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Copyright 2008, 2012
NORD is very grateful to Harry Ostrer, MD, Director, Human Genetics Program, Professor of Pediatrics, Pathology and Medicine, New York University School of Medicine, for assistance in the preparation of this report.
Swyer syndrome is a rare disorder characterized by the failure of the sex glands (i.e., testicles or ovaries) to develop. Swyer syndrome is classified as a disorder of sex development (DSD), which encompasses any disorder in which chromosomal, gonadal or anatomic sex development is abnormal. Girls with Swyer syndrome have an XY chromosomal makeup (as boys normally do) instead of an XX chromosomal makeup (as girls normally do). Despite having the XY chromosomal makeup, girls with Swyer syndrome look female and have functional female genitalia and structures including a vagina, uterus and fallopian tubes.
Girls with Swyer syndrome lack sex glands (ovaries). Instead of sex glands, women with Swyer syndrome have "gonadal streaks", in which the ovaries do not develop properly (aplasia) and are replaced by functionless scar (fibrous) tissue. Because they lack ovaries, girls with Swyer syndrome do not produce sex hormones and will not undergo puberty (unless treated with hormone replacement therapy). Mutations in several different genes are known to cause Swyer syndrome. This condition can occur as the result of a new gene mutation or can be inherited in an autosomal dominant, autosomal recessive, X-linked or Y-linked manner.
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.
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.
Genes are sequences of DNA that are found on a specific location of a chromosome and are the basic unit of inheritance. Genes determine a particular characteristic or trait in a person. Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and called autosomes. The sex chromosomes are designated X and Y. Males usually have one X and one Y chromosome and females usually have two X chromosomes.
In approximately 15-20 percent of cases, Swyer syndrome occurs due to mutations of the sex-determining region Y (SRY) gene on the Y chromosome or deletion of the segment of the Y chromosome containing the SRY gene. The SRY gene is believed to be critical in initiating male sex determination by triggering undifferentiated gonadal tissue to transform into testes. Absence or mutation of this gene results in the failure of the testes to form.
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.
Some women with Swyer syndrome have mutations in the NROB1 gene on the X chromosome. Investigators have linked other cases of Swyer syndrome to mutations of the desert hedgehog (DHH) gene located on chromosome 12. A few rare cases have been associated with mutations in the steroidogenic factor 1 (SF1 or NR5A1) gene, the protein Wnt-4 (WNT4) gene, and the MAP3K1 gene. Researchers believe that additional, as yet unidentified, genes may also be associated with the development of Swyer syndrome.
Some cases of Swyer syndrome are not believed to be inherited, but rather the result of a new genetic mutation (de novo mutation) or abnormality that occurs for unknown reasons (spontaneously). However, some women with Swyer syndrome due to mutation of the SRY gene have had fathers (and some even brothers) who also have the SRY mutation on the Y chromosome. It is not known why, in these cases, the fathers and/or brothers did not develop Swyer syndrome. Researchers speculate that other genes and/or factors in combination with a mutation of the SRY gene may be necessary for the development of Swyer syndrome in these cases.
Cases of Swyer syndrome due to mutation of the NROB1 gene may be inherited an X-linked trait. 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.
According to the medical literature, some cases of Swyer syndrome appear to follow autosomal dominant or recessive inheritance. Mutations of the WNT4 gene or the SF1 (NR5A1) genes may be inherited as autosomal dominant traits. Mutation of the DHH gene may be inherited in an autosomal recessive manner.
Genetic diseases are determined by two genes, one received from the father and one from the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child.
Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25 percent.
Affected individuals are encouraged to seek genetic counseling for answers to any questions regarding the complex genetic factors involved in Swyer syndrome. For information on genetic counseling, see the Resources section of this report.
Swyer syndrome affects girls who have an XY chromosomal makeup, no ovaries, but functional female organs including the uterus, fallopian tubes and vagina. The exact incidence is unknown. One estimate placed the incidence at 1 in 80,000 births. 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.
Swyer syndrome was first described in the medical literature by Dr. Swyer in 1955.
Symptoms of the following disorders can be similar to those of Swyer syndrome. Comparisons may be useful for a differential diagnosis.
46, XY disorder of sex development is a rare congenital disorder in which individuals have a 46, XY chromosomal makeup, external genitalia that are not fully developed and/or may have characteristics of both sexes (ambiguous genitalia), and abnormal formation of the testes (partial gonadal dysgenesis) with reduced or no sperm production. Some individuals may have the urinary opening on the underside of the penis (hypospadias) with downward curvature of the penis (chordee). Some individuals may have complete absence of the Mullerian structures (vagina, uterus and fallopian tubes) to fully a developed uterus and fallopian tubes. Individuals with 46, XY DSD are at a greater risk than the general population of developing a gonadal tumor such as a gonadoblastoma or dysgerminoma.
Disorders of sex development (DSDs) is a general term for a group of congenital disorders in which the development of abnormal chromosomal, gonadal, or anatomic sex is atypical. Symptoms of these disorders can vary greatly, but can include ambiguous genitalia, female genitalia with an enlarged clitoris, male genitalia with undescended testes, micropenis, improper placement of the urinary opening on the underside of the penis (hypospadias), and a defect in the part of the embryo that develops into the lower abdominal wall (cloaca), potentially exposing lower abdominal and nearby structures such as the urethra, bladder and bowel (cloacal extrophy). This group of disorders includes complete or partial androgen insensitivity, 5-alpha reductase deficiency, congenital adrenal hyperplasia, ovotesticular DSD (formerly true hermaphroditism), and other disorders. The causes of these disorders vary. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
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.
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. Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
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.
Although women with Swyer syndrome are infertile, they may become pregnant and carry to term through the use of donated eggs.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
For information about clinical trials sponsored by private sources, contact:
Contact for additional information about Swyer syndrome:
Harry Ostrer, MD
Director, Human Genetics Program
Professor of Pediatrics, Pathology and Medicine
New York University Langone Medical Center and School of Medicine
550 First Avenue
New York, NY 10016
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Michala L, Goswami D, Creighton SM, Conway GS. Swyer syndrome: presentation and outcomes. BJOG. 2008;115:737-741.
Kohler B, Lin L, Ferraz-de Souza B, et al. Five novel mutations in steriodogenic factor 1 (SF1, NR5A1) in 46,XY patients with severe underandrogenization but without adrenal insufficiency. Hum Mutat. 2008;29:59-64.
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Ostrer H. (Updated September 15, 2009). 46,XY Disorder of Sex Development and 46,XY Complete Gonadal Dysgenesis. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2012. Available at http://www.genetests.org. Accessed May 29, 2012.
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. 46,XY Sex Reversal 1; SRXY1. Entry No: 400044. Last Edited October 6, 2011. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed May 29, 2012.
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Report last updated: 2012/05/29 00:00:00 GMT+0