Fragile X syndrome
Fragile X syndrome (FXS) is now the most common known inherited cause of developmental disabilities, but was
not discovered until the late 1970s. By 1980 it was found that people showing certain mental and physical
characteristics had a chromosomal abnormality caused by a partial break on an X chromosome, called a "fragile site".
In 1991 the Fragile X gene was identified within this site.
FXS is named after a site on the long arm of the X chromosome that is elongated and appears partly broken or 'fragile'. The spectrum of Fragile X syndrome ranges from normal development to developmental delay, learning disabilities, mild to severe intellectual disability, autistic-like behaviour and attention problems. The majority of children are mildly to moderately affected. There may or may not be other known affected family members. Genetic testing has changed the approach to the diagnosis of the condition because there is now a reliable and relatively simple blood detection test which is available to all children with developmental delay of unknown cause.
The diagnosis of FXS is important to implement effective management and interventional strategies. Detection of carriers allows families to make informed decisions following genetic counseling.
Estimates suggest about 1 in 4,000 males are affected and that about 1 in 1,000 females carry the gene. Many affected family members are unaware of the genetic cause and have yet to be diagnosed. In comparison, 1 in 700 live births has Down's syndrome (which is not usually inherited).
The Fragile X syndrome
The clinical features of Fragile X syndrome include physical, developmental and behavioural characteristics and range from normal through mild to severe in presentation. Intellectual disability (IQ less than 70) is present in 80% of males and 50% of females. Children may have been labeled as having pervasive developmental disorder, Asperger's syndrome, autistic spectrum disorder, learning disability or developmental delay.
Developmental delay of different audiology, hearing loss, autism and autism-like behaviours.
Physical, Developmental and Behavioural Characteristics
Dysmorphic features are variable in both males and females and are not always present. The classic features include:
- Elongated face with prominent jaw, which is more obvious after puberty.
- Prominent, large ears.
- High arched palate.
- Large testicles, which are mainly seen after puberty.
- Recurrent ear infections.
- Connective tissue problems, such as flat feet, loose joints, congenital hip dislocation, scoliosis.
- Mitral valve prolapse.
- Seizures, including 'absences' or petit mal.
- Eye problems, such as strabismus or squint.
Remember, normal physical features may disguise the diagnosis.
- Intellectual disability in approximately 80% of males and up to 50% of females.
- Speech delay.
- Learning disabilities, may be subtle.
- Fine and gross motor delay.
- Coordination difficulties.
- Attention deficit in at least 80%, may be without hyperactivity.
- Autistic-like features (e.g.. hand flapping and biting, gaze aversion, preoccupation with objects).
- Difficulty adjusting to change.
- Social anxiety.
- Jocular, litanic speech.
- Speech perseveration and echolalia (repetition of words or phrases).
- Anxiety / hyperarousal.
- Sensory defensiveness (aversion to loud noise, touch, strong smells, eye contact).
- Mood instability with aggression, depression (particularly in adolescence).
These behaviours tend to moderate as the child grows older.
A speech problem is often one of the earliest presenting features and is very common in males. A characteristic speech pattern is often present with a narrative style, perseveration and echolalia. The child may skip rapidly from topic to topic while in conversation.
How is FXS Diagnosed?
Testing should be considered for anyone with
- Intellectual disability (borderline to severe), developmental delay or learning disabilities of unknown cause, no matter how subtle.
- Autism or autism-like characteristics.
- A family history of FXS or undiagnosed intellectual disability.
- A previous fragile X cytogenetic test result that was positive or inconclusive.
The diagnosis of Fragile X syndrome is made on a blood sample tested for analysis of the FMR1 gene. This DNA testing has been available since 1991 to detect Fragile X in normal carriers (male and female) and in affected children. This test cannot determine the degree of intellectual disability. DNA testing can only be done in special laboratories on referral from a clinical geneticist, a pediatrician or a general practitioner. A referral to a pediatrician with expertise in developmental and behavioural problems or a geneticist should be considered as other or concurrent conditions may need to be excluded. If the test is positive, the pediatrician may refer the family for genetic counseling. All relatives who are at risk and would like to know whether they are carriers, may be tested.
Parents who have children with Fragile X syndrome may be concerned about the likelihood that future children may also be affected. Prenatal diagnosis is available via chorionic villus biopsy at 9-10 weeks of pregnancy, to women known to be Fragile X carriers: DNA analysis is performed on the biopsy material and if the foetus is affected, the option of therapeutic abortion may be considered. Genetic counseling is best provided by specialists in the field.
Fragile X is due to an abnormality, involving a single gene called the FMR-1.
This gene is situated on the X chromosome. The abnormality is now known to be the result of
an increase in size ('expansion') of part of the gene. Male and female carriers who are
unaffected only have a small expansion, males and females who are affected have a much
Once the gene is above a certain size it 'switches' off production of a protein FMRP, which results in an affected individual. People who have the 'mosaic' form are partly affected individuals, who produce this protein in some but not all tissue.
Every child receives an X chromosome from the mother and either an X
or a Y from the father (to produce a girl or boy respectively).
Because a mother with a small 'expansion' of part of the gene can have a child with a large 'expansion', there can be a progressive increase in the severity of the condition in successive generations. This also explains how an affected child can come from an unaffected family. There can be males with smaller expansion of the gene who are phenotypically normal, known as 'normal transmitting males'.
Once the diagnosis of Fragile X syndrome has been made, a multidisciplinary
approach involving parents, genetic services, pediatricians, speech pathologists, special
educators, occupational therapists and psychologists is preferred. The child's level of
cognitive functioning should be assessed so as to offer appropriate educational strategies
based on the child's strengths. These assessments can support an application for the Child
Disability Allowance. Language delay is the most commonly experienced delay and speech
therapy is indicated. Early intervention professionals may be involved in assisting parents
to understand the child's developmental delay.
Although there is no cure for FXS, many intervention strategies have been shown to be beneficial in managing the multifaceted problems so common for this syndrome.
Suggested Educational Strategies
Children with FXS attending school either in mainstream and special
settings require an individual education plan (IEP) to be written with input of all
those involved with the child.
Overall, the child needs a stable environment which provides:
- Structured activities that are predictable and practical.
- Work practices suitable for a short attention span.
- Minimal auditory and visual distractions.
- Establishment of classroom routines and keeping the child informed of proposed changes.
- Establishment of regular communication between parent and school.
Pre-school and school teachers need to be involved together at transition times to prepare an appropriate educational program for the child.
The strengths in the child's schoolwork need to be highlighted both with the child and parents.
- FXS children learn best with visual methods, whole word, number and pattern recognition (preferably with picture); simultaneous processors - 'gestalt' learning rather than sequential approach.
- Strong imitation skills - pair them with a 'buddy'.
- Strong functional life skills.
- Poor auditory short-term memory.
- Difficulty with phonic method of learning to read.
- Difficulty with abstract thought (extends through life).
- Difficulty with maths / arithmetic, grammar.
- Sensory defensiveness (to touch, noise, bright light).
Suggested Home Strategies
- Establishment of structure, regular routines and predictable activities.
- Establishment of regular communication between parents and school and all people involved with the child.
- Firm, consistent discipline is necessary as it is for all children with developmental delay.
- Behaviour management strategies should be carried out consistently by all people involved with the child.
- Normal health surveillance is important for all children including children with Fragile X.
Additional support in the home may be needed for some families in times of family stress.
A variety of medications have been used for the treatment of associated conditions, including attentional deficits and aggression.
Parents need an ongoing relationship with a number of primary care professionals to access information about the condition and to talk through concerns, educational interventions and the child's future placement. The importance of medical management for health surveillance and pharmacological intervention in conjunction with other supportive services must be stressed.
Genetic counselors can advise about the genetics of the condition and implications for other family members. They offer ongoing support prior to testing, during and after decisions have been taken and offer ongoing follow-up face to face or by telephone. It is known that families go through the stages of feeling stigmatised, estranged and isolated and may exhibit poor self-esteem and self-image. As with any perceived loss, family members will tend to go through a range of feelings including guilt, anger, grief and denial. These feelings will also tend to reappear as the affected individual moves through the different life stages. Support systems need to be identified and encouraged, as there is an ongoing need for monitoring and support.
As the condition is present throughout life, the outcomes depend on the level of functioning of the child and their ability to live independently in the community. Many people with the condition are employed, live independently and make informed decisions about having a family. Others may need day-to-day support, work in day activity centres, be on a disability pension and live in supported accommodation or at home.
Fragile X is one of the most miss-understood syndromes, as they display very familiar charitistics as the many that display ADHD - Fragile X is a deficit on its own, so very careful assessments are needed to identify this particular disorder.
- Finuacane B. Fragile X syndrome-A Handbook for Families and Professionals. The National Fragile X Foundation, 1993.
- Hagerman R., Amery C., and Kronister A. Fragile X checklist. The American Journal of Medical Genetics, 1991, 38. 283- 287.
- Hagerman R.J., and Cronister, A. (eds). Fragile X syndrome: Diagnosis, Treatment and Research. John Hopkins University Press, 2nd ed, 1996.
- American Academy of Pediatrics. Health Supervision for Children with Fragile X syndrome . Pediatrics, 98 (2): August 1996