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: