XY gonadal dysgenesis
|XY gonadal dysgenesis|
|Other names||Swyer syndrome|
XY gonadal dysgenesis, also known as Swyer syndrome, is a type of hypogonadism in a person whose karyotype is 46,XY. They typically have normal female external genitalia, but functionless gonads (fibrous tissue termed "streak gonads"), and if left untreated, will not experience puberty. Such gonads are typically surgically removed (as they have a significant risk of developing cancer). The typical medical treatment is hormone replacement therapy. The syndrome was named after Gerald Swyer, an endocrinologist based in London.
Signs and symptoms
People with Swyer syndrome are born with the appearance of a normal female in most anatomic respects except that the child has nonfunctional gonads instead of ovaries or testes. As their ovaries produce no important body changes before puberty, a defect of the reproductive system typically remains unsuspected until puberty fails to occur. They appear to be normal girls and are generally considered so. They are usually diagnosed in their teens when they fail to begin having a menstrual period (primary amenorrhea).
The consequences of Swyer syndrome without treatment:
- Gonads cannot make estrogen, so the breasts will not develop and the uterus will not grow and menstruate until estrogen is administered. This is often given transdermally.
- Gonads cannot make progesterone, so menstrual periods will not be predictable until progestin is administered, usually as a pill.
- Gonads cannot produce eggs, so conceiving children is not possible without intervention. There has been a case of unassisted pregnancy in one woman with XY gonadal dysgenesis, who had a predominantly 46,XY Karyotype - a 46,XY karyotype in peripheral lymphocytes, mosaicism in cultured skin fibroblasts (80% 46,XY and 20% 45,X) and a predominantly 46,XY karyotype in the ovary (93% 46,XY and 6% 45,X) - who gave birth to a 46,XY female with complete gonadal dysgenesis.  A woman with a uterus and ovaries but without female gamete is able to become pregnant by implantation of another woman's fertilized egg (embryo transfer).
- Streak gonads with Y chromosome-containing cells have a high likelihood of developing cancer, especially gonadoblastoma. Streak gonads are usually removed within a year or so of diagnosis, since the cancer can begin during infancy.
- Osteopenia is often present
Genetic associations of Swyer syndrome include:
|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||DMRT1/2||9p24.3|
Seven other genes have been identified with probable associations that are as-yet less clearly understood.
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).
The first known step of sexual differentiation of a normal XY 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. Mutations of SRY account for many cases of Swyer syndrome.
When such a gene is defective, the indifferent gonads fail to differentiate into testes in an XY fetus. Without testes, no testosterone or antimüllerian 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 normal female genitalia. Without AMH, the Müllerian ducts develop into normal internal female organs (uterus, fallopian tubes, cervix, vagina).
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. 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.
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. 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.
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.
Swyer syndrome is an example of a condition in which an externally unambiguous female body carries dysgenetic, atypical, or abnormal gonads. Other examples include complete androgen insensitivity syndrome, partial X chromosome deletions, lipoid congenital adrenal hyperplasia, and Turner syndrome.
Hormone replacement therapy can also reduce the likelihood of osteoporosis.
It has been estimated that the incidence of Swyer syndrome is approximately 1 in 100,000 people. Fewer than 100 cases have been reported as of 2018. There are extremely rare instances of familial Swyer syndrome.
Swyer syndrome was first described by G. I. M. Swyer in 1955 in a report of two cases.
People with XY gonadal dysgenesis
- Arisleyda Dilone, director and actor
- Sasha Komarova, Russian model
- Sonia Komarova, Russian model
- Stanisława Walasiewicz (also known as Stella Walsh), Polish-American Olympic athlete whose genetic condition was confirmed after her death
- 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.
- Dumic, Miroslav; Lin-Su, Karen; Leibel, Natasha I.; Ciglar, Srecko; Vinci, Giovanna; Lasan, Ruzica; Nimkarn, Saroj; Wilson, Jean D.; McElreavey, Ken; New, Maria I. (1 January 2008). "Report of Fertility in a Woman with a Predominantly 46,XY Karyotype in a Family with Multiple Disorders of Sexual Development". The Journal of Clinical Endocrinology & Metabolism. 93 (1): 182–189. doi:10.1210/jc.2007-2155. PMC 2190741. PMID 18000096.
- 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.
- 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.
- Bomalaski, M. David (February 2005). "A practical approach to intersex". Urologic Nursing. 25 (1): 11–8, 23, quiz 24. PMID 15779688.
- "Swyer Syndrome". MedlinePlus Genetics.
- 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.
- "Mami Y Yo y Mi Gallito, by Director Arisleyda Dilone – Intersex Campaign for Equality". www.intersexequality.com. Retrieved 27 March 2021.
- "Vogue Russia on Instagram: "«Мы готовы говорить об этом столько, сколько понадобится, лишь бы толерантность к интерсекс-людям росла», — заявляют Соня и Саша Комаровы" ["We are ready to talk about it as much as necessary, if only tolerance for intersex people grows", say Sonia and Sasha Komarov]. www.instagram.com (in Russian). Retrieved 27 March 2021.
- "Ex-Olympian Stella Walsh legally a woman". Sarasota Journal. 12 February 1981. Retrieved 21 July 2014.
- Stoicanescu D, Belengeanu V, et al. (2006). "Complete gonadal dysgenesis with XY chromosomal constitution". Acta Endocrinologica (Buc). 2 (4): 465–70. doi:10.4183/aeb.2006.465.