have an X chromosome and a Y chromosome (the usual pattern for males) look female. They have normal female reproductive organs, including a uterus, fallopian tubes, and vagina. However, the ovaries do not develop and are replaced by clumps of tissue where they would normally form. Swyer syndrome is usually not diagnosed until puberty, when menstrual periods do not begin as they should. Having Swyer syndrome increases the risk of certain types of germ cell tumors. Adolescents with this condition do not go through normal puberty and are infertile.

Epidemiology

It has been estimated that 1 in 50,000 to 1 in 100,000 people are born with Swyer syndrome.The exact incidence is unknown.

Cause

Mutations in the SRY gene have been identified 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 sexual 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 mutations that cause Swyer syndrome prevent production of the sex-determining region Y protein or result in the production of a nonfunctioning protein. A fetus whose cells do not produce functional sex-determining region Y protein will not develop testes but will develop a uterus and fallopian tubes, despite having a typically male karyotype. Swyer syndrome can also be caused by mutations in the MAP3K1 gene; research indicates that mutations 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. These include the processes of determining sexual characteristics before birth. The mutations in this gene that cause Swyer syndrome decrease signaling that leads to male sexual differentiation and enhance signaling that leads to female sexual differentiation, preventing the development of testes and allowing the development of a uterus and fallopian tubes.

Mutations in the DHH and NR5A1 genes have also been identified in small numbers 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 the production of sex hormones and sexual differentiation. Mutations in the DHH and NR5A1 genes affect the process of sexual differentiation, preventing affected individuals with a typically male karyotype from developing testes and causing them to develop a uterus and fallopian tubes.

Changes affecting other genes have also been identified in a small number of people with Swyer syndrome. Nongenetic factors, such as hormonal medications taken by the mother during pregnancy, have also been associated with this condition. However, in most individuals with Swyer syndrome, the cause is unknown.

Inheritance

Most cases of Swyer syndrome are not inherited; they occur in people with no history of the condition in their family. These cases result either from nongenetic causes or from new (de novo) mutations in a gene that occur during the formation of reproductive cells (eggs or sperm) or in early embryonic development.

SRY-related Swyer syndrome is usually caused by a new mutation. However, some individuals with Swyer syndrome inherit an altered SRY gene from an unaffected father who is mosaic for the mutation. Mosaic means that an individual has the mutation in some cells (including some reproductive cells) but not in others. In rare cases, a father may carry the mutation 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 mutations is described as having a Y-linked inheritance pattern.

When Swyer syndrome is associated with an MAP3K1 or NR5A1 gene mutation, the condition is also usually caused by a new mutation. In the rare inherited cases, the mutation 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.

Swyer syndrome caused by mutations in the DHH gene is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition are carriers of one copy of the altered gene. Female carriers of a DHH gene mutation generally have typical sex development. Male carriers of a DHH gene mutation may also be unaffected, or they may have genital differences such as the urethra opening on the underside of the penis (hypospadias).

Signs and symptoms

Signs and symptoms may include:

• Female external genitals
• 46,XY chromosomes
• Delayed or absent puberty
• Absent menstrual periods (primary amenorrhea)
• Undeveloped ovaries or testes (streak gonads)

Most people with Swyer syndrome are raised and identify as female. They may have no symptoms until adolescence when they do not go through puberty and or start their periods. Hormone replacement therapy can help to develop secondary sexual characteristics such as breasts, pubic hair, and a regular menstrual cycle. People with Swyer syndrome are infertile, but may be able to get pregnant through egg donation and artificial reproductive technologies.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed.

80%-99% of people have these symptoms

• Hypogonadotropic hypogonadism
• Male pseudohermaphroditism
• Polycystic ovaries
• Testicular dysgenesis

Diagnosis

Swyer syndrome is diagnosed based on the medical history, clinical examination, presence of characteristic features, chromosome results, and imaging studies such as a MRI or CT scan. Often people with this condition are not diagnosed until adolescence or adulthood due to delayed puberty, not having menstrual cycles, or infertility. In some cases, Swyer syndrome is diagnosed at birth based on a prenatal test and ultrasound findings.

Treatment

The treatment of a person with Swyer syndrome may depend on the specific characteristics that each person has. Some people need surgery to repair the external genitalia and to create and/or enlarge the vagina.

Hormone replacement therapy (HRT) is typically needed from puberty onward and usually includes estrogen and progesterone. In addition to helping with normal development of secondary sexual characteristics, HRT can help prevent bone loss and thinning (osteoporosis) later in life.

Abdominal dysgenetic gonads (testes or ovaries with abnormal development) or streak gonads, which are common in people with Swyer syndrome, are at increased risk for gonadal tumors such as gonadoblastoma and should be surgically removed. Although women with Swyer syndrome are infertile, they may become pregnant and carry to term through egg donation.

Treatment for Swyer syndrome includes surgery to remove undeveloped gonads (streak gonads) and hormone replacement therapy during adolescence. Streak gonads are removed as soon as possible because of the risk of them becoming cancerous. Women with Swyer syndrome are infertile, but pregnancy is possible through egg donation and artificial reproductive technologies.

NIH genetic and rare disease info

• NIH info on Swyer syndrome

Swyer syndrome is a rare disease.

Swyer syndrome Resources
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