What are the other Names for this Condition? (Also known as/Synonyms)

• 47, XXX Aneuploidy Syndrome
• Super Female Syndrome
• Trisomy XXX Syndrome

What is Triple X Syndrome? (Definition/Background Information)

• Triple X Syndrome (or Trisomy X Syndrome) is a chromosomal abnormality that is characterized by the presence of an additional X chromosome in some of the cells. The disorder is exclusively observed in females and may present initially mild growth delays followed by rapid growth during adolescence, weak muscles, and behavioral and social issues
• In normal cases, there are two X chromosomes (called the sex chromosomes) found in a female. However, individuals with this syndrome are affected by a chromosomal aberration, and each cell might contain an additional X chromosome. Thus, it is also known as XXX Syndrome
• The severity of Triple X Syndrome is based on the proportion of normal cells (with XX chromosomes) to abnormal cells (with XXX chromosomes) occurring in the body. In a majority of the cases, there is no apparent visual difference between women with this condition and those with XX chromosomes (normal)
• Following a diagnosis, the condition may be managed based on the presenting symptoms and extent of involvement of the body systems. The long-term prognosis of females with Triple X Syndrome is generally good in a majority of the cases

Who gets Triple X Syndrome? (Age and Sex Distribution)

• Triple X Syndrome is exclusively seen in females; only girls and women are affected
• The incidence rate is about 1 in 1000 live births (among girls)
• In many cases, females with mild signs and symptoms may be undiagnosed in their lifetime. Hence, a true incidence of the disorder may be difficult to estimate
• Worldwide, all races and ethnic groups may be affected by this syndrome

What are the Risk Factors for Triple X Syndrome? (Predisposing Factors)

• Currently, there are no established risk factors for Triple X Syndrome
• Also, no environmental and lifestyle (including dietary) factors have been implicated
• The syndrome is not caused by what the expectant mother does or does not do, either prior to or during pregnancy

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Triple X Syndrome? (Etiology)

Humans have 46 chromosomes in the cell nucleus, in 23 pairs, of which one pair is named the sex chromosome. In males, it is designated XY, for chromosome X and chromosome Y; while, in females, it is designated XX, for a pair of chromosome X.

During conception, the embryo inherits one copy of each chromosome from each parent (i.e., mother and father). Any alteration in the chromosome numbers or structure, such as via addition or deletion of chromosomal material, can result in mild to severe genetic abnormalities that may manifest as birth defects, growth delays, and intellectual disabilities.

• During conception, if either the sperm cell (obtained from the father) or the egg cell (obtained from the mother) has an extra X chromosome, due to a genetic defect; then, following fertilization and formation of the fetus, this extra X chromosome is incorporated into the cells. This results in Triple X Syndrome (or XXX syndrome) affecting female babies
• The origin of Triple X Syndrome is due to a genetic process that is caused by a defective egg or sperm cell. The condition does not run in families, and so, is not inheritable
• Since, in some cases, not all the cells contain an additional X chromosome, the proportion of such abnormal cells to normal cells, creates a mosaic pattern, where only a certain percentage of cells are affected. This is known as Mosaic Triple X syndrome, and the following types are noted:
  • 47,XXX/46,XX - some cells have an additional X chromosome (hence 47,XXX), while other cells have a normal number of chromosomes (hence 46,XX)
  • 45,X/47,XXX - some cells have an additional X chromosome (47,XXX), while other cells have lost an X chromosome (hence 45,X)
  • 47,XXX/48,XXXX - some cells have an additional X chromosome (47,XXX), while other cells have a couple of additional X chromosomes (hence 48,XXXX)
• The severity of Triple X Syndrome is based on this proportion of abnormal to normal cells (or mosaicism). The greater the proportion of abnormal cells to normal cells in the individual, the more severe is the signs and symptoms

Additional (general) information on chromosomes, which is helpful in understanding the disorder:

Chromosomes are microscopic thread-like protein structures present in each cell nucleus that carry genetic information in the form of DNA (deoxyribonucleic acid). DNAs are nucleic acids that encodes the genetic information of any organisms; a basic unit of the DNA is termed a gene with a specific set of instructions and a defined function. Each chromosome is “X” shaped with a center, called the centromere, and two short arms (termed p arms) and two long arms (termed q arms).

Apart from the XX or XY chromosomes, the other 22 pairs of chromosomes are numbered chromosome 1 through 22, approximately according to size (with chromosome 1 being the largest; chromosome 21 being the smallest) and are referred to as autosomes or somatic chromosomes.

What are the Signs and Symptoms of Triple X Syndrome?

The signs and symptoms of Triple X Syndrome may be significantly different from one individual to another. The degree of signs and symptoms are often related to the amount of chromosome material added and the number of genes affected. As a general rule, a small gain in chromosome material generally results in milder signs and symptoms. Conversely, larger gains/duplications of the chromosome material generally results in severe signs and symptoms. It is important to note that exceptions may also occur, where individuals with small amount of chromosomal gains, may have disproportionately severe presentations.

The commonly noted signs and symptoms of Triple X Syndrome in girls and women include:

• Physical development delays, which are known to be typically mild
• Size of the head is not proportional to body size
• Rapid growth may be observed between ages 4 and 13 years. The girl may be tall for her age (especially with long legs)
• Epicanthal (skin) folds may be observed at the eye corners
• Delayed development causing learning and speech disabilities
• Weakness of muscles and weak motor skills (both fine and gross motor skills)
• Mild floppiness may be observed in infant children
• Increased vulnerability to behavioral issues and social stress; some girls may find it difficult to make friends at school, which tends to improve into adolescence
• Low self-esteem (into womanhood) may be observed
• Premature ovarian failure (POF)
• Constipation
• Epileptic seizures may be noted in some cases
• In rare cases, heart abnormalities have been noted that include:
  • Atrial septal defect and ventricular septal defect
  • Pulmonic stenosis 
  • Aortic coarctation

How is Triple X Syndrome Diagnosed?

Children can have varying signs and symptoms. Some children with mild signs and symptoms may go undiagnosed in their lifetimes. Given the nature of the condition, the healthcare provider should have a high index of suspicion to consider Triple X Syndrome in the differential diagnosis. Often, specialized tests are necessary to confirm the disorder.

Triple X Syndrome is diagnosed on the basis of the following information:

• Complete physical examination and thorough medical history evaluation, including family medical history
• Assessment of the presenting signs and symptoms
• Laboratory tests, as needed, such as electrolyte levels, serum calcium levels, thyroid function test, kidney function test, urine tests, sex hormone studies, etc.
• Radiological studies of the affected regions, as needed; imaging scans of the genitourinary tract is recommended
• Evaluation of heart defects
• Neurological examination that involves the central nervous system (brain and spinal cord)
• Behavioral studies
• Prenatal studies including abdominal ultrasonography: A pregnancy ultrasound may reveal signs and symptoms that are suggestive of a chromosomal or developmental disorder. Following this, additional tests may be conducted, including:
  • Chorionic villus sampling (CVS)
  • Amniocentesis
• Specialized genetic testing techniques are often required to confirm the diagnosis. This may include:
  • Fluorescence in situ hybridization (FISH) testing
  • Array comparative genomic hybridization (array-CGH)
  • DNA sequencing

Often, karyotyping of the chromosome is not adequate to diagnose the condition, since individuals with this condition can have normal karyotype chromosomal studies.

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Triple X Syndrome?

Some of the possible complications of Triple X Syndrome include:

• Emotional stress for parents and caregivers
• Pregnancy complications
• Milestone achievements, such as when the baby rolls, sits, crawls, or walks, may be mildly affected
• In some cases, delays in development could in later life, lead to social problems, poor performance at schools due to learning disabilities, stress, and isolation
• Anxiety issues and depression are commonly noted, including separation anxiety, generalized anxiety, and social avoidance
• In rare occasions, abnormalities of the ovaries (malformation) and kidneys may occur
• Severe heart anomalies
• Sometimes, seizures are observed

Complications may occur with or without treatment, and in some cases, due to treatment also.

How is Triple X Syndrome Treated?

There is no cure for Triple X Syndrome since it is a genetic condition. The treatment is usually given to manage the signs and symptoms and any complication that develops. It also depends on the severity of the signs and symptoms and the body systems affected. Individuals with mild signs and symptoms may require periodic monitoring without significant medical intervention. Any developmental progress concerns or any delayed development as the girl child grows, have to be addressed.

The treatment options for Triple X Syndrome may include:

• Periodic check-ups are recommended to assess the child’s developmental progress
• For feeding difficulties, feed thickeners, including special diets and nutritional supplements may be recommended
• Severe constipation may require dietary changes, including increased intake of fiber and wholegrains, along-with the administration of laxatives
• Seizure control using anticonvulsant medication and vitamin supplements
• Heart abnormalities may require surgical correction in some cases; some defects tend to improve over time
• Speech and language therapy
• Special education needs, especially to help children read and write
• Psychological counseling and providing strategies to cope with learning disabilities may be helpful

A supporting environment with encouragement and positivity can help cope with stress and social problems.

How can Triple X Syndrome be Prevented?

Currently, there are no specific methods or guidelines to prevent Triple X Syndrome genetic condition.

• If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders

What is the Prognosis of Triple X Syndrome? (Outcomes/Resolutions)

• In a majority of Triple X Syndrome cases, the girl child can have a normal quality of life at school, home, and at play
• In most cases, it may be hard to differentiate between females with XX and XXX chromosomes due to the presence of very mild signs and symptoms
• Girls and women who are severely affected may require suitable help and support in order to lead normal lives

Additional and Relevant Useful Information for Triple X Syndrome:

The following DoveMed website link is a useful resource for additional information:

http://www.dovemed.com/diseases-conditions/rare-disorders/