Information on the following diseases can be found in the Related Disorders section of this report:

• Tetra X Syndrome (48,XXXX Syndrome)
• Penta X Syndrome (49,XXXXX Syndrome)
• Turner Syndrome (45,X Syndrome)
• Associated Disorders (General)

As noted above, researchers indicate that no specific pattern of symptoms and malformations (phenotype) appears to be characteristically associated with Triplo X Syndrome (i.e., 47,XXX karyotype). However, Triplo X Syndrome has been determined to be a relatively common cause of developmental and learning disabilities in females.

Reports indicate that some affected females may tend to have a relatively low birth weight that is within normal limits. However, many develop an above average height during childhood as compared with others their age, tending toward tall stature in adulthood (e.g., above the 75th percentile).

In contrast, in some affected females, the head circumference may tend to be relatively smaller than expected for their age and gender. In some instances, additional physical findings have been reported, such as unusual shortness and broadness of the head (brachycephaly), vertical skin folds that may cover the eyes' inner corners (epicanthal folds), widely spaced eyes (ocular hypertelorism), abnormal deviation of one or more fingers or toes (clinodactyly), widely spaced nipples, and/or other findings.

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; and/or fertility problems. In addition, kidney abnormalities, such as absence of a kidney (unilateral renal agenesis); recurrent urinary tract infections; and/or other abnormalities have also been reported.

As noted above, evidence suggests that females with Triplo X Syndrome typically have normal intelligence with IQs that tend to be lower than that of their siblings (e.g., approximately 10 to 15 points lower). Mental retardation rarely occurs. (To be classified as having mental retardation, an individual must have an IQ that falls below 70.)

As early as infancy, mild developmental delays and learning difficulties may be apparent. For example, affected infants and children may have decreased muscle tone, poor coordination, awkwardness, and delayed acquisition of certain motor skills. In addition, delayed language and speech development (e.g., delays in receptive and expressive language) may become apparent by approximately one year to 18 months. Reports indicate that females with Triplo X Syndrome have an increased frequency of reading disorders, including dyslexia or other language-based learning disabilities.

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 are associated with mild symptoms and fewer developmental and learning problems. 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.)
.

Triplo X Syndrome 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 Triplo X Syndrome have 47 chromosomes, three of which are X chromosomes (47,XXX karyotype). The presence of the extra X chromosome results from errors during the division of reproductive cells in one of the parents (nondisjunction during meiosis). It is believed that the extra X chromosome is received from the mother in most cases. Some researchers suggest that the risk of such errors may increase with advanced parental age; for example, some have noted increased maternal age in some cases of Triplo X Syndrome.
.

Triplo X Syndrome is a chromosomal disorder that affects only females. Reported estimates concerning the disorder's frequency have varied, ranging from one in 1,000 female births to approximately one to two in 3,000 female births. However, because many females with the disorder may have few or no symptoms, they may never be diagnosed with the disorder. Many researchers suggest that the disorder is in fact underdiagnosed and that the reported number of cases as reflected in the medical literature is inappropriately low. Due to such factors, it is difficult to determine the true frequency of Triplo X Syndrome in the general population.

Certain symptoms of the following disorders may be similar to those of Triplo X Syndrome. Comparisons may be useful for a differential diagnosis:

Tetra X Syndrome is a rare chromosomal abnormality in which females have two extra X chromosomes in the nuclei of body cells (48,XXXX karyotype). As with Triplo X Syndrome, no specific pattern of symptoms and malformations (phenotype) has been associated with this chromosomal abnormality. However, mild to moderate (or, more rarely, severe) mental retardation appears to be a consistent finding. Affected individuals also commonly have speech difficulties and behavioral abnormalities. In some cases, Tetra X Syndrome may also be associated with certain facial abnormalities, such as widely set eyes (ocular hypertelorism), upslanting eyelid folds (palpebral fissures), vertical skin folds that may cover the eyes' inner corners (epicanthal folds), a relatively small jaw (micrognathia), and/or other findings. Other associated features may sometimes include deviation of the fifth fingers or "pinkies" (clinodactyly), abnormal fusion of the forearm bones (radioulnar synostosis), webbing of the neck, and/or other abnormalities. Affected females often have incomplete development of secondary sexual characteristics, such as sparse pubic and underarm hair, small breasts, absence or irregularity of menstrual cycles, and, in some cases, underdevelopment of external genitalia. Tetra X Syndrome results from errors during the division of a parent's reproductive cells (nondisjunction during meiosis).

Penta X Syndrome is a rare chromosomal abnormality in which females have three extra X chromosomes in the nuclei of body cells (49,XXXXX karyotype). The condition is typically characterized by certain abnormalities, including short stature, moderate to severe mental retardation, delays in the acquisition of skills requiring the coordination of mental and motor abilities (psychomotor retardation), malformations of the skull and facial (craniofacial) region, and/or other findings. Craniofacial abnormalities may include an abnormally small head (microcephaly), a round face, upslanting eyelid folds (palpebral fissures), malformed ears, a flat nasal bridge, a short neck with a low hairline, and dental abnormalities. Affected individuals may also have widely spaced eyes (ocular hypertelorism), droopy upper eyelids (ptosis), vertical skin folds that may cover the eyes' inner corners (epicanthal folds), thick lips, a small jaw (micrognathia), and/or other abnormalities. The facial features of females with Penta X Syndrome may resemble those of many children with Down Syndrome (Trisomy 21 Syndrome). Other physical findings associated with Penta X Syndrome may include abnormal fusion of the forearm bones (radioulnar synostosis); narrow shoulders; abnormal deviation (clinodactyly) or permanent flexion (camptodactyly) of one or more fingers; heart and/or kidney defects; deficient development of the ovaries and uterus; delayed puberty; and/or other abnormalities. Penta X Syndrome results from errors during the division of a parent's reproductive cells. (For more information on these disorders, choose "Penta X" and "Down*" as your search terms in the Rare Disease Database.)

Turner Syndrome is a rare chromosomal disorder that affects females. It is characterized by absence of all or a portion or impaired functioning of one of the X chromosomes (45,X karyotype). In some affected females, some cells may have the normal pair of X chromosomes while other cells do not (45,X/46,XX mosaicism). In addition, evidence suggests that some individuals with the disorder may have some Y chromosomal material in addition to the X chromosome in some or all cells.

Females with Turner Syndrome may have a short, webbed neck with a low hairline; short stature; widely spaced, inverted, and/or underdeveloped (hypoplastic) nipples; heart defects; and/or kidney abnormalities. In addition, some affected females may have certain craniofacial abnormalities, such as a small jaw (micrognathia), a narrow roof of the mouth (palate), droopy upper eyelids (ptosis), widely spaced eyes (ocular hypertelorism), and/or other findings. In many cases, immature (streak) ovaries are present that cannot produce the female hormone estrogen. As a result, normal secondary sexual characteristics may fail to develop (e.g., the appearance of pubic hair, breast development, menstruation [primary amenorrhea]). While intellectual abilities are usually normal, some individuals may have problems with visual-spatial relationships (e.g., right-left disorientation), poor coordination and clumsiness, difficulties with nonverbal problem solving, and/or other abnormalities . Turner Syndrome is thought to result from errors during the division of a parent's reproductive cells. (For more information on this disorder, choose "Turner" as your search term in the Rare Disease Database.)

Additional disorders may be characterized by developmental delays, learning difficulties, tall stature, and/or other symptoms and findings similar to those potentially associated with Triplo X Syndrome. (For more information on these disorders, choose the exact disease name in question as your search term in the Rare Disease Database.)

Diagnosis
Triplo X Syndrome is diagnosed based upon chromosomal analysis that reveals the presence of an extra X chromosome in body cells. It is usually detected unexpectedly in females with suspected developmental and learning disabilities. In addition, Triplo X Syndrome 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.

Treatment
Early intervention services are recommended for infants and children diagnosed with Triplo X Syndrome. Experts advise developmental assessment by age six months to evaluate muscle tone and strength; language and speech assessment by age two years to evaluate expressive and receptive language development; and reading assessment by school age to rule out or confirm dyslexia. Evidence suggests that affected children are greatly responsive to early intervention services and treatment.

Genetic counseling will be of benefit for affected individuals and their families. Because females with Triplo X Syndrome have a slightly increased risk for chromosomal abnormalities during pregnancy, prenatal counseling is recommended. Other treatment for this disorder is symptomatic and supportive.

Research on genetic disorders and their causes is ongoing. The National Institutes of Health (NIH) is sponsoring the Human Genome Project which is aimed at mapping every gene in the human body and learning why they sometimes malfunction. It is hoped that this new knowledge will lead to prevention and treatment of genetic and familial disorders in the future.

TEXTBOOKS
Jones KL. Smith's Recognizable Patterns of Human Malformation. 5th ed. Philadelphia, PA: W.B. Saunders Company; 1997:78-80.

Behrman RE, et al., eds. Nelson Textbook of Pediatrics. 15th ed. Philadelphia, PA: W.B. Saunders Company; 1996:317-18.

Money J. Sex errors of the body and related syndromes: a guide to counseling children, adolescents, and their families. 2nd ed. Paul H. Brookes Publishing Co., Inc.; 1994:9.

Gorlin RJ, et al., eds. Syndromes of the Head and Neck. 3rd ed. New York, NY: Oxford University Press; 1990:63-64.

Buyse ML. Birth Defects Encyclopedia. Dover, MA: Blackwell Scientific Publications, Inc.; 1990:399-400, 1717-19.

JOURNAL ARTICLES
Rovet J, et al. Intelligence and achievement in children with extra X aneuploidy: a longitudinal perspective. Am J Med Genet. 1995;60:356-63.

Ratcliffe SG, et al. The growth of XXX females: population-based studies. Ann Hum Biol. 1994;21:57-66.

Leal CA, et al. Parental origin of the extra chromosomes in polysomy X. Hum Genet. 1994;94:423-26.

Martini G, et al. On the parental origin of the X's in a prenatally diagnosed 49,XXXXX syndrome. Prenat Diagn. 1993;13:763-66.

Kocova M, et al. Detection of Y chromosome sequences in Turner's syndrome by southern blot analysis of amplified DNA. Lancet. 1993;342:140-43.

Lin HJ, et al. Exstrophy of the cloaca in a 47,XXX child: review of genitourinary malformations in triple-X patients. Am J Med Genet. 1993;45:761-63.

Favetta S, et al. Pentasomy X: a clinical case report. Pediatr Med Chir. 1992;14:551-54.

Kassai R, et al. Penta X syndrome: a case report with review of the literature. Am J Med Genet. 1991;40:51-56.

Nielsen J, et al. Chromosome abnormalities found among 34,910 newborn children: results from a 13-year incidence study in Arhus, Denmark. Human Genet. 1991;87:81-83.

Hood OJ, et al. Multiple congenital anomalies associated with a 47,XXX chromosome constitution. Am J Med Genet. 1990;36:73-75.

Hassold T, et al. The parental origin of the missing or additional chromosome in 45,X and 47,XXX females. Birth Defects. 1990;26:297-304.

Hassold T, et al. Analysis of non-disjunction in sex chromosome tetrasomy and pentasomy. Hum Genet. 1990;85:648-50.

Itu M, et al. Primary amenorrhoea in a triple X female. Aust N Z J Obstet Gynaecol. 1990;30:386-88.

Hassold T, et al. Analysis of non-disjunction in sex chromosome tetrasomy and pentasomy. Hum Genet. 1990;85:648-50.

May KM, et al. The parental origin of the extra X chromosome in 47,XXX females. Am J Hum Genet. 1990;46:754-61.

Linden MG, et al. 47,XXX: what is the prognosis? Pediatrics. 1988;82:619-30.

Plauchu H, et al. The 48,XXXX syndrome: study of psychomotor development from birth to 11 years of age and review of the literature. Ann Genet. 1988;31:105-10.

Fryn JP, et al. X-chromosome polysomy in the female: personal experience and review of the literature. Clinc Genet. 1983;23:341-49.

Stewart DA, et al. Summary of clinical findings: profiles of children with 47,XXY, 47,XYY, and 47,XXX karotypes. Birth Defects: Original Article Series. 1982;18:1-5.

Robinson A, et al. Summary of clinical findings: profiles of children with 47,XXY, 47,XXX and 47,XYY karotypes. Birth Defects: Original Article Series. 1979;15:261-66.