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This article exem- ragile X syndrome is caused by an Clinical Presentation
plifies the AAFP 2005 expansion mutation in the fragile X Although fragile X syndrome occurs in males
Annual Clinical Focus on mental retardation 1 (FMR1) gene and females, females generally present with
the legal, social, clinical,
and ethical issues of medi- located on the X chromosome. It milder symptoms. The first clinical clue in
cal genomics. characteristically leads to some degree of children often is delayed attainment of one
See editorial on page 33.
mental retardation. The phenotype is subtle, or more developmental milestones.2,3 On
with minor dysmorphic features and devel- average, boys with fragile X syndrome sit
A glossary of genomics opmental delay during childhood. Charac- without support at 10 months of age and
terms is available online at
http://www.aafp.org/afp/ teristic features during adolescence are an walk and talk at 20 months.2 With few excep-
genglossary.xml. elongated face, prominent jaw, large ears, tions, affected males have mental retardation,
macro-orchidism, and a range of behavioral generally of moderate degree. About one
anomalies and cognitive deficits (Figure 1). third of affected females have mild to severe
Recently recognized manifestations in pre- mental retardation.2 There is a specific pat-
mutation carriers include premature ovar- tern of deficits in abstract reasoning, sequen-
ian failure and tremor/ataxia.1 Premature tial processing, and mathematics. Clinical
ovarian failure occurs in up to 20 percent of findings during early childhood may include
women who are premutation carriers of the macrocephaly and frontal bossing (unusually
FMR1 gene.1 Fragile X–associated tremor/ prominent forehead). After puberty, macro-
ataxia syndrome (FXTAS) affects 30 percent orchidism is present in affected men. Addi-
of premutation carrier men between the tional findings may include strabismus and
ages of 50 and 60 years, and its prevalence mild connective tissue dysplasia, such as
increases with age.1 mitral valve prolapse, hyperextensible joints,
and pes planus. Behavior is characterized by
Epidemiology attention deficits, hand flapping, hand bit-
Fragile X syndrome, the phenotype associ- ing, and gaze aversion. Family physicians are
ated with full mutation, occurs in approxi- most likely to encounter the undiagnosed
mately one in 4,000 men and one in 6,000 to child before school age, when formal testing
8,000 women. The premutation in the FMR1 can confirm cognitive deficits. However, the
gene occurs in approximately one in 800 men average age of diagnosis currently is eight
and up to one in 100 to 200 women. Premu- years, reflecting the subtlety of features in
tation male carriers are susceptible to FXTAS young children.4
after age 50. Premature ovarian failure may FXTAS is a neurodegenerative disorder
be detected in as many as one third of women with progressive intention tremor and cere-
with a premutation. bellar ataxia.5 Affected persons present with
July 1, 2005 ◆ Volume 72, Number 1 www.aafp.org/afp American Family Physician 111
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Fragile X Syndrome
112 American Family Physician www.aafp.org/afp Volume 72, Number 1 ◆ July 1, 2005
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Figure 2.
testing, regardless of family history, for all Figure 2 provided by Darryl Leja, National Human
Genome Research Institute, National Institutes of Health,
males and females with mental retardation of Bethesda, Md.
unknown etiology.
This article is one in a series coordinated by the National
Human Genome Research Institute, National Institutes of
Management
Health, Bethesda, Md. Guest editor of the series is Daniel
Treatment is supportive, requiring a mul- J. Wattendorf, MAJ, MC, USAF.
tidisciplinary team and including anxiety-
reducing measures, behavior modification,
REFERENCES
and medications to manage associated psy-
chiatric disorders. Individual education plans 1. Hagerman PJ, Hagerman RJ. The fragile-X premutation:
are necessary for school-age children. a maturing perspective [published correction appears
in Am J Hum Genet 2004;75:352]. Am J Hum Genet
2004;74:805-16.
Resources 2. Maes B, Fryns JP, Ghesquiere P, Borghgraef M. Phe-
Additional information about the diagnosis notypic checklist to screen for fragile X syndrome in
people with mental retardation. Ment Retard 2000;38:
and management of fragile X syndrome is 207-15.
available at the following Web sites: National 3. Shevell M, Ashwal S, Donley D, Flint J, Gingold M, Hirtz
Fragile X Foundation (http://www.FragileX. D, et al. Practice parameter: evaluation of the child
org); GeneTests (http://www.genetests.org); with global developmental delay: report of the Quality
Standards Subcommittee of the American Academy of
and the American College of Medical Genet- Neurology and The Practice Committee of the Child
ics (www.acmg.net/resources/policies/pol- Neurology Society. Neurology 2003;60:367-80.
014.asp). 4. Delayed diagnosis of fragile X syndrome—United
States, 1990-1999. MMWR Morb Mortal Wkly Rep
Author disclosure: Nothing to disclose. 2002;51:740-2.
The opinions and assertions contained herein are the 5. Jacquemont S, Hagerman RJ, Leehey MA, Hall DA,
private views of the authors and are not to be construed Levine RA, Brunberg JA, et al. Penetrance of the fragile
as official or as reflecting the views of the U.S. Air Force X-associated tremor/ataxia syndrome in a premutation
Medical Service, the U.S. Air Force at large, the National carrier population. JAMA 2004;291:460-9.
Human Genome Research Institute, or the National 6. Machado-Ferreira Mdo C, Costa-Lima MA, Boy RT,
Institutes of Health. Esteves GS, Pimentel MM. Premature ovarian failure
and FRAXA premutation: positive correlation in a Bra-
The authors thank Brenda M. Finucane, M.S., Suzanne P. zilian survey. Am J Med Genet A 2004;126:237-40.
Hart, Ph.D., and Nasreen Malik, M.D., for assistance with
7. American College of Medical Genetics. Fragile X syn-
the preparation of the manuscript.
drome: diagnostic and carrier testing. Accessed online
Figure 1 used with permission from the National Fragile May 31, 2005, at: http://www.acmg.net/resources/
X Foundation, San Francisco. policies/pol-014.asp.
July 1, 2005 ◆ Volume 72, Number 1 www.aafp.org/afp American Family Physician 113