NORD gratefully acknowledges Carole Samango-Sprouse, EdD, Executive Director and Chief Science Officer, The Focus Foundation, for assistance in the preparation of this report.
The symptoms and physical features associated with trisomy X vary greatly from one person to another. Some females may have no symptoms (asymptomatic) or very mild symptoms and may go undiagnosed. Other women may have a wide variety of different abnormalities. It is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals should talk to their specialists and medical team about their specific case, associated symptoms and overall prognosis.
Trisomy X is often associated with neurodevelopmental differences and language-based learning disabilities. Intelligence is usually within the normal range. IQ may be 10-15 points below that of siblings or control groups if early intervention has not been successful or begun early enough. Infants and children with trisomy X experience delays in attaining developmental milestones, especially in the acquisition of motor and speech skills. For example, walking may be delayed and affected girls may exhibit poor coordination and clumsiness. Speech and language development is also commonly delayed and may become apparent by approximately one year to 18 months. Girls with trisomy X have an increased frequency of language-based learning disabilities including reading deficiencies such as dyslexia, reading comprehension deficits and/or reading fluency issues in conjunction with other language-based disabilities. They also have developmental dyspraxia which affects learning in every domain. Typically, motor planning skills are deficient, which affects gross and fine motor, speech and language as well as executive function. These deficits are very responsive to therapeutic intervention. Intervention should be initiated earlier so that the girls do not experience repeated exposure to failure.
Some infants with trisomy X may have mild facial abnormalities including vertical skin folds that may cover the eyes’ inner corners (epicanthal folds), widely spaced eyes (hypertelorism), and smaller than normal head circumference. Most infants also have decreased muscle tone (hypotonia) and the fifth finger may be abnormally bent or curved mildly, which is called clinodactyly. In general, these girls are very attractive and not discernible for neurotypical children in appearance.
During early childhood or adolescence, girls with trisomy X usually exhibit increased height as compared with other girls their age (tall stature). Most girls are at or above the 75th percentile for height with an average height of 5 foot 7 inches.
Individuals with trisomy X may have an increased incidence of anxiety and attention deficit hyperactivity disorder (ADHD). In some cases, such abnormalities improve with maturity as the girls reach adulthood. Some individuals have minimal to no behavioral or emotional abnormalities; other girls may have more issues that may necessitate intervention, which is typically only necessary short term. There are no controlled studies on behavioral or emotional abnormalities in trisomy X and the incidence of such conditions is unknown, although they are believed to occur with greater frequency than in the general population. Early detection and treatment are very beneficial for girls with trisomy X. In many cases, these girls have few issues later in life when identified early and treated appropriately.
For most girls, sexual development and fertility are normal. However, reports indicate that some affected females may have abnormal development of the ovaries (ovarian dysgenesis) and/or the uterus; delayed puberty or early onset of puberty (precocious puberty), and/or fertility problems. There have been reports of women with trisomy X developing premature ovarian failure (POF). POF is the loss of function of the ovaries before the age where menopause is expected to begin. POF can cause a decrease in the production of certain hormones and eggs may no longer be released each month.
Less often, additional abnormalities have been described in individuals with trisomy X including kidney abnormalities, such as absence of a kidney (unilateral renal agenesis) or malformation (dysplasia) of the kidneys; recurrent urinary tract infections; seizures; constipation; abdominal pain; flatfeet (pes planus); and pectus excavatum, a condition in which the breastbone is mildly depressed into the chest. Heart (cardiac) abnormalities have also been described in some isolated cases.
Trisomy X is a chromosomal abnormality characterized by the presence of an extra X chromosome. Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair that normally consists of an X and Y chromosome for males and two X chromosomes for females. Thus, females with a normal chromosomal make-up (karyotype) have 46 chromosomes, including two X chromosomes (46,XX karyotype); they receive one chromosome from the mother and one from the father in each of the 23 pairs.
However, females with trisomy X have 47 chromosomes, three of which are X chromosomes (47,XXX karyotype). Trisomy X is a genetic disorder, but it is not inherited. The presence of the extra X chromosome results from errors during the normal division of reproductive cells in one of the parents (nondisjunction during meiosis). These errors occur randomly for no apparent reason (sporadically). Studies have shown that the risk of such errors increases with advanced paternal age. In most children, the additional X chromosome comes from the mother. In approximately 20 percent of children, nondisjunction events occur after conception in the developing fetus (postzygotic nondisjunction).
In some affected females, only a certain percentage of their cells may have three X chromosomes, while other cells have a normal chromosomal make-up (46,XX/47,XXX mosaicism). These females may have milder symptoms and fewer developmental and learning problems, but further research is needed. Variants have also been described in which cells contain four or five X chromosomes (tetra X syndrome and penta X syndrome). Such variants are typically associated with more severe symptoms and findings. (For further information, please see the “Related Disorders” section of this report below.)
Researchers believe that the symptoms and physical features associated with trisomy X develop because of overexpression of the genes that escape normal X-inactivation. Although females have two X chromosomes, one of the X chromosomes is “partially turned off” and some but not all of the genes on that chromosome are inactivated (X-inactivation). Researchers suspect that the presence of a third X chromosome allows some genes normally “turned off” to be expressed. However, the exact manner in which the extra X chromosome ultimately causes the symptoms and physical features of trisomy X is not fully understood.
Trisomy X is a chromosomal disorder that affects only females. Reported estimates of frequency have varied with the most common estimate being one in 1,000 female births. Because many females with the disorder may have few or no symptoms, they may never be diagnosed. Researchers believe that the disorder is underdiagnosed and that the reported number of affected females as reflected in the medical literature is inappropriately low. Researchers believe that only approximately 10 percent of affected individuals are diagnosed. With increased detection, more in depth studies may be conducted and more girls with trisomy X can be appropriately treated.
Trisomy X may be suspected based upon the identification of characteristic neurodevelopmental, behavioral or learning disabilities. A diagnosis may be confirmed by a thorough clinical evaluation, a detailed family history, and certain specialized tests such as chromosomal analysis performed on blood samples that can reveal the presence of an extra X chromosome in body cells.
In addition, trisomy X is increasingly being diagnosed before birth (prenatally) based on chromosomal analysis performed subsequent to amniocentesis or chorionic villus sampling (CVS). During amniocentesis, a sample of fluid that surrounds the developing fetus is removed and analyzed, while CVS involves the removal of tissue samples from a portion of the placenta.
Approximately 5-15 percent of women with Turner syndrome also have a 47,XXX karyotype found in certain white blood cells (blood lymphocytes), but the characteristic Turner syndrome karyotype (45,X) in other cells.
Specific therapeutic strategies depend upon several factors including the age of an affected individual upon diagnosis, the specific symptoms that are present and the overall severity of the disorder in each case. Early intervention services are recommended for infants and children diagnosed with trisomy X. Experts advise developmental assessment by age four months to evaluate muscle tone and strength; language and speech assessment by 12 months of age to evaluate expressive and receptive language development; and pre-reading assessment during preschool years prior to first grade to look for early signs of reading dysfunction. An evaluation is recommended to help assess additional learning disabilities and social and emotional problems.
Evidence suggests that affected children are greatly responsive to early intervention services and treatment. Such services can include speech therapy, occupational therapy, physical therapy, and developmental therapy and counseling.
Infants and children with trisomy X should also receive kidney (renal) and heart (cardiac) evaluations to detect abnormalities of those organs potentially associated with the disorder. Adolescent and adult women who exhibit late periods (menarche), menstrual abnormalities, or fertility issues should be evaluated for primary ovarian failure.
Additional treatment should be targeted at infancy for physical therapy, between 12 and 15 months for speech delay, prior to first grade for early signs of reading dysfunction and by third grade for anxiety and ADHD. Adolescence is challenging for children, and girls with triple X often struggle as they enter middle school years so counseling short term may be necessary to help them during these turbulent years.
Genetic counseling is recommended for affected individuals and their families.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/for-patients-and-families/information-resources/news-patient-recruitment/
For information about clinical trials sponsored by private sources, in the main, contact: www.centerwatch.com
For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
(Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder [e.g., learning disabilities].)
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