around age 20. 47,xxx/48,xxxx mosaicism with a tetrasomy x cell line generally appears more severe than typical trisomy x. 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. causes maternal (top) and paternal (bottom) nondisjunction leading to trisomy x 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. nondisjunction can occur during gametogenesis, where the trisomy is present from conception, or zygote development, where it occurs after conception. when nondisjunction occurs after conception, the resulting karyotype is generally mosaic, with both 47,xxx and other cell lines. most cases of trisomy x occur through maternal nondisjunction, with around 90% of cases traced to errors in oogenesis. 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. 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. the risk of women with full trisomy x having chromosomally abnormal children is low, likely below 1%. recurrence may occur if the mother has mosaicism for trisomy x, particularly in ovarian cells, but this makes up a small fraction of cases. diagnosis and differential diagnosis chromosome aneuploidies such as trisomy x are diagnosed via karyotype, the process in which chromosomes are tested from blood, bone marrow, amniotic fluid, or placental cells. as trisomy x is generally mild or asymptomatic, most cases are never diagnosed. around 10% of cases of trisomy x are diagnosed in the person's lifetime; many are ascertained coincidentally during prenatal testing via amniocentesis or chorionic villi sampling, which is routinely performed for advanced maternal age. postnatal testing is typically prompted by tall stature, hypotonia, developmental disability or neurodivergence, mild dysmorphic features such as hypertelorism or clinodactyly, and premature ovarian failure. karyotype of trisomy x tetrasomy x, characterized by four copies of the x chromosome, has some signs in common with more severe cases 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 are mild, and some cases of trisomy x severe. like trisomy x, the full phenotypic range of tetrasomy x is unknown due to underdiagnosis. 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. 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. when the primary 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 both experiencing joint issues. beckwith-wiedemann syndrome, another disproportionate tall stature syndrome, can cause developmental disability similar to that seen in some cases of trisomy x. 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 alongside a 47,xxx karyotype. differential diagnosis remains indicated when the phenotype is particularly severe for what a 47,xxx karyotype alone explains, such as severe intellectual disability or significant malformation. prognosis "my doctor told us that if our unborn daughter had to have a genetic issue, trisomy x is the one to have, so to speak. he said that many girls with this condition are completely normal, and that it is not physically noticeable. the issues that we could have might be with speech and motor delays, or learning disabilities. the doctor did have us speak with a genetic counselor, but no one encouraged us to terminate and we did not consider it." parent of a daughter with trisomy x the prognosis of trisomy x is broadly good, with adult independence most often achieved, if delayed. most adults achieve normal life outcomes, pursuing education, employment, or homemaking. 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, particularly during secondary education, while adults report better adaptation after leaving education and entering the workforce. of the women in the cohort studies followed to early adulthood, 7 of 37 dropped out of high school, while three attended university. 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. physical health is generally good and many women with trisomy x live into old age. little data exists on aging in trisomy x. data from the danish cytogenetic central register, which covers 13% of women with trisomy x in denmark, suggests a life expectancy of 71 for women with full trisomy x and 78 for mosaics, compared to 84 for controls. 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. 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. some of the improved outcome in prenatal diagnosis appears to be a function of higher socioeconomic status amongst parents. epidemiology 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. 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. diagnosis in the united kingdom is particularly low, with an estimated 2% of cases medically recognized. 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. trisomy x only occurs in females, as the y chromosome is in most cases necessary for male sexual development. 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, 1 in 350 with sjögren syndrome, and 1 in 400 with systemic lupus erythematosus. rate and age of diagnosis expected and observed number of people diagnosed with trisomy x and turner syndrome in denmark violin plots of age at diagnosis for klinefelter syndrome, trisomy x, and xyy syndrome history the first known case of trisomy x, in a 176 cm (5 ft 9+1⁄2 in) woman who experienced premature ovarian failure at the age of 19, was diagnosed in 1959 by a team led by patricia jacobs. the late 1950s and early 1960s were a period of frequent ascertainment of previously unknown sex chromosome aneuploidies, with the 47,xxx karyotype discovered alongside 45,x0 and 47,xxy the same year. early studies on sex chromosome aneuploidy screened patients residing in institutions, depicting the karyotypes as incapacitating; even at the time, this research was criticized for giving an inaccurate portrait of sex chromosome aneuploidy. early reports of women with trisomy x have since been criticized for a dehumanizing ableist perspective, showing nude photographs of institutionalized women described as "mental deficiency patients". in response to the biased early studies, a newborn screening program for sex chromosome aneuploidy disorders was implemented in the 1960s. 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 20 years for most of the cohorts, and longer for the edinburgh and denver cohorts. 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, those diagnoses were hidden from the family. these studies dispelled the idea that sex chromosome aneuploidies were "tantamount to a life of serious handicaps" and revealed their high prevalence in the population. 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. in 2007, 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. in 2020, she introduced the extraordinary babies study, a planned cohort study on people prenatally diagnosed with sex chromosome aneuploidies. the first description of trisomy x used the term 'superfemale' to describe the karyotype by analogy to drosophila 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'. for some years, the disorder was predominantly known as 'triple x syndrome' or 'triple x', though the latter is now discouraged. society and culture awareness and diagnosis of sex chromosome aneuploidies is increasing. in the late 2010s, several state governments across the united states declared may to be national x & y chromosome variation awareness month. descriptions of trisomy x overwhelmingly consider the karyotype from a medical perspective, rather than a sociological or educational one. one topic in the sociological discussion of trisomy x and other sex chromosome aneuploidies is disability-selective abortion. fetuses with sex chromosome aneuploidies are more likely to be aborted, though fetuses with trisomy x are less likely than for such conditions as a whole. a literature review of 19 studies found that nearly one-third of pregnancies with a child with trisomy x were aborted; it also found that parents who were counselled by a genetic counseller with expertise in sex chromosome aneuploidies, rather than an obstetrician or gynecologist, were less likely to abort. abortion rates in sex chromosome aneuploidies have decreased over time with improved counselling. in other animals 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. 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. 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,