NHS Evidence

The Least You Need to Know
Coffee Break Summary
Pitfalls to Avoid
Find Out More
Clinical Scenarios

The Least You Need to Know

• The features are very variable and therefore no predictions can be made regarding symptoms.  There are no physical features apart from tall stature.
• It may be asymptomatic and diagnosed incidentally
• There is an increased incidence of motor and cognitive impairment, and psychological problems
• Fertility of affected females is normal
• There is a slight increased risk of offspring with chromosomal abnormalities
• Trisomy X usually is not inherited, but occurs as a random event during the formation of reproductive cells (eggs and sperm)

Coffee Break Summary

 Definition:  Chromosomal abnormality affecting only females, due to the presence of an extra X chromosome.

Synonyms: Trisomy X , 47,XXX, Triple-X syndrome, XXX syndrome .

1.      Overview

Sex Chromosome abnormalities are the most frequent chromosomal abnormality found during prenatal diagnosis.   Triple X syndrome affects approximately 1 in 1000 females, and is due to the presence of an extra X chromosome.  There is no physical phenotype but girls tend to be taller than average.  It is often diagnosed incidentally due to investigations for other causes.  It is under diagnosed due to many females being asymptomatic.  Those who do have symptoms are affected by cognitive and motor delay as well as psychological problems.  The IQ may be ten to fifteen points lower than their siblings.  Adult adaptation tends to be normal with independent living.  It has been shown that those diagnosed antenatally tend to have a better prognosis, and that a supportive and loving environment is beneficial.

2.   Inheritance

47,XXX occurs sporadically.  As with other chromosomal abnormalities there is an increased incidence with increasing maternal age.  Although there is some evidence to suggest that those with 47,XXX have an increased risk of having offspring with chromosomal abnormalities, mothers with 47,XXX do not usually have children with the same chromosome complement.

3.        Features – signs, symptoms and complications

The perinatal period may be complicated by hypotonia and weight may initially be lower than average.  Following this there is a growth spurt until the age of approximately eight years, resulting in a taller than average final height. 

The condition is often asymptomatic. Those with features, whilst looking physically normal, may have delays in the cognitive and motor development.  There may be problems with co-ordination and IQ may be a little lower than their siblings. 

There may be associated psychological problems which can result in behavioural problems including conduct disorders and a risk of social isolation.

Delayed motor development is the most obvious problem during infancy followed by delayed speech and language development.

There has been some evidence of early menopause although long term follow up studies are needed to confirm this, otherwise fertility is normal.

4.      Diagnosis

a.      Differential diagnosis

Diagnosis is based on cytogenetic analysis of the karyotype and therefore diagnosis is not in question.

b.      Diagnostic testing

Diagnosis is based on the existence of an extra X chromosome on cytogenetic analysis.  Samples can be taken antenatally (amniocentesis or chorionic villus sampling), or post-natally from blood.

Mosaic forms also exist where only a proportion of cells contain an extra X chromosome.

It is often an incidental finding when investigating for other reasons, such as behavioural problems or learning difficulties. Due to the variability of the features, many are never diagnosed. 

It is commonly diagnosed antenatally during screening for other chromosomal abnormalities such as trisomy 21 (Down syndrome) or for increased maternal age.

5.      Management

a.      Genetic counselling

Genetic counselling can be difficult.  Many cases referred are identified during antenatal screening for more serious disorders.  No definite prognosis can be given and there is a limited amount of information in the literature.  This creates a significant dilemma for parents when making decisions regarding the pregnancy. 

Prenatal testing can be offered to women with the triple X syndrome due to the increased incidence of chromosomal abnormalities in their offspring.

                        b.   Treatment/Follow up

No intervention is required at birth is normal, although there may be hypotonia. 

During infancy developmental milestones should be assessed as per standard protocol, intervention only being instigated if necessary.

School performance should be monitored.

Referrals should only be made if necessary, these may include Child Development Unit, Educational/Clinical Psychologist.

There is increasing evidence that a loving and supportive environment is beneficial.  It has also been shown that those diagnosed antenatally tend to have a better outcome.  It is thought this may be due to the children being treated and encouraged appropriately, rather than being regarded as a ‘problem child’.

There is no increased risk of other pathology.

Further Reading:

Linden M, Bender B, Harmon R, Mrazek D, Robinson A.  ‘47XXX. What is the prognosis?’  Pediatrics 82(4); October 1988

Linden M, Bender B.  ‘51 pre-natally diagnosed children and adolescents with sex chromosome abnormalities’.  American Journal of Medical Genetics 110; pp 11-18

Bender BG, Harman RJ, Linden MG, Robinson A.  ‘Psychological adaptation of 39 adolescents with sex chromosome abnormalities’.  Pediatrics Aug 1995, 96(2 pt 1), pp 302-308

Linden MG, Bender BG, Robinson A.  ‘Genetic Counseling for sex chromosome abnormalities’.  American Journal of Medical Genetics June 1, 2002, 110(1), pp 3-10

Radcliffe S Long-term outcome in children of sex chromosome abnormalities. Archives of Disease in Childhood 1999; 80(2): 192-5

Web Resources:

Triple X support group (UK):
http://triplexsupportgroup.homestead.com/TripleXWebPage.html

Triple X support group (US): http://www.triplo-x.org/

Contact a family support group: http://www.cafamily.org.uk/

Online Mendelian Inheritance in Man (OMIM): http://www.ncbi.nlm.nih.gov/omim/

Scenario 1

Mrs A is 38 years old and has had an amniocentesis on the basis of her age.  Antenatal serum screening and ultrasound scanning have been normal, and therefore she is not unduly concerned.  She has two other healthy children.  She is aware that amniocentesis is to look at the baby’s chromosomes, for conditions such as Down syndrome.

You are asked to see Mrs A and her husband as her amniocentesis shows a female karyotype with an extra X chromosome.  She is very upset and was unprepared for such a finding.  She has briefly been,  told by the attending midwife, what this means and is aware that it is less severe than Down syndrome, for which she would have had a termination.  Her husband has looked on the internet and found information from studies carried out over twenty years ago.  They are very concerned to learn that these girls have antisocial behaviour and significant learning difficulties, many of whom have been institutionalised. 

You need to make the difference between a condition such as Down syndrome and a sex chromosome anomaly clear.  Explain that there is no physical phenotype, apart from tall stature, and therefore the child will not be physically recognisable as having a chromosome abnormality. 

Explain that the early research was biased by researchers specifically studying females with behavioural and learning problems.  There are many women with an extra X chromosome who were diagnosed incidentally or who are not diagnosed at all due to a lack of problems. 

Whilst it is impossible to predict what problems their child may have it is known that those born into a supportive and encouraging environment do much better.  In this way being diagnosed antenatally is an advantage. 

Girls with 47,XXX may do less well than their siblings, with an IQ approximately ten to fifteen points lower, they are independent as adults but are in danger of becoming socially isolated, hence the importance of strong emotional support.

Offer to see the child soon after delivery for reassurance, and explain intervention will only occur if necessary.  There is no evidence of any risks to the child with respect to other pathology.