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.[1][2][3] While some individuals with this condition may be classified as intersex, others may have typical male or female characteristics.
Types
editTetragametic chimerism
editThe cause of the condition lies in conception or utero with the aggregation of two distinct zygotes or blastocysts (one of which expresses 46,XX and the other of which expresses 46,XY) into a single embryo,[4] which subsequently leads to the development of a single individual with two distinct cell lines, instead of a pair of fraternal twins.
In humans, sexual dimorphism is a consequence of the XY sex-determination system. In typical prenatal sex differentiation, the male and female embryo is anatomically identical until week 7 of the pregnancy, when the presence or the absence of the SRY gene on the Y chromosome causes the undetermined gonadal tissue to undergo differentiation and eventually will become either a pair of testes or ovaries respectively.[4] The cells of the developing testes produce Anti-Müllerian hormone, causing the regression of the Müllerian ducts.[5] As individuals with 46,XX/46,XY partially express the SRY gene, the normal process by which an embryo normally develops a phenotypic male or phenotypic female may be significantly affected causing variation will affect in the gonads, the reproductive tract, and the genitals.[6] Despite this, there have been cases of completely normal sex differentiation occurring in 46,XX/46,XY individuals reported in the medical literature.[7][8][9] 46,XX/46,XY chimerism can be identified during pregnancy by prenatal screening or in early childhood through genetic testing and direct observation.[10]
Mosaicism
editThe cause of this condition happens in early development resulting from a single fertilized zygote's cell line divided into two cell lines; a genome that contains a characterized by the presence of some cells that express a 46,XX karyotype and some cells that express a 46,XY karyotype.
Signs and symptoms
editPhysical
edit46,XX/46,XY chimeric or mosaic is associated with a wide spectrum of different physical presentations, with cases ranging from having a completely normal male or female phenotype[7][8][9] to some cases having ovotesticular syndrome. Due to this variation, genetic testing is the only way to reliably make a diagnosis.[11][12][13][6]
46,XX/46,XY is possible if there is direct observation of one or more of the following:
- Small phallus midway in size between a clitoris and a penis[6]
- Incompletely closed urogenital opening (shallow vagina)[6]
- Abnormal urethra opening on the perineum[6]
There have been no reported cases of both gonads being functional in the same person, the functional tissue is usually the ovarian tissue.[10] A mix of male and female characteristics may emerge at puberty. Some individuals will experience secondary characteristics, such as breast development during puberty in a male phenotype, while others may experience deepening of the voice, secondary hair development, and gynecomastia.[10]
Segmentation of skin (distinct patches of skin) has also been observed. However, this trait is not unique to 46,XX/46,XY chimerism nor mosaicism. It has also been observed in other types of chimerism.[6]
Cognitive
editIndividuals with the condition do not experience cognitive impairment.[4]
Genetic mechanism
edit46,XX/46,XY is an example of tetragametic chimerism because it requires four gametes – two sperm and two ova.
- 46,XX/46,XY is most commonly explained during in conception combination of two fertilized eggs zygotes. Two ova from the mother are fertilized by two sperm from the father. One sperm contains an X chromosome; the other contains a Y chromosome. The result is that a zygote with an XY genotype and a zygote with an XX genotype are produced. Under normal circumstances, the two resulting zygotes would have gone on to become fraternal twins. However, in 46,XX/46,XY, the two zygotes merge shortly before or after fertilization to become a two-cell zygote made up of two different nuclei. The zygotes merge early enough that there is no risk of them developing into conjoined twins.[14] Variations of this mechanism include fertilization of an ovum and its first or second polar body by two sperm.[15]
- 46,XX/46,XY can also be explained by a mosaic-based mechanism. A single zygote is formed from the fertilization of a normal X ovum. The resulting XX/XY zygote divides to give two cell lines: 46,XX/46,XY. The 46,XX/46,XY cell lines remain and go on to become a chimeric individual.[14]
- 46,XX/46,XY can also arise when a haploid ovum undergoes a round of mitosis, and the subsequent daughter cells are fertilized by an X and a Y sperm, respectively.[15]
Diagnosis
editDiagnosing a chimera or mosaic is particularly difficult due to the random distribution of 46,XX and 46,XY cells within the body. In a chimeric, an organ might be made up of a mix of 46,XX and 46,XY, but is made up entirely only one genotype. When that is the case, no abnormalities are noted and other types of tissues need to be analyzed.[15] Blood tests might contain both or red blood cells of different blood types.[4]
Before birth, ambiguous genitalia might be observed through ultrasound.[15] The karyotype might also be observed through amniocentesis[15] or cord blood sampling.
See also
editReferences
edit- ^ Khan, Mansura; Moniruzzaman, Mohammad; Mohsin, Fauzia; Chowdhury, Ashesh K (2018-10-15). "A 46, XX / 46, XY mosaicism or chimerism diagnosed by Karyotyping". Bangladesh Critical Care Journal. 6 (2): 111–113. doi:10.3329/bccj.v6i2.38591. ISSN 2307-7654.
The presence of both 46, XX and 46, XY cell lines in a person is known as either chimerism or mosaicism. A chimera is an individual with two or more cell lines derived from different zygotes. In mosaicism, on the other hand, two or more cell lines come from the same zygote as a result of non-disjunction during mitotic division.
- ^ Liao, Can; Yang, Xin; Pan, Min; Li, Dong‐Zhi (2008-01-01). "A 46,XY/46,XX mosaicism diagnosed at amniocentesis: another case report". Prenatal Diagnosis. 28 (1): 65–66. doi:10.1002/pd.1908. ISSN 0197-3851.
The vast majority of these cases are the result of contamination by maternal cells in an otherwise normal male fetus. Occasionally, the presence of 46,XX and 46,XY cell lines are true chimerism or mosaicism … This result is more suggestive of mosaicism
- ^ Yaron, Yuval; Feldman, Baruch; Kramer, Ralph L.; Kasperski, Stefanie B.; Vo, Trieu; Feldman, Gerald L.; Johnson, Mark P.; Evans, Mark I.; Ebrahim, Salah A.D. (1999-05-07). "Prenatal diagnosis of 46,XY/46,XX mosaicism: A case report". American Journal of Medical Genetics. 84 (1): 12–14. doi:10.1002/(SICI)1096-8628(19990507)84:1<12::AID-AJMG3>3.0.CO;2-U. ISSN 0148-7299.
It indicated that all three X chromosomes in both fetal cell lines are of maternal origin. This result is more suggestive of mosaicism, since, by definition, the 46,XX cell line in a chimera originates from a normal female zygote and must have one paternal X chromosome.
- ^ a b c d Aruna, N; Purushottam, RM; Rajangam, S (2006). "46,XX/46,XY chimerism - a case report". J Anat Soc India. 55 (1): 24–26.
- ^ Jarmińska-Jackowiak, T; Warenik-Szymankiewicz, A; Trzeciak, WH (1995). "Anti-Mullerian hormone. Structure and role in sexual differentiation". Ginekol Pol. 66 (1): 51–8. PMID 8522216.
- ^ a b c d e f Fitzgerald, PH; Donald, RA; Kirk, RL (1979). "A true hermaphrodite dispermic chimera with 46, XX and 46, XY karyotypes". Clin Genet. 15 (1): 89–96. doi:10.1111/j.1399-0004.1979.tb02032.x. PMID 759058. S2CID 39280592.
- ^ a b Schoenle, E (1983). "46,XX/46,XY chimerism in a phenotypically normal man". Hum Genet. 64 (1): 86–89. doi:10.1007/bf00289485. PMID 6575956. S2CID 25946104.
- ^ a b Binkhorst, Mathijs; de Leeuw, Nicole; Otten, Barto J. (January 2009). "A healthy, female chimera with 46,XX/46,XY karyotype". Journal of Pediatric Endocrinology & Metabolism. 22 (1): 97–102. doi:10.1515/jpem.2009.22.1.97. ISSN 0334-018X. PMID 19344081. S2CID 6074854.
- ^ a b Gencík, A.; Genciková, A.; Hrubisko, M.; Mergancová, O. (1980). "Chimerism 46,XX/46,XY in a phenotypic female". Human Genetics. 55 (3): 407–408. doi:10.1007/bf00290226. ISSN 0340-6717. PMID 7203474. S2CID 9117759.
- ^ a b c Malan, V; Gesny, R; Morichon-Delvallez, N; Aubry, MC; Benachi, A; Sanlaville, D; Turleau, C; Bonnefont, JP; Fekete-Nihoul, C (2007). "Prenatal diagnosis and outcome of a 46,XX/46,XY chimera: a case report". Hum Reprod. 22 (4): 1037–1041. doi:10.1093/humrep/del480. PMID 17272360.
- ^ Shah, V. C.; Krishna Murthy, D. S.; Roy, S.; Contractor, P. M.; Shah, A. V. (November 1982). "True hermaphrodite: 46, XX/46, XY, clinical cytogenetic and histopathological studies". Indian Journal of Pediatrics. 49 (401): 885–890. doi:10.1007/bf02976984. ISSN 0019-5456. PMID 7182365. S2CID 41204037.
- ^ Farag, T I; Al-Awadi, S A; Tippett, P; el-Sayed, M; Sundareshan, T S; Al-Othman, S A; el-Badramany, M H (December 1987). "Unilateral true hermaphrodite with 46,XX/46,XY dispermic chimerism". Journal of Medical Genetics. 24 (12): 784–786. doi:10.1136/jmg.24.12.784. ISSN 0022-2593. PMC 1050410. PMID 3430558.
- ^ Amrani, M.; Renoirte, P. (1990). "[True hermaphroditism. Late diagnosis. Surgical treatment and a 15-year follow-up]". Chirurgie Pédiatrique. 31 (4–5): 279–283. ISSN 0180-5738. PMID 2083468.
- ^ a b Niu, DM; Pan, CC; Lin, CY; Hwang, BT; Chung, MY (2002). "Mosaic or chimera? revisiting an old hypothesis about the cause of 46,XX/46,XY hermaphrodite". J Pediatr. 140 (6): 732–735. doi:10.1067/mpd.2002.124321. PMID 12072878.
- ^ a b c d e Chen, CP; Chern, SR; Sheu, JC; Lin, SP; Hsu, CY; Chang, TY; Lee, CC; Wang, W; Chen, CH (2005). "Prenatal diagnosis, sonographic findings and molecular genetic analysis of a 46,XX/46,XY true hermaphrodite chimera". Prenat Diagn. 25 (6): 502–506. doi:10.1002/pd.1181. PMID 15966046. S2CID 5757722.