Gonadal Dysgensis

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Gonadal dysgenesis refers to conditions that cause impaired or defective formation of the gonads, with clinical manifestations and varying degrees of genital ambiguity determined by the level of dysfunction or malformation. The complex process of sex determination and differentiation is dependent on specific responses to hormones produced by the gonads (1). Thus, any sex chromosome aberration or mutations in genes involved in this process can lead to complete or partial loss of gonadal development, hence dictating the variable phenotypic expression and disorders of sexual development. Depending on the resulting gonad morphology, the different forms of gonadal dysgenesis can be classified as either complete or partial.

Conditions causing gonadal dysgenesis are rare, some of which are associated with well-defined syndromes. Among these conditions, Turner syndrome (TS) and its variants are most notable and will be the focus in this review. TS is relatively more common than other forms of gonadal dysgenesis with a female phenotype. TS represents issues that are common to most of these conditions, namely issues with puberty and sexual maturation, ovarian failure, and limitations of future fertility. Additionally, TS may present with comorbid conditions, which are unique among the gonadal dysgenesis disorders, such as aortic malformation and renal dysgenesis, among other, this must be considered in the clinical management of TS.


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 patients, 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. Mutations in the Map3K1 are also a common cause of Swyer syndrome.

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. Mutations in the DEAH37 gene have been identified as a common cause. 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 CBX2, GATA4 and WWOX genes. 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 patients.

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.

According to the medical literature, some cases of Swyer syndrome appear to follow autosomal dominant or recessive inheritance. Mutations of the WNT4, MAP3K1 or the SF1 (NR5A1) genes may be inherited in as autosomal dominant pattern. Mutation of the DHH gene may be inherited in an autosomal recessive manner.

Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular 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 an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females. In some individuals, the disorder is due to a spontaneous (de novo) genetic mutation that occurs in the egg or sperm cell. In such situations, the disorder is not inherited from the parents.

Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits 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 altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.

All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.

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.

Risk factors

Abnormal development of a gonad (ovary or testicle). Men with gonadal dysgenesis have a greater risk of developing testicular cancer. Gonadal dysgenesis is usually part of a genetic syndrome

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In patients with gonadal dysgenesis that contains Y chromosomal material, there is also an increased risk for the development of gonadoblastoma, dysgerminoma, teratoma, and choriocarcinoma, which requires removal of the gonads early on in life to prevent tumor formation.