XY gonadal dysgenesis

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XY gonadal dysgenesis
Other namesSwyer syndrome
PBB Protein SRY image.jpg
Protein SRY
Specialty Medical genetics

XY complete gonadal dysgenesis, also known as Swyer syndrome, is a type of defect hypogonadism in a person whose karyotype is 46,XY. Though they typically have normal vulvas, [1] the person has underdeveloped gonads, fibrous tissue termed "streak gonads", and if left untreated, will not experience puberty. The cause is a lack or inactivation of an SRY gene which is responsible for sexual differentiation. Pregnancy is sometimes possible in Swyer syndrome with assisted reproductive technology. [2] [3] [4] The phenotype is usually similar to Turner syndrome (45,X0) due to a lack of X inactivation. The typical medical treatment is hormone replacement therapy. [5] The syndrome was named after Gerald Swyer, an endocrinologist based in London.

Contents

Signs and symptoms

Those with Swyer syndrome develop phenotypes typical of females and in most cases, non-reproductive gonads. Individuals are most commonly diagnosed during adolescence after puberty fails to occur. [6]

The consequences of Swyer syndrome without treatment:

Genetics

Genetic associations of Swyer syndrome include:

Type OMIM GeneLocus
46,XY gonadal dysgenesis, complete, SRY-related 400044 SRY Yp11.3
46,XY gonadal dysgenesis, complete or partial, DHH-related 233420 DHH 12q13.1
46,XY gonadal dysgenesis, complete or partial, with or without adrenal failure 612965 NR5A1 9q33
46,XY gonadal dysgenesis, complete, CBX2-related 613080 CBX2 17q25
46,XY gonadal dysgenesis, complete or partial, with 9p24.3 deletion 154230 DMRT1/29p24.3

Seven other genes have been identified with probable associations that are as yet less clearly understood. [9]

Pure gonadal dysgenesis

There are several forms of gonadal dysgenesis. The term "pure gonadal dysgenesis" (PGD) has been used to describe conditions with normal sets of sex chromosomes (e.g., 46,XX or 46,XY), as opposed to those whose gonadal dysgenesis results from missing all or part of the second sex chromosome. The latter group includes those with Turner syndrome (i.e., 45,X) and its variants, as well as those with mixed gonadal dysgenesis and a mixture of cell lines, some containing a Y chromosome (e.g., 46,XY/45,X).

Thus Swyer syndrome is referred to as PGD, 46,XY, and XX gonadal dysgenesis as PGD, 46,XX. [10] People with PGD have a normal karyotype but may have defects of a specific gene on a chromosome.

Pathogenesis

The first known step of sexual differentiation of a male fetus is the development of testes. The early stages of testicular formation in the second month of gestation requires the action of several genes, one of the earliest and most important of which is SRY : the sex-determining region of the Y chromosome. [11] [12]

When such a gene is defective, the indifferent gonads fail to differentiate into testes in an XY fetus. Without testes, no testosterone or anti-Müllerian hormone (AMH) is produced. Without testosterone, the Wolffian ducts fail to develop, so no internal male organs are formed. Also, the lack of testosterone means that no dihydrotestosterone is formed and consequently the external genitalia fail to virilize, resulting in a normal vulva. [13] Without AMH, the Müllerian ducts develop into normal internal female organs (uterus, fallopian tubes, cervix, vagina). [14]

Diagnosis

Due to the inability of the streak gonads to produce sex hormones (both estrogens and androgens), most of the secondary sex characteristics do not develop. This is especially true of estrogenic changes such as breast development, widening of the pelvis and hips, and menstrual periods. [15] As the adrenal glands can make limited amounts of androgens and are not affected by this syndrome, most of these persons will develop pubic hair, though it often remains sparse. [16]

Evaluation of delayed puberty usually reveals elevation of gonadotropins, indicating that the pituitary is providing the signal for puberty but the gonads are failing to respond. The next steps of the evaluation usually include checking a karyotype and imaging of the pelvis. [17] The karyotype reveals XY chromosomes and the imaging demonstrates the presence of a uterus but no ovaries (the streak gonads are not usually seen by most imaging). Although an XY karyotype can also indicate a person with complete androgen insensitivity syndrome, the absence of breasts, and the presence of a uterus and pubic hair exclude the possibility. At this point it is usually possible for a physician to make a diagnosis of Swyer syndrome. [18]

Swyer syndrome represents one phenotypic result of a failure of the gonads to develop properly, and hence is part of a class of conditions termed gonadal dysgenesis. There are many forms of gonadal dysgenesis. [19]

Swyer syndrome is an example of a condition in which an externally unambiguous female body carries dysgenetic, atypical, or abnormal gonads. [20] Other examples include complete androgen insensitivity syndrome, partial X chromosome deletions, lipoid congenital adrenal hyperplasia, and Turner syndrome. [21]

Treatment

Upon diagnosis, estrogen and progestogen therapy is typically commenced, promoting the development of female characteristics.

Hormone replacement therapy can also reduce the likelihood of osteoporosis. [1]

Epidemiology

A 2017 study estimated that the incidence of Swyer syndrome is approximately 1 in 100,000 females. [22] Fewer than 100 cases have been reported as of 2018. There are extremely rare instances of familial Swyer syndrome. [23] [24]

History

Swyer syndrome was first described by G. I. M. Swyer in 1955 in a report of two cases. [23]

People with XY gonadal dysgenesis

See also

Related Research Articles

<span class="mw-page-title-main">Androgen insensitivity syndrome</span> Medical condition

Androgen insensitivity syndrome (AIS) is a condition involving the inability to respond to androgens, typically due to androgen receptor dysfunction.

Amenorrhea or amenorrhoea is the absence of a menstrual period in a female who has reached reproductive age. Physiological states of amenorrhoea are seen, most commonly, during pregnancy and lactation (breastfeeding). Outside the reproductive years, there is absence of menses during childhood and after menopause.

<span class="mw-page-title-main">Androgen</span> Any steroid hormone that promotes male characteristics

An androgen is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This includes the embryological development of the primary male sex organs, and the development of male secondary sex characteristics at puberty. Androgens are synthesized in the testes, the ovaries, and the adrenal glands.

<span class="mw-page-title-main">Virilization</span> Biological development of male sex characteristics

Virilization or masculinization is the biological development of adult male characteristics in young males or females. Most of the changes of virilization are produced by androgens.

<span class="mw-page-title-main">Persistent Müllerian duct syndrome</span> Medical condition

Persistent Müllerian duct syndrome (PMDS) is the presence of Müllerian duct derivatives in what would be considered a genetically and otherwise physically normal male animal by typical human based standards. In humans, PMDS typically is due to an autosomal recessive congenital disorder and is considered by some to be a form of pseudohermaphroditism due to the presence of Müllerian derivatives. PMDS can also present in non-human animals.

<span class="mw-page-title-main">Sex-determining region Y protein</span> Protein that initiates male sex determination in therian mammals

Sex-determining region Y protein (SRY), or testis-determining factor (TDF), is a DNA-binding protein encoded by the SRY gene that is responsible for the initiation of male sex determination in therian mammals. SRY is an intronless sex-determining gene on the Y chromosome. Mutations in this gene lead to a range of disorders of sex development with varying effects on an individual's phenotype and genotype.

<span class="mw-page-title-main">XX male syndrome</span> Congenital condition where an individual with a 46,XX karyotype is male

XX male syndrome, also known as de la Chapelle syndrome, is a rare condition in which an individual with a 46,XX karyotype develops a male phenotype. Synonyms for XX male syndrome include 46,XX testicular difference of sex development

XX gonadal dysgenesis is a type of female hypogonadism in which the ovaries do not function to induce puberty in an otherwise normal girl whose karyotype is found to be 46,XX. With nonfunctional streak ovaries, she is low in estrogen levels (hypoestrogenic) and has high levels of FSH and LH. Estrogen and progesterone therapy is usually then commenced. Some cases are considered a severe version of premature ovarian failure where the ovaries fail before puberty.

Gonadal dysgenesis is classified as any congenital developmental disorder of the reproductive system characterized by a progressive loss of primordial germ cells on the developing gonads of an embryo. One type of gonadal dysgenesis is the development of functionless, fibrous tissue, termed streak gonads, instead of reproductive tissue. Streak gonads are a form of aplasia, resulting in hormonal failure that manifests as sexual infantism and infertility, with no initiation of puberty and secondary sex characteristics.

<span class="mw-page-title-main">Sexual differentiation in humans</span> Process of development of sex differences in humans

Sexual differentiation in humans is the process of development of sex differences in humans. It is defined as the development of phenotypic structures consequent to the action of hormones produced following gonadal determination. Sexual differentiation includes development of different genitalia and the internal genital tracts and body hair plays a role in sex identification.

Pseudohermaphroditism is an outdated term for when an individual's gonads were mismatched with their internal reproductive system and/or external genitalia. The term was contrasted with "true hermaphroditism", a condition describing an individual with both female and male reproductive gonadal tissues. Associated conditions includes Persistent Müllerian duct syndrome and forms of androgen insensitivity syndrome.

<span class="mw-page-title-main">Disorders of sex development</span> Medical conditions involving the development of the reproductive system

Disorders of sex development (DSDs), also known as differences in sex development or variations in sex characteristics (VSC), are congenital conditions affecting the reproductive system, in which development of chromosomal, gonadal, or anatomical sex is atypical.

<span class="mw-page-title-main">Steroidogenic factor 1</span> Protein-coding gene in humans

The steroidogenic factor 1 (SF-1) protein is a transcription factor involved in sex determination by controlling the activity of genes related to the reproductive glands or gonads and adrenal glands. This protein is encoded by the NR5A1 gene, a member of the nuclear receptor subfamily, located on the long arm of chromosome 9 at position 33.3. It was originally identified as a regulator of genes encoding cytochrome P450 steroid hydroxylases, however, further roles in endocrine function have since been discovered.

<span class="mw-page-title-main">Complete androgen insensitivity syndrome</span> Medical condition

Complete androgen insensitivity syndrome (CAIS) is an AIS condition that results in the complete inability of the cell to respond to androgens. As such, the insensitivity to androgens is only clinically significant when it occurs in individuals who are exposed to significant amounts of testosterone at some point in their lives. The unresponsiveness of the cell to the presence of androgenic hormones prevents the masculinization of male genitalia in the developing fetus, as well as the development of male secondary sexual characteristics at puberty, but does allow, without significant impairment, female genital and sexual development in those with the condition.

46,XX/46,XY is either a chimeric or mosaic genetic condition characterized by the presence of some cells that express a 46,XX karyotype and some cells that express a 46,XY karyotype in a single human being. While some individuals with this condition may be classified as intersex, others may have typical male or female characteristics.

Hypergonadotropic hypogonadism (HH), also known as primary or peripheral/gonadal hypogonadism or primary gonadal failure, is a condition which is characterized by hypogonadism which is due to an impaired response of the gonads to the gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), and in turn a lack of sex steroid production. As compensation and the lack of negative feedback, gonadotropin levels are elevated. Individuals with HH have an intact and functioning hypothalamus and pituitary glands so they are still able to produce FSH and LH. HH may present as either congenital or acquired, but the majority of cases are of the former nature. HH can be treated with hormone replacement therapy.

<span class="mw-page-title-main">Leydig cell hypoplasia</span> Medical condition

Leydig cell hypoplasia (LCH), also known as Leydig cell agenesis, is a rare autosomal recessive genetic and endocrine syndrome affecting an estimated 1 in 1,000,000 individuals with XY chromosomes. It is characterized by an inability of the body to respond to luteinizing hormone (LH), a gonadotropin which is normally responsible for signaling Leydig cells of the testicles to produce testosterone and other androgen sex hormones. The condition manifests itself as pseudohermaphroditism, hypergonadotropic hypogonadism, reduced or absent puberty, and infertility.

45,X/46,XY mosaicism, also known as X0/XY mosaicism and mixed gonadal dysgenesis, is a mutation of sex development in humans associated with sex chromosome aneuploidy and mosaicism of the Y chromosome. It is a fairly rare chromosomal disorder at birth, with an estimated incidence rate of about 1 in 15,000 live births. Mosaic loss of the Y chromosome in previously non-mosaic men grows increasingly common with age.

WNT4 deficiency is a rare genetic disorder that affects females and it results in the underdevelopment and sometimes absence of the uterus and vagina. WNT4 deficiency is caused by mutations of the WNT4 gene. Abnormally high androgen levels are found in the blood and can initiate and promote the development of male sex characteristics. This is seen as male pattern of hair growth on the chest and face. Those with this genetic defect develop breasts but do not have their period. Mayer–Rokitansky–Küster–Hauser syndrome is a related but distinct syndrome. Some women who have an initial diagnosis of MRKH have later been found to have WNT4 deficiency. Most women with MRKH syndrome do not have genetic mutations of the WNT4 gene. The failure to begin the menstrual cycle may be the initial clinical sign of WNT4 deficiency. WNT4 deficiency can cause significant psychological challenges and counseling is recommended.

Sexual anomalies, also known as sexual abnormalities, are a set of clinical conditions due to chromosomal, gonadal and/or genitalia variation. Individuals with congenital (inborn) discrepancy between sex chromosome, gonadal, and their internal and external genitalia are categorised as individuals with a disorder of sex development (DSD). Afterwards, if the family or individual wishes, they can partake in different management and treatment options for their conditions.

References

  1. 1 2 "Swyer Syndrome". MedlinePlus Genetics.
  2. ↑ Taneja, Jyoti; Ogutu, David; Ah-Moye, Michael (18 October 2016). "Rare successful pregnancy in a patient with Swyer Syndrome". Case Reports in Women's Health. 12: 1–2. doi:10.1016/j.crwh.2016.10.001. ISSN   2214-9112. PMC   5885995 . PMID   29629300.
  3. ↑ Urban, Aleksandra; Knap-Wielgus, Weronika; Grymowicz, Monika; Smolarczyk, Roman (September 2021). "Two successful pregnancies after in vitro fertilisation with oocyte donation in a patient with Swyer syndrome – a case report". Przegla̜d Menopauzalny = Menopause Review. 20 (3): 158–161. doi:10.5114/pm.2021.109361. ISSN   1643-8876. PMC   8525253 . PMID   34703418.
  4. ↑ Gupta, Anupam; Bajaj, Ritika; Jindal, Umesh N. (2019). "A Rare Case of Swyer Syndrome in Two Sisters with Successful Pregnancy Outcome in Both". Journal of Human Reproductive Sciences. 12 (3): 267–269. doi: 10.4103/jhrs.JHRS_14_19 . ISSN   0974-1208. PMC   6764226 . PMID   31576088.
  5. ↑ Massanyi EZ, Dicarlo HN, Migeon CJ, Gearhart JP (29 December 2012). "Review and management of 46,XY disorders of sex development". J Pediatr Urol. 9 (3): 368–379. doi:10.1016/j.jpurol.2012.12.002. PMID   23276787.
  6. ↑ "Swyer syndrome". National Organization for Rare Disorders (NORD).
  7. ↑ Eh, Zheng; Liu, Weili (June 1994). "A familial 46 XY gonadal dysgenesis and high incidence of embryonic gonadal tumors". Chinese Journal of Cancer Research. 6 (2): 144–148. doi:10.1007/BF02997250. S2CID   84107076. Originally published in Chinese as E, Z; Xu, XL; Li, C; Gao, FZ (May 1981). "家族性XY型性腺发育不全和高发胚胎性肿瘤研究：II．XY型性腺发育不全姐妹中第4人继发无性细胞瘤报告和细胞遗传学检查" [A familial XY gonadal dysgenesis causing high incidence of embryonic gonadal tumors- a report of the fourth dysgerminoma in sibling suffering from 46, XY gonadal dysgenesis]. Zhonghua Zhong Liu Za Zhi (in Chinese). 3 (2): 89–90. PMID   7307902.
  8. ↑ Michala, L.; Goswami, D.; Creighton, SM; Conway, GS (2008). "Swyer syndrome: Presentation and outcomes". BJOG: An International Journal of Obstetrics and Gynaecology. 115 (6): 737–741. doi:10.1111/j.1471-0528.2008.01703.x. PMID   18410658. S2CID   11953597. Archived from the original on 20 April 2021. Retrieved 11 January 2021.
  9. ↑ Kremen J, Chan YM, Swartz JM (January 2017). "Recent findings on the genetics of disorders of sex development". Curr Opin Urol. 27 (1): 1–6. doi:10.1097/MOU.0000000000000353. PMC   5877806 . PMID   27798415.
  10. ↑ Bomalaski, M. David (February 2005). "A practical approach to intersex". Urologic Nursing. 25 (1): 11–8, 23, quiz 24. PMID   15779688.
  11. ↑ "SRY gene: MedlinePlus Genetics". medlineplus.gov. Retrieved 23 March 2022.
  12. ↑ "SRY sex determining region Y [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 23 March 2022.
  13. ↑ Silverman, Ann-Judith. "Gonadal Development" (PDF). Department of Anatomy & Cell Biology. 14 (1) – via Columbia University.
  14. ↑ Wilson, Danielle; Bordoni, Bruno (2022), "Embryology, Mullerian Ducts (Paramesonephric Ducts)", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID   32491659 , retrieved 20 January 2023
  15. ↑ "Gonadal and Placental Hormones". The Endocrine System. 1 (1). 6 March 2013 – via University of Hawaii.
  16. ↑ Yildiz, Bulent O.; Azziz, Ricardo (2007). "The adrenal and polycystic ovary syndrome". Reviews in Endocrine & Metabolic Disorders. 8 (4): 331–342. doi:10.1007/s11154-007-9054-0. ISSN   1389-9155. PMID   17932770. S2CID   32857950.
  17. ↑ Abitbol, Leah; Zborovski, Stephen; Palmert, Mark R. (19 July 2016). "Evaluation of delayed puberty: what diagnostic tests should be performed in the seemingly otherwise well adolescent?". Archives of Disease in Childhood. 101 (8): 767–771. doi:10.1136/archdischild-2015-310375. ISSN   1468-2044. PMID   27190100. S2CID   25495530.
  18. ↑ "Swyer syndrome". NORD (National Organization for Rare Disorders). Retrieved 28 March 2022.
  19. ↑ King, Thomas F. J.; Conway, Gerard S. (2014). "Swyer syndrome". Current Opinion in Endocrinology, Diabetes, and Obesity. 21 (6): 504–510. doi:10.1097/MED.0000000000000113. ISSN   1752-2978. PMID   25314337. S2CID   20181415.
  20. ↑ Zieliñska, Dorota; Zajaczek, Stanislaw; Rzepka-Górska, Izabella (29 May 2007). "Tumors of dysgenetic gonads in Swyer syndrome". Journal of Pediatric Surgery. 42 (10): 1721–1724. doi:10.1016/j.jpedsurg.2007.05.029. ISSN   1531-5037. PMID   17923202.
  21. ↑ Gottlieb, Bruce; Trifiro, Mark A. (1993), Adam, Margaret P.; Everman, David B.; Mirzaa, Ghayda M.; Pagon, Roberta A. (eds.), "Androgen Insensitivity Syndrome", GeneReviews®, Seattle (WA): University of Washington, Seattle, PMID   20301602 , retrieved 20 January 2023
  22. ↑ Witchel, Selma Feldman (April 2018). "Disorders of Sex Development". Best Practice & Research. Clinical Obstetrics & Gynaecology. 48: 90–102. doi:10.1016/j.bpobgyn.2017.11.005. ISSN   1521-6934. PMC   5866176 . PMID   29503125.
  23. 1 2 Banoth M, Naru RR, Inamdar MB, Chowhan AK (May 2018). "Familial Swyer syndrome: a rare genetic entity". Gynecol. Endocrinol. 34 (5): 389–393. doi:10.1080/09513590.2017.1393662. PMID   29069951. S2CID   4452231.
  24. ↑ "Swyer syndrome". NORD (National Organization for Rare Disorders). Retrieved 23 March 2022.
  25. ↑ "Mami Y Yo y Mi Gallito, by Director Arisleyda Dilone – Intersex Campaign for Equality". www.intersexequality.com. Retrieved 27 March 2021.
  26. ↑ Kantola, Iida (27 October 2023). "Sara Forsberg kertoo olevansa intersukupuolinen". Ilta-Sanomat (in Finnish).

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