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48,XXXY syndrome

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Other Names: XXXY syndrome

48,XXXY syndrome is a type of chromosome abnormality characterized by the presence of 2 extra X chromosomes in males. It is sometimes referred to as a variant of Klinefelter syndrome, but differs from Klinefelter syndrome in many ways and is more severe. 48,XXXY syndrome is a chromosomal condition in boys and men that causes intellectual disability, developmental delays, physical differences, and an inability to father biological children (infertility).

Epidemiology

48,XXXY syndrome affects between 1 in 17,000 and 1 in 50,000 newborn boys. It is a relatively uncommon sex chromosome disorder, which is a group of conditions caused by changes in the number of sex chromosomes (the X chromosome and the Y chromosome).

Cause

48,XXXY syndrome is a sex chromosome disorder in boys and men that results from having two extra X chromosomes in each cell. People typically have 46 chromosomes in each cell, two of which are the sex chromosomes. Females have two X chromosomes (46,XX), and males have one X chromosome and one Y chromosome (46,XY). Boys and men with 48,XXXY syndrome have the usual single Y chromosome, but they have three copies of the X chromosome, for a total of 48 chromosomes in each cell.

Boys and men with 48,XXXY syndrome have extra copies of multiple genes on the X chromosome. The activity of these extra genes affects many aspects of development, including sexual development before birth and at puberty. Researchers are working to determine which genes contribute to the specific developmental and physical differences that occur with 48,XXXY syndrome.

48,XXXY syndrome is sometimes described as a variant of another sex chromosome disorder called Klinefelter syndrome. Boys and men with Klinefelter syndrome have one extra copy of the X chromosome, for a total of 47 chromosomes in each cell (47,XXY). Like 48,XXXY syndrome, Klinefelter syndrome affects male sexual development and can be associated with learning disabilities and problems with speech and language development. However, the features of 48,XXXY syndrome tend to be more severe than those of Klinefelter syndrome and affect more parts of the body. As doctors and researchers have learned more about the differences between these sex chromosome disorders, they have started to consider them as separate conditions.

Inheritance

This condition is not inherited; it occurs as a random event during the formation of reproductive cells (eggs or sperm) in one of an affected person's parents. During cell division, an error called nondisjunction prevents X chromosomes from being distributed normally among reproductive cells as they form. Typically, as cells divide, each egg cell gets a single X chromosome, and each sperm cell gets either an X chromosome or a Y chromosome. However, because of nondisjunction, an egg cell or a sperm cell can also end up with two extra copies of the X chromosome.

If an egg cell with two extra X chromosomes (XXX) is fertilized by a sperm cell with one Y chromosome, the resulting child will have 48,XXXY syndrome. Similarly, if a sperm cell with a Y chromosome and two extra X chromosomes (XXY) fertilizes an egg cell with a single X chromosome, the resulting child will have 48,XXXY syndrome.

Signs and symptoms

Most boys and men with 48,XXXY syndrome have mild intellectual disability with learning difficulties. Speech and language development is particularly affected. Most affected boys and men can understand what other people say more easily than they themselves can speak. The problems with speech and communication can contribute to behavioral issues, including irritability and outbursts or temper tantrums. Boys and men with 48,XXXY syndrome tend to have anxiety, a short attention span, and impaired social skills.

48,XXXY syndrome is also associated with weak muscle tone (hypotonia) and problems with coordination that delay the development of motor skills, such as sitting, standing, and walking. Affected boys and men tend to be taller than their peers, with an average adult height of over 6 feet.

Other physical differences associated with 48,XXXY syndrome include abnormal fusion of certain bones in the forearm (radioulnar synostosis), an unusually large range of joint movement (hyperextensibility), elbow abnormalities, curved pinky fingers (fifth finger clinodactyly), and flat feet (pes planus). Affected individuals may have distinctive facial features, including widely spaced eyes (ocular hypertelorism), outside corners of the eyes that point upward (upslanting palpebral fissures), and skin folds covering the inner corner of the eyes (epicanthal folds). However, some boys and men with 48,XXXY syndrome do not have these differences in their facial features.

48,XXXY syndrome disrupts male sexual development. The penis is shorter than usual, and the testes may be undescended, which means they are abnormally located inside the pelvis or abdomen. The testes are small and do not produce enough testosterone, which is the hormone that directs male sexual development. The shortage of testosterone often leads to incomplete puberty. Starting in adolescence, affected boys and men may have sparse body hair, and some experience breast enlargement (gynecomastia). Their testes typically do not produce sperm, so most men with this condition are infertile.

Diagnosis

Karyotype of 47,XXY. The only difference for 48,XXXY would be a third X chromosome.
Karyotype of 47,XXY. The only difference for 48,XXXY would be a third X chromosome.

Diagnosis of 48,XXXY is usually done by a standard karyotype. A karyotype is a chromosomal analysis in which a full set of chromosomes can be seen for an individual. The presence of the additional 2 X chromosomes on the karyotype are indicative of XXXY syndrome.

Another way to diagnosis 48,XXXY is by chromosomal microarray showing the presence of extra X chromosomes. Chromosomal microarray (CMA) is used to detect extra or missing chromosomal segments or whole chromosomes. CMA uses microchip-based testing to analyze many pieces of DNA. Males with 48,XXXY are diagnosed anywhere from before birth to adulthood as a result of the range in the severity of symptoms. The age range at diagnosis is likely due to the fact that XXXY is a rare syndrome, and does not cause as extreme phenotypes as other variants of Klinefelter syndrome (such as XXXXY).

Diagnostic testing could also be done via blood samples. Elevated levels of follicle stimulating hormone, luteinizing hormone, and low levels of testosterone can be indicative of this syndrome.

Treatment

There is no cure for 48,XXXY syndrome. Treatment depends on the symptoms present in each individual and is best managed by a team of specialists, including cardiologists, orthopedists, speech therapists, neurologists, and endocrinologists. Life expectancy is generally normal in the absence of major complications. Regular medical visits are often needed, in particular to monitor problems with hormone production, infections, and behavior.

NIH genetic and rare disease info

48,XXXY syndrome is a rare disease.

Latest research - 48,XXXY syndrome

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