Swyer syndrome
Swyer syndrome also called 46XY complete gonadal dysgenesis (lack of development of the gonads), is a condition in which people with one X chromosome and one Y chromosome (normally present in males) have a female appearance. 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 usually have one X chromosome and one Y chromosome (46,XY karyotype). In Swyer syndrome, individuals with one X chromosome and one Y chromosome in each cell, the pattern typically found in boys and men, have female reproductive structures. People with Swyer syndrome have typical female external genitalia. The uterus and fallopian tubes are normally-formed, but the gonads (ovaries or testes) are not functional; affected individuals have undeveloped clumps of tissue called streak gonads. Streak gonads often become cancerous, so they are usually surgically removed as early as possible. In addition to removal of streak gonads, treatment may include hormone replacement therapy from puberty onward.
People with Swyer syndrome are typically raised as females, have a female gender identity, and have typical female external genitalia. The uterus and Fallopian tubes may be normal, or they may be small or underdeveloped 1. Because they do not have functional ovaries, affected individuals usually begin hormone replacement therapy during adolescence to induce menstruation and development of female secondary sex characteristics such as breast enlargement and uterine growth. Hormone replacement therapy also helps reduce the risk of reduced bone density (osteopenia and osteoporosis). Women with Swyer syndrome do not produce eggs (ova) and are infertile, but they may be able to become pregnant with a donated egg or embryo 2.
Swyer syndrome may be caused by mutations in any of several genes. The inheritance pattern depends on the responsible gene 3.
Swyer syndrome usually affects only sexual development; such cases are called isolated Swyer syndrome. However, depending on the genetic cause, Swyer syndrome may also occur along with health conditions such as nerve problems (neuropathy) or as part of a syndrome such as campomelic dysplasia, which causes severe skeletal abnormalities.
Swyer syndrome occurs in approximately 1 in 80,000 people 4. Another estimate placed the incidence of Swyer syndrome (complete gonadal dysgenesis) and partial gonadal dysgenesis combined at 1 in 20,000 births. Genital anomalies in general occur in approximately 1 in 4,500 births.
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 5. In addition to helping with normal development of secondary sexual characteristics, hormone replacement therapy 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 5.
Is it possible for someone with Swyer syndrome to naturally start their period at a typical age (13)?
Spontaneous menstruation has been reported in people with Swyer syndrome 6. While people with Swyer syndrome typically have functional female genitalia and structures including a vagina, uterus and fallopian tubes, they typically do not have ovaries and are therefore infertile 7. For this reason, they ordinarily do not produce sex hormones and will not undergo puberty (including starting menstruation) unless treated with hormone replacement therapy 7. In most cases, Swyer syndrome is not diagnosed until the early teens because a girl with Swyer syndrome does not start her period (primary amenorrhea) 7. However, there have been a few reports in the medical literature of girls with Swyer syndrome having spontaneous menstrual cycles 6.
It has been suggested that normal pubertal development (including spontaneous menstruation) in people with Swyer syndrome may be associated with the presence of a hormonally active tumor 6. It has been reported that both male and female sex steroids may be produced by gonadoblastoma and that gonadoblastoma is often the source of hormones in females with an 46,XY karyotype 6. Gonadoblastoma is a benign tumor but it has the potential for malignant transformation (turning cancerous). Having Swyer syndrome is a known risk factor for the development of this type of tumor. Spontaneous menstruation due to neoplastic estrogen secretion in general has also been reported 6.
Should streak gonads be removed in individuals with Swyer syndrome?
It is typically recommended that individuals with streak gonads have them surgically removed. Individuals with streak gonads are at an increased risk for gonadal tumors 7.
Is it possible for a patient with Swyer syndrome to get pregnant? If so, what methods should be used to ensure a successful pregnancy?
Yes. Although women with Swyer syndrome are infertile, they may become pregnant and carry to term through egg donation and subsequent assisted reproductive technology (ART). Several successful pregnancies in women with Swyer syndrome have been described in the literature 8. Through hormone management, the uterus can achieve almost normal dimensions and is able to sustain pregnancy. However, it is still unclear whether the anatomic properties of the uterus would permit normal dilatation and labor 9. C-section has thus been the method of delivery in affected women 9. Based on reports, those with non-mosaic pure 46,XY gonadal dysgenesis do not appear to be at increased risk for adverse pregnancy outcomes other than those associated with C-section. However, additional reports of pregnancy outcomes in people with Swyer syndrome are needed to expand our knowledge and better define any specific risks 8.
Can women with Swyer syndrome experience orgasms?
There have been conflicting reports regarding the sexual experiences of individuals affected by disorders of sexual development . Some reports have stated that the majority of individuals with 46,XY disorders of sexual development (including Swyer syndrome) experience increased sexual problems and impairment of sexual function; others report that the majority of individuals with DSD report having experienced orgasm 10. More specifically, a 2006 study by McCarty et al 11 which investigated the psychosexual outcome of 3 women with Swyer syndrome stated that all 3 affected women reported the ability to achieve orgasm. Although these reports do not specify that affected individuals can regularly reach climax during sexual activity, they do indicate that women with Swyer syndrome can experience orgasm 10.
Swyer syndrome causes
In most cases of Swyer syndrome, the exact cause of the disorder is unknown. Researchers believe that disruptions or changes (mutations) of a gene or genes that are involved in normal sex differentiation of a fetus with an XY chromosomal makeup cause Swyer syndrome.
Mutations in the sex-determining region Y (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.
Since only 15-20 percent of women with Swyer syndrome have a mutation of the SRY gene, researchers believe that defects involving other genes can also cause the disorder. These other genes are all suspected to play a role in the promoting the development of the testes and, ultimately, the differentiation of an XY fetus into a male.
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.
Some women with Swyer syndrome have mutations in the NROB1 gene on the X chromosome.
Mutations in the desert hedgehog (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.
Swyer syndrome inheritance pattern
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.
Cases of Swyer syndrome due to mutation of the NROB1 gene may be inherited in an X-linked pattern. X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome. Females usually have two X chromosomes and one of the X chromosomes is “turned off” and all of the genes on that chromosome are inactivated. Females who have a disease gene present on one of their X chromosomes usually do not display symptoms of the disorder because it is usually the X chromosome with the abnormal gene that is “turned off”. However, because women with Swyer syndrome have an XY chromosomal makeup and lack a second X chromosome, they will express symptoms associated with a defect on their one X chromosome.
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).
People with specific questions about genetic risks or genetic testing for themselves or family members should speak with a genetics professional.
Resources for locating a genetics professional in your community are available online:
- The National Society of Genetic Counselors (https://www.findageneticcounselor.com/) offers a searchable directory of genetic counselors in the United States and Canada. You can search by location, name, area of practice/specialization, and/or ZIP Code.
- The American Board of Genetic Counseling (https://www.abgc.net/about-genetic-counseling/find-a-certified-counselor/) provides a searchable directory of certified genetic counselors worldwide. You can search by practice area, name, organization, or location.
- The Canadian Association of Genetic Counselors (https://www.cagc-accg.ca/index.php?page=225) has a searchable directory of genetic counselors in Canada. You can search by name, distance from an address, province, or services.
- The American College of Medical Genetics and Genomics (http://www.acmg.net/ACMG/Genetic_Services_Directory_Search.aspx) has a searchable database of medical genetics clinic services in the United States.
Swyer syndrome symptoms
Most individuals with Swyer syndrome do not experience any outward symptoms until their early teens when they fail to begin having a period (primary amenorrhea). At this point, it is usually discovered that these girls lack ovaries and, therefore, do not have sex hormones (estrogen or progesterone) that are required to undergo puberty. When hormone replacement therapy is started, these girls will develop enlarged breasts, underarm and pubic hair, regular menstrual cycles and other aspects of normal development during puberty.
Women with Swyer syndrome may be tall and often have a small uterus and a slightly enlarged clitoris in comparison to most women. Because women with Swyer syndrome lack ovaries, they are infertile. However, they can become pregnant through the implantation of donated eggs.
A chief medical concern of women with Swyer syndrome is an increased risk of developing cancer of the underdeveloped gonadal tissue. Approximately 30 percent of women with Swyer syndrome develop a tumor that arises from the cells that forms the testes or ovaries (gonadal tumor). The most common gonadal tumor in women with Swyer syndrome is a gonadoblastoma, a benign (non-cancerous) tumor that occurs exclusively in people with defective development of the gonads. A gonadoblastoma usually does not become malignant or spread. Gonadoblastomas, however, may be precursors to the development of a malignant (cancerous) tumor such as a dysgerminoma, which has also been reported to occur with greater frequency in women with Swyer syndrome than in the general population.
Gonadal tumors can develop at any age including during childhood before a diagnosis of Swyer syndrome is even suspected.
Swyer syndrome diagnosis
A diagnosis of Swyer syndrome is made based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic findings (e.g., no periods, streak gonads) and a variety of tests including chromosomal analysis. For example, a specific technique called fluorescent in situ hybridization (FISH) can be used to determine a person’s karyotype. A karyotype is a visual representation of a person’s chromosomal makeup, (i.e., the 46 chromosomes in a cell). These 46 chromosomes are broken down into 22 matched pairs (each pair has one chromosome received from the father and one receive from the mother). The sex chromosomes are seen as a separate pair, either XX or XY. A diagnosis of Swyer syndrome is usually made when young adults are tested for delayed puberty.
Molecular genetic testing can determine whether one of the specific gene mutations that are associated with Swyer syndrome is present in an affected individual.
Evaluation of immediate family members of an affected person can be helpful in determining if the condition is sporadic or inherited in that family.
Swyer syndrome treatment
The treatment of Swyer syndrome may require the coordinated efforts of a team of specialists. Pediatricians, pediatric endocrinologists, geneticists, urologists or gynecologists, psychologists or psychiatrists, social workers and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment.
Swyer syndrome is treated with hormonal replacement therapy including replacing estrogen and progesterone that is usually begun from puberty onward. In addition to helping with normal development of secondary sexual characteristics, hormone replacement therapy can also help prevent bone loss and thinning (osteoporosis) later during life.
Streak gonads are usually removed surgically because they place affected individuals at an increased risk of developing a gonadal tumor.
Individuals with SF1 mutations may have adrenal insufficiency. This should be investigated and treated, if present.
Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive.
Although women with Swyer syndrome are infertile, they may become pregnant and carry to term through the use of donated eggs.
References- Azidah AK, Nik Hazlina NH, Aishah MN. Swyer syndrome in a woman with pure 46, XY gonadal dysgenesis and a hypoplastic uterus. Malays Fam Physician. 2013; 8(2):58-61. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4170479
- Swyer syndrome. https://rarediseases.org/rare-diseases/swyer-syndrome/
- Salete Da Silva Rios, et. al. A Case of Swyer Syndrome Associated with Advanced Gonadal Dysgerminoma Involving Long Survival. Case Rep Oncol. January-April, 2015; 8(1):179-184.
- Swyer syndrome. https://ghr.nlm.nih.gov/condition/swyer-syndrome
- Mohnach L, Fechner PY, Keegan CE. Nonsyndromic Disorders of Testicular Development. 2008 May 21 [Updated 2016 Jun 2]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1547
- Çatli G. et. al. An Unusual Presentation of 46,XY Pure Gonadal Dysgenesis: Spontaneous Breast Development and Menstruation. J Clin Res Pediatr Endocrinol. June, 2015; 7(2):159-162.
- Swyer syndrome. https://rarediseases.org/rare-diseases/swyer-syndrome
- Tulic I, Tulic L, Micic J. Pregnancy in patient with Swyer syndrome. Fertil. Steril. April 2011; 95(5):1789.e1-2.
- Creatsas G, Deligeoroglou E, Tsimaris P, Pantos K, Kreatsa M. Successful pregnancy in a Swyer syndrome patient with preexisting hypertension. Fertil. Steril. August 2011; 96(2:e83-5.
- Schonbucher V, Schweizer K, Richter-Appelt H. Sexual quality of life of individuals with disorders of sex development and a 46,XY karyotype: a review of international research. J Sex Marital Ther. 2010; 36(3):193-215.
- Bryan M. McCarty, Claude J. Migeon, Heino F.L. Meyer-Bahlburg, Howard Zacur and Amy B. Wisniewski. Medical and Psychosexual Outcome in Women Affected by Complete Gonadal Dysgenesis. Journal of Pediatric Endocrinology & Metabolism. 2006; 19:873-877.
