Trisomy X

National Organization for Rare Disorders, Inc.

Important

It is possible that the main title of the report Trisomy X is not the name you expected. Please check the synonyms listing to find the alternate name(s) and disorder subdivision(s) covered by this report.

Synonyms

  • 47, XXX
  • 47, XXX karyotype
  • 47, XXX syndrome
  • triple X syndrome
  • triplo X
  • XXX syndrome

Disorder Subdivisions

  • None

General Discussion

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 in the nuclei of body cells. There are specific physical features (phenotype) associated with this chromosomal disorder. Common symptoms that can potentially occur include 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.

Symptoms

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 developmental 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.



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.



In some cases, 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.



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 and as the girls reach adulthood. Some individuals have minimal to no behavioral or emotional abnormalities; others 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.



In most cases, 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.

Causes

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 cases, the additional X chromosome comes from the mother. In approximately 20 percent of cases, nondisjunction events occur after conception in the developing fetus (postzygotic nondisjunction).



In some cases, only a certain percentage of an individual's cells may have three X chromosomes, while others have a normal chromosomal make-up (46,XX/47,XXX mosaicism). Evidence suggests that such cases may be associated with 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 "turned off" and all of the genes on that chromosome are inactivated (X-inactivation). Researchers suspect that the presence of a third X chromosome allows 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.

Affected Populations

Trisomy X is a chromosomal disorder that affects only females. Reported estimates concerning the disorder's 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 cases as reflected in the medical literature is inappropriately low. Researchers believe that only approximately 10 percent of cases are diagnosed. With increased detection, more in depth studies may be conducted and more girls with triple X can be appropriately treated.

Standard Therapies

Diagnosis

Trisomy X may be suspected based upon the identification of characteristic developmental, 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.



Treatment

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.



Genetic counseling will be of benefit for affected individuals and their families. Additional treatment for this disorder 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.

Investigational Therapies

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:



Tollfree: (800) 411-1222

TTY: (866) 411-1010

Email: prpl@cc.nih.gov



For information about clinical trials sponsored by private sources, contact:

www.centerwatch.com



For information about clinical trials conducted in Europe, contact:

https://www.clinicaltrialsregister.eu/

References

TEXTBOOKS

Speicher MR, Antonarakis SE, Motulsky AG. Eds. Vogel and Motulsky's Human Genetics: Problems and Approaches. 4th ed. Springer. New York, NY; 2009:124.



Samango-Sprouse CA. XXX Syndrome (Triple X Syndrome). NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:89.



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.



Rimoin D, Connor JM, Pyeritz RP, Korf BR. Eds. Emory and Rimoin's Principles and Practice of Medical Genetics. 4th ed. Churchill Livingstone. New York, NY; 2002:1195-1196.



JOURNAL ARTICLES

Otter M, Schrander-Stumpel CT, Curfs LM. Triple X syndrome: a review of the literature. Eur J Hum Genet. 2010;18:265-271.



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.



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.



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.



INTERNET

Tartaglia NR, Howell S, Sutherland A, Wilson R, Wilson L. A review of trisomy X (47,XXX). Orphanet encyclopedia, 2010. Available at: http://www.ojrd.com/content/5/1/8 Accessed March 25, 2014.



Mayo Clinic for Medical Education and Research. Triple X Syndrome. Nov. 08, 2012. Available at: http://www.mayoclinic.com/health/triple-x-syndrome/DS01090 Accessed March 25, 2014.

Resources

March of Dimes Birth Defects Foundation

1275 Mamaroneck Avenue

White Plains, NY 10605

Tel: (914)997-4488

Fax: (914)997-4763

Internet: http://www.marchofdimes.com



National Dissemination Center for Children with Disabilities (DELETED

1825 Connecticut Ave NW, Suite 700

Washington, DC 20009

USA

Tel: (202)884-8200

Fax: (202)884-8441

Tel: (800)695-0285

TDD: (800)695-0285

Email: nichcy@aed.org

Internet: http://www.nichcy.org



National Center for Learning Disabilities

381 Park Avenue South

1420 Suite

New York, NY 10016

Tel: (212)545-7510

Fax: (212)545-9665

Tel: (888)575-7373

Email: ncld@ncld.org

Internet: http://www.ncld.org/



Chromosome Disorder Outreach, Inc.

P.O. Box 724

Boca Raton, FL 33429-0724

USA

Tel: (561)395-4252

Fax: (561)395-4252

Email: info@chromodisorder.org

Internet: http://www.chromodisorder.org/CDO/



Learning Disabilities Association of America

4156 Library Road

Pittsburgh, PA 15234-1349

Tel: (412)341-1515

Fax: (412)344-0224

Tel: (888)300-6710

Email: info@ldaamerica.org

Internet: http://www.ldanatl.org



International Dyslexia Association

40 York Rd

4 Florr

Baltimore, MD 21204

USA

Tel: (410)296-0232

Fax: (410)321-5069

Tel: (800)222-3123

Email: info@interdys.org

Internet: http://www.interdys.org



UNIQUE - Rare Chromosome Disorder Support Group

Unique

The Rare Chromosome Disorder Support Group

G1 The Stables

Station Road West, Oxted

Surrey, RH8 9EE

United Kingdom

Tel: 441883723356

Email: info@rarechromo.org or rarechromo@aol.com

Internet: http://www.rarechromo.org



Genetic and Rare Diseases (GARD) Information Center

PO Box 8126

Gaithersburg, MD 20898-8126

Tel: (301)251-4925

Fax: (301)251-4911

Tel: (888)205-2311

TDD: (888)205-3223

Internet: http://rarediseases.info.nih.gov/GARD/



Madisons Foundation

PO Box 241956

Los Angeles, CA 90024

Tel: (310)264-0826

Fax: (310)264-4766

Email: getinfo@madisonsfoundation.org

Internet: http://www.madisonsfoundation.org



Klinefelter Syndrome & Associates

P.O. Box 872

Pine, CO 80470-0872

Tel: (303)400-9040

Fax: (303)838-0753

Tel: (888)999-9428

Email: info@genetic.org

Internet: http://www.genetic.org



Focus Foundation, Inc.

PO Box 190

Davidsonville, MD 21035

Tel: (443)223-7323

Fax: (410)798-4801

Email: info@thefocusfoundation.org

Internet: http://www.thefocusfoundation.org



For a Complete Report

This is an abstract of a report from the National Organization for Rare Disorders, Inc.® (NORD). Cigna members can access the complete report by logging into myCigna.com. For non-Cigna members, a copy of the complete report can be obtained for a small fee by visiting the NORD website. The complete report contains additional information including symptoms, causes, affected population, related disorders, standard and investigational treatments (if available), and references from medical literature. For a full-text version of this topic, see http://www.rarediseases.org/search/rdblist.html.