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Fragile X Syndrome

by Nina N. Powell-Hamilton, MD, FAAP, FACMG

Fragile X syndrome is a genetic abnormality in an X chromosome that leads to intellectual disability and behavioral disorders.

Fragile X syndrome is the most common inherited cause of moderate intellectual disability, with males being more commonly affected than females. (Down syndrome is the most common cause of intellectual disability in males; although it is a genetic disorder, most cases occur sporadically and are not inherited.) For more information, see National Fragile X Foundation .

The symptoms of Fragile X syndrome are caused by an abnormality of the FMR1 gene on the X chromosome. The abnormality is an unstable triplet repeat expansion; normal people have < 60 CGG repeats and people with Fragile X syndrome have > 200. People with 60 to 200 CGG repeats are considered to have a premutation because the increased number of repeats increases the likelihood that further mutation will result in > 200 repeats in a subsequent generation.

Fragile X syndrome affects about 1/4000 males and 1/8000 females. The premutation is more common. Females with the disorder are typically less impaired than males. Fragile X is inherited in an X-linked pattern and does not always cause clinical symptoms.

In the past, examination of the karyotype revealed a constriction at the end of the long arm of the X chromosome, followed by a thin strand of genetic material, which was why the syndrome was considered a chromosomal abnormality. However, this structural defect does not appear when modern cytogenetic techniques are used, and this is the reason why Fragile X syndrome is now considered a single-gene disorder and not a chromosomal abnormality.

Symptoms and Signs

People with Fragile X syndrome may have physical, cognitive, and behavioral abnormalities. Typical features include large, protuberant ears; a prominent chin and forehead; a high arched palate; and, in postpubertal males, macroorchidism. The joints may be hyperextensible, and heart disease (mitral valve prolapse) may occur. Cognitive abnormalities may include mild to moderate intellectual disability. Features of autism may develop, including perseverative speech and behavior, poor eye contact, and social anxiety. Women with the premutation may have premature ovarian failure; sometimes menopause occurs in the mid-30s.

Diagnosis

  • DNA testing

Fragile X syndrome is frequently not suspected until school age or adolescence, depending on the severity of the symptoms. Boys with autism and intellectual disability should be tested for Fragile X syndrome. Molecular DNA analysis is done to detect the increased number of CGG repeats.

Treatment

  • Supportive measures

Early intervention, including speech and language therapy and occupational therapy, can help children with Fragile X syndrome maximize their abilities. Stimulants, antidepressants, and antianxiety drugs may be beneficial for some children.

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