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รltima actualizaciรณn: 4/4/2024
Aรฑos publicados: 1995, 1996, 1997, 1998, 2001, 2011, 2014, 2017, 2020, 2024
NORD gratefully acknowledges Dr. Carole Samango-Sprouse, Associate Clinical Professor in the Department of Pediatrics at George Washington University and Adjunct Associate Professor in the Department of Human and Molecular Genetics at Florida International University, for assistance in the preparation of this report.
47, XXX (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, but females with 47, XXX have three X chromosomes. The characteristics (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). 47, XXX occurs randomly due to errors during the division of reproductive cells in one of the parents. This disorder occurs in one in 900 to 1,000 livebirths.
The severity of symptoms associated with 47, XXX may vary greatly from one person to another, but it is thought that many females are mildly affected or asymptomatic, as about 75% of girls remain undiagnosed for their whole lives (Frith, 2024). It is important to note that affected individuals may not have all 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, individuals with 47, XXX may have mild facial differences including vertical skin folds that may cover the inner corners of the eyes (epicanthal folds) and widely spaced eyes (hypertelorism). 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 47, XXX usually exhibit tall stature compared to other girls their age. By adolescence, most are at or above the 75th percentile for height. In general, these girls are like neurotypical children in their physical appearance but do show neurodevelopmental differences as early as infancy.
47, XXX is often associated with a broad range of neurodevelopmental differences compared to children without 47, XXX. Infants and children with 47, XXX have delays in attaining developmental milestones, especially the acquisition of motor skills, speech skills and social cognition. For example, walking may be delayed due to low muscle tone and older girls may experience poor coordination, clumsiness and deficient motor planning skills secondary to developmental dyspraxia.
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 may be impacted. Girls with 47, XXX 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 47, XXX, with most having average to above average non-verbal IQs and below average verbal IQs. This is because of the language-based learning dysfunction that girls with 47, XXX experience. However, these deficits are very responsive to treatment, with early intervention often resulting in a very good outcome.
Though less is known about the psychological symptoms associated with 47, XXX, studies have found an increased incidence of anxiety and attention deficit hyperactivity disorder-inattentive subtype (ADHD). It is believed that their impairments in verbal abilities may exacerbate anxiety in social settings, such as school or social gatherings. This may result in low self-esteem, social avoidance and more behavioral problems. The incidence of ADHD in girls with 47, XXX 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 girls have minimal to no behavioral or emotional abnormalities while others may need therapeutic services. Early diagnosis is important, and these girls tend to have fewer issues later in life when they are diagnosed prenatally or 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 47, XXX 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 47, XXX 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.
47, XXX is a chromosomal abnormality characterized by the presence of an extra X chromosome in females. Chromosomes are found in the nucleus of all the cells in the body and these chromosomes carry the genetic characteristics of all individuals. There are 23 pairs of human chromosomes with the 23rd pair determining the sex of an individual. Typical males have one X and one Y chromosome (46, XY) while typical females have two X chromosomes (46, XX).
Females with trisomy X have an extra X chromosome resulting in a 47, XXX karyotype. 47, XXX is not inherited. The presence of the extra X chromosome results from sporadic and 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% of children when nondisjunction events occur after conception in the developing fetus (postzygotic nondisjunction). 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 โRelated Disordersโ section of this report below.)
Researchers believe that the 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 โpartially turned offโ 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 โturned offโ to be expressed. However, the link between X-inactivation and symptoms in 47, XXX is not fully understood.
47, XXX 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. Since 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 is inappropriately low (about 10%). With increased diagnosis, more in depth studies may be conducted and more girls with 47, XXX can be appropriately treated.
47, XXX may be suspected based upon the identification of characteristic neurodevelopmental, behavioral or learning disabilities. A diagnosis may be confirmed by specialized tests such as chromosomal microarray analysis performed on blood or buccal samples that can reveal the presence of an extra X chromosome in the bodyโs cells.
In addition, 47, XXX is increasingly being diagnosed before birth (prenatally) based on cell-free DNA testing formerly called non-invasive prenatal screening test or NIPT, which reveals if the fetus is at risk for selected chromosomal disorders. Diagnoses are later confirmed with amniocentesis, in which a sample of the fluid that surrounds the developing fetus is removed and analyzed. Another option is chorionic villus sampling (CVS) which involves the removal of tissue samples from a portion of the placenta.
Treatment
Due to the wide range of characteristics associated with this disorder, treatment depends on several factors including the age of an affected individual upon diagnosis, the specific symptoms that are present and the overall severity of the disorder.
Genetic counseling is recommended for affected individuals and their families.
Early intervention services are recommended for infants and children diagnosed with 47, XXX. It is necessary to have a physical assessment by four months old to evaluate muscle tone and strength; a language and speech assessment by 12 months old to evaluate expressive and receptive language development, and to identify any speech delay; a pre-reading assessment during preschool years prior to first grade to look for early signs of reading dysfunction; and a behavioral assessment by first grade to address any issues with anxiety and/or ADHD. A neurodevelopmental evaluation is recommended to help assess neurodevelopmental issues, learning disabilities and social and emotional problems. Infants and children with 47, XXX should also receive kidney (renal) and heart (cardiac) evaluations to detect potential abnormalities associated with the disorder.
Evidence suggests that girls with 47, XXX are very 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 females 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 all children, and girls with 47, XXX often struggle as they enter their middle school years, therefore, short-term counseling 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/living-with-a-rare-disease/find-clinical-trials/
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/
TEXTBOOKS
Carey J, Battaglia A, Viskochil D and Cassidy S.Management of Genetic Syndromes (4th ed.) John Wiley & Sons, 2021.
Samango-Sprouse, C, and Gropman, AL. X & Y chromosomal variations: hormones, brain development, and neurodevelopmental performance. San Rafael, CA: Morgan & Claypool Publishers, 2017.
Samango-Sprouse CA and Gropman AL. X & Y Chromosomal Variations: Hormones, Brain Development, and Neurodevelopmental Performance. Colloquium Series on The Developing Brain. October, 2016.
Samango-Sprouse CA Frontal Lobe Development in Childhood. The Human Frontal Lobe: Functions and Disorders, 2nd Edition, Eds. BL Miller, and JL Cummings, Guilford Press, New York, 2007.
JOURNAL ARTICLES
Freilinger P, Kliegel D, Hรคnig S, Oehl-Jaschkowitz B, Henn W, Meyer J. Behavioral and psychological features in girls and women with triple-X syndrome. Am J Med Genet A. 2018;176(11):2284-2291. doi:10.1002/ajmg.a.40477
Wigby K, DโEpagnier C, Howell S, et al. Expanding the phenotype of Triple X syndrome: A comparison of prenatal versus postnatal diagnosis. Am J Med Genet A. 2016;170(11):2870-2881. doi:10.1002/ajmg.a.37688
Otter M, Schrander-Stumpel CT, Curfs LM. Triple X syndrome: a review of the literature. Eur J Hum Genet. 2010;18:265-271.
Tartaglia NR, Howell S, Sutherland A, Wilson R, Wilson L. A review of trisomy X (47,XXX). Orphanet J Rare Dis. 2010;5:8. Published 2010 May 11. doi:10.1186/1750-1172-5-8.
Krusinskie V, Alvesalo L, Sidlauskas A. The craniofacial complex in 47,XXX females. Eur J Orthod. 2005;27:396-401.
Liebezeit BU, Rohrer TR, Singer H, Doerr HG. Tall stature as presenting symptom in a girl with triple X syndrome. J Pediatr Endocrinol Metab. 2003;16:233-235.
Samango-Sprouse CA, Rogol A. XXY: The Hidden Disability and Prototype for Infantile Presentation of Developmental Dyspraxia (IDD). Infants and Young Children. 2002;15:11-18.
Bender, BG, Linden, MG, Harmon, RJ. Neuropsychological and functional cognitive skills of 35 unselected adults with chromosome abnormalities. Am J Med Genet. 2001; 102(4):309-313.
Rovet J, Netley C, Bailey J, Keenan M, Stewart D. Intelligence and achievement in children extra X aneuploidy: a longitudinal perspective. Am J Med Genet. 1995;60:356-363.
Raticliffe SG, Pan H, McKie M. The growth of XXX females: population-based studies. Ann Hum Biol. 1994;21:57-66.
Pennington, B, Puck, M, Robinson, A. Language and cognitive development in 47,XXX females followed since birth. Behavior Genet. 1980; 10(1):31-41.
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The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).
View reportOrphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.
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