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When was it discovered XY chromosomes decide the sex of a child in humans?

When was it discovered XY chromosomes decide the sex of a child in humans?


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Several stories are told from before-genetic-age (books and movies are my reference, the one present in my mind is Marie-Antoinette by Copola) in which we can always see that women are blamed for giving birth to a girl - when it was a boy which was "required".

How did mankind's (man) society took the discovery of the fact that the sex of a human baby is decided by the Y or X chromosome carried in the masculin genes within the sperm fertilizing the female's egg. (at least this is what I learned in school decades ago).

When was this fact discovered and by whom?

(The occasion for this question is Nettie Stevens 155th birthday today)


The discovery of genetic sex determination, and determination of sex via male gametes (in XY species, female in ZW), occurred over some time in the late 1800's and early 1900's. Advances were made with methods to stain chromosomes and, in 1891, Henking noted that wasps produced sperm with a varying number of chromosomes. However, he was unable to gather evidence that the "x-element" was determining sex. Nettie Stevens, in 1905, then used beetles and noted an odd set of chromosomes in sperm, which later became known as the sex chromosomes. This was the discovery of sex determination through male gametes.

"In 1905, while studying the gametes of the beetle Tenebrio molitor, Stevens noted an unusual-looking pair of chromosomes that separated to form sperm cells in the male beetles. Based on her comparisons of chromosome appearance in cells from male and female beetles, Stevens proposed that these accessory chromosomes were related to the inheritance of sex." - Link

In 1905, Beecher-Williams also made the same discovery, so they are both credited with discovering sex determination by the sex chromosomes. However, Clarence Erwing McClung also contributed to theory that Henkings X-elements may determine sex in 1901.

Thomas Hunt Morgan also contributed some major work on heredity and sex chromosomes, having been initially sceptical of Stevens' discovery. He found that eye mutations in Drosophila appeared to be sex linked, and concluded that the mutations were likely carried on the sex chromosomes.

There is a paper from 1910 where Michael Guyer concludes that accessory chromosomes (the sex chromosomes) likely determined sex in humans.

"It is probable that in man and certain other vertebrates, as in the insects, myriapods and arachnids, the accessory chromosomes are in some way associated with the determination of sex."

However, Theophilus Painter, in 1921, concluded for the first time that human sex determination was by the presence of X or Y in the sperm; Guyer had gone for an XO system. While Painter got the chromosome count wrong, being hampered by the techniques of the day (an issue that wasn't resolved until the 1950's), he got the sex determination system right.


Sex assignment

Sex assignment (sometimes known as gender assignment) is the discernment of an infant's sex at birth. [1] Assignment may be done prior to birth through prenatal sex discernment. In the majority of births, a relative, midwife, nurse or physician inspects the genitalia when the baby is delivered and sex is assigned without ambiguity. [2]

Sex assignment at birth usually aligns with a child's anatomical sex and phenotype. The number of births where the baby is intersex—where they do not fit into typical definitions of male and female at birth—has been reported to be as low as 0.018%, but is often estimated at around 0.2%. [3] [4] [5] The number of births with ambiguous genitals is in the range of 0.02% to 0.05%. [6] These conditions may complicate sex assignment. [7] Other intersex conditions involve atypical chromosomes, gonads or hormones. [3] [8] Reinforcing sex assignments through surgical or hormonal interventions is often considered to violate the individual's human rights. [9] [10] [11] [12]

The act of assignment carries the implicit expectation that future gender identity will develop in alignment with the physical anatomy, assignment, and rearing. [13] In about 99.7% of cases, the child's gender identity matches their sex assignment. [14] If sex assignment and gender identity do not align, the person may be transgender or gender non-conforming (GNC). [15] [16] [17] [18] The sex assignment of an intersex individual may also contradict their future gender identity. [19]


Contents

In general, nondisjunction can occur in any form of cell division that involves ordered distribution of chromosomal material. Higher animals have three distinct forms of such cell divisions: Meiosis I and meiosis II are specialized forms of cell division occurring during generation of gametes (eggs and sperm) for sexual reproduction, mitosis is the form of cell division used by all other cells of the body.

Meiosis II Edit

Ovulated eggs become arrested in metaphase II until fertilization triggers the second meiotic division. [5] Similar to the segregation events of mitosis, the pairs of sister chromatids resulting from the separation of bivalents in meiosis I are further separated in anaphase of meiosis II. In oocytes, one sister chromatid is segregated into the second polar body, while the other stays inside the egg. During spermatogenesis, each meiotic division is symmetric such that each primary spermatocyte gives rise to 2 secondary spermatocytes after meiosis I, and eventually 4 spermatids after meiosis II.
Meiosis II-nondisjunction may also result in aneuploidy syndromes, but only to a much smaller extent than do segregation failures in meiosis I. [6]

Mitosis Edit

Division of somatic cells through mitosis is preceded by replication of the genetic material in S phase. As a result, each chromosome consists of two sister chromatids held together at the centromere. In the anaphase of mitosis, sister chromatids separate and migrate to opposite cell poles before the cell divides. Nondisjunction during mitosis leads to one daughter receiving both sister chromatids of the affected chromosome while the other gets none. [2] [3] This is known as a chromatin bridge or an anaphase bridge. Mitotic nondisjunction results in somatic mosaicism, since only daughter cells originating from the cell where the nondisjunction event has occurred will have an abnormal number of chromosomes. [3] Nondisjunction during mitosis can contribute to the development of some forms of cancer, e.g. retinoblastoma (see below). [7] Chromosome nondisjunction in mitosis can be attributed to the inactivation of topoisomerase II, condensin, or separase. [8] Meiotic nondisjunction has been well studied in Saccharomyces cerevisiae. This yeast undergoes mitosis similarly to other eukaryotes. Chromosome bridges occur when sister chromatids are held together post replication by DNA-DNA topological entanglement and the cohesion complex. [9] During anaphase, cohesin is cleaved by separase. [10] Topoisomerase II and condensin are responsible for removing catenations. [11]

Central role of the spindle assembly checkpoint Edit

The spindle assembly checkpoint (SAC) is a molecular safe-guarding mechanism that governs proper chromosome segregation in eukaryotic cells. [12] SAC inhibits progression into anaphase until all homologous chromosomes (bivalents, or tetrads) are properly aligned to the spindle apparatus. Only then, SAC releases its inhibition of the anaphase promoting complex (APC), which in turn irreversibly triggers progression through anaphase.

Sex-specific differences in meiosis Edit

Surveys of cases of human aneuploidy syndromes have shown that most of them are maternally derived. [5] This raises the question: Why is female meiosis more error prone? The most obvious difference between female oogenesis and male spermatogenesis is the prolonged arrest of oocytes in late stages of prophase I for many years up to several decades. Male gametes on the other hand quickly go through all stages of meiosis I and II. Another important difference between male and female meiosis concerns the frequency of recombination between homologous chromosomes: In the male, almost all chromosome pairs are joined by at least one crossover, while more than 10% of human oocytes contain at least one bivalent without any crossover event. Failures of recombination or inappropriately located crossovers have been well documented as contributors to the occurrence of nondisjunction in humans. [5]

Age-related loss of cohesin ties Edit

Due to the prolonged arrest of human oocytes, weakening of cohesive ties holding together chromosomes and reduced activity of the SAC may contribute to maternal age-related errors in segregation control. [6] [13] The cohesin complex is responsible for keeping together sister chromatids and provides binding sites for spindle attachment. Cohesin is loaded onto newly replicated chromosomes in oogonia during fetal development. Mature oocytes have only limited capacity for reloading cohesin after completion of S phase. The prolonged arrest of human oocytes prior to completion of meiosis I may therefore result in considerable loss of cohesin over time. Loss of cohesin is assumed to contribute to incorrect microtubule-kinetochore attachment and chromosome segregation errors during meiotic divisions. [6]

The result of this error is a cell with an imbalance of chromosomes. Such a cell is said to be aneuploid. Loss of a single chromosome (2n-1), in which the daughter cell(s) with the defect will have one chromosome missing from one of its pairs, is referred to as a monosomy. Gaining a single chromosome, in which the daughter cell(s) with the defect will have one chromosome in addition to its pairs is referred to as a trisomy. [3] In the event that an aneuploidic gamete is fertilized, a number of syndromes might result.

Monosomy Edit

The only known survivable monosomy in humans is Turner syndrome, where the affected individual is monosomic for the X chromosome (see below). Other monosomies are usually lethal during early fetal development, and survival is only possible if not all the cells of the body are affected in case of a mosaicism (see below), or if the normal number of chromosomes is restored via duplication of the single monosomic chromosome ("chromosome rescue"). [2]

Turner syndrome (X monosomy) (45, X0) Edit

Complete loss of an entire X chromosome accounts for about half the cases of Turner syndrome. The importance of both X chromosomes during embryonic development is underscored by the observation that the overwhelming majority (>99%) of fetuses with only one X chromosome (karyotype 45, X0) are spontaneously aborted. [14]

Autosomal trisomy Edit

The term autosomal trisomy means that a chromosome other than the sex chromosomes X and Y is present in 3 copies instead of the normal number of 2 in diploid cells.

Down syndrome (trisomy 21) Edit

Down syndrome, a trisomy of chromosome 21, is the most common anomaly of chromosome number in humans. [2] The majority of cases result from nondisjunction during maternal meiosis I. [14] Trisomy occurs in at least 0.3% of newborns and in nearly 25% of spontaneous abortions. It is the leading cause of pregnancy wastage and is the most common known cause of mental retardation. [15] It is well documented that advanced maternal age is associated with greater risk of meiotic nondisjunction leading to Down syndrome. This may be associated with the prolonged meiotic arrest of human oocytes potentially lasting for more than four decades. [13]

Edwards syndrome (trisomy 18) and Patau syndrome (trisomy 13) Edit

Human trisomies compatible with live birth, other than Down syndrome (trisomy 21), are Edwards syndrome (trisomy 18) and Patau syndrome (trisomy 13). [1] [2] Complete trisomies of other chromosomes are usually not viable and represent a relatively frequent cause of miscarriage. Only in rare cases of a mosaicism, the presence of a normal cell line, in addition to the trisomic cell line, may support the development of a viable trisomy of the other chromosomes. [2]

Sex chromosome aneuploidy Edit

The term sex chromosome aneuploidy summarizes conditions with an abnormal number of sex chromosomes, i.e. other than XX (female) or XY (male). Formally, X chromosome monosomy (Turner syndrome, see above) can also be classified as a form of sex chromosome aneuploidy.

Klinefelter syndrome (47, XXY) Edit

Klinefelter syndrome is the most common sex chromosome aneuploidy in humans. It represents the most frequent cause of hypogonadism and infertility in men. Most cases are caused by nondisjunction errors in paternal meiosis I. [2] About eighty percent of individuals with this syndrome have one extra X chromosome resulting in the karyotype XXY. The remaining cases have either multiple additional sex chromosomes (48,XXXY 48,XXYY 49,XXXXY), mosaicism (46,XY/47,XXY), or structural chromosome abnormalities. [2]

XYY Male (47, XYY) Edit

The incidence of XYY syndrome is approximately 1 in 800-1000 male births. Many cases remain undiagnosed because of their normal appearance and fertility, and the absence of severe symptoms. The extra Y chromosome is usually a result of nondisjunction during paternal meiosis II. [2]

Trisomy X (47,XXX) Edit

Trisomy X is a form of sex chromosome aneuploidy where females have three instead of two X chromosomes. Most patients are only mildly affected by neuropsychological and physical symptoms. Studies examining the origin of the extra X chromosome observed that about 58-63% of cases were caused by nondisjunction in maternal meiosis I, 16-18% by nondisjunction in maternal meiosis II, and the remaining cases by post-zygotic, i.e. mitotic, nondisjunction. [16]

Uniparental disomy Edit

Uniparental disomy denotes the situation where both chromosomes of a chromosome pair are inherited from the same parent and are therefore identical. This phenomenon most likely is the result of a pregnancy that started as a trisomy due to nondisjunction. Since most trisomies are lethal, the fetus only survives because it loses one of the three chromosomes and becomes disomic. Uniparental disomy of chromosome 15 is, for example, seen in some cases of Prader-Willi syndrome and Angelman syndrome. [14]

Mosaicism syndromes Edit

Mosaicism syndromes can be caused by mitotic nondisjunction in early fetal development. As a consequence, the organism evolves as a mixture of cell lines with differing ploidy (number of chromosomes). Mosaicism may be present in some tissues, but not in others. Affected individuals may have a patchy or assymmetric appearance. Examples of mosaicism syndromes include Pallister-Killian syndrome and Hypomelanosis of Ito. [14]

Mosaicism in malignant transformation Edit

Development of cancer often involves multiple alterations of the cellular genome (Knudson hypothesis). Human retinoblastoma is a well studied example of a cancer type where mitotic nondisjunction can contribute to malignant transformation: Mutations of the RB1 gene, which is located on chromosome 13 and encodes the tumor suppressor retinoblastoma protein, can be detected by cytogenetic analysis in many cases of retinoblastoma. Mutations of the RB1 locus in one copy of chromosome 13 are sometimes accompanied by loss of the other wild-type chromosome 13 through mitotic nondisjunction. By this combination of lesions, affected cells completely lose expression of functioning tumor suppressor protein. [7]

Preimplantation genetic diagnosis Edit

Pre-implantation genetic diagnosis (PGD or PIGD) is a technique used to identify genetically normal embryos and is useful for couples who have a family history of genetic disorders. This is an option for people choosing to procreate through IVF. PGD is considered difficult due to it being both time consuming and having success rates only comparable to routine IVF. [17]

Karyotyping Edit

Karyotyping involves performing an amniocentesis in order to study the cells of an unborn fetus during metaphase 1. Light microscopy can be used to visually determine if aneuploidy is an issue. [18]

Polar body diagnosis Edit

Polar body diagnosis (PBD) can be used to detect maternally derived chromosomal aneuploidies as well as translocations in oocytes. The advantage of PBD over PGD is that it can be accomplished in a short amount of time. This is accomplished through zona drilling or laser drilling. [19]

Blastomere biopsy Edit

Blastomere biopsy is a technique in which blastomeres are removed from the zona pellucida. It is commonly used to detect aneuploidy. [20] Genetic analysis is conducted once the procedure is complete. Additional studies are needed to assess the risk associated with the procedure. [21]

Exposure of spermatozoa to lifestyle, environmental and/or occupational hazards may increase the risk of aneuploidy. Cigarette smoke is a known aneugen (aneuploidy inducing agent). It is associated with increases in aneuploidy ranging from 1.5 to 3.0-fold. [22] [23] Other studies indicate factors such as alcohol consumption, [24] occupational exposure to benzene, [25] and exposure to the insecticides fenvalerate [26] and carbaryl [27] also increase aneuploidy.


Contents

The primary features are infertility and small poorly functioning testicles. [3] [9] Often, symptoms may be subtle and many people do not realize they are affected. [1] Sometimes, symptoms are more prominent and may include weaker muscles, greater height, poor coordination, less body hair, breast growth, and less interest in sex. [1] Often it is only at puberty that these symptoms are noticed. [5]

Prenatal Edit

It has been estimated that 60% of infants with Klinefelter syndrome result in miscarriage. [16]

Physical Edit

As babies and children, XXY males may have weaker muscles and reduced strength. As they grow older, they tend to become taller than average. They may have less muscle control and coordination than other boys of their age. [17]

During puberty, the physical traits of the syndrome become more evident because these boys do not produce as much testosterone as other boys, they have a less muscular body, less facial and body hair, and broader hips. As teens, XXY males may develop breast tissue [18] and also have weaker bones, and a lower energy level than other males. [17]

By adulthood, XXY males look similar to males without the condition, although they are often taller. In adults, possible characteristics vary widely and include little to no sign of affectedness, a lanky, youthful build and facial appearance, or a rounded body type with some degree of gynecomastia (increased breast tissue). [19] Gynecomastia is present in about a third of affected individuals, a slightly higher percentage than in the XY population. About 10% of XXY males have gynecomastia noticeable enough that they may choose to have cosmetic surgery. [20]

Affected males are often infertile, or have reduced fertility. Advanced reproductive assistance is sometimes possible. [21] It has been estimated that 50% of males with Klinefelter syndrome can produce sperm. [22]

The term hypogonadism in XXY symptoms is often misinterpreted to mean "small testicles" when it means decreased testicular hormone/endocrine function. Because of (primary) hypogonadism, individuals often have a low serum testosterone level, but high serum follicle-stimulating hormone and luteinizing hormone levels. [23] Despite this misunderstanding of the term, however, XXY men may also have microorchidism (i.e., small testicles). [23]

The testicles of affected males are usually less than 2 cm in length (and always shorter than 3.5 cm [24] ), 1 cm in width, and 4 ml in volume. [25] [26]

XXY males are more likely than other men to have certain health problems, such as autoimmune disorders, breast cancer, venous thromboembolic disease, and osteoporosis. [17] [27] In contrast to these potentially increased risks, rare X-linked recessive conditions are thought to occur less frequently in XXY males than in normal XY males, since these conditions are transmitted by genes on the X chromosome, and people with two X chromosomes are typically only carriers rather than affected by these X-linked recessive conditions. [ citation needed ]

Cognitive and developmental Edit

Some degree of language learning or reading impairment may be present, [28] and neuropsychological testing often reveals deficits in executive functions, although these deficits can often be overcome through early intervention. [29] Also, delays in motor development may occur, which can be addressed through occupational and physical therapies. [30] XXY males may sit up, crawl, and walk later than other infants they may also struggle in school, both academically and with sports. [17] It’s estimated that 10% of men with Klinefelter syndrome are autistic. [31]

Klinefelter syndrome is not an inherited condition. [32] Maternal age is the only known risk factor. [11] Women at 40 years have a four times higher risk for a child with Klinefelter syndrome than women aged 24 years. [33] [34]

The extra chromosome is retained because of a nondisjunction event during paternal meiosis I, maternal meiosis I, or maternal meiosis II (gametogenesis). The relevant nondisjunction in meiosis I occurs when homologous chromosomes, in this case the X and Y or two X sex chromosomes, fail to separate, producing a sperm with an X and a Y chromosome or an egg with two X chromosomes. Fertilizing a normal (X) egg with this sperm produces an XXY offspring (Klinefelter). Fertilizing a double X egg with a normal sperm also produces an XXY offspring (Klinefelter). [35]

Another mechanism for retaining the extra chromosome is through a nondisjunction event during meiosis II in the egg. Nondisjunction occurs when sister chromatids on the sex chromosome, in this case an X and an X, fail to separate. An XX egg is produced, which when fertilized with a Y sperm, yields an XXY offspring. This XXY chromosome arrangement is one of the most common genetic variations from the XY karyotype, occurring in about one in 500 live male births. [17] See also Triple X syndrome.

In mammals with more than one X chromosome, the genes on all but one X chromosome are not expressed this is known as X inactivation. This happens in XXY males, as well as normal XX females. [36] However, in XXY males, a few genes located in the pseudoautosomal regions of their X chromosomes have corresponding genes on their Y chromosome and are capable of being expressed. [37]

Variations Edit

48,XXYY or 48,XXXY occurs in one in 18,000–50,000 male births. The incidence of 49,XXXXY is one in 85,000 to 100,000 male births. [38] These variations are extremely rare. Additional chromosomal material can contribute to cardiac, neurological, orthopedic, and other anomalies.

Approximately 15–20% [39] of males with KS may have a mosaic 47,XXY/46,XY constitutional karyotype and varying degrees of spermatogenic failure. Often symptoms are milder in mosaic cases, with regular male secondary sex characteristics and testicular volume even falling within typical adult ranges. [39] Another possible mosaicism is 47,XXY/46,XX with clinical features suggestive of KS and male phenotype, but this is very rare. Thus far, only about 10 cases of 47,XXY/46,XX have been described in literature. [40]

Analogous XXY syndromes are known to occur in cats—specifically, the presence of calico or tortoiseshell markings in male cats is an indicator of the relevant abnormal karyotype. As such, male cats with calico or tortoiseshell markings are a model organism for KS, because a color gene involved in cat tabby coloration is on the X chromosome. [41]

The standard diagnostic method is the analysis of the chromosomes' karyotype on lymphocytes. A small blood sample is sufficient as test material. In the past, the observation of the Barr body was common practice, as well. [42] To investigate the presence of a possible mosaicism, analysis of the karyotype using cells from the oral mucosa is performed. Physical characteristics of a Klinefelter syndrome can be tall stature, low body hair and occasionally an enlargement of the breast. There is usually a small testicle volume of 1–5 ml per testicle (standard values: 12–30 ml). [43] During puberty and adulthood, low testosterone levels with increased levels of the pituitary hormones FSH and LH in the blood can indicate the presence of Klinefelter syndrome. A spermiogram can also be part of the further investigation. Often there is an azoospermia present, rarely an oligospermia. [11] Furthermore, Klinefelter syndrome can be diagnosed as a coincidental prenatal finding in the context of invasive prenatal diagnosis (amniocentesis, chorionic villus sampling). About 10% of KS cases are found by prenatal diagnosis. [44]

The symptoms of KS are often variable therefore, a karyotype analysis should be ordered when small testes, infertility, gynecomastia, long arms/legs, developmental delay, speech/language deficits, learning disabilities/academic issues, and/or behavioral issues are present in an individual. [9]

The genetic variation is irreversible, thus there is no causal therapy. From the onset of puberty, the existing testosterone deficiency can be compensated by appropriate hormone replacement therapy. [45] Testosterone preparations are available in the form of syringes, patches or gel. If gynecomastia is present, the surgical removal of the breast may be considered for both the psychological reasons and to reduce the risk of breast cancer. [46]

The use of behavioral therapy can mitigate any language disorders, difficulties at school, and socialization. An approach by occupational therapy is useful in children, especially those who have dyspraxia. [47]

Infertility treatment Edit

Methods of reproductive medicine, such as intracytoplasmic sperm injection (ICSI) with previously conducted testicular sperm extraction (TESE), have led to men with Klinefelter syndrome producing biological offspring. [48] By 2010, over 100 successful pregnancies have been reported using IVF technology with surgically removed sperm material from males with KS. [49]

The lifespan of individuals with Klinefelter syndrome appears to be reduced by approximately 2.1 years compared to the general male population. [50] These results are still questioned data, are not absolute, and need further testing. [51]

This syndrome, evenly distributed in all ethnic groups, has a prevalence of four subjects per every 10000 males in the general population. [33] [52] [53] [54] However, it is estimated that only 25% of the individuals with Klinefelter syndrome are diagnosed throughout their lives. [45] The rate of Klinefelter syndrome among infertile males is 3.1%. The syndrome is also the main cause of male hypogonadism. [55]

The syndrome was named after American endocrinologist Harry Klinefelter, who in 1942 worked with Fuller Albright and E. C. Reifenstein at Massachusetts General Hospital in Boston, Massachusetts, and first described it in the same year. [19] [56] The account given by Klinefelter came to be known as Klinefelter syndrome as his name appeared first on the published paper, and seminiferous tubule dysgenesis was no longer used. Considering the names of all three researchers, it is sometimes also called Klinefelter–Reifenstein–Albright syndrome. [57] In 1956 it was discovered that Klinefelter syndrome resulted from an extra chromosome. [14] Plunkett and Barr found the sex chromatin body in cell nuclei of the body. This was further clarified as XXY in 1959 by Patricia Jacobs and John Anderson Strong. [58] The first published report of a man with a 47,XXY karyotype was by Patricia Jacobs and John Strong at Western General Hospital in Edinburgh, Scotland, in 1959. [58] This karyotype was found in a 24-year-old man who had signs of KS. Jacobs described her discovery of this first reported human or mammalian chromosome aneuploidy in her 1981 William Allan Memorial Award address. [59] Lili Elbe, one of the early recipients of sex reassignment surgery, may have had Klinefelter syndrome. [60] [61] John Randolph of Roanoke had a genetic condition, possible Klinefelter syndrome, that left him beardless and with a soprano prepubescent voice throughout his life. [62]


Contents

Biologists

Anisogamy, or the size differences of gametes (sex cells), is the defining feature of the two sexes. [12] [13] [14] [15] According to biologist Michael Majerus there is no other universal difference between males and females. [16]

By definition, males are organisms that produce small, mobile gametes (sperm) while females are organisms that produce large and generally immobile gametes (ova or eggs). [17] [18] [19] [20]

Richard Dawkins stated that it’s possible to interpret all the differences between the sexes stemming from this single difference in gametes. [21]

The consensus among scientists is that all behaviors are phenotypes complex interactions of both biology and environment—and thus nature vs. nurture is a misleading categorization. [ clarification needed ] [22] [23] The term sex differences is typically applied to sexually dimorphic traits that are hypothesized to be evolved consequences of sexual selection. For example, the human "sex difference" in height is a consequence of sexual selection, while the "gender difference" typically seen in head hair length (women with longer hair) is not. [10] [11] Scientific research shows an individual's sex influences his or her behavior. [24] [25] [26] [27] [28]

Dictionaries

Sex is annotated as different from gender in the Oxford English Dictionary, where it says sex "tends now to refer to biological differences". [29]

Public health organizations

The World Health Organization (WHO) similarly states that "'sex' refers to the biological and physiological characteristics that define men and women" and that "'male' and 'female' are sex categories". [30] According to the CDC people whose internal psychological experience differs from their assigned sex are transgender, transsexual, or non-binary. [31]

History

Historian Thomas W. Laqueur suggests that from the Renaissance to the 18th century, there was a prevailing inclination among doctors towards the existence of only one biological sex (the one-sex theory, that women and men had the same fundamental reproductive structure). [32] In some discourses, this view persisted into the eighteenth and nineteenth centuries. [33] [34] Laqueur asserts that even at its peak, the one-sex model was supported among highly educated Europeans but is not known to have been a popular view nor one entirely agreed upon by doctors who treated the general population. [35]

Scholars such as Joan Cadden and Michael Stolberg have criticized Laqueur's theory. Stolberg provides evidence to suggest that significant two-sex understandings of anatomy existed before Laqueur claims, arguing that sexual dimorphism was accepted as early as the sixteenth century. [36] : 276 Joan Cadden has stated that 'one-sex' models of the body were already treated with scepticism in the ancient and medieval periods, and that Laqueur's periodisation of the shift from one-sex to two-sex was not as clear-cut as he made it out to be. [37]

Sex and gender took center stage in America in the time of wars, when women had to work and men were at war. [38]

Dictationaries

In the Oxford English Dictionary, gender is defined as, "[i]n mod[ern] (esp[ecially] feminist) use, a euphemism for the sex of a human being, often intended to emphasize the social and cultural, as opposed to the biological, distinctions between the sexes", with the earliest example cited being from 1963. [39] The American Heritage Dictionary (5th edition) states that gender may be defined by identity as "neither entirely female nor entirely male" its Usage Note adds: [40]

Some people maintain that the word sex should be reserved for reference to the biological aspects of being male or female or to sexual activity, and that the word gender should be used only to refer to sociocultural roles. . In some situations this distinction avoids ambiguity, as in gender research, which is clear in a way that sex research is not. The distinction can be problematic, however. Linguistically, there isn't any real difference between gender bias and sex bias, and it may seem contrived to insist that sex is incorrect in this instance.

Public medical organizations

A working definition in use by the World Health Organization for its work is that "'[g]ender' refers to the socially constructed roles, behaviours, activities, and attributes that a given society considers appropriate for men and women" and that "'masculine' and 'feminine' are gender categories." [30] The Food and Drug Administration (FDA) used to use gender instead of sex when referring to physiological differences between male and female organisms. [41] In 2011, they reversed their position on this and began using sex as the biological classification and gender as "a person's self representation as male or female, or how that person is responded to by social institutions based on the individual's gender presentation." [42] Gender is also now commonly used even to refer to the physiology of non-human animals, without any implication of social gender roles. [6]

Political organizations

GLAAD (formerly the Gay & Lesbian Alliance Against Defamation) makes a distinction between sex and gender in their most recent [ timeframe? ] Media Reference Guide: Sex is "the classification of people as male or female" at birth, based on bodily characteristics such as chromosomes, hormones, internal reproductive organs, and genitalia. Gender identity is "one's internal, personal sense of being a man or woman (or a boy or a girl)". [43]

History

Gender in the sense of social and behavioral distinctions, according to archaeological evidence, arose "at least by some 30,000 years ago". [44] More evidence was found as of "26,000 years ago", [45] at least at the archeological site Dolní Věstonice I and others, in what is now the Czech Republic. [46] This is during the Upper Paleolithic time period. [47]

The historic meaning of gender, ultimately derived from Latin genus, was of "kind" or "variety". By the 20th century, this meaning was obsolete, and the only formal use of gender was in grammar. [5] This changed in the early 1970s when the work of John Money, particularly the popular college textbook Man & Woman, Boy & Girl, was embraced by feminist theory. This meaning of gender is now prevalent in the social sciences, although in many other contexts, gender includes sex or replaces it. [6] Gender was first only used in languages to describe the feminine and masculine words, up until around the 1960s. [48]

Since the social sciences now distinguish between biologically defined sex and socially constructed gender, the term gender is now also sometimes used by linguists to refer to social gender as well as grammatical gender. Traditionally, however, a distinction has been made by linguists between sex and gender, where sex refers primarily to the attributes of real-world entities – the relevant extralinguistic attributes being, for instance, male, female, non-personal, and indeterminate sex – and grammatical gender refers to a category, such as masculine, feminine, and neuter (often based on sex, but not exclusively so in all languages), that determines the agreement between nouns of different genders and associated words, such as articles and adjectives. [49] [50]

By GENDER is meant a grammatical classification of nouns, pronouns, or other words in the noun phrase according to certain meaning-related distinctions, especially a distinction related to the sex of the referent. [51]

Thus German, for instance, has three genders: masculine, feminine, and neuter. Nouns referring to people and animals of known sex are generally referred to by nouns with the equivalent gender. Thus Mann (meaning man) is masculine and is associated with a masculine definite article to give der Mann, while Frau (meaning woman) is feminine and is associated with a feminine definite article to give die Frau. However the words for inanimate objects are commonly masculine (e.g. der Tisch, the table) or feminine (die Armbanduhr, the watch), and grammatical gender can diverge from biological sex for instance the feminine noun [die] Person refers to a person of either sex, and the neuter noun [das] Mädchen means "the girl".

In modern English, there is no true grammatical gender in this sense, [49] though the differentiation, for instance, between the pronouns "he" and "she", which in English refers to a difference in sex (or social gender), is sometimes referred to as a gender distinction. A Comprehensive Grammar of the English Language, for instance, refers to the semantically based "covert" gender (e.g. male and female, not masculine and feminine) of English nouns, as opposed to the "overt" gender of some English pronouns this yields nine gender classes: male, female, dual, common, collective, higher male animal, higher female animal, lower animal, and inanimate, and these semantic gender classes affect the possible choices of pronoun for coreference to the real-life entity, e.g. who and he for brother but which and it or she for cow. [51]

Used primarily in sociology and gender studies, "doing gender" is the socially constructed performance which takes place during routine human interactions, rather than as a set of essentialized qualities based on one's biological sex. [52] The term first appeared in Candace West and Don Zimmerman’s article "Doing Gender", published in the peer-reviewed journal, Gender and Society. [53] Originally written in 1977 but not published until 1987, [54] "Doing Gender" is the most cited article published in Gender and Society. [53]

West and Zimmerman state that to understand gender as activity, it is important to differentiate between sex, sex category, and gender. [52] : 127 They say that sex refers to the socially agreed upon specifications that establish one as male or female sex is most often based on an individual's genitalia, or even their chromosomal typing before birth. [52] They consider sex categories to be dichotomous, and that the person is placed in a sex category by exhibiting qualities exclusive to one category or the other. During most interactions, others situate a person's sex by identifying their sex category however, they believe that a person's sex need not align with their sex category. [52] West and Zimmerman maintain that the sex category is "established and sustained by the socially required identificatory displays that proclaim one’s membership in one or the other category". [52] : 127 Gender is the performance of attitudes and actions that are considered socially acceptable for one's sex category. [52] : 127

West and Zimmerman suggested that the interactional process of doing gender, combined with socially agreed upon gender expectations, holds individuals accountable for their gender performances. [52] They also believe that while "doing gender" appropriately strengthens and promotes social structures based on the gender dichotomy, it inappropriately does not call into question these same social structures only the individual actor is questioned. [52] The concept of "doing gender" recognizes that gender both structures human interactions and is created through them. [52]

The current distinction between the terms sex difference versus gender difference has been criticized as misleading and counterproductive. These terms suggest that the behavior of an individual can be partitioned into separate biological and cultural factors. [ original research? ] (However, behavioral differences between individuals can be statistically partitioned, as studied by behavioral genetics.) Instead, all behaviors are phenotypes—a complex interweaving of both nature and nurture. [55]

Diane Halpern, in her book Sex Differences in Cognitive Abilities, argued problems with sex vs. gender terminology:

I cannot argue (in this book) that nature and nurture are inseparable and then. use different terms to refer to each class of variables. The . biological manifestations of sex are confounded with psychosocial variables. The use of different terms to label these two types of contributions to human existence seemed inappropriate in light of the biopsychosocial position I have taken.

She quotes Steven Pinker's summary of the problems with the terms sex and gender: "Part of it is a new prissiness—many people today are as squeamish about sexual dimorphism as the Victorians were about sex. But part of it is a limitation of the English language. The word 'sex' refers ambiguously to copulation and to sexual dimorphism. " [56] Richard Lippa writes in Gender, Nature and Nurture that: [57]

Some researchers have argued that the word sex should be used to refer to (biological differences), whereas the word gender should be used to refer to (cultural differences). However, it is not at all clear the degree to which the differences between males and females are due to biological factors versus learned and cultural factors. Furthermore, indiscriminate use of the word gender tends to obscure the distinction between two different topics: (a) differences between males and females, and (b) individual differences in maleness and femaleness that occur within each sex.

It has been suggested that more useful distinctions to make would be whether a behavioral difference between the sexes is first due to an evolved adaptation, then, if so, whether the adaptation is sexually dimorphic (different) or sexually monomorphic (the same in both sexes). The term sex difference could then be re-defined as between-sex differences that are manifestations of a sexually dimorphic adaptation (which is how many scientists use the term), [58] [59] while the term gender difference could be re-defined as due to differential socialization between the sexes of a monomorphic adaptation or byproduct. For example, greater male propensity toward physical aggression and risk taking would be termed a "sex difference" the generally longer head hair length of females would be termed a "gender difference". [60]

Transgender people experience a mismatch between their gender identity or gender expression, and their assigned sex. [61] [62] [63] Transgender people are sometimes called transsexual if they desire medical assistance to transition from one sex to another.

Transgender is also an umbrella term: in addition to including people whose gender identity is the opposite of their assigned sex (trans men and trans women), it may include people who are not exclusively masculine or feminine (e.g. people who are genderqueer, non-binary, bigender, pangender, genderfluid, or agender). [62] [64] [65] Other definitions of transgender also include people who belong to a third gender, or conceptualize transgender people as a third gender. [66] [67] Infrequently, the term transgender is defined very broadly to include cross-dressers. [68]

According to the Intersex Society of North America, "nature doesn't decide where the category of 'male' ends and the category of 'intersex' begins, or where the category of 'intersex' ends and the category of 'female' begins. Humans decide. Humans (today, typically doctors) decide how small a penis has to be, or how unusual a combination of parts has to be, before it counts as intersex." [69]

General

Many feminists consider sex to only be a matter of biology and something that is not about social or cultural construction. For example, Lynda Birke, a feminist biologist, states that " 'biology' is not seen as something which might change." [70] However, the sex/gender distinction, also known as the Standard Model of Sex/Gender, [ original research? ] is criticized by feminists who believe that there is undue emphasis placed on sex being a biological aspect, something that is fixed, natural, unchanging, and consisting of a male/female dichotomy. They believe the distinction fails to recognize anything outside the strictly male/female dichotomy and that it creates a barrier between those that fit as 'usual' and those that are 'unusual'. [ who? ] [ original research? ] In Anne Fausto-Sterling’s Sexing the Body she addresses the birth of children who are intersex. In this case, the standard model (sex/gender distinction) is seen as incorrect with regard to its notion that there are only two sexes, male and female. This is because "complete maleness and complete femaleness represent the extreme ends of a spectrum of possible body types." [71] In other words, Fausto-Sterling argues that sex is a continuum.

Rather than viewing sex as a biological construct, there are feminists who view both sex and gender as a social construct. Fausto-Sterling believes that sex is socially constructed because nature does not decide on who is seen as a male or female physically. Rather, doctors decide what seems to be a "natural" sex for the inhabitants of society. In addition, the gender, behavior, actions, and appearance of males/females is also seen as socially constructed because codes of femininity and masculinity are chosen and deemed fit by society for societal usage.

Some feminist philosophers maintain that gender is totally undetermined by sex. See, for example, The Dialectic of Sex: The Case for Feminist Revolution, a widely influential feminist text. [72]

Limitations

Some feminists go further and argue that neither sex nor gender are strictly binary concepts. Judith Lorber, for instance, has stated that many conventional indicators of sex are not sufficient to demarcate male from female. For example, not all women lactate, while some men do. [73] Similarly, Suzanne Kessler, in a 1990 survey of medical specialists in pediatric intersexuality, found out that when a child was born with XY chromosomes but ambiguous genitalia, its sex was often determined according to the size of its penis. [74] Thus, even if the sex/gender distinction holds, Lorber and Kessler suggest that the dichotomies of female/male and masculine/feminine are not themselves exhaustive. Lorber writes, "My perspective goes beyond accepted feminist views that gender is a cultural overlay that modifies physiological sex differences . I am arguing that bodies differ in many ways physiologically, but they are completely transformed by social practices to fit into the salient categories of a society, the most pervasive of which are 'female' and 'male' and 'women' and 'men.'" [73]

Moreover, Lorber has alleged that there exists more diversity within the individual categories of sex and gender—female/male and feminine/masculine, respectively—than between them. [73] Hence, her fundamental claim is that both sex and gender are social constructions, rather than natural kinds.

A comparable view has been advanced by Linda Zerilli, who writes regarding Monique Wittig, that she is "critical of the sex/gender dichotomy in much feminist theory because such a dichotomy leaves unquestioned the belief that there is a 'core of nature which resists examination, a relationship excluded from the social in the analysis—a relationship whose characteristic is ineluctability in culture, as well as in nature, and which is the heterosexual relationship.'" [75] Judith Butler also criticizes the sex/gender distinction. Discussing sex as biological fact causes sex to appear natural and politically neutral. However, she argues that "the ostensibly natural facts of sex [are] discursively produced in the service of other political and social interests." Butler concludes, "If the immutable character of sex is contested, perhaps this construct called 'sex' is as culturally constructed as gender indeed, perhaps it was always already gender, with the consequence that the distinction between sex and gender turns out to be no distinction at all." [76]

Governments, corporations, and organizations have varying recognition of, and approaches to the distinction between sex and gender. [ citation needed ]

U.S. Census

The United States Census Bureau performs a census of the U.S. population every ten years. The questionnaire asks one question about sex, phrased as "What is person 1's sex?" and provides two checkboxes for the response, labeled "Male" and "Female". [77] An explanatory page explains this question, using the term sex: as "We ask one question about a person’s sex to better understand demographic characteristics." [77] The U.S. Census has had a question about sex on the census since the 1790 census. [77] The U.S. Census recognizes the difference between the terms sex and gender, the fact they are often confused or used interchangeably, and may differ across cultures and time, and explains that what the census attempts to measure, is "the sex composition of the population". [78]

Australian government

The Australian government provides guidelines on sex and gender to the public based on legislation passed in 2013. The guidelines recognize that "individuals may identify as a gender other than the sex they were assigned at birth, or may not identify as exclusively male or female". [79] [80] [81] The Australian Bureau of Statistics (ABS) gathers data about the population broken down in various ways, including by sex and gender. They require precise formulations of these terms, and go into some detail about sex recorded at birth, possible changes in sex assignment later in life, the meaning of gender and how it differs from sex. ABS recognizes the popular confusion among the two terms, and provide descriptions of how to phrase surveys so as to elicit accurate responses for the purposes of the data they collect. [82]

The government of the state of Western Australia recognizes a clear distinction between sex and gender providing a nuanced definition of each, including complications involved in sex beyond just sex assigned at birth, and the socially constructed nature of gender, including possible non-binary aspects. [83]

United Kingdom government

The United Kingdom Office for National Statistics (ONS) describes definitions provided by the UK government that make clear distinctions between the "biological aspects" aspects of sex, "generally male or female", and "assigned at birth", while describing gender as a "social construction relating to behaviours and attributes based on labels of masculinity and femininity". [84]

Health organizations

The World Health Organization's defines gender as "socially constructed", and sex as characteristics that are "biologically determined", drawing a distinction between the sex categories of male and female, and the genders "girls and boys who grow into men and women". [85]

Mental health associations

The American Psychiatric Association (APA) in their Guide for Working With Transgender and Gender Nonconforming Patients (TGNC Guide) [86] has guidance for psychiatrists about gender, sex, and orientation. The TGNC defines gender as comprising two components, that of gender identity and gender expression. They define sex in biological terms, as "anatomical, hormonal, or genetic", and mentions birth assignment of sex based on external genital appearance. [87]


Contents

Biologists

Anisogamy, or the size differences of gametes (sex cells), is the defining feature of the two sexes. [12] [13] [14] [15] According to biologist Michael Majerus there is no other universal difference between males and females. [16]

By definition, males are organisms that produce small, mobile gametes (sperm) while females are organisms that produce large and generally immobile gametes (ova or eggs). [17] [18] [19] [20]

Richard Dawkins stated that it’s possible to interpret all the differences between the sexes stemming from this single difference in gametes. [21]

The consensus among scientists is that all behaviors are phenotypes complex interactions of both biology and environment—and thus nature vs. nurture is a misleading categorization. [ clarification needed ] [22] [23] The term sex differences is typically applied to sexually dimorphic traits that are hypothesized to be evolved consequences of sexual selection. For example, the human "sex difference" in height is a consequence of sexual selection, while the "gender difference" typically seen in head hair length (women with longer hair) is not. [10] [11] Scientific research shows an individual's sex influences his or her behavior. [24] [25] [26] [27] [28]

Dictionaries

Sex is annotated as different from gender in the Oxford English Dictionary, where it says sex "tends now to refer to biological differences". [29]

Public health organizations

The World Health Organization (WHO) similarly states that "'sex' refers to the biological and physiological characteristics that define men and women" and that "'male' and 'female' are sex categories". [30] According to the CDC people whose internal psychological experience differs from their assigned sex are transgender, transsexual, or non-binary. [31]

History

Historian Thomas W. Laqueur suggests that from the Renaissance to the 18th century, there was a prevailing inclination among doctors towards the existence of only one biological sex (the one-sex theory, that women and men had the same fundamental reproductive structure). [32] In some discourses, this view persisted into the eighteenth and nineteenth centuries. [33] [34] Laqueur asserts that even at its peak, the one-sex model was supported among highly educated Europeans but is not known to have been a popular view nor one entirely agreed upon by doctors who treated the general population. [35]

Scholars such as Joan Cadden and Michael Stolberg have criticized Laqueur's theory. Stolberg provides evidence to suggest that significant two-sex understandings of anatomy existed before Laqueur claims, arguing that sexual dimorphism was accepted as early as the sixteenth century. [36] : 276 Joan Cadden has stated that 'one-sex' models of the body were already treated with scepticism in the ancient and medieval periods, and that Laqueur's periodisation of the shift from one-sex to two-sex was not as clear-cut as he made it out to be. [37]

Sex and gender took center stage in America in the time of wars, when women had to work and men were at war. [38]

Dictationaries

In the Oxford English Dictionary, gender is defined as, "[i]n mod[ern] (esp[ecially] feminist) use, a euphemism for the sex of a human being, often intended to emphasize the social and cultural, as opposed to the biological, distinctions between the sexes", with the earliest example cited being from 1963. [39] The American Heritage Dictionary (5th edition) states that gender may be defined by identity as "neither entirely female nor entirely male" its Usage Note adds: [40]

Some people maintain that the word sex should be reserved for reference to the biological aspects of being male or female or to sexual activity, and that the word gender should be used only to refer to sociocultural roles. . In some situations this distinction avoids ambiguity, as in gender research, which is clear in a way that sex research is not. The distinction can be problematic, however. Linguistically, there isn't any real difference between gender bias and sex bias, and it may seem contrived to insist that sex is incorrect in this instance.

Public medical organizations

A working definition in use by the World Health Organization for its work is that "'[g]ender' refers to the socially constructed roles, behaviours, activities, and attributes that a given society considers appropriate for men and women" and that "'masculine' and 'feminine' are gender categories." [30] The Food and Drug Administration (FDA) used to use gender instead of sex when referring to physiological differences between male and female organisms. [41] In 2011, they reversed their position on this and began using sex as the biological classification and gender as "a person's self representation as male or female, or how that person is responded to by social institutions based on the individual's gender presentation." [42] Gender is also now commonly used even to refer to the physiology of non-human animals, without any implication of social gender roles. [6]

Political organizations

GLAAD (formerly the Gay & Lesbian Alliance Against Defamation) makes a distinction between sex and gender in their most recent [ timeframe? ] Media Reference Guide: Sex is "the classification of people as male or female" at birth, based on bodily characteristics such as chromosomes, hormones, internal reproductive organs, and genitalia. Gender identity is "one's internal, personal sense of being a man or woman (or a boy or a girl)". [43]

History

Gender in the sense of social and behavioral distinctions, according to archaeological evidence, arose "at least by some 30,000 years ago". [44] More evidence was found as of "26,000 years ago", [45] at least at the archeological site Dolní Věstonice I and others, in what is now the Czech Republic. [46] This is during the Upper Paleolithic time period. [47]

The historic meaning of gender, ultimately derived from Latin genus, was of "kind" or "variety". By the 20th century, this meaning was obsolete, and the only formal use of gender was in grammar. [5] This changed in the early 1970s when the work of John Money, particularly the popular college textbook Man & Woman, Boy & Girl, was embraced by feminist theory. This meaning of gender is now prevalent in the social sciences, although in many other contexts, gender includes sex or replaces it. [6] Gender was first only used in languages to describe the feminine and masculine words, up until around the 1960s. [48]

Since the social sciences now distinguish between biologically defined sex and socially constructed gender, the term gender is now also sometimes used by linguists to refer to social gender as well as grammatical gender. Traditionally, however, a distinction has been made by linguists between sex and gender, where sex refers primarily to the attributes of real-world entities – the relevant extralinguistic attributes being, for instance, male, female, non-personal, and indeterminate sex – and grammatical gender refers to a category, such as masculine, feminine, and neuter (often based on sex, but not exclusively so in all languages), that determines the agreement between nouns of different genders and associated words, such as articles and adjectives. [49] [50]

By GENDER is meant a grammatical classification of nouns, pronouns, or other words in the noun phrase according to certain meaning-related distinctions, especially a distinction related to the sex of the referent. [51]

Thus German, for instance, has three genders: masculine, feminine, and neuter. Nouns referring to people and animals of known sex are generally referred to by nouns with the equivalent gender. Thus Mann (meaning man) is masculine and is associated with a masculine definite article to give der Mann, while Frau (meaning woman) is feminine and is associated with a feminine definite article to give die Frau. However the words for inanimate objects are commonly masculine (e.g. der Tisch, the table) or feminine (die Armbanduhr, the watch), and grammatical gender can diverge from biological sex for instance the feminine noun [die] Person refers to a person of either sex, and the neuter noun [das] Mädchen means "the girl".

In modern English, there is no true grammatical gender in this sense, [49] though the differentiation, for instance, between the pronouns "he" and "she", which in English refers to a difference in sex (or social gender), is sometimes referred to as a gender distinction. A Comprehensive Grammar of the English Language, for instance, refers to the semantically based "covert" gender (e.g. male and female, not masculine and feminine) of English nouns, as opposed to the "overt" gender of some English pronouns this yields nine gender classes: male, female, dual, common, collective, higher male animal, higher female animal, lower animal, and inanimate, and these semantic gender classes affect the possible choices of pronoun for coreference to the real-life entity, e.g. who and he for brother but which and it or she for cow. [51]

Used primarily in sociology and gender studies, "doing gender" is the socially constructed performance which takes place during routine human interactions, rather than as a set of essentialized qualities based on one's biological sex. [52] The term first appeared in Candace West and Don Zimmerman’s article "Doing Gender", published in the peer-reviewed journal, Gender and Society. [53] Originally written in 1977 but not published until 1987, [54] "Doing Gender" is the most cited article published in Gender and Society. [53]

West and Zimmerman state that to understand gender as activity, it is important to differentiate between sex, sex category, and gender. [52] : 127 They say that sex refers to the socially agreed upon specifications that establish one as male or female sex is most often based on an individual's genitalia, or even their chromosomal typing before birth. [52] They consider sex categories to be dichotomous, and that the person is placed in a sex category by exhibiting qualities exclusive to one category or the other. During most interactions, others situate a person's sex by identifying their sex category however, they believe that a person's sex need not align with their sex category. [52] West and Zimmerman maintain that the sex category is "established and sustained by the socially required identificatory displays that proclaim one’s membership in one or the other category". [52] : 127 Gender is the performance of attitudes and actions that are considered socially acceptable for one's sex category. [52] : 127

West and Zimmerman suggested that the interactional process of doing gender, combined with socially agreed upon gender expectations, holds individuals accountable for their gender performances. [52] They also believe that while "doing gender" appropriately strengthens and promotes social structures based on the gender dichotomy, it inappropriately does not call into question these same social structures only the individual actor is questioned. [52] The concept of "doing gender" recognizes that gender both structures human interactions and is created through them. [52]

The current distinction between the terms sex difference versus gender difference has been criticized as misleading and counterproductive. These terms suggest that the behavior of an individual can be partitioned into separate biological and cultural factors. [ original research? ] (However, behavioral differences between individuals can be statistically partitioned, as studied by behavioral genetics.) Instead, all behaviors are phenotypes—a complex interweaving of both nature and nurture. [55]

Diane Halpern, in her book Sex Differences in Cognitive Abilities, argued problems with sex vs. gender terminology:

I cannot argue (in this book) that nature and nurture are inseparable and then. use different terms to refer to each class of variables. The . biological manifestations of sex are confounded with psychosocial variables. The use of different terms to label these two types of contributions to human existence seemed inappropriate in light of the biopsychosocial position I have taken.

She quotes Steven Pinker's summary of the problems with the terms sex and gender: "Part of it is a new prissiness—many people today are as squeamish about sexual dimorphism as the Victorians were about sex. But part of it is a limitation of the English language. The word 'sex' refers ambiguously to copulation and to sexual dimorphism. " [56] Richard Lippa writes in Gender, Nature and Nurture that: [57]

Some researchers have argued that the word sex should be used to refer to (biological differences), whereas the word gender should be used to refer to (cultural differences). However, it is not at all clear the degree to which the differences between males and females are due to biological factors versus learned and cultural factors. Furthermore, indiscriminate use of the word gender tends to obscure the distinction between two different topics: (a) differences between males and females, and (b) individual differences in maleness and femaleness that occur within each sex.

It has been suggested that more useful distinctions to make would be whether a behavioral difference between the sexes is first due to an evolved adaptation, then, if so, whether the adaptation is sexually dimorphic (different) or sexually monomorphic (the same in both sexes). The term sex difference could then be re-defined as between-sex differences that are manifestations of a sexually dimorphic adaptation (which is how many scientists use the term), [58] [59] while the term gender difference could be re-defined as due to differential socialization between the sexes of a monomorphic adaptation or byproduct. For example, greater male propensity toward physical aggression and risk taking would be termed a "sex difference" the generally longer head hair length of females would be termed a "gender difference". [60]

Transgender people experience a mismatch between their gender identity or gender expression, and their assigned sex. [61] [62] [63] Transgender people are sometimes called transsexual if they desire medical assistance to transition from one sex to another.

Transgender is also an umbrella term: in addition to including people whose gender identity is the opposite of their assigned sex (trans men and trans women), it may include people who are not exclusively masculine or feminine (e.g. people who are genderqueer, non-binary, bigender, pangender, genderfluid, or agender). [62] [64] [65] Other definitions of transgender also include people who belong to a third gender, or conceptualize transgender people as a third gender. [66] [67] Infrequently, the term transgender is defined very broadly to include cross-dressers. [68]

According to the Intersex Society of North America, "nature doesn't decide where the category of 'male' ends and the category of 'intersex' begins, or where the category of 'intersex' ends and the category of 'female' begins. Humans decide. Humans (today, typically doctors) decide how small a penis has to be, or how unusual a combination of parts has to be, before it counts as intersex." [69]

General

Many feminists consider sex to only be a matter of biology and something that is not about social or cultural construction. For example, Lynda Birke, a feminist biologist, states that " 'biology' is not seen as something which might change." [70] However, the sex/gender distinction, also known as the Standard Model of Sex/Gender, [ original research? ] is criticized by feminists who believe that there is undue emphasis placed on sex being a biological aspect, something that is fixed, natural, unchanging, and consisting of a male/female dichotomy. They believe the distinction fails to recognize anything outside the strictly male/female dichotomy and that it creates a barrier between those that fit as 'usual' and those that are 'unusual'. [ who? ] [ original research? ] In Anne Fausto-Sterling’s Sexing the Body she addresses the birth of children who are intersex. In this case, the standard model (sex/gender distinction) is seen as incorrect with regard to its notion that there are only two sexes, male and female. This is because "complete maleness and complete femaleness represent the extreme ends of a spectrum of possible body types." [71] In other words, Fausto-Sterling argues that sex is a continuum.

Rather than viewing sex as a biological construct, there are feminists who view both sex and gender as a social construct. Fausto-Sterling believes that sex is socially constructed because nature does not decide on who is seen as a male or female physically. Rather, doctors decide what seems to be a "natural" sex for the inhabitants of society. In addition, the gender, behavior, actions, and appearance of males/females is also seen as socially constructed because codes of femininity and masculinity are chosen and deemed fit by society for societal usage.

Some feminist philosophers maintain that gender is totally undetermined by sex. See, for example, The Dialectic of Sex: The Case for Feminist Revolution, a widely influential feminist text. [72]

Limitations

Some feminists go further and argue that neither sex nor gender are strictly binary concepts. Judith Lorber, for instance, has stated that many conventional indicators of sex are not sufficient to demarcate male from female. For example, not all women lactate, while some men do. [73] Similarly, Suzanne Kessler, in a 1990 survey of medical specialists in pediatric intersexuality, found out that when a child was born with XY chromosomes but ambiguous genitalia, its sex was often determined according to the size of its penis. [74] Thus, even if the sex/gender distinction holds, Lorber and Kessler suggest that the dichotomies of female/male and masculine/feminine are not themselves exhaustive. Lorber writes, "My perspective goes beyond accepted feminist views that gender is a cultural overlay that modifies physiological sex differences . I am arguing that bodies differ in many ways physiologically, but they are completely transformed by social practices to fit into the salient categories of a society, the most pervasive of which are 'female' and 'male' and 'women' and 'men.'" [73]

Moreover, Lorber has alleged that there exists more diversity within the individual categories of sex and gender—female/male and feminine/masculine, respectively—than between them. [73] Hence, her fundamental claim is that both sex and gender are social constructions, rather than natural kinds.

A comparable view has been advanced by Linda Zerilli, who writes regarding Monique Wittig, that she is "critical of the sex/gender dichotomy in much feminist theory because such a dichotomy leaves unquestioned the belief that there is a 'core of nature which resists examination, a relationship excluded from the social in the analysis—a relationship whose characteristic is ineluctability in culture, as well as in nature, and which is the heterosexual relationship.'" [75] Judith Butler also criticizes the sex/gender distinction. Discussing sex as biological fact causes sex to appear natural and politically neutral. However, she argues that "the ostensibly natural facts of sex [are] discursively produced in the service of other political and social interests." Butler concludes, "If the immutable character of sex is contested, perhaps this construct called 'sex' is as culturally constructed as gender indeed, perhaps it was always already gender, with the consequence that the distinction between sex and gender turns out to be no distinction at all." [76]

Governments, corporations, and organizations have varying recognition of, and approaches to the distinction between sex and gender. [ citation needed ]

U.S. Census

The United States Census Bureau performs a census of the U.S. population every ten years. The questionnaire asks one question about sex, phrased as "What is person 1's sex?" and provides two checkboxes for the response, labeled "Male" and "Female". [77] An explanatory page explains this question, using the term sex: as "We ask one question about a person’s sex to better understand demographic characteristics." [77] The U.S. Census has had a question about sex on the census since the 1790 census. [77] The U.S. Census recognizes the difference between the terms sex and gender, the fact they are often confused or used interchangeably, and may differ across cultures and time, and explains that what the census attempts to measure, is "the sex composition of the population". [78]

Australian government

The Australian government provides guidelines on sex and gender to the public based on legislation passed in 2013. The guidelines recognize that "individuals may identify as a gender other than the sex they were assigned at birth, or may not identify as exclusively male or female". [79] [80] [81] The Australian Bureau of Statistics (ABS) gathers data about the population broken down in various ways, including by sex and gender. They require precise formulations of these terms, and go into some detail about sex recorded at birth, possible changes in sex assignment later in life, the meaning of gender and how it differs from sex. ABS recognizes the popular confusion among the two terms, and provide descriptions of how to phrase surveys so as to elicit accurate responses for the purposes of the data they collect. [82]

The government of the state of Western Australia recognizes a clear distinction between sex and gender providing a nuanced definition of each, including complications involved in sex beyond just sex assigned at birth, and the socially constructed nature of gender, including possible non-binary aspects. [83]

United Kingdom government

The United Kingdom Office for National Statistics (ONS) describes definitions provided by the UK government that make clear distinctions between the "biological aspects" aspects of sex, "generally male or female", and "assigned at birth", while describing gender as a "social construction relating to behaviours and attributes based on labels of masculinity and femininity". [84]

Health organizations

The World Health Organization's defines gender as "socially constructed", and sex as characteristics that are "biologically determined", drawing a distinction between the sex categories of male and female, and the genders "girls and boys who grow into men and women". [85]

Mental health associations

The American Psychiatric Association (APA) in their Guide for Working With Transgender and Gender Nonconforming Patients (TGNC Guide) [86] has guidance for psychiatrists about gender, sex, and orientation. The TGNC defines gender as comprising two components, that of gender identity and gender expression. They define sex in biological terms, as "anatomical, hormonal, or genetic", and mentions birth assignment of sex based on external genital appearance. [87]


Ambiguous (Uncertain) Genitalia

Every minute of every day, a baby is born. Most babies are easily seen to be a girl or a boy. Imagine how confusing it must be when we don't know the sex of a newborn?

This is rare, and it can be very upsetting for parents. What causes this to happen and what can be done? The information here can answer questions about ambiguous genitalia.

What Does "Ambiguous Genitalia" Mean?

Sex organs develop with three basic steps. If something goes wrong with this process, a sexual development disorder (DSD) can happen. DSDs are caused by hormones. Genitals can develop in ways that aren't normal looking. They can be unclear or "ambiguous." A baby can have features from both genders. The medical term "intersex" is also used to describe ambiguous genitals.

The sex of a baby can be tested to help parents raise a child. Surgery can be used to help clarify a baby's gender.

Please note: DSD's are not the same as transsexualism. A transsexual is a person who doesn't see themselves as their defined gender. DSD's are different. They are caused by hormones that change the way a fetus develops.

How Do Genitalia Normally Form?

Sex organs develop with three basic steps:

  1. The genetic sex is set when the sperm fertilizes the egg. An XX pair of chromosomes means that the baby is female. An XY pair means that the baby is male.
  2. Next, gonads (sex glands) form into either testis for a boy or ovaries for a girl.
  3. Then, the inner reproductive system, and outer genitals develop. Hormones from either the testis or ovaries shape the outer genitals.

At conception, the mother shares an X chromosome and the father an X or Y chromosome. The pair creates either a female embryo (XX), or a male embryo (XY). At this point, the male and female embryos look the same.

Embryos start with two gonads. They can become either testes or ovaries. Each embryo also starts with both male and female inner genital structures. They become male OR female reproductive structures.

For girls, very little change is needed for the vagina to look normal. The vagina forms right away, before the ovaries have fully formed. For boys, a series of steps must take place. This starts with the growth of testes. The cells of the testes must begin to make testosterone, the male hormone. Then a more powerful hormone (dihydrotestosterone or DHT) causes genital tissues to change. It forms the slit-like groove of the urethra. Then the penis, which was first the size of a clitoris, becomes larger. The tissue on either side forms into the scrotum. Later, the testes move down into the scrotum. At the same time, structures known as mullerian ducts form inner organs. They either become fallopian tubes and a uterus (in a girl), or disappear (in a boy).

All of these steps take place during the first three months of pregnancy. After that, the outer sex organs look like either a penis or vagina.


Contents

Trisomy X has a variable phenotype, ranging from cases with no symptoms at all to relatively significant disability, and the clinical portrait is not entirely clear. Nonetheless, a number of consistent physiological, psychological, and developmental traits associated with trisomy X have emerged in the medical literature. [3] Several factors can affect the presentation of trisomy X, including mosaicism, where both 47,XXX cell lines and cell lines with other chromosomes are present. [4] Severity is known to vary between prenatally (before birth) and postnatally (after birth) diagnosed cases, with postnatal cases having more severe phenotypes on average. [5] Symptoms associated with trisomy X include tall stature, mild developmental delay, subtle physical and skeletal anomalies, increased rates of mental health concerns, and earlier age of menopause. [3] [6]

Physiological Edit

Minor skeletal and craniofacial anomalies are associated with trisomy X. One study found a tendency toward a shorter facial length and overall reduction in craniofacial growth. [10] Subtle dysmorphisms seen in some females with trisomy X include hypertelorism (wide-spaced eyes), epicanthic folds (an additional fold of skin in the corners of the eyes), and upslanting palpebral fissures (the opening between the eyelids). These differences are usually minor and do not have an impact on the daily lives of girls and women with the condition. [3] Dental abnormalities are associated with sex chromosome aneuploidy, including trisomy X taurodontism, where the pulp of the teeth extends into the roots, [11] increased enamel thickness, and increased root length have all been connected to the condition. [12] Other skeletal anomalies associated with trisomy X include clinodactyly (incurved pinky fingers), radioulnar synostosis (the fusion of the long bones in the forearm), [13] flat feet, and hyper-extensible joints. [14] These findings are not unique to trisomy X, but rather are seen in sex chromosome aneuploidy disorders as a whole. [15]

Severe internal disease is rare in trisomy X although heart defects are common in some more severe X-chromosome polysomy (multiple chromosomes) conditions, [16] they are no more frequent in trisomy X than the general population. [6] Nonetheless, some such conditions appear more frequent in the karyotype. Genitourinary conditions are more common than in the general population, particularly kidney malformations, [3] although severe malformations are uncommon. [17] Autoimmune disorders, particularly lupus, are more common in trisomy X than in the general population. [18] [19] Conditions such as sleep apnea, asthma, scoliosis, and hip dysplasia have also been linked to sex chromosome aneuploidies as a whole, including trisomy X. [15]

Puberty starts around the expected age and progresses as normal. [20] Precocious puberty has been reported, [6] [21] but is not considered a characteristic of the syndrome. [3] Endocrinological research in trisomy X is sparse, but implies a higher level of luteinizing hormone (involved in ovulation) than age-matched controls. [6] [22] Fertility is thought to be normal when not complicated by early menopause [3] a large population study found women with 47,XXX karyotypes to average 1.9 lifetime pregnancies, compared to 2.3 for women with "normal" 46,XX karyotypes, and to be no more likely to miscarry. [23] Premature ovarian failure (POF), or early menopause, is a known complication of trisomy X. Premature ovarian failure is defined as menopause before the age of 40 in the general population, 1 in 100 women experience menopause before this age, 1 in 1,000 before age 30, and 1 in 10,000 before age 20. Amongst women with POF, 3% have trisomy X, compared to 1 in 1,000 in the general population. [24] The average age of menopause for women with trisomy X is 45 years, compared to 50 years for women with 46,XX karyotypes. [23] POF is more common in women with trisomy X who also have autoimmune disorders. [3]

Neurodevelopmental Edit

General cognitive functioning is reduced in trisomy X, with an average intelligence quotient of 85–90 compared to 100 in the general population. [3] Performance IQ tends to be higher than verbal IQ. [25] Though intellectual disability is rare, it is more prevalent than in the general population, occurring in about 5–10% of females with trisomy X [3] compared to approximately 1% of the broader population. [26] While the average is depressed, some women with trisomy X are highly intelligent, [27] and some patients in the medical literature have acquired advanced degrees or worked in cognitive fields. [25]

Infant milestones are normal to slightly delayed. A patient support organization reports crawling around the age of ten months and walking around sixteen to eighteen months, with first words acquired shortly after one year of age and fluent speech around age two. [20] Speech therapy is indicated for between 40% and 90% of girls with trisomy X. [25] Expressive language skills tend to be more affected than receptive skills. [28]

Neuroimaging in trisomy X demonstrates decreased whole brain volumes, correlated with overall intellectual functioning. Amygdala volume may also be smaller than expected after controlling for whole brain size. White matter abnormalities have been reported, although their significance is unknown. These findings are common to X-chromosome polysomy syndromes, being seen in males with Klinefelter syndrome. [3] [25] A minority [6] of patients have epilepsy or electroencephalogram abnormalities, [29] particularly partial seizures these findings may be more common in intellectually disabled patients. [3] [30] Epilepsy in sex chromosome aneuploidies as a whole is mild, amenable to treatment, and often attenuates or disappears with time. Tremor is reported in approximately a quarter of women with trisomy X and responds to the same treatments as in the general population. [31]

Autism spectrum disorders are more common in trisomy X, occurring in approximately 15% of patients [28] compared to less than 1% of girls in the general population. [32] Though much of the research is in children, research in adult women with trisomy X suggests higher rates of autistic symptomatology than control women. [33] Executive dysfunction, where people have difficulty regulating their actions and emotions, is more prevalent amongst those with trisomy X than the general population. [25] [28]

Psychological Edit

The psychological portrait of trisomy X is not entirely clear and appears to be complicated by a more severe phenotype in postnatally than prenatally diagnosed groups. [20] Studies indicate a generally shy and placid personality tendency with low self-esteem, [34] [35] which is also observed in other X-chromosome polysomies. [36] These traits vary in severity though some women with trisomy X are significantly impaired, many are within the normal range of variance, and some are high-functioning and high-achieving. [27]

Some mental health diagnoses are more frequent in women with trisomy X. Dysthymia and cyclothymia, milder forms of depression and bipolar disorder respectively, are more common than in the general population. [3] [6] Compared to control women, women with trisomy X average higher schizotypy, reporting higher levels of introversion, magical thinking, and impulsivity. [25] Approximately one-fifth of women with trisomy X report clinically significant levels of anxiety. [28] Women with trisomy X are often "late bloomers", experiencing high rates of psychological distress into early adulthood, but by their mid-thirties having stronger interpersonal bonds and healthy relationships. [25]

Sex chromosome aneuploidies are associated with psychosis, and schizophrenic women are more likely to have trisomy X than the general female population. [37] The prevalence of trisomy X in women with adult-onset schizophrenia is estimated to be around 1 in 400, compared to 1 in 1,000 in women as a whole the prevalence in childhood onset schizophrenia is unclear, but may be as high as 1 in 40. [38] Schizophrenia in trisomy X may be associated with intellectual disability. [39] [40]

The study of mental health in trisomy X is complicated by the fact girls and women who were diagnosed before birth seem to be more mildly affected by those diagnosed after. For instance, psychogenic stomach pains are reported in a disproportionate number of postnatally diagnosed patients, but fewer prenatally diagnosed ones. [20] Studies comparing prenatally and postnatally diagnosed cases of trisomy X find differences in severity on a number of medical, neurological, and psychological features, including verbal intelligence and adaptive functioning. [5]

The psychosocial adaptation of girls and women with trisomy X is dependent on environmental factors. Girls growing up in stable environments with healthy home lives tend to have relatively high adaptive and social functioning, while significant behavioural and psychological issues are predominantly seen in cases from troubled social environments. [6] Though girls with trisomy X usually have good relationships with peers, they trend towards immaturity [25] behavioural issues in children with trisomy X are thought to be a consequence of the disconnect between apparent age, as understood via increased height, and cognitive and emotional maturity encouraging hard-to-reach expectations. [6]

Mosaic forms Edit

The most common karyotype in trisomy X is 47,XXX, where all cells have an additional copy of the X chromosome. Mosaicism, where both 47,XXX and other cell lines are present, occurs in approximately 10% of cases. Mosaic trisomy X has different outcomes to the non-mosaic condition, depending on the exact cell lines involved. Common mosaic forms observed include 46,XX/47,XXX, 45,X0/47,XXX (with a Turner syndrome cell line), and 47,XXX/48,XXXX (with a tetrasomy X cell line). Complex mosaicism, with cell lines such as 45,X0/46,XX/47,XXX, can also be seen. [3]

46,XX/47,XXX Edit

The simplest form of mosaic trisomy X, with a 46,XX/47,XXX karyotype, has a milder presentation compared to full trisomy X. Cognitive development is more typical, with improved long-term life outcomes. Although the general profile is milder than that of a non-mosaic 47,XXX karyotype, 46,XX/47,XXX mosaicism is associated with a higher risk of chromosome anomalies in offspring than full trisomy X. The increased risk of abnormal offspring in mosaicism has been hypothesized to be a consequence of oocyte abnormality in 46,XX/47,XXX women not seen in full 47,XXX. Some writers have recommended women with 46,XX/47,XXX karyotypes undergo screening for chromosomal disorders during pregnancy. [3] [41] [42]

45,X0/47,XXX Edit

Between 3% and 15% of females with Turner syndrome, defined by a karyotype with a single copy of the X chromosome, have a 47,XXX cell line. [3] [43] Mosaic karyotypes with both 45,X0 and 47,XXX cells are considered cases of Turner syndrome rather than trisomy X, but trisomy X mosaicism has a significant impact on the Turner syndrome phenotype. Non-mosaic Turner syndrome is characterized by primary amenorrhea and failure to begin or complete puberty, while 80–90% of women with 45,X0/47,XXX mosaicism begin puberty naturally and approximately 60–80% have spontaneous menses. [43] [44] Around two-thirds of 45,X0/47,XXX mosaics have clinically significant short stature, compared with virtually all women with non-mosaic Turner syndrome. [44]

Turner syndrome is characteristically associated with sterility, and only 2% of women with Turner's, including mosaic cases, are capable of becoming pregnant. Turner's women with 47,XXX cell lines are more likely to be fertile than women with non-mosaic Turner syndrome, more likely to have live births, and more likely to have children with normal karyotypes in one exceptional case, a woman with a 45,X0/46,XX/47,XXX karyotype had fourteen pregnancies with six live children, including a daughter with Turner syndrome. [45] The proportion of patients with this mosaicism who are capable of having children is unclear, as the medical literature is thought to overrepresent women with reproductive potential due to their clinical exceptionality. Women with the mosaicism experience premature ovarian failure a literature review found the average age of menopause to be 28, with the onset of likely perimenopausal irregular menses occurring around age 22. [44]

Outside of sexual development and fertility, the impact of a 47,XXX cell line in Turner syndrome is little understood. Although women with trisomy X have lower IQs than the general population and women with Turner syndrome do not, intellectual disability does not appear to be more common in the mosaicism than for non-mosaic Turner's. [46] Mosaic patients tend to have similar dysmorphic features to those observed in non-mosaic Turner's patients, but less marked, and some have none of the traditional Turner's stigmata. [47]

47,XXX/48,XXXX Edit

Mosaicism with a tetrasomy X cell line generally presents closer to the phenotype of tetrasomy than trisomy X. [48] Like trisomy X, tetrasomy X has a variable phenotype muddled by underdiagnosis. The tetrasomy is generally more severe than the trisomy intellectual disability is characteristic, dysmorphic features more visible, and puberty often altered. [3] [16] [49]

Trisomy X, like other aneuploidy disorders, is caused by a process called nondisjunction. Nondisjunction occurs when homologous chromosomes or sister chromatids fail to separate properly during meiosis, the process that produces gametes (eggs or sperm), and result in gametes with too many or too few chromosomes. [52] Nondisjunction can occur during gametogenesis, where the trisomy is present from conception, or zygote development, where it occurs after conception. [3] When nondisjunction occurs after conception, the resulting karyotype is generally mosaic, with both 47,XXX and other cell lines. [53]

The majority of trisomy X occurs through maternal nondisjunction, with around 90% of cases being traced to errors in oogenesis. [50] The vast majority of cases of trisomy X occur randomly they have nothing to do with the chromosomes of the parents and little chance of recurring in the family. [20] Nondisjunction is related to advanced maternal age, and trisomy X specifically appears to have a small but significant maternal age effect. In a cohort of women with trisomy X born in the 1960s, the average maternal age was 33. [3] Compared to other disorders such as Down syndrome or Klinefelter syndrome, the effect of maternal age in trisomy X is less understood. [6] [54] [55]

The risk of women with full trisomy X having chromosomally abnormal children is low, likely below 1%. Mosaic trisomy X is associated with a higher rate of offspring with chromosomal disorders. [3] In the vast majority of cases, trisomy X occurs randomly and has nothing to do with the chromosomes of the parents, and little chance of recurring in the family. Recurrence may occur if the mother has mosaicism for trisomy X, particularly in ovarian cells, but this makes up a small fraction of cases. [20]

Chromosome aneuploidies such as trisomy X are diagnosed via karyotype, [56] the process in which chromosomes are tested from blood, bone marrow, amniotic fluid, or placental cells. [57] As trisomy X generally has a mild or asymptomatic phenotype, most cases are never diagnosed. It is estimated that around 10% of cases of trisomy X are diagnosed in their lifetimes many cases are ascertained coincidentally during prenatal testing via amniocentesis or chorionic villi sampling, which is routinely performed for advanced maternal age. [3] Indications for postnatal testing for trisomy X include tall stature, [58] hypotonia, developmental disability or neurodivergence, mild dysmorphic features such as hypertelorism or clinodactyly, and premature ovarian failure. [3] As postnatal karyotyping generally occurs in the setting of clinical concern, postnatally diagnosed trisomy X tends to have a more severe phenotype than prenatal. [5] [20]

Cases of trisomy X with more severe phenotypes can pose a problem for differential diagnosis, or determining what exact condition is causing the symptoms. Tetrasomy X, characterized by four copies of the X chromosome, is a particular differential diagnosis of trisomy X. Intellectual disability, generally mild, is more frequently seen in the tetrasomy than the trisomy. There is more of a tendency towards noticeable dysmorphic features such as hypertelorism, clinodactyly, and epicanthic folds. Unlike trisomy X, approximately half of women with tetrasomy X have no or incomplete pubertal development. Although in most cases tetrasomy X is significantly more severe than trisomy X, some cases of tetrasomy X have mild phenotypes, and some cases of trisomy X severe ones. Like trisomy X, the full phenotypic range of tetrasomy X is unknown due to underdiagnosis. [13] [59] Pentasomy X, with five X chromosomes, may rarely be a differential diagnosis for trisomy X. The phenotype of pentasomy X is more severe than the trisomy or tetrasomy, with significant intellectual disability, heart defects, microcephaly, and short stature. [13] [60]

Due to overlapping dysmorphic features, such as epicanthic folds and upslanting palpebral fissures, some cases of trisomy X may be ascertained due to suspicion of Down syndrome. [3] A phenotype with some similarities to Down syndrome is more frequent in tetrasomy than trisomy X. [61]

When the primary presenting symptom is tall stature, trisomy X may be considered alongside other conditions depending on the rest of the phenotype. Marfan syndrome may be considered due to the disproportion between limb and torso length observed in both syndromes, as well as the joint issues. Beckwith-Wiedemann syndrome, another disproportionate tall stature syndrome, can be associated with developmental disability similar to that seen in some cases of trisomy X. [58]

As karyotypic diagnosis is conclusive, differential diagnosis can be abandoned after karyotype in most cases of trisomy X. However, due to the relatively high prevalence of trisomy X, other congenital disorders may occur comorbid with a 47,XXX karyotype. Differential diagnosis remains indicated when the phenotype is particularly severe for what a 47,XXX karyotype alone explains, such as in the setting of severe intellectual disability or significant malformation. [3]

Parent of a daughter with trisomy X [62]

The prognosis of trisomy X is, broadly speaking, good, and adult independence, while oft-delayed, is generally achieved. The majority of adults are able to achieve normal life outcomes, pursuing education, employment, or homemaking. [62] Adult employment is generally in lower-skill pink-collar occupations, [6] [63] with reduced household income compared to women as a whole, [23] and unemployment or underemployment is more common than expected amongst women with trisomy X who hold higher education qualifications. [64]

Childhood and adolescence, particularly in compulsory education, tends to be more difficult for those with trisomy X than adult life. Parents report their daughters struggling both academically and socially at school, [65] particularly during secondary education, [62] while adults report better adaptation after leaving education and entering the workforce. [6] Of the women in the cohort studies followed to early adulthood, seven of 37 dropped out of high school, while three attended university. [6] A literature review found that compared to age-matched women in the general population, women with trisomy X are 68% as likely to live with a partner, 64% as likely to have children, 36% as likely to hold higher education qualifications, and almost twice as likely to be retired from the workforce. [66]

Physical health is generally good, with many women with trisomy X living into old age. [20] Little data exists on aging in trisomy X. [6] Data from the Danish Cytogenetic Central Register, which covers 13% of women with trisomy X in Denmark, [67] suggests a life expectancy of 71 for women with full trisomy X and 78 for mosaics. [68] The limited sample, composed only of women with trisomy X who have come to medical attention, has led to speculation this number is an underestimate. [66]

Women with trisomy X who were diagnosed prenatally have better outcomes as a group than those diagnosed postnatally, and 46,XX/47,XXX mosaics better than those with full trisomy X. [3] Some of the improved outcome in prenatal diagnosis appears to be a function of higher socioeconomic status amongst parents. [6]

Trisomy X is a relatively common genetic disorder, occurring in around 1 in 1,000 female births. Despite this prevalence, only around 10% of cases are diagnosed during their lifetime. [3] Large cytogenetic studies in Denmark find a diagnosed prevalence of 6 in 100,000 females, around 7% of the actual number of girls and women with trisomy X expected to exist in the general population. [67] Diagnosis in the United Kingdom is particularly low, with an estimated 2% of cases medically recognized. [66] Amongst the 244,000 women in the UK Biobank research sample, 110 were found to have 47,XXX karyotypes, corresponding to approximately half the number expected in the population. The fact this number is still reduced compared to the broader population is thought to be an effect of UK Biobank participants being less likely to be of low IQ and low socioeconomic status than the general population, both of which are more frequent in trisomy X. [23] Trisomy X's severe underdiagnosis makes it problematic to determine the condition's phenotype, as diagnosed cases are likely more severe than the general 47,XXX population. [66]

Trisomy X only occurs in females, as the Y chromosome is in most cases necessary for male sexual development. [20] [note 4] In addition to its high base rate, trisomy X is more common in some clinical subpopulations. The karyotype occurs in an estimated 3% of women with early menopause, [24] 1 in 350 with Sjögren syndrome, and 1 in 400 with systemic lupus erythematosus. [19]

Expected and observed number of people diagnosed with trisomy X and Turner syndrome in Denmark

Age at diagnosis for trisomy X, Klinefelter syndrome, and XYY syndrome

In response to the biased early studies, a newborn screening program for sex chromosome aneuploidy disorders was implemented in the 1960s. [76] Almost 200,000 neonates were screened in Aarhus, Toronto, New Haven, Denver, Edinburgh, and Winnipeg those found to have sex chromosome aneuploidies were followed up for twenty years for most of the cohorts, and longer (until the death of one of the researchers, for Denver [77] ) for the Edinburgh and Denver cohorts. [6] The children with trisomy X and Klinefelter's had their karyotypes disclosed to their parents, but due to the then-present perception that XYY syndrome was associated with violent criminality, the diagnosis in that case was hidden from the family. [76]

These cohort studies served to dispell the burgeoning idea that sex chromosome aneuploidies were "tantamount to a life of serious handicaps" and reveal the high prevalence of them in the population. [78] They provided extensive information on the outcomes of trisomy X and other sex chromosome aneuploidies, forming much of the medical literature on the topic to this day. However, the small sample sizes of the long-term follow-ups in particular stymies extrapolation by 1999, only 16 women in Edinburgh were still being followed. [20] In 2007, rare chromosome disorder organization Unique collaborated with Jacobs and University of Reading pediatrics professor Gary Butler to hold a study day on trisomy X. [79] That same year, Nicole Tartaglia founded the eXtraordinarY Kids Clinic in Denver to study children with sex chromosome aneuploidies around one-fifth of patients at the clinic had trisomy X as of 2015 [update] . [15] In 2020, she introduced the eXtraordinarY Babies Study, a planned new cohort study on people prenatally diagnosed with sex chromosome aneuploidies. [80]

The first description of trisomy X used the term 'superfemale' to describe the karyotype by analogy to Drosophilia flies, a term that was immediately disputed. Curt Stern proposed the use of 'metafemale', which Jacobs criticized as both medically inaccurate and an "illegitimate product of a Graeco-Roman alliance". Bernard Lennon, opposing the use of 'superfemale' as misleading and possessed of an inappropriate "emotional element", suggested 'XXX syndrome'. [81] [82] For some years, the disorder was predominantly known as 'triple X syndrome' or 'triple X', though the latter in particular is now discouraged. [20]

Diagnosis of sex chromosome aneuploidies is increasing, [15] as is the amount of support available for families. [83] Awareness of these conditions is growing in the late 2010s, several state governments across the United States declared May to be National X & Y Chromosome Variation Awareness Month. [84] [85] The parents and caregivers of children with sex chromosome aneuploidies have created campaigns to raise awareness and increase available support. These campaigns made significant strides over the course of the 2010s to increase awareness, [83] decrease stigma, and improve the state of research. [86]

The literature on trisomy X overwhelmingly considers the karyotype from a medical perspective. Little sociological or educational research exists on trisomy X, a state of affairs criticized by both families and academics. [65] Women with trisomy X discussing their experiences express optimism about the karyotype [77] and hope for other people with it. [87]

Trisomy X has been observed in other species that use the XY sex-determination system. Six cases of trisomy X have been recorded in dogs, for which the karyotype is 79,XXX compared to 78,XX for an euploid female dog. [88] Unlike in humans, trisomy X in dogs is strongly linked to infertility, either primary anestrus or infertility with an otherwise normal estrous cycle. Canine trisomy X is thought to be underascertained, as most pet dogs are desexed and so underlying infertility will not be discovered. [89] Three of the six known cases of canine trisomy X demonstrated behavioural issues such as fearfulness, inciting speculation about a link between the karyotype and psychological concerns as seen in humans with the condition. An additional dog with normal fertility and no reported behavioural issues was found to have a mosaic 78,XX/79,XXX karyotype. The canine X chromosome has a particularly large pseudoautosomal region, and dogs accordingly have a lower rate of monosomy X than observed in other species however, a large pseudoautosomal region is not considered a contraindication for trisomy X, and canine trisomy X may have a comparable prevalence to the human form. [88]

Trisomy X is also observed in cattle, where it corresponds to a 61,XXX karyotype. A survey of 71 heifers who failed to become pregnant after two breeding seasons found two cases of trisomy X. [90] A heifer in another case series of 12 found to have trisomy X was found, on investigation, to have a prepubertal internal reproductive system. [91] In addition to domesticated cattle, trisomy X has been observed in river buffalo, where it is also associated with infertility. [92]


Contents

Genetics Edit

A 2008 study compared 112 male-to-female transsexuals (MtFs), both androphilic and gynephilic, and who were mostly already undergoing hormone treatment, with 258 cisgender male controls. Male-to-female transsexuals were more likely than cisgender males to have a longer version of a receptor gene (longer repetitions of the gene) for the sex hormone androgen, which reduced its effectiveness at binding testosterone. [5] The androgen receptor (NR3C4) is activated by the binding of testosterone or dihydrotestosterone, where it plays a critical role in the forming of primary and secondary male sex characteristics. The research suggests reduced androgen and androgen signaling contributes to the female gender identity of male-to-female transsexuals. The authors say that a decrease in testosterone levels in the brain during development might prevent complete masculinization of the brain in male-to-female transsexuals and thereby cause a more feminized brain and a female gender identity. [5] [6]

A variant genotype for a gene called CYP17, which acts on the sex hormones pregnenolone and progesterone, has been found to be linked to female-to-male (FtMs) transsexuality but not MtF transsexuality. Most notably, the FtM subjects not only had the variant genotype more frequently, but had an allele distribution equivalent to male controls, unlike the female controls. The paper concluded that the loss of a female-specific CYP17 T -34C allele distribution pattern is associated with FtM transsexuality. [7]

Transsexuality among twins Edit

In 2013, a twin study combined a survey of pairs of twins where one or both had undergone, or had plans and medical approval to undergo, gender transition, with a literature review of published reports of transgender twins. The study found that one third of identical twin pairs in the sample were both transgender: 13 of 39 (33%) monozygotic or identical pairs of assigned males and 8 of 35 (22.8%) pairs of assigned females. Among dizygotic or genetically non-identical twin pairs, there was only 1 of 38 (2.6%) pairs where both twins were trans. [4] The significant percent of identical twin pairs in which both twins are trans and the virtual absence of dizygotic twins (raised in the same family at the same time) in which both were trans would provide evidence that transgender identity is significantly influenced by genetics if both sets were raised in different families. [4]

Brain structure Edit

General Edit

Several studies have found a correlation between gender identity and brain structure. [8] A first-of-its-kind study by Zhou et al. (1995) found that in a region of the brain called the bed nucleus of the stria terminalis (BSTc), a region which is known for sex and anxiety responses (and which is affected by prenatal androgens), [9] cadavers of six persons who were described as having been male-to-female transsexual or transgender persons in life had female-normal BSTc size, similar to the study's cadavers of cisgender women. While those identified as transsexual had taken hormones, this was accounted for by including cadavers of non-transsexual male and female controls who, for a variety of medical reasons, had experienced hormone reversal. The controls still had sizes typical for their gender. No relationship to sexual orientation was found. [10]

In a follow-up study, Kruijver et al. (2000) looked at the number of neurons in BSTc instead of volumes. They found the same results as Zhou et al. (1995), but with even more dramatic differences. One MtF subject, who had never gone on hormones, was also included and matched up with the female neuron counts nonetheless. [11]

In 2002, a follow-up study by Chung et al. found that significant sexual dimorphism (variation between sexes) in BSTc did not become established until adulthood. Chung et al. theorized that either changes in fetal hormone levels produce changes in BSTc synaptic density, neuronal activity, or neurochemical content which later lead to size and neuron count changes in BSTc, or that the size of BSTc is affected by the generation of a gender identity inconsistent with one's assigned sex. [12]

It has been suggested that the BSTc differences may be due to the effects of hormone replacement therapy. It has also been suggested that because pedophilic offenders have also been found to have a reduced BSTc, a feminine BSTc may be a marker for paraphilias rather than transsexuality. [2]

In a review of the evidence in 2006, Gooren considered the earlier research as supporting the concept of transsexuality as a sexual differentiation disorder of the sex dimorphic brain. [13] Dick Swaab (2004) concurs. [14]

In 2008, a new region with properties similar to that of BSTc in regards to transsexuality was found by Garcia-Falgueras and Swaab: the interstitial nucleus of the anterior hypothalamus (INAH3), part of the hypothalamic uncinate nucleus. The same method of controlling for hormone usage was used as in Zhou et al. (1995) and Kruijver et al. (2000). The differences were even more pronounced than with BSTc control males averaged 1.9 times the volume and 2.3 times the neurons as control females, yet regardless of hormone exposure, MtF transsexuals were within the female range and the FtM transsexual within the male range. [15]

A 2009 MRI study by Luders et al. of 24 MtF transsexuals not yet treated with cross-sex hormones found that regional gray matter concentrations were more similar to those of cisgender men than to those of cisgender women, but there was a significantly larger volume of gray matter in the right putamen compared to cisgender men. Like earlier studies, it concluded that transsexuality was associated with a distinct cerebral pattern. [16] (MRI allows easier study of larger brain structures, but independent nuclei are not visible due to lack of contrast between different neurological tissue types, hence other studies on e.g. BSTc were done by dissecting brains post-mortem.)

An additional feature was studied comparing 18 female-to-male transsexuals who had not yet received cross-sex hormones with 24 cisgender male and 19 female gynephilic controls, using an MRI technique called diffusion tensor imaging or DTI. [17] DTI is a specialized technique for visualizing white matter of the brain, and white matter structure is one of the differences in neuroanatomy between men and women. The study took into account fractional anisotropy values for white matter in the medial and posterior parts of the right superior longitudinal fasciculus (SLF), the forceps minor, and the corticospinal tract. Rametti et al. (2010) discovered that, "Compared to control females, FtM showed higher FA values in posterior part of the right SLF, the forceps minor and corticospinal tract. Compared to control males, FtM showed only lower FA values in the corticospinal tract." [17] The white matter pattern in female-to-male transsexuals was found to be shifted in the direction of biological males.

Hulshoff Pol et al. (2006) studied the gross brain volume of 8 male-to-female transsexuals and in six female-to-male transsexuals undergoing hormone treatment. They found that hormones changed the sizes of the hypothalamus in a gender consistent manner: treatment with male hormones shifted the hypothalamus towards the male direction in the same way as in male controls, and treatment with female hormones shifted the hypothalamus towards the female direction in the same way as female controls. They concluded: "The findings suggest that, throughout life, gonadal hormones remain essential for maintaining aspects of sex-specific differences in the human brain." [18]

A 2016 review agreed with the other reviews when considering androphilic trans women and gynephilic trans men. It reported that hormone treatment may have large effects on the brain, and that cortical thickness, which is generally thicker in cisgender women's brains than in cisgender men's brains, may also be thicker in trans women's brains, but is present in a different location to cisgender women's brains. [2] It also stated that for both trans women and trans men, "cross-sex hormone treatment affects the gross morphology as well as the white matter microstructure of the brain. Changes are to be expected when hormones reach the brain in pharmacological doses. Consequently, one cannot take hormone-treated transsexual brain patterns as evidence of the transsexual brain phenotype because the treatment alters brain morphology and obscures the pre-treatment brain pattern." [2]

Androphilic male-to-female transsexuals Edit

Studies have shown that androphilic male-to-female transsexuals show a shift towards the female direction in brain anatomy. In 2009, a German team of radiologists led by Gizewski compared 12 androphilic transsexuals with 12 cisgender males and 12 cisgender females. Using functional magnetic resonance imaging (fMRI), they found that when shown erotica, the cisgender men responded in several brain regions that the cisgender women did not, and that the sample of androphilic transsexuals was shifted towards the female direction in brain responses. [19]

In another study, Rametti and colleagues used diffusion tensor imaging (DTI) to compare 18 androphilic male-to-female transsexuals with 19 gynephilic males and 19 androphilic cisgender females. The androphilic transsexuals differed from both control groups in multiple brain areas, including the superior longitudinal fasciculus, the right anterior cingulum, the right forceps minor, and the right corticospinal tract. The study authors concluded that androphilic transsexuals were halfway between the patterns exhibited by male and female controls. [20]

A 2016 review reported that early-onset androphilic transgender women have a brain structure similar to cisgender women's and unlike cisgender men's, but that they have their own brain phenotype. [2]

Gynephilic male-to-female transsexuals Edit

Research on gynephilic trans women is considerably limited. [2] While MRI taken on gynephilic male-to-female transsexuals have likewise shown differences in the brain from non-transsexuals, no feminization of the brain's structure have been identified. [2] Neuroscientists Ivanka Savic and Stefan Arver at the Karolinska Institute used MRI to compare 24 gynephilic male-to-female transsexuals with 24 cisgender male and 24 cisgender female controls. None of the study participants were on hormone treatment. The researchers found sex-typical differentiation between the MtF transsexuals and cisgender males, and the cisgender females but the gynephilic transsexuals "displayed also singular features and differed from both control groups by having reduced thalamus and putamen volumes and elevated GM volumes in the right insular and inferior frontal cortex and an area covering the right angular gyrus". [21]

The researchers concluded that:

Contrary to the primary hypothesis, no sex-atypical features with signs of 'feminization' were detected in the transsexual group . The present study does not support the dogma that [male-to-female transsexuals] have atypical sex dimorphism in the brain but confirms the previously reported sex differences. The observed differences between MtF-TR and controls raise the question as to whether gender dysphoria may be associated with changes in multiple structures and involve a network (rather than a single nodal area). [21]

Berglund et al. (2008) tested the response of gynephilic MtF transsexuals to two steroids hypothesized to be sex pheromones: the progestin-like 4,16-androstadien-3-one (AND) and the estrogen-like 1,3,5(10),16-tetraen-3-ol (EST). Despite the difference in sexual orientation, the MtFs' hypothalamic networks activated in response to the AND pheromone, like the androphilic female control groups. Both groups experienced amygdala activation in response to EST. Gynephilic male control groups experienced hypothalamic activation in response to EST. However, the MtF subjects also experienced limited hypothalamic activation to EST. The researchers concluded that in terms of pheromone activation, MtFs occupy an intermediate position with predominantly female features. [22] The MtF transsexual subjects had not undergone any hormonal treatment at the time of the study, according to their own declaration beforehand, and confirmed by repeated tests of hormonal levels. [22]

A 2016 review reported that gynephilic trans women differ from both cisgender male and female controls in non-dimorphic brain areas. [2]

Gynephilic female-to-male transsexuals Edit

Fewer studies have been performed on the brain structure of transgender men than on transgender women. [2] A team of neuroscientists, led by Nawata in Japan, used a technique called single-photon emission computed tomography (SPECT) to compare the regional cerebral blood flow (rCBF) of 11 gynephilic FtM transsexuals with that of 9 androphilic cis females. Although the study did not include a sample of biological males so that a conclusion of "male shift" could be made, the study did reveal that the gynephilic FtM transsexuals showed significant decrease in blood flow in the left anterior cingulate cortex and a significant increase in the right insula, two brain regions known to respond during sexual arousal. [23]

A 2016 review reported that the brain structure of early-onset gynephilic trans men generally corresponds to their assigned sex, but that they have their own phenotype with respect to cortical thickness, subcortical structures, and white matter microstructure, especially in the right hemisphere. [2] Morphological increments observed in the brains of trans men might be due to the anabolic effects of testosterone. [2]

Prenatal androgen exposure Edit

Prenatal androgen exposure, the lack thereof, or poor sensitivity to prenatal androgens are commonly cited mechanisms to explain the above discoveries. To test this, studies have examined the differences between transsexual and cisgender individuals in digit ratio (a generally accepted marker for prenatal androgen exposure). A meta-analysis concluded that the effect sizes for this association were small or nonexistent. [24]

Congenital adrenal hyperplasia in persons with XX sex chromosomes results in what is considered to be excess exposure to prenatal androgens, resulting in masculinization of the genitalia and, typically, controversial prenatal hormone treatment [25] and postnatal surgical interventions. [26] Individuals with CAH are usually raised as girls and tend to have similar cognitive abilities to the typical female, including spatial ability, verbal ability, language lateralization, handedness and aggression. Research has shown that people with CAH and XX chromosomes will be more likely to be same sex attracted, [25] and at least 5.2% of these individuals develop serious gender dysphoria. [27]

In males with 5-alpha-reductase deficiency, conversion of testosterone to dihydrotestosterone is disrupted, decreasing the masculinization of genitalia. Individuals with this condition are typically raised as females due to their feminine appearance at a young age. However, more than half of males with this condition raised as females become males later in their life. Scientists speculate that the definition of masculine characteristics during puberty and the increased social status afforded to men are two possible motivations for a female-to-male transition. [27]

Psychiatrist and sexologist David Oliver Cauldwell [28] argued in 1947 that transsexuality was caused by multiple factors. He believed that small boys tend to admire their mothers to such a degree that they end up wanting to be like them. However, he believed that boys would lose this desire as long as his parents set limits when raising him, or he had the right genetic predispositions or a normal sexuality. In 1966, Harry Benjamin [29] considered the causes of transsexuality to be badly understood, and argued that researchers were biased towards considering psychological causes over biological causes.

Ray Blanchard has developed a taxonomy of male-to-female transsexualism [30] built upon the work of his colleague Kurt Freund, [31] which assumes that trans women have one of two primary causes for gender dysphoria. [32] [33] [34] Blanchard theorizes that "homosexual transsexuals" (a taxonomic category he uses to refer to trans women who are sexually attracted to men) are attracted to men and develop gender dysphoria typically during childhood, and characterizes them as displaying overt and obvious femininity since childhood he characterizes "non-homosexual transsexuals" (a taxonomic category he uses to refer to trans women who are sexually attracted to women) as developing gender dysphoria primarily because they are autogynephilic (sexually aroused by the thought or image of themselves as a woman [30] ), and as being either attracted to women, attracted to both women and men (a concept he calls pseudo-bisexuality as attraction to males is part of the performance of an autogynephilic sexual fantasy), or asexual.

Autogynephilia is common among late-onset transgender women. [35] A study on autogynephilic men found that they were more gender dysphoric than non-autogynephilic men. [36] Michael Bailey speculated that autogynephilia may be genetic. [32]

Blanchard's theory has gained support from J. Michael Bailey, Anne Lawrence, James Cantor, and others who argue that there are significant differences between the two groups, including sexuality, age of transition, ethnicity, IQ, fetishism, and quality of adjustment. [37] [38] [30] [39] [32] However, the theory has been criticized in papers from Veale, Nuttbrock, Moser, and others who argue that it is poorly representative of MtF transsexuals and non-instructive, and that the experiments behind it are poorly controlled and/or contradicted by other data. [40] [41] [42] [43] Many authorities, including some supporters of the theory, criticize Blanchard's choice of wording as confusing or degrading because it focuses on trans women's assigned sex and disregards their sexual orientation identity. [2] Lynn Conway, Andrea James, and Deidre McClosky attacked Bailey's reputation following the release of The Man Who Would Be Queen. [44] Evolutionary biologist and trans woman Julia Serano wrote that "Blanchard's controversial theory is built upon a number of incorrect and unfounded assumptions, and there are many methodological flaws in the data he offers to support it." [45] The World Professional Association for Transgender Health (WPATH) argued against including Blanchard's typology in the DSM, stating that there was no scientific consensus on the theory, and that there was a lack of longitudinal studies on the development of transvestic fetishism. [46]

A 2016 review found support for the predictions of Blanchard's typology that androphilic and gynephilic trans women have different brain phenotypes. It stated that although Cantor seems to be right that Blanchard's predictions have been validated by two independent structural neuroimaging studies, there is "still only one study on nonhomosexual MtFs to fully confirm the hypothesis, more independent studies on nonhomosexual MtFs are needed. A much better verification of the hypothesis could be supplied by a specifically designed study including homosexual and nonhomosexual MtFs." The review stated that "confirming Blanchard's prediction still needs a specifically designed comparison of homosexual MtF, homosexual male, and heterosexual male and female people." [2]

The failure of an attempt to raise David Reimer from infancy through adolescence as a girl after his genitals were accidentally mutilated is cited as disproving the theory that gender identity is determined solely by parenting. [47] [48] Between the 1960s and 2000, many other newborn and infant boys were surgically reassigned as females if they were born with malformed penises, or if they lost their penises in accidents. Many surgeons believed such males would be happier being socially and surgically reassigned female. Available evidence indicates that in such instances, parents were deeply committed to raising these children as girls and in as gender-typical a manner as possible. Six of seven cases providing orientation in adult follow-up studies identified as heterosexual males, with one retaining a female identity, but who is attracted to women. Such cases do not support the theory that parenting influences gender identity or sexual orientation of those assigned male at birth. [49] : 72–73 Reimer's case is used by organizations such as the Intersex Society of North America to caution against needlessly modifying the genitals of unconsenting minors. [50]

In 2015, the American Academy of Pediatrics released a webinar series on gender, gender identity, gender expression, transgender, etc. [51] [52] In the first lecture Dr. Sherer explains that parents' influence (through punishment and reward of behavior) can influence gender expression but not gender identity. [53] She cites a Smithsonian article that shows a photo of a 3 year old President Franklin D. Roosevelt with long hair, wearing a dress. [54] [52] Children as old as 6 wore gender neutral clothing, consisting of white dresses, until the 1940s. [54] In 1927, Time magazine printed a chart showing sex-appropriate colors, which consisted of pink for boys and blue for girls. [54] Dr. Sherer argued that kids will modify their gender expression to seek reward from their parents and society but this will not affect their gender identity (their internal sense of self). [53]


Contents

Most young children do not show any physical signs of FXS. [10] It is not until puberty that physical features of FXS begin to develop. [10] Aside from intellectual disability, prominent characteristics of the syndrome may include an elongated face, large or protruding ears, flat feet, larger testes (macroorchidism), and low muscle tone. [11] [12] Recurrent otitis media (middle ear infection) and sinusitis is common during early childhood. Speech may be cluttered or nervous. Behavioral characteristics may include stereotypic movements (e.g., hand-flapping) and atypical social development, particularly shyness, limited eye contact, memory problems, and difficulty with face encoding. Some individuals with fragile X syndrome also meet the diagnostic criteria for autism.

Males with a full mutation display virtually complete penetrance and will therefore almost always display symptoms of FXS, while females with a full mutation generally display a penetrance of about 50% as a result of having a second, normal X chromosome. [13] Females with FXS may have symptoms ranging from mild to severe, although they are generally less affected than males.

Physical phenotype Edit

  • Large, protruding ears (both)
  • Long face (vertical maxillary excess) (related to the above)
  • Hyperextensible thumbs ('double-jointed')
  • Soft skin [vague]
  • Postpubescent macroorchidism (large testicles in men after puberty) [14] (low muscle tone) [15]

Intellectual development Edit

Individuals with FXS may present anywhere on a continuum from learning disabilities in the context of a normal intelligence quotient (IQ) to severe intellectual disability, with an average IQ of 40 in males who have complete silencing of the FMR1 gene. [12] Females, who tend to be less affected, generally have an IQ which is normal or borderline with learning difficulties. The main difficulties in individuals with FXS are with working and short-term memory, executive function, visual memory, visual-spatial relationships, and mathematics, with verbal abilities being relatively unaffected. [12] [16]

Data on intellectual development in FXS are limited. However, there is some evidence that standardized IQ decreases over time in the majority of cases, apparently as a result of slowed intellectual development. A longitudinal study looking at pairs of siblings where one child was affected and the other was not found that affected children had an intellectual learning rate which was 55% slower than unaffected children. [16]

Individuals with FXS often demonstrated language and communicative problems. [17] This may be related to muscle function of the mouth and frontal-lobe deficits. [17]

Autism Edit

Fragile X syndrome co-occurs with autism in many cases and is a suspected genetic cause of the autism in these cases. [11] [18] This finding has resulted in screening for FMR1 mutation to be considered mandatory in children diagnosed with autism. [11] Of those with fragile X syndrome, prevalence of concurrent autism spectrum disorder (ASD) has been estimated to be between 15 and 60%, with the variation due to differences in diagnostic methods and the high frequency of autistic features in individuals with fragile X syndrome not meeting the DSM criteria for an ASD. [18]

Although individuals with FXS have difficulties in forming friendships, those with FXS and ASD characteristically also have difficulties with reciprocal conversation with their peers. Social withdrawal behaviors, including avoidance and indifference, appear to be the best predictors of ASD in FXS, with avoidance appearing to be correlated more with social anxiety while indifference was more strongly correlated to ASD. [18] When both autism and FXS are present, a greater language deficit and lower IQ is observed as compared to children with only FXS. [19]

Genetic mouse models of FXS have also been shown to have autistic-like behaviors. [20] [21] [22] [23] [24]

Social interaction Edit

FXS is characterized by social anxiety, including poor eye contact, gaze aversion, prolonged time to commence social interaction, and challenges forming peer relationships. [25] Social anxiety is one of the most common features associated with FXS, with up to 75% of males in one series characterized as having excessive shyness and 50% having panic attacks. [18] Social anxiety in individuals with FXS is related to challenges with face encoding, the ability to recognize a face that one has seen before. [26]

It appears that individuals with FXS are interested in social interaction and display greater empathy than groups with other causes of intellectual disability, but display anxiety and withdrawal when placed in unfamiliar situations with unfamiliar people. [18] [25] This may range from mild social withdrawal, which is predominantly associated with shyness, to severe social withdrawal, which may be associated with co-existing autism spectrum disorder. [18]

Females with FXS frequently display shyness, social anxiety and social avoidance or withdrawal. [12] In addition, premutation in females has been found to be associated with social anxiety.

Individuals with FXS show decreased activation in the prefrontal regions of the brain.

Mental health Edit

Attention deficit hyperactivity disorder (ADHD) is found in the majority of males with FXS and 30% of females, making it the most common psychiatric diagnosis in those with FXS. [11] [25] Children with fragile X have very short attention spans, are hyperactive, and show hypersensitivity to visual, auditory, tactile, and olfactory stimuli. These children have difficulty in large crowds due to the loud noises and this can lead to tantrums due to hyperarousal. Hyperactivity and disruptive behavior peak in the preschool years and then gradually decline with age, although inattentive symptoms are generally lifelong. [25]

Aside from the characteristic social phobia features, a range of other anxiety symptoms are very commonly associated with FXS, with symptoms typically spanning a number of psychiatric diagnoses but not fulfilling any of the criteria in full. [25] Children with FXS pull away from light touch and can find textures of materials to be irritating. Transitions from one location to another can be difficult for children with FXS. Behavioral therapy can be used to decrease the child's sensitivity in some cases. [15] Behaviors such as hand flapping and biting, as well as aggression, can be an expression of anxiety.

Perseveration is a common communicative and behavioral characteristic in FXS. Children with FXS may repeat a certain ordinary activity over and over. In speech, the trend is not only in repeating the same phrase but also talking about the same subject continually. Cluttered speech and self-talk are commonly seen. Self-talk includes talking with oneself using different tones and pitches. [15] Although only a minority of FXS cases will meet the criteria for obsessive–compulsive disorder (OCD), a significant majority will have symptoms of obsession. However, as individuals with FXS generally find these behaviors pleasurable, unlike individuals with OCD, they are more frequently referred to as stereotypic behaviors.

Mood symptoms in individuals with FXS rarely meet diagnostic criteria for a major mood disorder as they are typically not of sustained duration. [25] Instead, these are usually transient and related to stressors, and may involve labile (fluctuating) mood, irritability, self-injury and aggression.

Individuals with fragile X-associated tremor/ataxia syndrome (FXTAS) are likely to experience combinations of dementia, mood, and anxiety disorders. Males with the FMR1 premutation and clinical evidence of FXTAS were found to have increased occurrence of somatization, obsessive–compulsive disorder, interpersonal sensitivity, depression, phobic anxiety, and psychoticism. [27]

Vision Edit

Ophthalmologic problems include strabismus. This requires early identification to avoid amblyopia. Surgery or patching are usually necessary to treat strabismus if diagnosed early. Refractive errors in patients with FXS are also common. [19]

Neurology Edit

Individuals with FXS are at a higher risk of developing seizures, with rates between 10% and 40% reported in the literature. [28] In larger study populations the frequency varies between 13% and 18%, [12] [28] consistent with a recent survey of caregivers which found that 14% of males and 6% of females experienced seizures. [28] The seizures tend to be partial, are generally not frequent, and are amenable to treatment with medication.

Individuals who are carriers of premutation alleles are at risk for developing fragile X-associated tremor/ataxia syndrome (FXTAS), a progressive neurodegenerative disease. [13] [29] It is seen in approximately half of male carriers over the age of 70, while penetrance in females is lower. Typically, onset of tremor occurs in the sixth decade of life, with subsequent progression to ataxia (loss of coordination) and gradual cognitive decline. [29]

Working memory Edit

From their 40s onward, males with FXS begin developing progressively more severe problems in performing tasks that require the central executive of working memory. Working memory involves the temporary storage of information 'in mind', while processing the same or other information. Phonological memory (or verbal working memory) deteriorates with age in males, while visual-spatial memory is not found to be directly related to age. Males often experience an impairment in the functioning of the phonological loop. The CGG length is significantly correlated with central executive and the visual–spatial memory. However, in a premutation individual, CGG length is only significantly correlated with the central executive, not with either phonological memory or visual–spatial memory. [30]

Fertility Edit

About 20% of women who are carriers for the fragile X premutation are affected by fragile X-related primary ovarian insufficiency (FXPOI), which is defined as menopause before the age of 40. [13] [29] The number of CGG repeats correlates with penetrance and age of onset. [13] However premature menopause is more common in premutation carriers than in women with the full mutation, and for premutations with more than 100 repeats the risk of FXPOI begins to decrease. [31] Fragile X-associated primary ovarian insufficiency (FXPOI) is one of three Fragile X-associated Disorders (FXD) caused by changes in the FMR1 gene. FXPOI affects female premutation carriers of Fragile X syndrome, which is caused by the FMR1 gene, when their ovaries are not functioning properly. Women with FXPOI may develop menopause-like symptoms but they are not actually menopausal. Women with FXPOI can still get pregnant in some cases because their ovaries occasionally release viable eggs. [32]

FMRP is a chromatin-binding protein that functions in the DNA damage response. [33] [34] FMRP also occupies sites on meiotic chromosomes and regulates the dynamics of the DNA damage response machinery during spermatogenesis. [33]

Fragile X syndrome is a genetic disorder which occurs as a result of a mutation of the fragile X mental retardation 1 (FMR1) gene on the X chromosome, most commonly an increase in the number of CGG trinucleotide repeats in the 5' untranslated region of FMR1. [13] [29] Mutation at that site is found in 1 out of about every 2000 males and 1 out of about every 259 females. Incidence of the disorder itself is about 1 in every 3600 males and 1 in 4000–6000 females. [35] Although this accounts for over 98% of cases, FXS can also occur as a result of point mutations affecting FMR1. [13] [29]

In unaffected individuals, the FMR1 gene contains 5–44 repeats of the sequence CGG, most commonly 29 or 30 repeats. [13] [29] [36] Between 45-54 repeats is considered a "grey zone", with a premutation allele generally considered to be between 55 and 200 repeats in length. Individuals with fragile X syndrome have a full mutation of the FMR1 allele, with over 200 CGG repeats. [11] [36] [37] In these individuals with a repeat expansion greater than 200, there is methylation of the CGG repeat expansion and FMR1 promoter, leading to the silencing of the FMR1 gene and a lack of its product.

This methylation of FMR1 in chromosome band Xq27.3 is believed to result in constriction of the X chromosome which appears 'fragile' under the microscope at that point, a phenomenon that gave the syndrome its name. One study found that FMR1 silencing is mediated by the FMR1 mRNA. The FMR1 mRNA contains the transcribed CGG-repeat tract as part of the 5' untranslated region, which hybridizes to the complementary CGG-repeat portion of the FMR1 gene to form an RNA·DNA duplex. [38]

A subset of people with intellectual disability and symptoms resembling fragile X syndrome are found to have point mutations in FMR1. This subset lacked the CGG repeat expansion in FMR1 traditionally associated with fragile x syndrome. [39]

Inheritance Edit

Fragile X syndrome has traditionally been considered an X-linked recessive condition with variable expressivity and possibly reduced penetrance. [12] However, due to genetic anticipation and X-inactivation in females, the inheritance of Fragile X syndrome does not follow the usual pattern of X-linked dominant inheritance, and some scholars have suggested discontinuing labeling X-linked disorders as dominant or recessive. [40] Females with full FMR1 mutations may have a milder phenotype than males due to variability in X-inactivation.

Before the FMR1 gene was discovered, analysis of pedigrees showed the presence of male carriers who were asymptomatic, with their grandchildren affected by the condition at a higher rate than their siblings suggesting that genetic anticipation was occurring. [13] This tendency for future generations to be affected at a higher frequency became known as the Sherman paradox after its description in 1985. [13] [41] Due to this, male children often have a greater degree of symptoms than their mothers. [42]

The explanation for this phenomenon is that male carriers pass on their premutation to all of their daughters, with the length of the FMR1 CGG repeat typically not increasing during meiosis, the cell division that is required to produce sperm. [13] [29] Incidentally, males with a full mutation only pass on premutations to their daughters. [29] However, females with a full mutation are able to pass this full mutation on, so theoretically there is a 50% chance that a child will be affected. [29] [36] In addition, the length of the CGG repeat frequently does increase during meiosis in female premutation carriers due to instability and so, depending on the length of their premutation, they may pass on a full mutation to their children who will then be affected. Repeat expansion is considered to be a consequence of strand slippage either during DNA replication or DNA repair synthesis. [43]

FMRP is found throughout the body, but in highest concentrations within the brain and testes. [11] [13] It appears to be primarily responsible for selectively binding to around 4% of mRNA in mammalian brains and transporting it out of the cell nucleus and to the synapses of neurons. Most of these mRNA targets have been found to be located in the dendrites of neurons, and brain tissue from humans with FXS and mouse models shows abnormal dendritic spines, which are required to increase contact with other neurons. The subsequent abnormalities in the formation and function of synapses and development of neural circuits result in impaired neuroplasticity, an integral part of memory and learning. [11] [13] [44] Connectome changes have long been suspected to be involved in the sensory pathophysiology [45] and most recently a range of circuit alterations have been shown, involving structurally increased local connectivity and functionally decreased long-range connectivity. [46]

In addition, FMRP has been implicated in several signalling pathways that are being targeted by a number of drugs undergoing clinical trials. The group 1 metabotropic glutamate receptor (mGluR) pathway, which includes mGluR1 and mGluR5, is involved in mGluR-dependent long term depression (LTD) and long term potentiation (LTP), both of which are important mechanisms in learning. [11] [13] The lack of FMRP, which represses mRNA production and thereby protein synthesis, leads to exaggerated LTD. FMRP also appears to affect dopamine pathways in the prefrontal cortex which is believed to result in the attention deficit, hyperactivity and impulse control problems associated with FXS. [11] [13] [25] The downregulation of GABA pathways, which serve an inhibitory function and are involved in learning and memory, may be a factor in the anxiety symptoms which are commonly seen in FXS.

Cytogenetic analysis for fragile X syndrome was first available in the late 1970s when diagnosis of the syndrome and carrier status could be determined by culturing cells in a folate deficient medium and then assessing for "fragile sites" (discontinuity of staining in the region of the trinucleotide repeat) on the long arm of the X chromosome. [47] This technique proved unreliable, however, as the fragile site was often seen in less than 40% of an individual's cells. This was not as much of a problem in males, but in female carriers, where the fragile site could generally only be seen in 10% of cells, the mutation often could not be visualised.

Since the 1990s, more sensitive molecular techniques have been used to determine carrier status. [47] The fragile X abnormality is now directly determined by analysis of the number of CGG repeats using polymerase chain reaction (PCR) and methylation status using Southern blot analysis. [12] By determining the number of CGG repeats on the X chromosome, this method allows for more accurate assessment of risk for premutation carriers in terms of their own risk of fragile X associated syndromes, as well as their risk of having affected children. Because this method only tests for expansion of the CGG repeat, individuals with FXS due to missense mutations or deletions involving FMR1 will not be diagnosed using this test and should therefore undergo sequencing of the FMR1 gene if there is clinical suspicion of FXS.

Prenatal testing with chorionic villus sampling or amniocentesis allows diagnosis of FMR1 mutation while the fetus is in utero and appears to be reliable. [12]

Early diagnosis of fragile X syndrome or carrier status is important for providing early intervention in children or fetuses with the syndrome, and allowing genetic counselling with regards to the potential for a couple's future children to be affected. Most parents notice delays in speech and language skills, difficulties in social and emotional domains as well as sensitivity levels in certain situations with their children. [48]

There is no cure for the underlying defects of FXS. [2] Management of FXS may include speech therapy, behavioral therapy, occupational therapy, special education, or individualised educational plans, and, when necessary, treatment of physical abnormalities. Persons with fragile X syndrome in their family histories are advised to seek genetic counseling to assess the likelihood of having children who are affected, and how severe any impairments may be in affected descendants. [49]

Medication Edit

Current trends in treating the disorder include medications for symptom-based treatments that aim to minimize the secondary characteristics associated with the disorder. If an individual is diagnosed with FXS, genetic counseling for testing family members at risk for carrying the full mutation or premutation is a critical first-step. Due to a higher prevalence of FXS in boys, the most commonly used medications are stimulants that target hyperactivity, impulsivity, and attentional problems. [12] For co-morbid disorders with FXS, antidepressants such as selective serotonin reuptake inhibitors (SSRIs) are utilized to treat the underlying anxiety, obsessive-compulsive behaviors, and mood disorders. Following antidepressants, antipsychotics such as risperidone and quetiapine are used to treat high rates of self-injurious, aggressive and aberrant behaviors in this population (Bailey Jr et al., 2012). Anticonvulsants are another set of pharmacological treatments used to control seizures as well as mood swings in 13%–18% of individuals suffering from FXS. Drugs targeting the mGluR5 (metabotropic glutamate receptors) that are linked with synaptic plasticity are especially beneficial for targeted symptoms of FXS. [12] Lithium is also currently being used in clinical trials with humans, showing significant improvements in behavioral functioning, adaptive behavior, and verbal memory. Few studies suggested using folic acid, but more researches are needed due to the low quality of that evidence. [50] Alongside pharmacological treatments, environmental influences such as home environment and parental abilities as well as behavioral interventions such as speech therapy, sensory integration, etc. all factor in together to promote adaptive functioning for individuals with FXS. [49] While metformin may reduce body weight in persons with fragile X syndrome, it is uncertain whether it improves neurological or psychiatric symptoms. [51]

Current pharmacological treatment centers on managing problem behaviors and psychiatric symptoms associated with FXS. However, as there has been very little research done in this specific population, the evidence to support the use of these medications in individuals with FXS is poor. [52]

ADHD, which affects the majority of boys and 30% of girls with FXS, is frequently treated using stimulants. [11] However, the use of stimulants in the fragile X population is associated with a greater frequency of adverse events including increased anxiety, irritability and mood lability. [25] Anxiety, as well as mood and obsessive-compulsive symptoms, may be treated using SSRIs, although these can also aggravate hyperactivity and cause disinhibited behavior. [12] [25] Atypical antipsychotics can be used to stabilise mood and control aggression, especially in those with comorbid ASD. However, monitoring is required for metabolic side effects including weight gain and diabetes, as well as movement disorders related to extrapyramidal side effects such as tardive dyskinesia. Individuals with coexisting seizure disorder may require treatment with anticonvulsants.

A 2013 review stated that life expectancy for FXS was 12 years lower than the general population and that the causes of death were similar to those found for the general population. [53]

Fragile X syndrome is the most "translated" human neurodevelopmental disorder under study. Hence, research into the etiology of FXS has given rise to many attempts at drug discovery. [54] The increased understanding of the molecular mechanisms of disease in FXS has led to the development of therapies targeting the affected pathways. Evidence from mouse models shows that mGluR5 antagonists (blockers) can rescue dendritic spine abnormalities and seizures, as well as cognitive and behavioral problems, and may show promise in the treatment of FXS. [11] [55] [56] Two new drugs, AFQ-056 (mavoglurant) and dipraglurant, as well as the repurposed drug fenobam are currently undergoing human trials for the treatment of FXS. [11] [57] There is also early evidence for the efficacy of arbaclofen, a GABAB agonist, in improving social withdrawal in individuals with FXS and ASD. [11] [18]

In addition, there is evidence from mouse models that minocycline, an antibiotic used for the treatment of acne, rescues abnormalities of the dendrites. An open trial in humans has shown promising results, although there is currently no evidence from controlled trials to support its use. [11]

The first complete DNA sequence of the repeat expansion in someone with the full mutation was generated by scientists in 2012 using SMRT sequencing. [58]

In 1943, British neurologist James Purdon Martin and British geneticist Julia Bell described a pedigree of X-linked mental disability, without considering the macroorchidism (larger testicles). [59] In 1969, Herbert Lubs first sighted an unusual "marker X chromosome" in association with mental disability. [60] In 1970, Frederick Hecht coined the term "fragile site". And, in 1985, Felix F. de la Cruz outlined extensively the physical, psychological, and cytogenetic characteristics of those afflicted in addition to prospects for therapy. [61] Continued advocacy later won him an honour through the FRAXA Research Foundation in December 1998. [62]


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