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FRAGILE X SYNDROME

Background
Medical Management Considerations
References
Resources for Families
Advisory Committee
Publication Information

Learning Points

  • Recognize that Fragile X syndrome is the most common inherited cause of mental retardation that is known, and the second most common chromosomal cause of mental retardation (after Down Syndrome).
  • Restate the prevalence of Fragile X Syndrome in males (1 in 3,600) and the prevalence of Fragile X carriers in the general population (1 in 250 women, and 1 in 700 males).
  • Describe general characteristics of Fragile X Syndrome; e.g., physical, developmental, and behavioral characteristics including hyperactivity, language delays, autistic-like features and frequent tantrums.
  • Recognize four physical characteristics features of Fragile X Syndrome: e.g.,
    • Large head
    • Large, or prominent ears often with cupping of pinnae
    • Long face
    • Macro-orchidism
  • Delineate the recommended clinical, behavioral, and psychosocial management considerations for the individual with Fragile X Syndrome in: infancy, early and late childhood, adolescence and adulthood.
  • Refer families to appropriate resources on Fragile X Syndrome.
FRAGILE X SYNDROME VIDEO
This 5 minute video clip describes physical, cognitive, developmental and behavioral characteristics of Fragile X Syndrome.
Credit: National Fragile X Foundation
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BACKGROUND
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Description and Cause

Fragile X syndrome is the most common inherited cause of mental retardation that is known, and it is the second most common chromosomal cause of mental retardation (after Down Syndrome). It is characterized by physical, developmental, and behavioral characteristics including hyperactivity, language delays, autistic-like features and frequent tantrums. Cognitive functioning can range from mild problems in the learning disabled to more severe deficits including autism and severe mental retardation. It is caused by a CGG repeat expansion within the fragile X mental retardation 1 gene (FMR1) that is located at the bottom end of the X chromosome. Those who are significantly affected by fragile X have greater than 200 CGG repeats in the FMR1 gene. Approximately 2-3% of individuals with mental retardation have fragile X syndrome, and approximately 3-6% of individuals diagnosed with autism will turn out to have fragile X syndrome.

Occurrence

The prevalence of fragile X syndrome in males is approximately 1 in 3,600 in the general population. The prevalence in females has not been well studied, but it appears to be similar to the prevalence in males. Carriers of fragile X are usually unaffected cognitively, and they have between 50 to 200 CGG repeats in the FMR1 gene. Older carriers may develop neurological symptoms including fragile x-associated tremor ataxia syndrome (FXTAS) or premature ovarian failure. The prevalence of carriers is approximately 1 in 250 women, and 1 in 700 males in the general population.

Characteristic Features

Note: These features are more distinctive and recognizable in males, and often do not appear until late childhood or early adolescence.

  • Large head
  • Large, or prominent ears often with cupping of pinnae
  • Long face
  • Macro-orchidism (increased testicular volume – usually not seen until puberty)
  • Hypotonia and joint hypermobility
  • Inattention and hyperactivity
  • Language delays and repetitive or perseverative speech
  • Autistic features (poor eye contact, hand flapping, hand biting)
  • Difficulty in adapting to change
  • Mental retardation
  • Developmental delays, including delayed motor milestones in early childhood
  • Anxiety and mood instability sometimes leading to intermittent outbursts

Common Associations

  • Autism
  • Hand biting
  • Mitral valve prolapse
  • Strabismus
  • Serous otitis or recurrent otitis media
  • Dislocated hips
  • Epilepsy/seizure disorders
  • Attention deficit hyperactivity disorder

MEDICAL MANAGEMENT CONSIDERATIONS
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Note: These considerations are in addition to the normal medical care provided to an individual without Fragile X Syndrome. All recommendations can be addressed through clinical examination by the primary care provider, unless otherwise noted.

Infancy (Birth to 1 year)

  • Perform complete physical and neurological exam to detect congenital anomalies
  • Perform FMR1 – DNA test to detect CGG expansion
  • Check for mitral valve prolapse
  • Check for hernias
  • Examine for serous otitis/otitis media
  • Monitor for hypotonia, irritability and seizures
  • Check for strabismus at 6 to 12 months
  • Refer to early intervention programs and Fragile X/disability support groups
  • Provide genetic counseling, including a discussion of recurrence risk and FMR1 DNA testing of at risk relatives
  • Recommend an oral health assessment by age 1
  • Discuss possibility of SSI enrollment

Early Childhood (1 to 5 years)

  • Monitor closely for recurrent otitis media including hearing testing
  • Refer to ENT for PE tube placement if recurring otitis or hearing loss is present
  • Examine for inguinal hernias at 1 to 3 years
  • Check eyes for strabismus, myopia, ptosis and nystagmus
  • Check for flat feet, scoliosis and loose joints
  • Assess history of seizures
  • Assess motor and language development
  • Recommend and arrange for dental care (note: children with congenital heart disease should receive antimicrobial prophylaxis before dental procedures)
  • Check for hyperactive behavior, head banging and hand biting; refer to appropriate mental health provider for behavior modification therapy or management with psychotropic medication as needed

Late Childhood (5 to 13 years)

  • Assess history of seizures
  • Monitor for decrease in intellectual performance
  • Reassure that macro-orchidism has no relation to sexual function or puberty
  • Monitor speech and language progress
  • Assess self-care skills
  • Monitor school progress
  • Emphasize importance of educational techniques like small classes; visual learning; individualized attention; and speech and occupational therapy
  • Counsel about potential behavioral health problems like aggression; refer to appropriate mental health provider as needed
  • Consider use of stimulants to treat ADHD (see Hagerman 1999, and Tranfaglia 1996 below for more information)

Adolescence and Adulthood (13 years and over)

  • Assess for seizures
  • Reassure that macro-orchidism has no relation to sexual function or puberty
  • Monitor for decrease in intellectual performance
  • Monitor behavior and mental health
  • Recommend the establishment of and communication about an oral health care prevention plan
  • Reinforce importance of self-care skills
  • Discuss long-term financial plans
  • Discuss alternative community living resources
  • Monitor prevocational training and vocational activities
  • Discuss community-supported employment opportunities

REFERENCES
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Peer-reviewed Journal Articles/Academies

American Academy of Pediatrics. (1996). Health Supervision for Children With Fragile X Syndrome. Pediatrics, 98(2), 297-300.

Hatton D, Bailey DB, Roberts JP, Skinner M, Mayhew L, Duffee Clark R, Waring E, Roberts JE. (2000). Early Intervention Services for Young Boys with Fragile X Syndrome,Journal of Early Intervention, 23, 235-251.

Hagerman RJ, Hagerman PJ. (2001). Fragile X Syndrome: A Model of Gene-Brain-Behavior Relationships. Molecular Genetics & Metabolism, 74, 89-97.

Hagerman, RJ. Hagerman PJ. (2004). The Fragile X Premutaiton: a Maturing Perspective. American Journal of Human Genetics, 74(5), 805-816.

Hagerman RJ, Hagerman PJ, (2002). Fragile X Syndrome: Diagnosis, Treatment, and Research, 3rd Edition. Baltimore: The Johns Hopkins University Press.

Special Interest Groups/Other Publications

Braden ML. (2000). Fragile, Handle with Care: More About Fragile X Syndrome, Adolescents and Adults. Dillon, CO: Spectra Publishing Co.

Capute, Arnold J. and Pasquale J. Accardo. (1996). Developmental Disabilities in Infancy and Childhood vol I: Neurodevelopmental Diagnosis and Treatment. Baltimore: Paul H. Brookes Publishing Co., Inc.

Capute, Arnold J. and Pasquale J. Accardo. (1996). Developmental Disabilities in Infancy and Childhood vol II: The Spectrum of Developmental Disabilities. Baltimore: Paul H. Brookes Publishing Co., Inc.

GeneCare Medical Genetics Center. Fragile X DNA Testing. Accessed December 13, 2005.

Hagerman RJ (1999).Fragile X Syndrome: Diagnosis and Biochemistry and Intervention. InHagerman RJ., Neurodevelopmental Disorders: Diagnosis and Treatment (pp 61-132). New York: Oxford University Press.

Tranfaglia MR. (1996) A parent’s guide to drug treatment of fragile X syndrome. FRAXA Research Foundation. West Newbury, MA.

Weber, J.D. (1994) Transitioning Special Children into Elementary School. Books Beyond Borders, Inc., 1881 4th St. #108, Boulder, CO 80302.

RESOURCES FOR FAMILIES
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National Fragile X Foundation
800-688-8765

FRAXA Research Foundation
978-462-1866

California Department of Developmental Services
916-654-1690

California Regional Centers
916-654-1958

Exceptional Parent Magazine
800-247-8080

March of Dimes Birth Defects Foundation
914-428-7100

ADVISORY COMMITTEE
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Theodore A. Kastner, M.D., M.S.
Felice Weber Parisi, M.D., M.P.H.
Randi J. Hagerman, M.D.
Patrick J. Maher, M.D.
Mary B. Tierney, M.D.

PUBLICATION INFORMATION
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This document does not provide advice regarding medical diagnosis or treatment for any individual case, and any opinions or statements contained in this document are not intended to serve as a standard of medical care. Physicians are encouraged to view the considerations presented in this document in light of evolving scientific information. This document is not intended for use by the layperson. Reproduction of this document may be done with proper credit given to California Department of Developmental Services.