Triple X is not caused by anything the parents did or did not do. The disorder is a random error in cell division. This error can happen before conception in the reproductive cells of the mother or the father, or early in the embryo's development. When the extra chromosome is due to incorrect cell division in the embryo, a girl may have a mosaic form of triple X syndrome. This means some cells have an extra X chromosome, but not all do.
Girls with this type of triple X syndrome usually have fewer symptoms. Noticeable signs and symptoms of triple X syndrome can vary greatly. Some girls have no obvious signs, while others have mild symptoms. Occasionally, the disorder causes significant problems. Girls with triple X syndrome also may have delayed development of their social, language, and learning skills. They also can have problems with reading and understanding math, and may have mild delays with coordination. Girls with triple X syndrome may develop anxiety , depression , and attention deficit hyperactivity disorder ADHD.
These problems might ease as they get older and reach adulthood. Otherwise, treatment can help manage them. Rarely, a girl may develop kidney and heart problems, frequent urinary tract infections UTIs , stomach pain, constipation, flat feet , and an abnormally shaped chest wall and ribcage called pectus excavatum. Many girls with triple X syndrome are healthy and have no obvious symptoms.
So sometimes the condition isn't diagnosed or is only found while a doctor checks for a different issue. Often triple X syndrome is found because parents talked with a doctor about concerns with their daughter's development.
This can help girls receive a diagnosis early. Research has shown that early interventions and treatments are more effective. To diagnose triple X syndrome, doctors do a blood test to look for the extra X chromosome. Causes People normally have 46 chromosomes in each cell. Learn more about the chromosome associated with Triple X syndrome x chromosome. Inheritance Most cases of triple X syndrome are not inherited.
Research Studies from ClinicalTrials. Am J Med Genet A. Genetic counseling for sex chromosome abnormalities. Am J Med Genet. Fifty-one prenatally diagnosed children and adolescents with sex chromosome abnormalities. Triple X syndrome: a review of the literature. Eur J Hum Genet. Epub Jul 1. A review of trisomy X 47,XXX. Orphanet J Rare Dis. Expanding the phenotype of Triple X syndrome: A comparison of prenatal versus postnatal diagnosis.
Language deficits may also impact social adjustment in some children when they have difficulty communicating with playmates and when self-expression is limited in older children and adolescents. Social immaturity relative to peers may be present, and this, along with cognitive and executive function impairments, can make some girls with trisomy X vulnerable to social pressures from peers and victimization. Other mental health disorders including adjustment disorders, mood disorders and psychotic disorders have been described in case series and reports [ 2 , 41 — 43 ], and comprehensive studies evaluating features of these disorders in the trisomy X population are needed.
A comprehensive review of trisomy X literature with an emphasis on mental health has recently been published by Otter et al. Again, the variability in the phenotype needs to be emphasized, since many females with trisomy X have minimal cognitive, social, or emotional difficulties. Since the longitudinal studies of the 's and 80's of females with trisomy X followed into adulthood, there have been very few additional research studies focused exclusively on this genetic disorder.
A neuroimaging study conducted in in 10 girls with trisomy X from the original longitudinal cohort in Denver mean age Another MRI study of 12 girls with trisomy X mean age The significance or neuropathological findings of these white matter abnormalities are not yet known, however, they suggest that gene dosage effects from sex chromosome genes affect white matter development. In typical 46,XX females, only one X chromosome in each cell is genetically active and the other is inactivated through DNA methylation and the accumulation of a histone variant throughout the chromosome [ 49 ].
X-inactivation occurs early in blastogenesis and is controlled by the X chromosome inactivation center XIC , which counts the X chromosomes present and randomly inactivates all but one X chromosome per diploid set.
However, particular segments of the X chromosome, known as the pseudoautosomal regions PAR1 and PAR2 , have Y chromosome homologs and therefore are not inactivated and remain genetically active [ 50 , 51 ]. Thus, in trisomy X, two of the three X chromosomes are inactivated, however, genes in the PAR regions and other genes that escape X-inactivation are expressed from the three X chromosomes.
It is hypothesized that the phenotypic abnormalities associated with trisomy X result from overexpression of these genes on the X chromosome that escape X-inactivation [ 30 , 52 , 53 ]. While there is some microarray evidence of overexpression of X-chromosome genes in cells lines with supernumerary X chromosomes [ 54 ], the specific genes involved in the phenotype of trisomy X and other sex chromosome aneuploidies have not been identified.
One exception is the SHOX gene, which escapes X-inactivation and is associated with the short stature seen in Turner syndrome and the tall stature in supernumerary sex chromosome aneuploidy conditions [ 55 , 56 ]. Trisomy X occurs from a nondisjunction event, in which the X chromosomes fail to properly separate during cell division either during gametogenesis resulting in a trisomic conceptus , or after conception known as post-zygotic nondisjunction.
Similar to other trisomies, trisomy X has been shown to have a statistically significant correlation with advancing maternal age, as the likelihood of nondisjunction events during meiosis increases with increasing maternal age.
Karyotype analysis of peripheral blood is the most standard test used to make the diagnosis. It is also important to identify mosaicism with a Turner syndrome 45,X cell line in order to determine appropriate medical evaluations and treatments needed for Turner syndrome. The physical and psychological manifestations of trisomy X are variable, and a karyotype should be considered in females presenting with:.
Developmental and behavioral features in trisomy X can be similar to those seen in females with fragile X syndrome. Females suspected of having fragile X with a negative fragile X test should have a karyotype completed to evaluate for trisomy X [ 16 ]. Tetrasomy X and pentasomy X syndromes share most features of trisomy X, however, they are usually associated with more significant developmental delays, dysmorphic features absent in trisomy X , and congenital malformations compared to trisomy X [ 16 , 53 ].
Females with pentasomy X typically have short stature [ 56 ]. Due to features in the newborn period such as hypotonia, hypertelorism and epicanthal folds, some patients with trisomy X are ascertained by karyotype performed due to suspicion for trisomy 21 or trisomy 21 mosaicism. Other genetic conditions associated with tall stature could also be considered depending on the clinical presentation, such as Marfan syndrome long limbs, hyperextensibility , and the Sotos' and Beckwith-Weidemann syndromes cognitive impairments.
Adolescents or adult females presenting with POF should be tested for trisomy X, Turner syndrome, and the fragile X premutation, and should have further evaluation to identify other possible medical causes of POF. Individuals with these diagnoses should be further evaluated medically to determine if testing for trisomy X or other medical conditions is indicated.
The differential diagnosis is eliminated after results of a karyotype analysis show trisomy X 47,XXX , unless there are significant impairments moderate or severe intellectual disability , congenital malformations, or medical problems not consistent with the trisomy X phenotype.
In these cases, additional genetic and medical evaluation is warranted to rule out other disorders, since these may co-exist with trisomy X due to the high incidence of births.
Karyotype testing of females presenting with short stature and a Turner syndrome phenotype have shown findings of nonmosaic 47,XXX in blood lymphocytes, however, genetic testing of another tissue such as skin biopsy or buccal cells identified 45,X mosaicism [ 59 ].
Thus, individuals found to have trisomy X with a Turner syndrome phenotype should have a second tissue type analyzed by cytogenetic or FISH studies to further evaluate for a 45,X cell line since this changes treatment recommendations.
Genetic counseling for prenatally diagnosed cases of trisomy X should address the medical, developmental, and psychological manifestations of the condition as outlined in this review. As noted, there is significant variability in developmental delays, learning disabilities and psychological characteristics in trisomy X and it is not yet possible to predetermine which child will exhibit any or all of these concerns.
Couples with a recent diagnosis may be eager to search the internet for information about trisomy X and they should be cautioned about the excessive inaccurate and biased information they may find. Couples should be informed of the high frequency of trisomy X 1 per female births and that most girls go undiagnosed, in order to support them in understanding and accepting that their diagnosis is not an isolated case with a predetermined outcome [ 46 ].
Couples should be informed that the occurrence of trisomy X is due to a random event, that there is nothing that they did to cause or prevent the occurrence. It is important for parents to appreciate the significant role of other genes inherited, stressing that the child's prognosis is relative to their entire genetic makeup, as well as the impact of environmental factors.
In addition, a study of females with trisomy X by Robinson et al. However, this study may be biased as it was based on a small sample of patients and did not control for several environmental influences, such as socioeconomic status and family support. Studies reporting elective termination rates following a prenatal diagnosis vary by location of the study, with the most recent reports from the U. These rates are lower compared to other sex chromosome aneuploidy conditions due to the lack of association with infertility and other serious medical problems, and the broad phenotypic variability.
For couples who choose to continue an affected pregnancy, it is recommended that the genetic counselor assist the family in identifying community resources for developmental assessments and early intervention services due to the increased risk for developmental delays as outlined in this review. When discussing the diagnosis with the child, it is important to use terminology that is straightforward and developmentally appropriate. Young children should be given simple, age-appropriate information on a fairly regular basis allowing them to grow, cope and adjust to the information over time.
With a young child, it is important to dispel fears of the disorder being lethal or contagious, and to explain that it is not her parents' fault. Discussions with adolescents and young adult children should be straightforward with full disclosure. Use of the term "sex" or "sex chromosome" should be used with caution, as children and adolescents can confuse the diagnosis with their sexuality or misconstrue the diagnosis as having a "sex abnormality.
If the parent does not feel well-informed or prepared to answer questions, seeking input from professionals, such as a physician or genetic counselor, is recommended. Genetic counseling for adult patients should additionally address potential reproductive issues, specifically POF and the risk of transmission.
While fertility in women with trisomy X is generally considered normal, there is an increased risk for POF as noted within this review, which may be important to consider in family planning.
Furthermore, patients should be counseled that the transmission of X aneuploidy extra or missing X chromosomes from women with trisomy X is rare, although it has been reported [ 68 ]. It is important that this risk be presented independently of the risks due to maternal age. These transmission risks apply only to women with non-mosaic 47,XXX, as mosaicism may increase the risk of X aneuploidy and potential outcomes, so each scenario should be considered individually [ 3 , 72 , 73 ]. Evaluation and treatment recommendations depend on the age of the patient and severity of the phenotype, however, all individuals should undergo a medical history and physical examination with an emphasis on features requiring monitoring and intervention as outlined in this review.
Infants and children with trisomy X should undergo evaluation for the psychological and medical features of the disorder.
In infants and young children, a renal ultrasound and cardiac evaluation should be obtained. Constipation should be treated as needed. Medical history should include questions regarding staring spells or atypical movements, since seizure disorders and electroencephalogram EEG abnormalities can be present in females with trisomy X and may present as partial or absence seizures.
In these cases, EEG studies should be performed to rule out possible seizure activity. Adolescents and adult women presenting with late menarche, menstrual irregularities, or problems with fertility should be evaluated by an endocrinologist or gynecologist for hormonal abnormalities that may signal ovarian insufficiency which can be associated with trisomy X. Other autoimmune problems including thyroid problems should also be considered.
A comprehensive developmental evaluation is important for newly diagnosed infants and young children, and between months of age for infants diagnosed in the prenatal period. The assessment should include special emphasis on language, motor, and social development. Common problems including learning disabilities, speech-language disorders including apraxia of speech , ADHD with predominantly inattentive symptoms, executive dysfunction, anxiety disorders, social difficulties, and other mental health problems should be considered and treated if problematic.
In females with trisomy X who have these conditions, medication treatments are the same as for the general population, however, low starting doses are recommended due to the more complex neurodevelopmental involvement in trisomy X.
It is important for evaluators to recognize that behavioral symptoms related to learning disabilities, ADHD, language comprehension deficits, and anxiety may have significant overlap, and thus consideration and treatment of all the comorbidities are important in developing a treatment plan.
Psychological therapy and counselling can be effective as a part of the treatment plan if needed, however, may need to be modified based on the receptive-expressive language and cognitive abilities of the patient.
If present, developmental concerns and educational struggles should be addressed aggressively instead of taking a "wait and see" approach, since they are unlikely to improve or "catch up" without targeted interventions, and delaying treatment will lead to poorer outcomes. Assessment and documentation of adaptive functioning life skills in domains including self-care, communication, social, community use, safety, and self-direction is important to identify strengths and weaknesses in these areas.
A subset of females with trisomy X has borderline cognitive abilities or learning disabilities with adaptive functioning in the disability range, and in this group adaptive functioning assessment is important to support the need for community services and disability supports through adulthood. Family support can be a very important part of treatment, especially for families of girls with more severe medical or psychological features of trisomy X.
Families of children and young adults with trisomy X and associated developmental delays or mental health problems should also be encouraged to seek out local support groups for general developmental disabilities or mental health problems since these organizations have access to resources in the local area for the family.
The prognosis of trisomy X is variable, with some individuals doing extremely well with minimal manifestations of the disorder, and others with more significant cognitive and psychological involvement as described above. Outcomes of those diagnosed in the prenatal period have been found to be better than those of patients described in the prospective studies birth cohorts and than those in case reports of girls identified after birth ascertained due to developmental delays [ 64 ].
There are many unresolved questions in trisomy X, as this genetic disorder has received very little attention by scientists or clinicians since the completion of the prospective, descriptive studies of the 's and 80's.
Additional research on the pathophysiology and genetic mechanisms involved in the associated medical problems such as seizures and POF is needed. Elucidation of the specific genes, gene pathways, and genetic mechanisms involved in the phenotype and phenotypic variability will help to understand the pathophysiology, improve genetic counseling, and perhaps lead to targeted treatments in the future.
Clinical studies are also needed to further characterize the psychological features and neurodevelopmental disorders, and to study specific interventions for developmental delays, learning disabilities, and psychiatric problems in this population, in order to guide parents, educators, and mental health professionals. Written informed consent was obtained from the patients for publication and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Google Scholar. Ratcliffe S: Long-term outcome in children of sex chromosome abnormalities. Arch Dis Child.
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