trisomy x trisomy x trisomy x, also known as triple x syndrome and characterized by the karyotype 47,xxx, is a chromosome disorder in which a female has an extra copy of the x chromosome. it is relatively common and occurs in 1 in 1,000 females but it is rarely diagnosed; fewer than 10% of those with the condition know they have it. trisomy xother names47,xxx, triple x syndrome, triplo-x syndrome, xxx syndromethree individuals with trisomy xspecialtymedical genetics symptomstall stature, skeletal anomalies, minor neurocognitive and behavioural difficultiesusual onsetconceptiondurationlifelongcausesnondisjunctiondiagnostic methodkaryotypefrequencyapproximately 1 in 1,000 (female) those who have symptoms can have learning disabilities, mild dysmorphic features such as hypertelorism (wide-spaced eyes) and clinodactyly (incurved little fingers), early menopause, and increased height. the average intelligence quotient (iq) in trisomy x is 85–90. as the symptoms of trisomy x are often not serious enough to prompt a karyotype test, many cases of trisomy x are diagnosed before birth via prenatal screening tests such as amniocentesis. research on girls and women with the disorder finds that cases which were diagnosed postnatally, having been referred for testing because of obvious symptoms, are generally more severe than those diagnosed prenatally. most women with trisomy x live normal lives, although their socioeconomic status is reduced compared to the general population. trisomy x occurs via a process called nondisjunction, in which normal cell division is interrupted and produces gametes with too many or too few chromosomes. nondisjunction is a random occurrence, and most girls and women with trisomy x have no family histories of chromosome aneuploidy. advanced maternal age is mildly associated with trisomy x. women with trisomy x can have children of their own, who in most cases do not have an increased risk of chromosome disorders; women with mosaic trisomy x, who have a mix of 46,xx (the typical female karyotype) and 47,xxx cells, may have an increased risk of chromosomally abnormal children. first reported in 1959 by the geneticist patricia jacobs, the early understanding of trisomy x was that of a debilitating disability observed in institutionalized women. beginning in the 1960s, studies of people with sex chromosome aneuploidies from birth to adulthood found that they are often only mildly affected, fitting in with the general population, and that many never needed the attention of clinicians because of the condition. presentation trisomy x has variable effects, ranging from no symptoms at all to significant disability. severity varies between people diagnosed prenatally (before birth) and postnatally (after birth), and postnatal cases are more severe on average. 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. physiological the physical and physiological impacts of trisomy x tend to be subtle. tall stature is one of the major physical associations of trisomy x. prior to age four, most girls with trisomy x are average height; growth picks up after this age, and is particularly rapid between the ages of four and eight. of girls with trisomy x aged six to thirteen, 40% are above the 90th percentile in height. the average adult height in trisomy x has been estimated as 172 cm (5 ft 7+1⁄2 in) and head circumference as 20th percentile. the added height in trisomy x is primarily in the limbs, with long legs and a shorter sitting height. though head circumference is generally below the 50th percentile, microcephaly, a head circumference below the 5th percentile, is rare. minor skeletal and craniofacial anomalies are associated with trisomy x. 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 impact the daily lives of girls and women with the condition. other skeletal anomalies associated with trisomy x include clinodactyly (incurved little fingers), radioulnar synostosis (the fusion of the long bones in the forearm), flat feet, and hyper-extensible joints. these findings are not unique to trisomy x, but rather are seen in sex chromosome aneuploidy disorders as a whole. severe internal disease is rare in trisomy x. genitourinary conditions are more common than in the general population, particularly kidney and ovary malformations. one study found that the autoimmune disorders lupus and sjögren syndrome are more common in trisomy x than in the general population. conditions such as sleep apnea, asthma, scoliosis, and hip dysplasia have also been linked to sex chromosome aneuploidies as a whole, including trisomy x. although heart defects are common in pentasomy x, they are no more frequent in trisomy x than the general population. puberty starts around the expected age and progresses as normal. fertility is normal when not complicated by early menopause; 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. 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. the average age of menopause for women with trisomy x is 45 years, compared to 50 years for women with 46,xx karyotypes. pof is more common in women with trisomy x who also have autoimmune disorders. neurodevelopmental iq curve for trisomy x compared to controls general cognitive functioning is reduced in trisomy x, with an average intelligence quotient of 85–90. performance iq tends to be higher than verbal iq. though intellectual disability is rare, it is more prevalent than in the general population, occurring in about 5–10% of females with trisomy x compared to approximately 1% of the broader population. while the average is depressed, the effect of trisomy x varies substantially, and some women are highly intelligent. 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. speech therapy is needed in 40%–90% of girls with trisomy x at some point in their lives, compared to around 3–8% of children in the general population. expressive language skills tend to be more affected than receptive skills. neuroimaging in trisomy x demonstrates decreased whole brain volumes, correlated with overall intellectual functioning. amygdala volume may 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, and is seen in males with klinefelter syndrome. epilepsy or electroencephalogram abnormalities may be more common in those with trisomy x, particularly those who are also intellectually disabled. 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. autism spectrum disorders are more common in trisomy x, occurring in approximately 15% of girls with trisomy x compared to less than 1% of girls in the general population. though much of the research is in children, research in adult women with trisomy x suggests higher rates of autistic symptomatology than the general population. executive dysfunction, where people have difficulty regulating their actions and emotions, is more prevalent amongst those with trisomy x than the general population. psychological 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 those from troubled social environments. though girls with trisomy x usually have good relationships with peers, they trend towards immaturity; some 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. girls whose motor and language skills are more severely affected by trisomy x often experience low confidence and self-esteem. 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. some mental health issues 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. women with trisomy x average higher schizotypy, reporting higher levels of introversion, magical thinking, and impulsivity. sex chromosome aneuploidies are associated with psychosis, and schizophrenic women are more likely to have trisomy x than the general female population. 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. approximately one-fifth of women with trisomy x report clinically significant levels of anxiety. 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. the study of mental health in trisomy x is complicated by the fact that girls and women who were diagnosed before birth seem to be more mildly affected than those diagnosed after. for instance, psychogenic stomach pains are reported in a disproportionate number of postnatally diagnosed patients, but fewer prenatally diagnosed ones. mosaic forms 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. 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. 46,xx/47,xxx the simplest form of mosaic trisomy x, with a 46,xx/47,xxx karyotype, is milder compared to full trisomy x. cognitive development is more typical, with improved long-term life outcomes. although generally milder, 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. 45,x0/47,xxx a nine-year-old girl with a 45,x0/47,xxx karyotype 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. mosaic karyotypes with both 45,x0 and 47,xxx cells are considered turner syndrome rather than trisomy x, but the presence of 47,xxx cells influences the disorder. 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. around two-thirds of 45,x0/47,xxx mosaics have clinically significant short stature, compared with virtually all women with non-mosaic turner syndrome. 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 mosaic than for non-mosaic turner's. women with mosaic turner syndrome tend to have similar dysmorphic features to those with non-mosaic turner's syndrome, but less marked, and some have none of the traditional turner's stigmata. turner syndrome is characteristically associated with sterility, and only 2–7% of women with turner's, including mosaic cases, are capable of pregnancy. in contrast, turner's women with 47,xxx cell lines often complete puberty and are typically fertile. women with this mosaicism experience premature ovarian failure; the average age of menopause in these women is around 30, with the onset of likely perimenopausal irregular menses occurring