para>Full mutation (>200 CGG repeats)
Premutation (~6-200 CGG repeats)
Most males with full mutation have mental impairment in addition to some form of the physical and behavioral features.Males with premutation have normal intelligence but have an increased risk for tremor-ataxia syndrome between age 50 and 60 years.Females with full mutation have a ~50% chance of having mental impairment in addition to some form of physical and behavioral features.Females with premutation have normal intelligence but have a 20% risk for premature ovarian failure.Because a male has only 1 X chromosome, it is never passed on to his son. He will pass the affected chromosome to all of his daughters.An affected female has a 50% chance of passing her affected chromosome to all of her children.
Commonly Associated Conditions
- Autistic spectrum disorder (3)
- Connective tissue manifestations, including flat feet and inguinal hernias (3)
- Mitral valve prolapse (develops during adolescence and adulthood) (3)
- Recurrent otitis media and sinusitis in childhood (3)
- Seizure disorder (15-20% for boys and 5% for girls) (4)
- Social phobias and other anxiety disorders (4)
Diagnosis
History
- Family history of mental impairment, particularly with multiple male relatives
- Family history of premature ovarian failure or fragile X-related tremor ataxia syndrome
- Delay of ≥1 developmental milestones, especially when there is mental impairment in the family (2)
- After the 1st year of life, delay in speech and language along with impaired fine motor skills
Pediatric Considerations
Average age at the time of diagnosis is 8 years, reflecting the subtlety of features in young children (2).
Physical Exam
- Physical characteristics become more prominent with advancing age (5).
- Birth-1 month
Examine for orthopedic abnormalities, especially congenital hip dysplasia and clubfoot.
Evaluate occipitofrontal circumference, which may be increased.
Monitor for feeding difficulties and gastroesophageal reflux (GERD).
- 1 month-1 year
Monitor for hypotonia that frequently results in mild motor delay.
Monitor for irritability secondary to sensory problems.
Evaluate for feeding problems and the presence of vomiting secondary to GERD.
- 1-5 years
Perform an ophthalmologic evaluation to check for strabismus and refractory errors.
Monitor for ptosis and nystagmus.
Evaluate for orthopedic problems related to connective tissue dysplasia such as pes planus, hypermobile joints, and scoliosis.
Examine for inguinal hernias.
Monitor for recurrent otitis media, conductive hearing loss, and recurrent sinusitis.
Monitor for language delay.
Monitor for emotional and behavioral status closely, especially tantrums and hyperactivity, and signs of autism.
- 5-12 years
Evaluate for macroorchidism and hernias in boys and precocious puberty in females.
Monitor for the child's developmental status.
Assess for hyperactivity, obsessive-compulsive behaviors, and anxiety.
Assess for cognitive impairments.
- 13-21 years
- Adulthood
Assess for mitral valve prolapse.
Evaluate for premature menopause (up to 20% before age 40 years).
Assess for fragile X-associated tremor/ataxia syndrome as patients approach the age of 50 years.
Differential Diagnosis
- Pervasive developmental disorder
- Learning disability
- Autism
- Attention deficit hyperactivity disorder (ADHD)
- Other causes of mental impairment
Diagnostic Tests & Interpretation
Diagnosis of FXS is made by DNA-based molecular tests, such as Southern blot test and polymerase chain reaction (PCR), to isolate the FMR1 gene mutation. Indications for testing include the following (1):
- Patients with a family history of mental impairment or FXS
- Any child with developmental delay of uncertain etiology or autism
- Individual with mental impairment of unknown etiology
- Women with premature ovarian failure of unknown cause
- Individuals with late-onset intentional tremor or ataxia, especially with a family history of movement disorders, FXS, or undiagnosed mental impairment
- Prenatal testing is offered only if maternal premutation or full mutation is present.
Chorionic villus sampling or amniocentesis is used for prenatal diagnosis.
Preimplantation genetic diagnosis may be another option for women with a premutation FXS; however, there are several limitations to this approach.
Initial Tests (lab, imaging)
Newborn screening for FXS is not routine at present (6)[B].
Treatment
- Treatment is usually supportive and includes the use of stimulants, selective serotonin reuptake inhibitors (SSRIs), atypical antipsychotics, and Ī±-agonists; treatment is individualized according to symptoms.
- However, there currently is no robust evidence to support recommendations on pharmacologic treatments in patients with FXS in general or in those with an additional diagnosis of ADHD or autism (7).
Medication
Depending on the clinical presentation, pharmacotherapy may include the following (8)[B]:
- Atypical antipsychotics
- SSRIs
- Antiepileptics
- Methylphenidate
- Dextroamphetamines
- Clonidine
- Guanfacine
Second Line
Impossible to draw conclusions about the effect of folic acid on FXS patients due to the low quality of current evidence (9)
Issues for Referral
- The proband and family should be referred for genetic counseling and tested for the FMR1 gene.
- Also see "Additional Treatment" section.
Additional Therapies
Nonpharmacologic therapies are of tremendous value (10)[B] and include the following:
- Behavior therapy
- Speech and language therapy
- Psychotherapy and counseling
- Occupational and physical therapy
- Social skill training, support group
- Special education and preschool intervention programs (10)
Ongoing Care
Patient Education
- In young females with FXS who are planning for future pregnancies, review the reproductive options such as egg donation, prenatal diagnosis, adoption, and preimplantation genetic diagnosis.
- Useful Web sites
The National Fragile X Foundation (www.fragilex.org)
FRAXA research foundation(http://www.fraxa.org)
Gene tests(www.genetests.org, www.geneclinics.org)
American College of Medical Genetics (www.acmg.net)
Dolan DNA learning center: your genes, your health (www.ygyh.org)
National Institute of Child Health and Human Development (www.nichd.nih.gov)
Prognosis
- Patients with FXS have a normal lifespan.
- About 20-33% of women carrying a premutation for FXS are at increased risk for premature ovarian failure.
- 1/3 of males and, to a lesser extent, females carrying the premutation are at increased risk for late-onset (>50 years) progressive neurodegenerative disorder. It is characterized by intentional tremor and ataxia, called fragile X-associated tremor/ataxia syndrome (FXTAS). Other associated findings include parkinsonism, autonomic dysfunction, peripheral neuropathy, and dementia.
References
1.Santoro MR, Bray SM, Warren ST. Molecular mechanisms of fragile X syndrome: a twenty-year perspective. Annu Rev Pathol. 2012;7:219-245. [View Abstract]2.Wattendorf DJ, Muenke M. Diagnosis and management of fragile X syndrome. Am Fam Physician. 2005;72(1):111-113. [View Abstract]3.Visootsak J, Warren ST, Anido A, et al. Fragile X syndrome: an update and review for the primary pediatrician. Clin Pediatr (Phila). 2005;44(5):371-381. [View Abstract]4.Tsiouris JA, Brown WT. Neuropsychiatric symptoms of fragile X syndrome: pathophysiology and pharmacotherapy. CNS Drugs. 2004;18(11):687-703. [View Abstract]5.Hersh JH, Saul RA, Committee on Genetics. Health supervision for children with fragile X syndrome. Pediatrics. 2011;127(5):994-1006. [View Abstract]6.Bailey DB Jr, Skinner D, Davis AM, et al. Ethical, legal, and social concerns about expanded newborn screening: fragile X syndrome as a prototype for emerging issues. Pediatrics. 2008;121(3):e693-e704. [View Abstract]7.Rueda JR, Ballesteros J, Tejada MI. Systematic review of pharmacological treatments in fragile X syndrome. BMC Neurol. 2009;9:53. [View Abstract]8.Hagerman RJ, Berry-Kravis E, Kaufmann WE, et al. Advances in the treatment of fragile X syndrome. Pediatrics. 2009;123(1):378-390. [View Abstract]9.Rueda JR, Ballesteros J, Guillen V, et al. Folic acid for fragile X syndrome. Cochrane Database Syst Rev. 2011;(5):CD008476. [View Abstract]10.Solomon M, Hessl D, Chiu S, et al. A genetic etiology of pervasive developmental disorder guides treatment. Am J Psychiatry. 2007;164(4):575-580. [View Abstract]
Additional Reading
- American College of Obstetricians and Gynecologists Committee on Genetics. ACOG committee opinion. No. 338: screening for fragile X syndrome. Obstet Gynecol. 2006;107(6):1483-1485. [View Abstract]
- Cornish KM, Gray KM, Rinehart NJ. Fragile X syndrome and associated disorders. Adv Child Dev Behav. 2010;39:211-235. [View Abstract]
- McConkie-Rosell A, Finucane B, Cronister A, et al. Genetic counseling for fragile x syndrome: updated recommendations of the national society of genetic counselors. J Genet Couns. 2005;14(4):249-270. [View Abstract]
- McLennan Y, Polussa J, Tassone F, et al. Fragile x syndrome. Curr Genomics. 2011;12(3):216-224. [View Abstract]
- Orr HT, Zoghbi HY. Trinucleotide repeat disorders. Annu Rev Neurosci. 2007;30:575-621. [View Abstract]
See Also
Algorithm: Mental Retardation
Codes
ICD10
- Q99.2 Fragile X chromosome
ICD09
- 759.83 Fragile X syndrome
SNOMED
- 613003 fragile X syndrome (disorder)
Clinical Pearls
- FXS is the most common inherited form of mental retardation.
- FXS is an X-linked dominant disorder with variable penetrance. Therefore, although this condition is seen in both sexes, males are usually more severely affected than females.
- Newborn screening for FXS is not routine.
- The average age at the time of diagnosis is 8 years.