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. 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 mixture 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. Lupus, an autoimmune disease, 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
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