Chromosome disorder in women
Medical condition
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 is rarely diagnosed; fewer than 10% of those with the condition know they have it.
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. 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 females 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 females 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 young females 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 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. The autoimmune disease SLE is more common in women than men by a factor of 9 and the risk is further exacerbated in Trisomy X by a factor of approximately 2.5. According to one study Sjögren syndrome is also 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. Median anti-Müllerian hormone levels are lower corresponding to a smaller ovarian reserve, menopause begins five years earlier on average and there is an increased risk of premature ovarian failure (POF). Among women with POF Trisomy X is over-represented by a factor of five and those with both trisomy and autoimmune disease are at extra high risk. The rate of miscarriage is normal and fertility has been reported to be either unaffected or somewhat lower than expected. IVF and similar interventions are seldom necessary.
Neurodevelopmental.
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. Speech delay is more common than delays in early motor function. Speech therapy is needed in 40%–90% of girls with trisomy X at some point in their lives. More than 75% experience learning disabilities, frequently related to reading skills, but expressive language skills tend to be more affected than receptive skills. Visuospatial ability may also be diminished.
Neuroimaging in trisomy X demonstrates decreased whole brain volumes, correlated with overall intellectual functioning, although cortical thickness is unaffected. These findings are common to X-chromosome polysomy syndromes including 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.
Executive dysfunction, where people have difficulty regulating their actions and emotions, is more prevalent amongst those with trisomy X than the general population. Autism spectrum disorders are more common in trisomy X, and approximately 15% of girls with trisomy X have significant symptoms indicative of such disorders, compared to less than 1% of girls in the general population. The risk of ADHD is also increased and up to 50% of those with Trisomy X are affected.
Psychological.
Impaired social regulation is more common in trisomy X, and is in part dependent on emotional dysregulation but also 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. Around 30% are affected by thought problems and 13% have been diagnosed with psychotic or bipolar disorders. 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. One in five women with trisomy X report clinically significant levels of anxiety. Estimates of the prevalence of clinical depression vary between 18 and 54%. 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 over 30% of cases. Mosaic trisomy X can have different outcomes to the non-mosaic condition and further contributes to the variability seen in Trisomy X. Common mosaic forms observed include 46,XX/47,XXX, 45,X/47,XXX (with a Monosomy X cell line), and 47,XXX/48,XXXX (with a tetrasomy X cell line). Complex mosaicism, with cell lines such as 45,X/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. There is still an increased occurrence of birth defects, as well as skin and urogenital disorders. 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,X/47,XXX.
Around 5% 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,X and 47,XXX cells are considered Turner syndrome rather than trisomy X, but the presence of 47,XXX cells influences the disorder, with milder effects than non-mosaic Turner syndrome. Most are still affected by short stature and early premature ovarian failure (before age 30) is common, but a majority reach puberty and menarche spontaneously. Almost all women with regular Turner syndrome are sterile, but those with 47,XXX cell lines are typically fertile. 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 visible Turner traits.
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.
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