Fragile X Syndrome
Swati Kolpuru (Gadewar)
Consultant Pediatrician, USA
First Created: 12/31/2013 

Introduction

Fragile X syndrome is a common cause of mental retardation. The incidence has been estimated at approximately 1 in 1,500 males and 1 in 2,500 females.

Genetics

Mutation of a gene on the long arm of the X chromosome is responsible for FXS and involves instability of trinucleotide repeat sequence. Normally there are 6 to 50 repeats, but with the mutation, the repetition sequence begins to expand and may increase from generation to generation eventually making this region unstable. When there are more than 200 repetitions, the fragile X mental retardation-I gene at Xq27.3 becomes hypermethylated and is inactive. This affects the gene product, the FMR-I protein, which is responsible to cause the physical, behavioral, and cognitive aspects of the fragile X syndrome. A premutation carrier state exists when there are 50 to 200 repetitions of the CGG trinucleotide. The gene remains unmethylated in the premutation state and normal production of the FMR-I protein occurs.

Inheritance

Fragile X syndrome has an unusual inheritance pattern. There is no increase in repetition size with the transmission of premutations from males to their daughters; daughters usually have similar premutation sizes and are not affected. The instability and expansion of the premutation occur when females pass the gene on to the offspring.

The risk of expansion to a full mutation increases with the size of the premutation, as it expands from generation to generation. When the repeat size is greater than 90, the risk of expansion to a full mutation is almost 100 percent when a mother transmits the gene to her children.

Clinical Manifestations


PHENOTYPENEUROCOGNITIVE
Large earsMental retardation
Large testes (testicular volume >30 ml in adults)Hyperactivity
Plantar creaseAttentional problems
Hyperextensible jointsLanguage delays
Simian creaseHand flapping
Broad foreheadHand bitingIrritability
Increased hand widthIncreased hand lengthPerseveration
Elongated faceExcessive temper tantrums
High arched palateGaze avoidance
Mitral valve prolapseSensory aversion
HypotoniaHerniaSelf-stimulatory behavior
Double jointed thumbsAutism
Scoliosis

Flat feet

Fragile X Syndrome In Females

The phenotype can vary from having no craniofacial features to having all features in males and variable intellectual involvement ranging from normal intellectual functioning to profound mental retardation.

Diagnosis

DNA-analysis of the FMR-I gene is the best way to diagnose which is usually done on lymphocytes. Buccal smears can also be used.

Who should be Tested?

  • Individuals seeking reproductive counseling who have a family history of fragile X syndrome or a family history of undiagnosed mental retardation.

  • Prenatally, if the mother is known to be a carrier.

  • Any child with mental retardation, autism, hyperactivity in addition to a cognitive defect, language delay, previously diagnosed with Sotos' syndrome, Asperger's syndrome, and Pierre Robin sequence, selective mutism, schizotypal personality disorder, a pervasive developmental disorder.

Treatment

Presently no cure is available for Fragile X syndrome. However, a variety of interventions are available. But now with the Human Genome Project, it is not long that gene therapy or protein replacement therapy may become a reality. A team approach is always needed for better care and it usually includes a special education teacher, a speech and language pathologist, an occupational therapist, and a genetic counselor.

Genetic Counselling

Having a child with a genetic disease has many social and psychological issues. Feelings of blame, guilt, embarrassment, and stigmatization are commonly experienced. The role of the genetic counselor is to help families adjust and cope with the stresses of having a child with Fragile X Syndrome. This can be accomplished by

  • Educating them by presenting medical information about diagnosis and prognosis

  • Reviewing the inheritance and recurrence risks since Fragile X syndrome is inherited.

  • Discussing family planning options

  • Help families make informed decisions regarding treatment, management, and testing by educating them and providing emotional support.

  • DNA testing of the mother to find her degree of involvement with the Fragile X syndrome, particularly if she has learning or behavioral problems.

  • Prenatal diagnosis in future pregnancies

In Infancy

Infants with Fragile X syndrome are usually identified if there is a previous affected member in the family. The newly diagnosed infant should be closely examined for the following problems:

Connective tissue problems: There is an increased risk of following in an infant with Fragile X syndrome due to an underlying connective tissue disorder:

  • Clubfoot

  • Congenital hip dislocation

  • Hernia

Routine intervention should be undertaken.

Sudden infant death syndrome:
There is an increased incidence of SIDS in these patients. Episodes of apnea, snoring or a seizure require a detailed investigation and subsequent careful monitoring.

Gastrointestinal problems:
Although many babies with Fragile X syndrome do well in the newborn period some of them may have problems with feeding. Recurrent vomiting with feeding is not uncommon. Gastroesophageal reflux may be present because of underlying connective tissue abnormality.

Treatment of GER:

  • Positioning upright after meals

  • Thickening of the feeds
  • Medication

  • Surgery if not controlled with medication

Otitis media:
Frequent otitis media begins in the first year of life and is a problem for approximately 40-60% of boys. The cause of this predisposition is not known. The suggested hypothesis is:

  • The facial structure, including a long face and a high-arched palate, may affect the angle of the eustachian tube, which would also affect drainage

  • The connective tissue dysplasia and hypotonia may lead to a collapsible eustachian tube, which would also affect drainage

  • Possibility of transient hypogammaglobulinemia

Recurrent otitis media can lead to hearing loss and subsequent language and articulation deficits. It is therefore imperative that children with Fragile X syndrome be vigorously monitored and treated for otitis media with pressure-equalization tube placement or prophylactic antibiotics to avoid further damage to language development than what already occurs with this syndrome.

Toddler Period

Developmental Delay:
Language development is almost always delayed. If language delays, articulation problems, or unusual characteristics such as cluttering, echolalia, or stuttering develop, the child should be referred to a speech therapist.

Formal developmental tests, such as the Bayley Scales of Infant development should be done as it allows the physician to monitor progress and focus on areas of delay.

Motor Problems:
Motor problems and hypotonia are common and continued therapy with an occupational therapist is recommended.

Behavioral problems:
Problems noted in the second and third years include temper tantrums, eating problems, and sleeping difficulties. Basic principles of child-rearing and discipline should be discussed with the parents. If problems arise, referral to therapists should be made who can teach appropriate behavioral modification techniques to the parents. Folic acid therapy can be considered.

Preschool

Seizures:
Children with Fragile X syndrome have a risk of seizure disorder. Hence a history for possible seizures must be taken. If such a history is present, an electroencephalogram should be done and the child should be started on seizure medications.

Ophthalmologic problems:
An ophthalmologic examination should be done because strabismus or other difficulties including ptosis, nystagmus, and myopia can occur. Amblyopia is common if the ophthalmologic problems, particularly strabismus, are not treated early.

Management of behavioral, language, and motor problems should be continued.

School Age

Attention deficit hyperactivity disorder:
The assessment and treatment of attention deficit hyperactivity is important in this age group. A detailed history should be taken and behavior should be monitored. Successful treatment includes behavioral management, special education, individual therapies, and pharmacotherapy

Connective tissue dysplasia:
Signs of connective tissue dysplasia that are evident at this age are:

  • Scoliosis

  • Flat feet

  • Hernias

  • Mitral valve prolapse

Scoliosis:
The child should be referred to an orthopedist because the progression of scoliosis may require treatment.

Mitral valve prolapse:
Careful physical examination should be done on every child with Fragile X syndrome. If mitral valve prolapse is detected, echocardiography should be done. The child should be given prophylaxis for subacute bacterial endocarditis for procedures that may be contaminated by endogenous bacteria.

Speech and language and occupational intervention should be continued.

Adolescence

Transition into adulthood:
The transition into adulthood is particularly difficult because of learning disability. The cognitive abilities may prevent independent living and supervision is necessary. Vocational training should be given. Special education approaches that use a person's strength, particularly with imitation, visual skills, and computers, can enhance the educational experience of children with this syndrome.

Behavioral problems:
Aggressive behavior is a common problem and it requires a thorough medical and environmental assessment. Counseling and medication may be helpful.

Sexuality:
Masturbation and other forms of self-stimulatory behavior are common. Fertility is usually normal in men with Fragile X syndrome. Sex education and genetic counseling should be given to them. Mildly retarded individuals will require support in parenting.

PROGNOSIS:
The life span is normal. Integration into society depends upon the degree of intellectual impairment.


Fragile X Syndrome Fragile X Syndrome 12/31/2013
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