XX male syndrome

Last updated

XX male syndrome
Other namesDe la Chapelle syndrome [1]
Human karyotype (259 34) Karyotype Human 46,XX (woman).jpg
Human karyotype 46 XX
Specialty Medical genetics   OOjs UI icon edit-ltr-progressive.svg

XX male syndrome, also known as de la Chapelle syndrome, is a rare intersex condition in which an individual with a 46,XX karyotype develops a male phenotype. [2] Synonyms for XX male syndrome include 46,XX testicular difference of sex development (or 46,XX DSD) [3] [4] [5] [6]

Contents

In 90 percent of these individuals, the syndrome is caused by the Y chromosome's SRY gene, which triggers male reproductive development, being atypically included in the crossing over of genetic information that takes place between the pseudoautosomal regions of the X and Y chromosomes during meiosis in the father. [2] [7] When the X with the SRY gene combines with a normal X from the mother during fertilization, the result is an XX male. Less common are SRY-negative XX males, which can be caused by a mutation in an  autosomal  or X chromosomal gene. [2] The masculinization of XX males is variable.

This syndrome is diagnosed and occurs in approximately 1:20,000 new-born males, making it much less common than  Klinefelter syndrome. [8] [9] [10] Medical treatment of the condition varies, with medical treatment usually not necessary. The alternative name for XX male syndrome, de la Chapelle syndrome, refers to Finnish scientist Albert de la Chapelle, who first described the condition. [11]

Signs and symptoms

While there is some degree of variability, a vast majority of XX males have a typical male phenotype, with male-typical external genitalia, making early diagnosis uncommon. [12] [13] Genital ambiguity is seen most commonly in men without the SRY gene/other Y chromosome-derived genes, though reported rates are inconsistent. [13] [14] [9] These ambiguities can include traits such as hypospadias, micropenis, and cryptorchidism. [15] In most SRY-positive men, there are few significant signs before puberty, though small testes appear an almost universal finding; following puberty, some XX males develop gynaecomastia. [13] [1] [16] XX males appear to be shorter on average than XY males. [2] [1]

Based on limited evidence, most XX males appear to have typical body and pubic hair, penis size, libido, and erectile function. [13] In all reported cases, individuals have been sterile, with azoospermia (no sperm in the ejaculate). [17] [16] One study found spermatogonia - undifferentiated cells which develop into sperm - present in some XX male children, the oldest of which was 5 years old, but none in the older XX males tested. [18] Multiple studies in mice have also found largely normal male-type germ cells in XX males soon after birth, but a progressive loss with maturation. [19] [20]

Due to its often-subtle presentation, many XX males remain undiagnosed until seeking treatment for infertility in adulthood; it's likely a significant proportion of cases remain undiagnosed. [12] [9]

Masculinization

The degree to which individuals with XX male syndrome develop the male phenotype is variable, even among SRY-positive individuals. [21]

Masculinization of SRY-positive XX males is believed to be dependent on which X chromosome is made inactivate. Typical XX females undergo X inactivation during which one copy of the X chromosome is silenced. It is thought that X inactivation in XX males may account for the genital ambiguities and incomplete masculinization seen in SRY-positive XX males. [22] [21] The X chromosome with the SRY gene is preferentially chosen to be the active X chromosome 90% of the time, which explains complete male phenotype being observed often in SRY-positive XX males. [22] [21] In the remaining 10%, however, X inactivation occurs on the X chromosome with the SRY gene, thereby silencing it and resulting in incomplete masculinization. [22] [21]

Masculinization of SRY-negative XX males is dependent upon which genes have mutations and at what point in development these mutations occur. [23]

Genetics

SRY Protein PBB Protein SRY image.jpg
SRY Protein

Males typically have one X chromosome and one Y chromosome in each diploid cell of their bodies. Females typically have two X chromosomes. XX males that are SRY-positive have two X chromosomes, with one of them containing genetic material (the SRY gene) from the Y chromosome; this gene causes them to develop a male phenotype despite having chromosomes more typical of females. [2] Some XX males, however, do not have the SRY gene (SRY-negative); the reason a male phenotype develops in these individuals is poorly understood, and subject to further research. [24]

SRY-positive

An example of translocation between two chromosomes Translocation of chromosomes (close-up) illustration.jpg
An example of translocation between two chromosomes

The SRY gene, normally found on the Y chromosome, plays an important role in sex determination by initiating testicular development. In about 80 percent of XX males, the SRY gene is present on one of the X chromosomes. [16] [25]

The condition results from an abnormal exchange of genetic material between chromosomes (translocation). This exchange occurs as a random event during the formation of sperm cells in the affected person's father. The tip of the Y chromosome contains the SRY gene and, during recombination, a translocation occurs in which the SRY gene becomes part of the X chromosome. [15] [26] If a fetus is conceived from a sperm cell with an X chromosome bearing the SRY gene, it will develop as a male despite not having a Y chromosome. This form of the condition is called SRY-positive 46,XX testicular disorder of sex development. [3]

SRY-negative

About 20 percent of those with 46 XX testicular disorder of sex development do not have the SRY gene. This form of the condition is called SRY-negative 46,XX testicular disorder of sex development. The cause of the disorder in these individuals is often unknown, although changes affecting other genes have been identified. Individuals with SRY-negative 46,XX testicular disorder of sex development are more likely to have ambiguous genitalia than are people with the SRY-positive form. [3] [2]

The exact cause of this condition is unknown, but three theories have been proposed: first, undetected gonadal mosaicism for SRY; second, de-repression of male development due to mutations in genes on chromosomes other than the Y chromosome; third, altered expression of other genes downstream of SRY, resulting in masculinisation. [27] For example, it has been proposed that mutations in the SOX9 gene may contribute to this syndrome, as SOX9 plays a role in testes differentiation during development. [28] [23] Another proposed cause is mutations to the DAX1 gene, which may suppress masculinisation; if there is a loss of function of DAX1, then testes can develop in an XX individual. [29] [30] Mutations in SF1 and WNT4 genes have also been studied in connection with SRY-negative XX male syndrome. [29]

Diagnosis

There is no consensus on the diagnostic criteria; diagnosis typically involves evaluating the individual's physical development in combination with karyotyping, and presence of the SRY gene or associated genes, such as SOX9. Tests for hormone levels and azoospermia may also be completed. [31]

Most XX males have a typical male-type phenotype at birth, so diagnosis tends to occur either at the onset of puberty, if traits such as gynaecomastia develop and are investigated, or later, when investigating infertility. [9] [24] Diagnosis at birth occurs more frequently in SRY-negative XX males, who are more likely to have ambiguous genitalia. [14] [9]

In cases where the individual is being evaluated for ambiguous genitalia, such as a small phallus, hypospadias, or labioscrotal folds, exploratory surgery may be used to determine if male and/or female internal genitalia is present. [32] Indicators include two testes which have not descended the inguinal canal, although this is seen in a minority of XX males, and the absence of Müllerian tissue. [33] External indicators include decreased body weight, gynecomastia, and small testes. [2]

A standard karyotype can be completed to cytogenetically determine that an individual with a partial or complete male phenotype has an XX genotype. [15] [32] [5]

The presence and location of the SRY gene can by determined using fluorescence in situ hybridization (FISH). [2] [21]

Treatment

Treatments are generally focused on affirming the gender presentation of affected men, vary to a large degree based on the phenotype of the individual, and may include counselling. [34] In some XX males, testosterone therapy may be used to increase virilisation. [25] While the vast majority of XX males have typical male external genital development, cases of genital ambiguity may be treated with hormonal therapy, surgery, or both. In some cases, gonadal surgery can be performed to remove partial or whole female genitalia. This may be followed by plastic and reconstructive surgery to make the individual appear more externally male. [35] Conversely, the individual may wish to become more feminine and feminizing genitoplasty can be performed to make the ambiguous genitalia appear more female. [36]

There is no treatment for infertility in XX males - supportive management and alternatives such as sperm donation or adoption are recommended. [37]

Epidemiology

It is estimated that 1 of every 20,000 to 30,000 males has a 46,XX karyotype, making it much less common than other related syndromes, such as Klinefelter syndrome. [2] [8] [9] [10]

See also

Related Research Articles

<span class="mw-page-title-main">5α-Reductase 2 deficiency</span> Medical condition

5α-Reductase 2 deficiency (5αR2D) is an autosomal recessive condition caused by a mutation in SRD5A2, a gene encoding the enzyme 5α-reductase type 2 (5αR2). The condition is rare, affects only genetic males, and has a broad spectrum.

<span class="mw-page-title-main">XY sex-determination system</span> Method of determining sex

The XY sex-determination system is a sex-determination system used to classify many mammals, including humans, some insects (Drosophila), some snakes, some fish (guppies), and some plants.

<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.

<span class="mw-page-title-main">Y chromosome</span> Sex chromosome in the XY sex-determination system

The Y chromosome is one of two sex chromosomes in therian mammals and other organisms. Along with the X chromosome, it is part of the XY sex-determination system, in which the Y is the sex-determining chromosome because the presence of the Y chromosome causes offspring produced in sexual reproduction to be of male sex. In mammals, the Y chromosome contains the SRY gene, which triggers development of male gonads. The Y chromosome is passed only from male parents to male offspring.

<span class="mw-page-title-main">XY gonadal dysgenesis</span> Medical condition

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, 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. 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. The syndrome was named after Gerald Swyer, an endocrinologist based in London.

<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">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.

Ovotesticular syndrome is a rare congenital condition where an individual is born with both ovarian and testicular tissue. It is one of the rarest DSDs, with only 500 reported cases. Commonly, one or both gonads is an ovotestis containing both types of tissue. Although it is similar in some ways to mixed gonadal dysgenesis, the conditions can be distinguished histologically.

<span class="mw-page-title-main">XXYY syndrome</span> Extra X and Y chromosome in males

XXYY syndrome is a sex chromosome anomaly in which males have two extra chromosomes, one X and one Y chromosome. Human cells usually contain two sex chromosomes, one from the mother and one from the father. Usually, females have two X chromosomes (XX) and males have one X and one Y chromosome (XY). The appearance of at least one Y chromosome with a properly functioning SRY gene makes a male. Therefore, humans with XXYY are genotypically male. Males with XXYY syndrome have 48 chromosomes instead of the typical 46. This is why XXYY syndrome is sometimes written as 48, XXYY syndrome or 48, XXYY. It affects an estimated one in every 18,000–40,000 male births.

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">Sex chromosome</span> Chromosome that differs from an ordinary autosome in form, size, and behavior

Sex chromosomes are chromosomes that carry the genes that determine the sex of an individual. The human sex chromosomes are a typical pair of mammal allosomes. They differ from autosomes in form, size, and behavior. Whereas autosomes occur in homologous pairs whose members have the same form in a diploid cell, members of an allosome pair may differ from one another.

<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.

<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.

46,XX/46,XY is a chimeric 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. The cause of the condition lies in conception or utero with the aggregation of two distinct zygotes or blastocysts into a single embryo, which subsequently leads to the development of a single individual with two distinct cell lines, instead of a pair of fraternal twins. This is not to be confused with mosaicism or hybridism, neither of which are chimeric conditions, but is considered as an intersex condition.

<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.

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.

<span class="mw-page-title-main">Definitions of intersex</span>

Various criteria have been offered for the definition of intersex, including ambiguous genitalia, atypical genitalia, and differential sexual development. Ambiguous genitalia occurs in roughly 0.05% of all births, usually caused by masculinization or feminization during pregnancy, these conditions range from full androgen insensitivity syndrome to ovotesticular syndrome.

References

  1. 1 2 3 de la Chapelle A (January 1972). "Analytic review: nature and origin of males with XX sex chromosomes". American Journal of Human Genetics. 24 (1): 71–105. PMC   1762158 . PMID   4622299.
  2. 1 2 3 4 5 6 7 8 9 Vorona E, Zitzmann M, Gromoll J, Schüring AN, Nieschlag E (September 2007). "Clinical, endocrinological, and epigenetic features of the 46,XX male syndrome, compared with 47,XXY Klinefelter patients". The Journal of Clinical Endocrinology and Metabolism. 92 (9): 3458–3465. doi: 10.1210/jc.2007-0447 . PMID   17579198.
  3. 1 2 3 "46,XX testicular disorder of sex development - Genetics Home Reference". Archived from the original on 2019-05-17. Retrieved 2017-01-08.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  4. "Orphanet: 46,XX testicular disorder of sex development". www.orpha.net. Archived from the original on 2017-01-13. Retrieved 2017-01-12.
  5. 1 2 Délot EC, Vilain EJ (2003). "Nonsyndromic 46,XX Testicular Disorders/Differences of Sex Development". In Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean L, Bird TD, Fong CT, Mefford HC, Smith R, Stephens K (eds.). GeneReviews. University of Washington, Seattle. PMID   20301589. Archived from the original on 18 January 2017. Retrieved 12 January 2017.updated 2015
  6. "46,XX testicular disorder of sex development: MedlinePlus Genetics". medlineplus.gov. Archived from the original on 2020-09-15. Retrieved 2020-09-06.
  7. Andersson M, Page DC, de la Chapelle A (August 1986). "Chromosome Y-specific DNA is transferred to the short arm of X chromosome in human XX males". Science. 233 (4765): 786–788. Bibcode:1986Sci...233..786A. doi:10.1126/science.3738510. PMID   3738510. S2CID   32456133.
  8. 1 2 de la Chapelle A (August 1981). "The etiology of maleness in XX men". Human Genetics. 58 (1): 105–116. doi:10.1007/bf00284157. PMID   6945286. S2CID   26425178.
  9. 1 2 3 4 5 6 Berglund A, Johannsen TH, Stochholm K, Aksglaede L, Fedder J, Viuff MH, et al. (August 2017). "Incidence, prevalence, diagnostic delay, morbidity, mortality and socioeconomic status in males with 46,XX disorders of sex development: a nationwide study". Human Reproduction. 32 (8): 1751–1760. doi:10.1093/humrep/dex210. PMID   28854582.
  10. 1 2 Berglund A, Stochholm K, Gravholt CH (June 2020). "The epidemiology of sex chromosome abnormalities". American Journal of Medical Genetics. Part C, Seminars in Medical Genetics. 184 (2): 202–215. doi:10.1002/ajmg.c.31805. PMID   32506765.
  11. Delachapelle A, Hortling H, Niemi M, Wennstroem J (1964-01-12). "XX sex chromosomes in a human male. First case". Acta Medica Scandinavica. 175 (SUPPL 412): 25–28. doi:10.1111/j.0954-6820.1964.tb04630.x. PMID   14154995.
  12. 1 2 Frühmesser A, Kotzot D (2011-04-29). "Chromosomal variants in klinefelter syndrome". Sexual Development. 5 (3): 109–123. doi:10.1159/000327324. PMID   21540567.
  13. 1 2 3 4 Terribile M, Stizzo M, Manfredi C, Quattrone C, Bottone F, Giordano DR, et al. (July 2019). "46,XX Testicular Disorder of Sex Development (DSD): A Case Report and Systematic Review". Medicina. 55 (7): 371. doi: 10.3390/medicina55070371 . PMC   6681203 . PMID   31336995.
  14. 1 2 McElreavey K, Vilain E, Abbas N, Herskowitz I, Fellous M (April 1993). "A regulatory cascade hypothesis for mammalian sex determination: SRY represses a negative regulator of male development". Proceedings of the National Academy of Sciences of the United States of America. 90 (8): 3368–3372. Bibcode:1993PNAS...90.3368M. doi: 10.1073/pnas.90.8.3368 . PMC   46301 . PMID   8475082.
  15. 1 2 3 Chen H (2012). "XX Male". Atlas of Genetic Diagnosis and Counseling. pp. 2191–2196. doi:10.1007/978-1-4614-1037-9_250. ISBN   978-1-4614-1036-2.
  16. 1 2 3 Majzoub A, Arafa M, Starks C, Elbardisi H, Al Said S, Sabanegh E (2017). "46 XX karyotype during male fertility evaluation; case series and literature review". Asian Journal of Andrology. 19 (2): 168–172. doi: 10.4103/1008-682X.181224 . PMC   5312213 . PMID   27297128.
  17. Castiñeyra G, Copelli S, Levalle O (January 2002). "46,XX male: clinical, hormonal/genetic findings". Archives of Andrology. 48 (4): 251–257. doi:10.1080/01485010290031556. PMID   12137585.
  18. Toublanc JE, Boucekkine C, Abbas N, Barama D, Vilain E, McElreavey K, et al. (February 1993). "Hormonal and molecular genetic findings in 46,XX subjects with sexual ambiguity and testicular differentiation". European Journal of Pediatrics. 152 (Suppl 2): S70–S75. doi:10.1007/BF02125443. PMID   8339747.
  19. Ishii M, Tachiwana T, Hoshino A, Tsunekawa N, Hiramatsu R, Matoba S, et al. (February 2007). "Potency of testicular somatic environment to support spermatogenesis in XX/Sry transgenic male mice". Development. 134 (3): 449–454. doi:10.1242/dev.02751. PMID   17185318.
  20. Cattanach BM, Pollard CE, Hawker SG (1971). "Sex-reversed mice: XX and XO males". Cytogenetics. 10 (5): 318–337. doi:10.1159/000130151. PMID   5156366.
  21. 1 2 3 4 5 Kusz K, Kotecki M, Wojda A, Szarras-Czapnik M, Latos-Bielenska A, Warenik-Szymankiewicz A, et al. (June 1999). "Incomplete masculinisation of XX subjects carrying the SRY gene on an inactive X chromosome". Journal of Medical Genetics. 36 (6): 452–456. doi:10.1136/jmg.36.6.452. PMC   1734388 . PMID   10874632.
  22. 1 2 3 Bouayed Abdelmoula N, Portnoi MF, Keskes L, Recan D, Bahloul A, Boudawara T, et al. (2003-01-01). "Skewed X-chromosome inactivation pattern in SRY positive XX maleness: a case report and review of literature". Annales de Génétique. 46 (1): 11–18. doi:10.1016/S0003-3995(03)00011-X. PMID   12818524.
  23. 1 2 Rajender S, Rajani V, Gupta NJ, Chakravarty B, Singh L, Thangaraj K (May 2006). "SRY-negative 46,XX male with normal genitals, complete masculinization and infertility". Molecular Human Reproduction. 12 (5): 341–346. doi: 10.1093/molehr/gal030 . PMID   16556678.
  24. 1 2 Ergun-Longmire B, Vinci G, Alonso L, Matthew S, Tansil S, Lin-Su K, et al. (August 2005). "Clinical, hormonal and cytogenetic evaluation of 46,XX males and review of the literature". Journal of Pediatric Endocrinology & Metabolism. 18 (8): 739–748. doi:10.1515/jpem.2005.18.8.739. PMID   16200839.
  25. 1 2 Anık A, Çatlı G, Abacı A, Böber E (2013-12-10). "46,XX male disorder of sexual development:a case report". Journal of Clinical Research in Pediatric Endocrinology. 5 (4): 258–260. doi:10.4274/Jcrpe.1098. PMC   3890225 . PMID   24379036.
  26. Margarit E, Coll MD, Oliva R, Gómez D, Soler A, Ballesta F (January 2000). "SRY gene transferred to the long arm of the X chromosome in a Y-positive XX true hermaphrodite". American Journal of Medical Genetics. 90 (1): 25–28. doi:10.1002/(sici)1096-8628(20000103)90:1<25::aid-ajmg5>3.0.co;2-5. PMID   10602113.
  27. Wang T, Liu JH, Yang J, Chen J, Ye ZQ (February 2009). "46, XX male sex reversal syndrome: a case report and review of the genetic basis". Andrologia. 41 (1): 59–62. doi: 10.1111/j.1439-0272.2008.00889.x . PMID   19143733.
  28. Vetro A, Ciccone R, Giorda R, Patricelli MG, Della Mina E, Forlino A, et al. (October 2011). "XX males SRY negative: a confirmed cause of infertility". Journal of Medical Genetics. 48 (10): 710–712. doi:10.1136/jmedgenet-2011-100036. PMC   3178810 . PMID   21653197.
  29. 1 2 Domenice S, Corrêa RV, Costa EM, Nishi MY, Vilain E, Arnhold IJ, et al. (January 2004). "Mutations in the SRY, DAX1, SF1 and WNT4 genes in Brazilian sex-reversed patients". Brazilian Journal of Medical and Biological Research = Revista Brasileira de Pesquisas Medicas e Biologicas. 37 (1): 145–150. doi: 10.1590/S0100-879X2004000100020 . PMID   14689056.
  30. Swain A, Narvaez V, Burgoyne P, Camerino G, Lovell-Badge R (February 1998). "Dax1 antagonizes Sry action in mammalian sex determination". Nature. 391 (6669): 761–767. Bibcode:1998Natur.391..761S. doi:10.1038/35799. PMID   9486644. S2CID   4416667.
  31. Délot EC, Vilain EJ (1993), Adam MP, Feldman J, Mirzaa GM, Pagon RA (eds.), "Nonsyndromic 46,XX Testicular Disorders/Differences of Sex Development", GeneReviews®, Seattle (WA): University of Washington, Seattle, PMID   20301589 , retrieved 2024-06-27
  32. 1 2 "46,XX SEX REVERSAL 1; SRXX1". Online Mendelian Inheritance in Man (OMIM). 400045. Archived from the original on 2019-12-13. Retrieved 2017-11-07.
  33. Lisker R, Flores F, Cobo A, Rojas FG (December 1970). "A case of XX male syndrome". Journal of Medical Genetics. 7 (4): 394–398. doi:10.1136/jmg.7.4.394. PMC   1468937 . PMID   5501706.
  34. Ahmad A, Siddiqui MA, Goyal A, Wangnoo SK (July 2012). "Is 46XX karyotype always a female?". BMJ Case Reports. 2012: bcr2012006223. doi:10.1136/bcr-2012-006223. PMC   4542431 . PMID   22814614.
  35. Parada-Bustamante A, Ríos R, Ebensperger M, Lardone MC, Piottante A, Castro A (November 2010). "46,XX/SRY-negative true hermaphrodite". Fertility and Sterility. 94 (6): 2330.e13–2330.e16. doi: 10.1016/j.fertnstert.2010.03.066 . PMID   20451191. Archived from the original on 2019-12-13. Retrieved 2017-11-29.
  36. Kurita M, Aiba E, Matsumoto D, Sato K, Nagase T, Yoshimura K (May 2006). "Feminizing genitoplasty for treatment of XX male with masculine genitalia". Plastic and Reconstructive Surgery. 117 (6): 107e–111e. doi:10.1097/01.prs.0000214653.30135.a1. PMID   16651931.
  37. Ryan NA, Akbar S (April 2013). "A case report of an incidental finding of a 46,XX, SRY-negative male with masculine phenotype during standard fertility workup with review of the literature and proposed immediate and long-term management guidance". Fertility and Sterility. 99 (5): 1273–1276. doi:10.1016/j.fertnstert.2012.11.040. PMID   23290744.

Further reading