Fragile X Syndrome: Resources for Pediatric Clinicians

​Fragile X Syndrome: Resources for Pediatric Clinicians

​Fragile X syndrome (FXS) is an identifiable genetic disorder that is one of the more common inherited causes of intellectual disability. FXS and other fragile X-associated disorders are caused by mutations in the Fragile X Mental Retardation 1 gene (FMR1), also known as the fragile X gene.  Females with FXS do not typically show any physical characteristics.  Males with FXS can exhibit tall stature, macrocephaly, long face, large ears, and macroorchidism; however these features are unusual in early childhood, often emerging after puberty, and are not seen in all individuals.  Due to the difficulties in recognizing FXS in the young child, any child with unexplained developmental delay, intellectual disability, and/or autism spectrum disorder should be tested for FXS.

Historically, testing for FXS was done with cell culture using an agent that provoked the expression of the "fragile" site on the X chromosome (the tip of the chromosome appeared bent or broken under the microscope).  This testing was less reliable than the current testing, which uses DNA analysis to discern the number of CGG repeats (a pattern of DNA) in the FMR1 gene.  The normal number of triplet repeats is 5-44, and a full mutation in the FMR1 gene is >200 repeats.  Males carrying full mutations are usually affected with FXS.  Females are variably affected.  Those with repeat numbers of 55-200 have a "premutation" which is unstable and prone to expand further into the full mutation range.  Premutation carriers may have Fragile X Tremor-Ataxia syndrome (FXTAS) and primary ovarian insufficiency (POI).  Repeat numbers of 45-54 are a "grey zone" which don't cause disease but could expand in subsequent generations to the premutation range.

Support for Patients and Families

Pediatricians can support early identification and evaluation, which helps to empower families to make informed decisions about FXS-specific services for their child, as well as family planning. A diagnosis also helps assess comorbidities and associated conditions. Following are ways pediatricians can improve early identification of FXS and other fragile X-associated disorders:

  • Ensure that all children with developmental delay, intellectual disability, and/or autism spectrum disorder are considered for a genetic evaluation. The only way to confirm a FXS diagnosis is with the FMR1 DNA Test for Fragile X.

  • Use a health history tool to evaluate for a family history of related problems that can be seen in fragile X-associated disorders.

    • A history of ataxia or "Parkinson-like" tremors in older males and some females on the maternal side, which could indicate FXTAS

    • A history of early menopause or fertility problems on the maternal side, which could indicate premature ovarian failure (POF)

Fragile X Myth Busters

There are many myths associated with FXS that can contribute to a delayed or missed diagnosis. Here are some of the more common myths:

    Myth: There is no value in making a diagnosis of FXS if there is no cure.

    Fact: Although currently there is no cure for FXS, there are important supportive treatments that can be applied once the diagnosis is known. These include educational and therapeutic approaches tailored to individual strengths and weaknesses, screening for and treatment of medical issues, and behavioral treatment methods.  Having a diagnosis also enables families to receive counseling for family planning, participate in clinical research if desired, and connect with support groups of other families affected by FXS.

    Myth: All FXS patients can be recognized by their unusual physical features

    Fact: Individuals with FXS may have dysmorphic features like prominent ears, a long, narrow face, and large testes after puberty, but many children do not have any characteristic features. While some physical features may be seen in younger boys, most do not become evident until puberty, and girls do not have an unusual appearance.

    Myth: Girls cannot have FXS, and boys with FXS are always severely affected.

    Fact: Both girls and boys can have FXS. Symptoms are usually more severe in boys, but both boys and girls can exhibit symptoms ranging from normal functioning to severe intellectual disability.

    MYTH: FXS is diagnosed using a chromosome test or microarray.

    Fact: FXS cannot be detected with a standard chromosome test or microarray. A specific test called the "FMR1 DNA Test for Fragile X (Fragile X DNA analysis)" must be ordered.

    Myth: There has to be a family history of FXS for a child to have the condition.

    ​Fact: Because the FXS mutation is an expanding mutation that can become bigger when passed on to the next generation, diagnosed individuals may lack a recognized family history of FXS. However, a family history of other fragile X-associated disorders, such as tremors and early menopause, can be an indication that a child with unexplained developmental delay, intellectual disability or autism has these features because of unrecognized FXS in the family.

Applicable AAP Policies

Health Supervision for Children with Fragile X Syndrome (Pediatrics, May 2011) summarizes issues associated with FXS regarding clinical diagnosis, laboratory diagnosis, genetic counseling, related health problems, behavior management, and age-related health supervision guidelines.

Comprehensive Evaluation of the Child with Intellectual Disability or Global Developmental Delays (Pediatrics, September 2014) is based on a review of published reports and describes the recommended clinical genetics diagnostic approach, the importance of co-management among families, the medical home, and the clinical genetics specialty clinic.

Ethical and Policy Issues in Genetic Testing and Screening of Children (Pediatrics, March 2013) includes overall genetic testing and screening recommendations from the American Academy of Pediatrics and the American College of Medical Genetics and Genomics.

Identification and Evaluation of Children With Autism Spectrum Disorders (Pediatrics, November 2007) indicates that FXS is the most common cause of autism and that as many as 50% of FXS patients display autism spectrum disorder characteristics.

The Individuals With Disabilities Education Act (IDEA) for Children With Special Educational Needs (Pediatrics, December 2015) provides important information about supporting the development and learning of disabled children in a school environment. 

Early Intervention, IDEA Part C Services, and the Medical Home: Collaboration for Best Practice and Best Outcomes (Pediatrics, October 2013) describes the many common purposes of early intervention services, IDEA, and the medical home.

Recognition and Management of Medical Complexity (Pediatrics, December 2016) defines the population of children with medical complexity and provides strategies to optimize health and medical outcomes.  

Supporting the Health Care Transition From Adolescence to Adulthood in the Medical Home (Pediatrics, July 2011) represents expert opinion and consensus on the practice-based implementation of health care transition for all youth beginning in early adolescence.

The content on this page was supported by the Cooperative Agreement Number 5 U38 OT000167, funded by the Centers for Disease Control and Prevention. Its contents are solely the responsibility of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention or the Department of Health and Human Services. 

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