NORD gratefully acknowledges Carole Samango-Sprouse, EdD, Executive Director and Chief Science Officer, The Focus Foundation, for assistance in the preparation of this report.
Trisomy X is a disorder that affects females and is characterized by the presence of an additional X chromosome. Normally, females have two X chromosomes; however, females with trisomy X carry three X chromosomes. The phenotype associated with this chromosomal disorder varies widely, but most commonly includes language-based learning disabilities, developmental dyspraxia, tall stature, low muscle tone (hypotonia), and abnormal bending or curving of the pinkies toward the ring fingers (clinodactyly). Trisomy X occurs randomly as a result from errors during the division of reproductive cells in one of the parents. This disorder occurs in one in 900 to 1,000 live births.
The severity of symptoms associated with trisomy X may vary greatly from one person to another, though it is thought that many present mildly or as asymptomatic as about 90% of females with XXX remain undiagnosed throughout life (Nielsen, 1990). 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.
While this disorder is not associated with any striking physical features, some individuals 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 also have decreased muscle tone (hypotonia) and the fifth finger may be abnormally bent or curved mildly, which is called clinodactyly. During early childhood, girls with trisomy X usually exhibit increased stature as compared with other girls their age, and by adolescence, most are at or above the 75th percentile for height. In general, these girls are not discernible from neurotypical children in appearance.
Trisomy X is often associated with a broad range of neurodevelopmental differences. Infants and children with trisomy X experience delays in attaining developmental milestones, especially the acquisition of motor and speech skills. For example, in infants, walking may be delayed due to the low muscle tone and in older affected girls poor coordination, clumsiness, deficient motor planning skills, and developmental dyspraxia may be exhibited. Speech and language development is also commonly delayed and first words may not occur until 18 months. Expressive ability is almost always more impaired than receptive skills, though both are impacted. 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. There is a wide range of cognitive abilities in girls with trisomy X, with most having mildly impaired or average non-verbal IQs and below average verbal IQs. However, these deficits are very responsive to treatment, with early intervention often resulting in the most optimal outcome.
Though less is known about the psychological symptoms associated with trisomy X, studies have found an increased incidence of anxiety and attention deficit hyperactivity disorder (ADHD). It is believed that their impairments in verbal abilities may exacerbate anxiety in social settings, such as school, and result in low self-esteem, social avoidance, and more behavioral problems. The incidence of ADHD in girls with trisomy X is reported to be about 25-35% with symptoms including inattention, poor executive function, and distractibility rather than hyperactivity (Pennington et al., 1980; Bender et al., 1993). Again, some individuals have minimal to no behavioral or emotional abnormalities while others may need therapeutic services. Early detection is important and 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 or early onset of puberty (precocious puberty), and/or fertility problems. There have also been reports of women with trisomy X developing premature ovarian failure (POF), which is the loss of function of the ovaries before the age where menopause is expected to begin due to a decrease in the production of certain hormones.
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 in females. Chromosomes are found in the nucleus of all body cells and carry the genetic characteristics of each individual. There are 23 pairs of human chromosomes with the 23rd pair determining the sex of the individual. Typical males have one X and one Y chromosome (46,XY) while typical females have two X chromosomes resulting in a 46,XX karyotype.
However, females with trisomy X have an extra X chromosome resulting in a 47,XXX karyotype. Trisomy X is a genetic disorder, but it is not inherited. The presence of the extra X chromosome results from sporadic, random errors during the normal division of reproductive cells in one of the parents (nondisjunction during meiosis). Studies suggest that the risk of such errors increases with advanced maternal age. In most children, the additional X chromosome comes from the mother.
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). This happens in approximately 20 percent of children when nondisjunction events occur after conception in the developing fetus (postzygotic ondisjunction).These females are thought to 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 overexpression of genes that escape normal X-inactivation may lead to the neurodevelopmental symptoms associated with 47,XXX. In typical females that 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 that are normally “turned off” to be expressed. However, the link between X-inactivation and symptoms in 47,XXX 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, researchers believe that the disorder is substantially underdiagnosed and that the reported number of affected females reflected in the medical literature is inappropriately low (about 10%). 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 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 non-invasive prenatal testing (NIPT), which reveals if the fetus is at risk for chromosomal disorders. Diagnoses are later confirmed with amniocentesis, in which a sample of fluid that surrounds the developing fetus is removed and analyzed, or chorionic villus sampling (CVS) which involves the removal of tissue samples from a portion of the placenta.
Due to the wide phenotype of this disorder, 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.
Genetic counseling is recommended for affected individuals and their families and early intervention services are recommended for infants and children diagnosed with trisomy X. Experts advise a physical 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, as well as identify any speech delay; pre-reading assessment during preschool years prior to first grade to look for early signs of reading dysfunction; and behavioral assessment by third grade to address any issues with anxiety and/or ADHD. A neurodevelopmental evaluation is recommended to help assess additional developmental issues, learning disabilities, and social and emotional problems. Infants and children with trisomy X should also receive kidney (renal) and heart (cardiac) evaluations to detect potential abnormalities associated with the disorder.
Evidence suggests that affected children are greatly responsive to early intervention services and treatment, so early identification is essential to promote optimal outcome. Such services can include speech therapy, occupational therapy, physical therapy, and developmental therapy and counseling.
Adolescent and adult women with 47,XXX who exhibit late periods (menarche), menstrual abnormalities, or fertility issues should be evaluated for primary ovarian failure (POF). 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.
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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