46,XX/46,XY

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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 utero with the aggregation of two distinct blastocysts or zygotes (one of which expresses 46,XX and the other of which expresses 46,XY) into a single embryo, [1] which subsequently leads to the development of a single individual with two distinct cell lines, instead of a pair of fraternal twins. 46,XX/46,XY chimeras are the result of the merging of two non-identical twins. This is not to be confused with mosaicism or hybridism, neither of which are chimeric conditions.

Contents

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. [1] The cells of the developing testes produce anti-Müllerian hormone (AMH) and androgens, causing the reproductive tract and the genitals of the fetus to differentiate. [2] As individuals with 46,XX/46,XY partially express the SRY gene, the normal process by which an embryo normally develops into a phenotypic male or phenotypic female may be significantly affected causing variation in the gonads, the reproductive tract and the genitals. [3] Despite this, there have been cases of completely normal sex differentiation occurring in 46,XX/46,XY individuals reported in the medical literature. [4] [5] [6] 46,XX/46,XY chimerism can be identified during pregnancy by prenatal screening or in early childhood through genetic testing and direct observation. [7]

The rate of incidence is difficult to determine as the majority of diagnoses go unreported in the literature.

Signs and symptoms

Physical

46,XX/46,XY is associated with a wide spectrum of different physical presentations, with cases ranging from having a completely normal male or female phenotype [4] [5] [6] to some cases having ovotesticular syndrome. Due to this variation, genetic testing is the only way to reliably make a diagnosis. [8] [9] [10] [3]

46,XX/46,XY is possible if there is direct observation of one or more of the following:

  1. Small phallus midway in size between a clitoris and a penis [3]
  2. Incompletely closed urogenital opening (shallow vagina) [3]
  3. Abnormal urethra opening on the perineum [3]

Though some individuals with 46,XX/46,XY having ovotesticular syndrome (having both ovarian tissue and testicular tissue simultaneously) there have been no reported cases of both gonads being functional in the same person, with most of the time, the functional tissue is usually the ovarian tissue. [7] In the cases with Ovotesticular syndrome, a mix of male and female characteristics may emerge at puberty. Some individuals will experience deepening of the voice and secondary hair development in a male phenotype, while others may experience breast tissue development. [7]

Segmentation of skin (distinct patches of skin) has also been observed. However, this trait is not unique to 46,XX/46,XY chimerism. It has also been observed in other types of chimerism. [3]

Cognitive

Individuals with the condition do not experience cognitive impairment. [1]

Genetic mechanism

46,XX/46,XY is an example of tetragametic chimerism because it requires four gametes – two sperm and two ova.

Diagnosis

Diagnosing a chimera is particularly difficult due to the random distribution of 46,XX and 46,XY cells within the body. An organ might be made up of a mix of 46,XX and 46,XY, but it may also be made up entirely of one genotype only. When that is the case, no abnormalities are noted and other types of tissues need to be analyzed. [12]

Pre-birth testing

  1. Ultrasound - looking for ambiguous genitalia [12]
  2. Amniocentesis - looking for a karyotype of 46,XX/46,XY [12]
  3. Cord blood sampling - looking for a karyotype of 46,XX/46,XY

Post-birth testing

  1. Blood testing - looking for red blood cells of different blood types [1]
  2. Tissue sampling - looking for more than one set of DNA within the sample [1]

Related Research Articles

<span class="mw-page-title-main">Sex</span> Trait that determines an organisms sexually reproductive function

Sex is the trait that determines whether a sexually reproducing organism produces male or female gametes. During sexual reproduction, a male and a female gamete fuse to form a zygote, which develops into an offspring that inherits traits from each parent. By convention, organisms that produce smaller, more mobile gametes are called male, while organisms that produce larger, non-mobile gametes are called female. An organism that produces both types of gamete is hermaphrodite.

<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. In this system, the sex of an individual is determined by a pair of sex chromosomes. Females have two of the same kind of sex chromosome (XX), and are called the homogametic sex. Males have two different kinds of sex chromosomes (XY), and are called the heterogametic sex.

<span class="mw-page-title-main">Chimera (genetics)</span> Single organism composed of two or more different populations of genetically distinct cells

A genetic chimerism or chimera is a single organism composed of cells with more than one distinct genotype. In animals and human chimeras, this means an individual derived from two or more zygotes, which can include possessing blood cells of different blood types, and subtle variations in form (phenotype). Animal chimeras are produced by the merger of two embryos. In plant chimeras, however, the distinct types of tissue may originate from the same zygote, and the difference is often due to mutation during ordinary cell division. Normally, genetic chimerism is not visible on casual inspection; however, it has been detected in the course of proving parentage. In contrast, an individual where each cell contains genetic material from two organisms of different breeds, varieties, species or genera is called a hybrid.

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

XY 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 often 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">Mosaic (genetics)</span> Condition in multi-cellular organisms

Mosaicism or genetic mosaicism is a condition in which a multicellular organism possesses more than one genetic line as the result of genetic mutation. This means that various genetic lines resulted from a single fertilized egg. Mosaicism is one of several possible causes of chimerism, wherein a single organism is composed of cells with more than one distinct genotype.

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

Sexual differentiation is the process of development of the sex differences between males and females from an undifferentiated zygote. Sex determination is often distinct from sex differentiation; sex determination is the designation for the development stage towards either male or female, while sex differentiation is the pathway towards the development of the phenotype.

<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">Male reproductive system</span> Reproductive system of the human male

The male reproductive system consists of a number of sex organs that play a role in the process of human reproduction. These organs are located on the outside of the body, and within the pelvis.

<span class="mw-page-title-main">Human reproductive system</span> Organs involved in reproduction

The human reproductive system includes the male reproductive system which functions to produce and deposit sperm; and the female reproductive system which functions to produce egg cells, and to protect and nourish the fetus until birth. Humans have a high level of sexual differentiation. In addition to differences in nearly every reproductive organ, there are numerous differences in typical secondary sex characteristics.

<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 congenital intersex condition in which an individual with a 46,XX karyotype develops a male phenotype. Synonyms include 46,XX testicular difference of sex development, 46,XX sex reversal, nonsyndromic 46,XX testicular DSD, and XX sex reversal.

<span class="mw-page-title-main">Ovotesticular syndrome</span> A condition where a person has a gonad that contains both ovarian and testicular tissue.

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 2 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.

<span class="mw-page-title-main">Gonadal dysgenesis</span> Congenital disorder of the reproductive system

Gonadal dysgenesis is classified as any congenital developmental disorder of the reproductive system in humans. It is atypical development of gonads in 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.

<span class="mw-page-title-main">Klinefelter syndrome</span> Human chromosomal condition

Klinefelter syndrome (KS), also known as 47,XXY, is a chromosome anomaly where a male has an extra X chromosome. As the presence of a Y chromosome denotes male sex, people with Klinefelter syndrome are genetically male. These complications commonly include infertility and small, poorly functioning testicles. These symptoms are often noticed only at puberty, although this is one of the most common chromosomal disorders, occurring in one to two per 1,000 live births. It is named after American endocrinologist Harry Klinefelter, who identified the condition in the 1940s.

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.

Androgenesis occurs when a zygote is produced with only paternal nuclear genes. During standard sexual reproduction, one female and one male parent each produce haploid gametes, which recombine to create offspring with genetic material from both parents. However, in androgenesis, there is no recombination of maternal and paternal chromosomes, and only the paternal chromosomes are passed down to the offspring. The offspring produced in androgenesis will still have maternally inherited mitochondria, as is the case with most sexually reproducing species.

A human chimera is a human with a subset of cells with a distinct genotype than other cells, that is, having genetic chimerism. In contrast, an individual where each cell contains genetic material from a human and an animal is called a human–animal hybrid, while an organism that contains a mixture of human and non-human cells would be a human-animal chimera.

References

  1. 1 2 3 4 5 Aruna, N; Purushottam, RM; Rajangam, S (2006). "46,XX/46,XY chimerism - a case report". J Anat Soc India. 55 (1): 24–26.
  2. ↑ "Sexual differentiation in humans", Wikipedia, 2019-10-11, retrieved 2019-10-23
  3. 1 2 3 4 5 6 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.
  4. 1 2 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.
  5. 1 2 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.
  6. 1 2 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.
  7. 1 2 3 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.
  8. ↑ 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.
  9. ↑ 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.
  10. ↑ 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.
  11. 1 2 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.
  12. 1 2 3 4 5 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.
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