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Gonadal dysgenesis is the name given to any of a multitude of conditions that can cause impaired development of the gonads, i.e., the testes or ovaries [1]. The most notable of these conditions is Turner syndrome, a disorder affecting 1 in every 2500 live female births, with an array of associated symptoms and complications [2]. Although there are many syndromes of which gonadal dysgenesis is a component, this article will focus on Turner syndrome, 46, XX, 46, XY, and mosaic forms of gonadal dysgenesis. Understanding the genetics behind gonadal dysgenesis allows clinicians to better predict the disorder’s phenotypic presentation, in turn, improving both screening methods for associated medical problems and the ongoing care of those medical problems. This article will explore the cellular, biochemical, and molecular basis behind the genetic processes that cause gonadal dysgenesis and study the clinical implications of this subset of disorders.

Gonadal dysgenesis develops due to genetic alterations leading to impaired gonadal development. When the gonads do not develop properly, it leads to issues in the development of both internal and external genitalia. All patients with gonadal dysgenesis will have at least some dysfunction within the hypothalamic-pituitary-gonadal axis. The hypothalamus secretes GnRH, which acts on the pituitary to release LH and FSH. LH and FSH act on the gonads, which in turn produce sex hormones in the form of estrogen and testosterone.[17] Due to a lack of gonadal development seen in gonadal dysgenesis, the gonads respond either minimally or not at all to LH and FSH stimulation, leading to decreased production of estrogen and testosterone as well as decreased production of ovarian follicles and sperm. Complete 46 XY gonadal dysgenesis in which the lack of the SRY gene activating the body’s processes to enact male development results in the body relies on the default processes which allow the Mullerian structures to develop internally. Mullerian structures develop into the female anatomy, including the fallopian tubes, uterus, and cervix. Due to the lack of testicular development in these males, there is a lack of testosterone production, which inhibits the development of male external genitalia, so these males will tend to present with female external genitalia. Patients with incomplete or partial 46 XY gonadal dysgenesis, or patients with mosaic forms of the disease with a Y chromosome, it appears that there is a mixture of development of both male and female internal genitalia. In the 46 XY with incomplete gonadal dysgenesis, it appears there is incomplete differentiation of the internal genitalia likely due to insufficient amounts of testosterone and Mullerian inhibiting hormone during the early stages of development. These patients range from having non-functional streak gonads to partially functioning gonads due to the incomplete development. Patients with mosaic forms of the disease, as seen in Turner syndrome with cell lines containing a Y chromosome, will also have a mixture of development resulting in partial or non-functioning gonads and internal genitalia. These patients will have ambiguous external genitalia due to the reduced influence of the Y chromosome.[7]

Complete 46 XY gonadal dysgenesis in which the lack of the SRY gene activating the body’s processes to enact male development results in the body relies on the default processes which allow the Mullerian structures to develop internally. Mullerian structures develop into the female anatomy, including the fallopian tubes, uterus, and cervix. Due to the lack of testicular development in these males, there is a lack of testosterone production, which inhibits the development of male external genitalia, so these males will tend to present with female external genitalia. Patients with incomplete or partial 46 XY gonadal dysgenesis, or patients with mosaic forms of the disease with a Y chromosome, it appears that there is a mixture of development of both male and female internal genitalia. In the 46 XY with incomplete gonadal dysgenesis, it appears there is incomplete differentiation of the internal genitalia likely due to insufficient amounts of testosterone and Mullerian inhibiting hormone during the early stages of development. These patients range from having non-functional streak gonads to partially functioning gonads due to the incomplete development. Patients with mosaic forms of the disease, as seen in Turner syndrome with cell lines containing a Y chromosome, will also have a mixture of development resulting in partial or non-functioning gonads and internal genitalia. These patients will have ambiguous external genitalia due to the reduced influence of the Y chromosome.[7] Patients with complete 46 XX gonadal dysgenesis will tend to have female internal and external genitalia and will typically have streaked or hypoplastic ovaries.[7] Turner syndrome patients have the same processes that affect their gonadal development resulting in atrophy of the ovarian follicles and the development of streak ovaries. As discussed above, due to the gonads being unresponsive to FSH and LH, female patients with gonadal dysgenesis will have amenorrhea, and most will be infertile. Some cases of spontaneous pregnancy in mosaic Turner syndrome patients have been documented, likely due to the partial functioning of the ovary.[4] Males with gonadal dysgenesis will also tend to be infertile due to underdeveloped or lack of testes. The symptoms other than gonadal dysgenesis seen in syndromes such as Turner syndrome are due to the mutations and alterations in some of the secondary genes described above, for example, the short stature seen in Turner syndrome, which is believed to be caused by decreased sensitivity to growth hormone, decreased availability of growth hormone, or decreased production of growth hormone.[10]