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XX male syndrome

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XX male syndrome
Other namesDe la Chapelle syndrome[1]
Human karyotype 46 XX
SpecialtyMedical genetics Edit this on Wikidata

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]

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

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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

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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

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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

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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

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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 46 XX female xx male syndrome.[29]

Diagnosis

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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

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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

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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

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References

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  1. ^ a b c 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. ^ a b c d e f g h i 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. ^ a b c "46,XX testicular disorder of sex development – Genetics Home Reference". Archived from the original on 2019-05-17. Retrieved 2017-01-08.Public Domain 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. ^ a b 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. ^ a b 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.
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  16. ^ a b c 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.
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  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.
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  22. ^ a b c 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. ^ a b 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. ^ a b 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. ^ a b 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. ^ a b 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. ^ a b "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

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