National Center for Advancing and Translational Sciences Genetic and Rare Diseases Information Center, a program of the National Center for Advancing and Translational Sciences

Fragile XE syndrome


Other Names:
FRAXE syndrome; Fragile site, folic acid type; X-linked mental retardation associated with fragile site FRAXE
Categories:
Fragile XE syndrome (FRAXE) is a genetic condition associated with mild to borderline intellectual disabilities with physical features differing from person to person. The characteristic features are learning difficulties, often a consequence of communication problems (speech delay, poor writing skills), hyperactivity, and a shortened attention span. Nearly all cases of FRAXE are caused by a specific type of mutation, called a trinucleotide repeat expansion, in the AFF2 gene, which is located on the X chromosome. A trinucleotide repeat expansion occurs when there is an abnormally large number of repeats of a specific sequence of three nucleotides (building block of DNA) within our DNA. The repeating nucleotides in FRAXE syndrome are CCG. When the number of CCG repeats is over 200, people typically have the signs and symptoms seen in FRAXE. FRAXE is inherited in an X-linked manner.[1][2][3] Although there is no specific treatment for FRAXE, there may be ways to manage the symptoms. A team of doctors or specialists is often needed to figure out the treatment options for each person.
Last updated: 9/9/2016

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

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Medical Terms Other Names
Learn More:
HPO ID
30%-79% of people have these symptoms
Aggressive behavior
Aggression
Aggressive behaviour
Aggressiveness
[ more ] 		0000718
Agitation 0000713
Autistic behavior 0000729
Clumsiness 0002312
Delayed speech and language development
Deficiency of speech development
Delayed language development
Delayed speech
Delayed speech acquisition
Delayed speech development
Impaired speech and language development
Impaired speech development
Language delay
Language delayed
Language development deficit
Late-onset speech development
Poor language development
Speech and language delay
Speech and language difficulties
Speech delay
[ more ] 		0000750
Epicanthus
Eye folds
Prominent eye folds
[ more ] 		0000286
Hoarse voice
Hoarseness
Husky voice
[ more ] 		0001609
Hyperactivity
More active than typical
0000752
Impulsivity
Impulsive
0100710
Intellectual disability
Mental deficiency
Mental retardation
Mental retardation, nonspecific
Mental-retardation
[ more ] 		0001249
Intrauterine growth retardation
Prenatal growth deficiency
Prenatal growth retardation
[ more ] 		0001511
Obsessive-compulsive behavior
Obsessive compulsive behavior
0000722
Prominent ear helix 0009904
Prominent nasal bridge
Elevated nasal bridge
High nasal bridge
Prominent bridge of nose
Prominent nasal root
Protruding bridge of nose
Protruding nasal bridge
[ more ] 		0000426
Recurrent hand flapping 0100023
Short stature
Decreased body height
Small stature
[ more ] 		0004322
Specific learning disability 0001328
Thick vermilion border
Full lips
Increased volume of lip
Plump lips
Prominent lips
Thick lips
[ more ] 		0012471
5%-29% of people have these symptoms
Clinodactyly of the 5th finger
Permanent curving of the pinkie finger
0004209
Macrocephaly
Increased size of skull
Large head
Large head circumference
[ more ] 		0000256
Stereotypical body rocking 0012172
Percent of people who have these symptoms is not available through HPO
Abnormality of metabolism/homeostasis
Laboratory abnormality
Metabolism abnormality
[ more ] 		0001939
X-linked inheritance 0001417
X-linked recessive inheritance 0001419
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Last updated: 7/1/2020
FRAXE is a genetic disorder caused by mutations in the AFF2 gene. This gene provides instructions for making a protein whose function is not well understood. Nearly all cases of FRAXE are caused by a specific type of mutation, called a trinucleotide repeat. A trinucleotide repeat is an abnormal expansion of three repeats of our DNA building blocks (nucleotides). The repeating nucleotides in FRAXE are CCG. Normally, the involved segment of three nucleotides is repeated approximately 4 to 40 times. However, in people with FRAXE, the CCG segment is repeated more than 200 times, which makes this region of the gene unstable or fragile. As a result, the AFF2 gene is turned off (silenced), and no AFF2 protein is produced. It is unclear how a shortage of this protein leads to intellectual disability in people with FRAXE. Some people with FRAXE have a deletion of genetic material in the AFF2 gene.[4][2][3]

People with 50 to 200 CCG repeats are said to have an AFF2 gene premutation. Current research suggests that people with a premutation do not have associated cognitive problems.[2]

Last updated: 9/9/2016
The diagnosis of FRAXE is made based on signs and symptoms and genetic testing to confirm either a trinucleotide repeat expansion or a deletion within the AFF2 gene.[3]
Last updated: 9/9/2016

Testing Resources

  • The Genetic Testing Registry (GTR) provides information about the genetic tests for this condition. The intended audience for the GTR is health care providers and researchers. Patients and consumers with specific questions about a genetic test should contact a health care provider or a genetics professional.

If you need medical advice, you can look for doctors or other healthcare professionals who have experience with this disease. You may find these specialists through advocacy organizations, clinical trials, or articles published in medical journals. You may also want to contact a university or tertiary medical center in your area, because these centers tend to see more complex cases and have the latest technology and treatments.

If you can’t find a specialist in your local area, try contacting national or international specialists. They may be able to refer you to someone they know through conferences or research efforts. Some specialists may be willing to consult with you or your local doctors over the phone or by email if you can't travel to them for care.

You can find more tips in our guide, How to Find a Disease Specialist. We also encourage you to explore the rest of this page to find resources that can help you find specialists.

Healthcare Resources

Research helps us better understand diseases and can lead to advances in diagnosis and treatment. This section provides resources to help you learn about medical research and ways to get involved.

Clinical Research Resources

  • The National Fragile X Foundation provides a state by state list of clinical trials involving fragile X-associated disorders. Click on National Fragile X Foundation to view the list.

Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

Organizations Supporting this Disease

Organizations Providing General Support

These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

Where to Start

  • The National Center on Birth Defects and Developmental Disabilities (NCBDDD) at the Center for Disease Control and Prevention (CDC) provides information about developmental disabilities, including intellectual disability.  To view this information, click on the link below.
    Link: http://www.cdc.gov/ncbddd/dd/ddmr.htm
  • Genetics Home Reference (GHR) contains information on Fragile XE syndrome. This website is maintained by the National Library of Medicine.

In-Depth Information

  • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
  • Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine. 
  • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
  • PubMed is a searchable database of medical literature and lists journal articles that discuss Fragile XE syndrome. Click on the link to view a sample search on this topic.

Questions sent to GARD may be posted here if the information could be helpful to others. We remove all identifying information when posting a question to protect your privacy. If you do not want your question posted, please let us know. Submit a new question

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  1. Gecz J. The FMR2 gene, FRAXE and non-specific X-linked mental retardation: clinical and molecular aspects. Ann. Hum. Genet. Mar 2000; 64(Pt 2):95-106. http://www.ncbi.nlm.nih.gov/pubmed/?term=11246464.
  2. fragile XE syndrome. Genetics Home Reference. January 2014; https://ghr.nlm.nih.gov/condition/fragile-xe-syndrome.
  3. Victor A. McKusick. MENTAL RETARDATION, X-LINKED, ASSOCIATED WITH FRAGILE SITE FRAXE. In: Cassandra L. Kniffin. OMIM. 9/22/2011; http://omim.org/entry/309548.
  4. Rimoin DL, Connor JM, Pyeritz RE, Korf BR. Emery and Rimoin's Principles and Practice of Medical Genetics, 5th ed. Philadelphia: Churchill Livingstone Elsevier; 2007;