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Fragile X Syndrome - Initial Diagnosis
Overview
Consider the diagnosis of fragile X syndrome (FXS) for all male patients with developmental delay/mental retardation and a normal-sized or large head. This diagnosis is even more likely if the child has autistic features or relatives with mental retardation, autistic features, or physical features of FXS. Also ask about female relatives with premature ovarian insufficiency (problems with infertility, irregular periods, or menopausal symptoms before 40, such as hot flashes) and older relatives with Parkinson-like symptoms that might have fragile X-associated tremor/ataxia syndrome (FXTAS). Note that younger children are not as likely as older children to display the classic physical features of the syndrome. The diagnosis of most children with FXS is delayed from 6 to 12 months past the time parents first express their concerns. In some cases, this delay does not allow parents to make informed decisions about having more children. [Bailey: 2002] [CDC: 2002]Pearls And Alerts
Molecular genetic testing is more accurate than the cytogenetic analysis. Individuals with a negative cytogenetic analysis but with suspicious findings should be retested using molecular methodology (see Genetic Testing below).
Approximately 30% of boys with FXS meet formal criteria for autism from the DSM IV [American: 2000]. [Hatton: 2002]
Rarely, children with the Prader-Willi phenotype, e.g. hyperphagia and obesity occurring in early childhood, are negative for the 15q11 abnormalities seen in PWS and have FXS.
Practice Guidelines
Differential Diagnosis
Beacuse the facial features of children with FXS may be very non-specific, a presumptive diagnosis should be avoided. Similar facial features can be seen in Sotos syndrome and other conditions of overgrowth, and early clinical features of FXS may be similar to those seen in children with autism spectrum disorders or Prader-Willi syndrome. Genetic testing will confirm a presumptive diagnosis of FXS. See also the Diagnosis Module on Intellectual disability/mental retardation.History And Examination
Family History
Ask about a family history of mental retardation (with or without a specific diagnosis), FXS, and/or autistic spectrum disorder. Individuals with premature ovarian insufficiency (menopause-like symptoms before the age of 40, frequent missed or absent periods, infertility) or older adults with progressive tremor and balance problems (fragile X-associated tremor/ataxia syndrome - FXTAS). See Premature ovarian insufficiency (National Fragile X Foundation) and FXTAS (National Fragile X Foundation) for more information.Pregnancy/Perinatal History
No problems are associated with FXS. As premature ovarian insufficiency has been observed in premutation carrier females (approximately 21%), also ask about frequent missed periods, difficulty getting pregnant, and menopause-like symptoms including hot flashes and vaginal dryness.Medical History
Ask about chronic ear infections, seizures, feeding problems, and gastroesophageal reflux. Evidence of hearing or visual deficits should be sought.Developmental and Educational History
Language and mild gross motor delays are typical in children with FXS. Behavior problems, hyperactivity, tantrums, and autistic behaviors may also lead to suspicion of FXS.Social and Family History
Females with FXS and males after puberty commonly exhibit shyness and lack of eye contact. Additionally, female mutation carriers may demonstrate anxiety, and social and emotional immaturity.Physical Exam
General
Before puberty, look for a long face, with a prominent chin and forehead, and large ears. After puberty, strabismus, low muscle tone, and large testicles may be present. See Clinical features in FXS for a graphic summary.Heart
Look for signs of mitral valve prolapse (mitral click or regurgitant murmur) or aortic annular dilatation (regurgitant murmur).Testing
Sensory Testing
Vision and hearing impairments are common in children with FXS, the latter possibly related to frequent ear infections. Testing for hearing impairment is important, as it may contribute to language delay. Refractive errors are frequent in children with FXS and referral for ophthalmologic exam should be triggered by an abnormal vision screen or suspicion of visual problems.Imaging and EEG
Imaging: Although neuroradiologic abnormalities may be found in FXS (e.g., periventricular heteropia [Moro: 2006]), neither brain MRI examination nor other imaging is recommended routinely in the absence of an abnormal neurological examination.EEG: Unless seizures are clinically present, EEGs are not recommended.
Genetic Testing
Testing for FXS is widely available, and molecular genetic testing is recommended - see Genetic testing algorithm for FXS (GeneReviews). Preauthorization from the patient's insurance company is often required to assure payment. See Fragile X testing (GeneTests) for relevant laboratories and Ltr Med Nec – Fragile X syndrome, chromosome analysis (
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for more information. The American College of Medical Genetics recommends FXS testing [Shevell: 2003] for individuals of either sex with mental retardation, developmental delay, or autism, especially if they have:
- any physical or behavioral characteristics of fragile X syndrome;
- a family history of fragile X syndrome; or
- male or female relatives with undiagnosed mental retardation.
Subspecialist Collaborations and Other Resources
Pediatric Medical Genetics (see Services below for relevant providers)
A pediatric geneticist may be helpful in sorting out heritable causes of developmental delay, mental retardation, or unusual facies. They may also help identify at-risk family members. Once the diagnosis is made, the families of children with FXS should receive genetic counseling and consideration of testing for other family members. Counseling may be obtained through a geneticist or by referral to a genetic counselor.
Pediatric Genetic Counseling (see Services below for relevant providers)
Genetic counselors can educate and advise regarding parental reproductive choices, testing of other family members, and accessing relevant services. Guidance regarding developmental issues and education strategies may also be provided.
Pediatric Cardiology (see Services below for relevant providers)
If a click or murmur is found, a visit to cardiology for an echocardiogram may be warranted. Antibiotic prophylaxis before dental or other procedures may be recommended depending on findings.
Pediatric Ophthalmology (see Services below for relevant providers)
Presence or suspicion of strabismus, visual deficit, ptosis, or nystagmus should trigger referral to a pediatric ophthalmologist.
Pediatric Orthopedics (see Services below for relevant providers)
Periodic screening for joint laxity may be helpful. Children with club feet and dislocated hips should be followed by a pediatric orthopedic surgeon.
Developmental Pediatrics (see Services below for relevant providers)
For developmental assessment and coordination of related services, such as PT, OT, and speech therapy (see Resources>Services below).
Child Psychology (see Services below for relevant providers)
Assessments may be helpful in guiding educational placement and approaches. Psychologists may also help manage behavior problems, such as aggression and attentional deficits.
Child Psychiatry (see Services below for relevant providers)
Some children with fragile X syndrome will benefit from medication for behavior problems. Evaluation by a child psychiatrist should be considered.
Resources
Information & Support
For Professionals
FMR-1-related disorders (GeneReviews)
Excellent in-depth information regarding fragile X including diagnosis, testing, pathophysiology
For Parents and Patients
Support
FRAXA
A national organization providing research and support for individuals with fragile X syndrome and their families.
National Fragile X Foundation
Information and support from the National Fragile X Foundation
Patient Education
Fragile X syndrome (MedLinePlus)
Introduction and links to a variety of reliable sources of information about FXS, from the National Library of Medicine and
National Insitutes of Health.
Services
Pediatric Genetic Counseling
See all Pediatric Genetic Counseling services providers (4) in our database.
Pediatric Medical Genetics
See all Pediatric Medical Genetics services providers (3) in our database.
For other services related to this condition, browse our Services categories or search our database.
Studies
Clinical trials in Fragile X (clinicaltrials.gov)
Listing of current and recent studies related to Fragile X.
Helpful Articles
PubMed search for Fragile X Syndrome: reviews over the last 3 years
Hersh, JH, Saul, RA, and Committee on Genetics.
Health supervision for children with fragile x syndrome.
Pediatrics.
2011;127(5):994-1006.
PubMed abstract / Full Text
Hagerman RJ, Berry-Kravis E, Kaufmann WE, Ono MY, Tartaglia N, Lachiewicz A, Kronk R, Delahunty C, Hessl D, Visootsak J, Picker
J, Gane L, Tranfaglia M.
Advances in the treatment of fragile X syndrome.
Pediatrics.
2009;123(1):378-90.
PubMed abstract
Wiesner GL, Cassidy SB, Grimes SJ, Matthews AL, Acheson LS.
Clinical consult: developmental delay/fragile X syndrome.
Prim Care.
2004;31(3):621-5, x.
PubMed abstract
Information for the primary care provider regarding children with fragile X syndrome.
Moeschler JB.
Genetic evaluation of intellectual disabilities.
Semin Pediatr Neurol.
2008;15(1):2-9.
PubMed abstract
Authors
| Author: | Lynne M Kerr MD, PhD, 12/2008 |
| Reviewing Author: | Karin Dent MS, CGC, 9/2008 |
| Content Last Updated: | 12/2008 |
Page Bibliography
American Psychiatric Association.
DSM-IV-TR Diagnostic and Statistical Manual of Mental Disorders.
Fourth Edition ed. Washington, D.C.: American Psychiatric Association;
2000.
Bailey, DB, Skinner, D, Sparkman, K, .
Delayed diagnosis of fragile X syndrome: United States 1990-1999.
(2002)
http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5133a3.htm.
CDC.
Delayed diagnosis of fragile X syndrome--United States, 1990-1999.
MMWR Morb Mortal Wkly Rep.
2002;51(33):740-2.
PubMed abstract
Hatton DD, Hooper SR, Bailey DB, Skinner ML, Sullivan KM, Wheeler A.
Problem behavior in boys with fragile X syndrome.
Am J Med Genet.
2002;108(2):105-16.
PubMed abstract
Hersh, JH, Saul, RA, and Committee on Genetics.
Health supervision for children with fragile x syndrome.
Pediatrics.
2011;127(5):994-1006.
PubMed abstract / Full Text
Moeschler JB, Shevell M.
Clinical genetic evaluation of the child with mental retardation or developmental delays.
Pediatrics.
2006;117(6):2304-16.
PubMed abstract / Full Text
This report describes the "optimal clinical genetics evaluation" for children with developmental delay or mental retardation
for medical home providers.
Moro F, Pisano T, Bernardina BD, Polli R, Murgia A, Zoccante L, Darra F, Battaglia A, Pramparo T, Zuffardi O, Guerrini R.
Periventricular heterotopia in fragile X syndrome.
Neurology.
2006;67(4):713-5.
PubMed abstract
Shevell M, Ashwal S, Donley D, Flint J, Gingold M, Hirtz D, Majnemer A, Noetzel M, Sheth RD.
Practice parameter: evaluation of the child with global developmental delay: report of the Quality Standards Subcommittee
of the American Academy of Neurology and The Practice Committee of the Child Neurology Society.
Neurology.
2003;60(3):367-80.
PubMed abstract / Full Text