Triple X Syndrome is estimated to occur in approximately 1 in every 1,000 female births globally. However, a large proportion of individuals with Triple X Syndrome do not display sufficiently significant symptoms to seek genetic testing. It is estimated only about 10% of those affected ever receive a diagnosis.

Triple X syndrome is caused by a random genetic error in cell division.  It is not a heritable condition. There are two main mechanisms that can give rise to Triple X Syndrome: Nondisjunction, and Mosaicism.

Nondisjunction is a random event that occurs during meiosis, or the cell division process that leads to the creation of sex cells (gametes) such as egg and sperm. Normally, gametes contain one copy of each chromosome. When a cell that gives rise to the mother's egg cell or the father's sperm cell fails to divide correctly, it can lead to a gamete that contains two X chromosomes instead of one. If this egg or sperm eventually gives rise to offspring, that individual will have an extra X chromosome. This is the most common cause of Triple X Syndrome.

Mosaicism arises when there is a cell division error during development that occurs after initial fertilization. Normally, cells in the body other than gametes have two copies of each chromosome (23 from the mother and 23 from the father, making 46 total). In mosaicism, as cells are dividing during fetal development, a division occurs incorrectly, and one of the resulting cells receives three copies of the X chromosome instead of two. As these cells continue to divide, all of the following cells in that lineage have three copies of the X chromosome. This results in an individual who has distinct populations of cells in their body, some of which have three copies of the X chromosome, leading to Triple X Syndrome. Often, individuals with mosaicism have a more mild form of the disease.

The number of X chromosomes in the other cells of patients with mosaicism depends on the nature of the cell division error. Some individuals will have cells with 46,XX, and have two X chromosomes. Other individuals will have different chromosomal abnormalities in their remaining non-triple X cells. Some have 45,X cells, meaning there is complete loss of an X chromosome, and only one X chromosome is present. Other individuals have remaining cells which are 48,XXXX, or tetrasomy X, meaning these cells have four X chromosomes. Which type of mosaicism is present, and which cell populations have one, two, three or four X chromosomes, will affect clinical manifestation and symptom severity, leading to wide variation.

One reason symptom severity ranges so widely in Triple X Syndrome patients may be because of X chromosome inactivation. In 46,XX individuals, one of the two X chromosomes is silenced by a molecular mechanism called dosage compensation, which functions to keep levels of genes found on the X chromosome similar between 46,XX females and 46,XY males. In individuals with Triple X Syndrome, dosage compensation generally inactivates two of the three X chromosomes. However, this X-inactivation is often incomplete, and some genes “escape” silencing, leading to a higher dose of expression which can disrupt developmental pathways. How many genes “escape” X-inactivation can vary widely between individuals and even between cells within an individual, and this may help explain why some people are never even aware they have Triple X Syndrome, while others experience severe symptoms. However, the link between X-inactivation and Triple X Syndrome is not fully understood.

Symptoms of Triple X Syndrome are complex and vary widely. Some individuals experience very mild or no symptoms, while others may have more significant challenges. Symptoms can include:

• Physical Symptoms

  • The most common physical symptom is increased height. Most females with Triple X Syndrome are in the 75th percentile or higher in height for their age, and can have disproportionately long legs.

  • Other more subtle physical characteristics are vertical folds of skin covering the inner corner of the eyes, widely spaced eyes, and curved or bent pinky fingers.

  • Affected individuals may also exhibit weak muscle tone, flat feet, or a breastbone with an inward bowed shape.

  • There can be structural differences in the kidneys that can increase susceptibility to urinary tract infections.

  • Congenital heart defects have also been reported.

• Neurodevelopmental Symptoms

  • Neurodevelopmental challenges are the most frequent cause of clinical investigation and diagnosis. 

  • Individuals with Triple X Syndrome can have delayed development of motor skills, and often experience impaired speech and language processing. Many experience a delay in speaking their first words, often not until 18 months of age or later.

  • Learning difficulties are common, affecting about 75% of cases identified in school aged children, and can include dyslexia, auditory processing disorders, and issues with memory, judgement, and reading comprehension. 

  • As a result of learning and language difficulties, girls and women with Triple X Syndrome can be vulnerable to anxiety and depression.

• Sexual Development and Fertility Symptoms

  • While most women with Triple X Syndrome experience normal sexual development and fertility, there is an increased prevalence of premature ovarian failure, which causes the ovaries to stop functioning properly at a young age.

Triple X Syndrome is diagnosed through genetic testing. Karyotyping, or the visual analysis of an individual’s chromosomes, is the most straightforward method since it clearly shows the presence of a third X chromosome. Depending when the individual is diagnosed, genetic material may be obtained in different ways: 

• Prenatal diagnosis - In some cases, an individual with Triple X Syndrome may be identified before they are born, usually either by Amniocentesis or Chorionic Villus Sampling (CVS).

  • Amniocentesis is performed between the 14th and 20th week of pregnancy, and tests the genetic material of fetal cells found in amniotic fluid.

  • CVS takes tissue from the placenta for genetic analysis between the 10th and 13th week of pregnancy.

• Postnatal diagnosis - In other cases, genetic testing is done after an individual is born when symptoms cause suspicion of Triple X Syndrome. Diagnosis is usually done by karyotyping or Chromosomal Microarray Analysis (CMA).

  • CMA is similar to karyotyping, but higher resolution, with an ability to detect microdeletions or microduplications of small regions of the chromosomes. It isn’t necessary to use this level of resolution to identify Triple X Syndrome, but it may be used during the diagnostic process so the clinician can identify any other possible chromosomal abnormalities.

• Adult diagnosis - Occasionally, Triple X Syndrome will be diagnosed in an adult incidentally, usually when they are receiving genetic testing for another purpose, such as family planning, or evaluating the cause of infertility or repeated miscarriage.

Triple X Syndrome is a chromosomal disorder, and has no cure. However, there are many supportive therapies that when implemented early, can help mitigate the impact of the disease.

Early interventions that can help individuals cope with developmental delays include: 

• Speech Therapy: Crucial for addressing the highly prevalent delays in speaking and difficulties with auditory processing.

• Physical Therapy (PT): Used to address hypotonia and delays in motor skills, such as sitting up and walking.

• Occupational Therapy (OT): Used to improve fine motor skills and address sensory processing challenges.

• Educational Support: Given the high frequency of learning disabilities, particularly those related to reading and language comprehension, tailored educational assistance is beneficial.

• Psychological Support: Psychology referrals for managing psychosocial impacts like anxiety and depression, and assistance in developing stable social and interpersonal skills, can be helpful.

Most individuals affected by Triple X Syndrome can grow up to be healthy and lead productive lives. The extent to which the syndrome impacts an individual's life correlates directly with the severity of their symptoms and the timing of supportive services.  Early physical and behavioral assessments and intervention with speech, occupational, and physical therapies as well as counseling is associated with positive outcomes. Triple X Syndrome does not significantly impact lifespan.

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