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Fragile X Syndrome

Overview

Fragile X syndrome (FXS), caused by a mutation of the FMR1 gene of the X chromosome, is the most common form of inherited intellectual disability. The FXS phenotype is usually more apparent in males than in females.
The following phenotypic descriptions are from FMR1-Disorders (GeneReviews).
The classic phenotype of FXS in males includes:
  • Intellectual disability, with an average IQ of 40-45 and a range of <10 to normal. Most affected males have an IQ under 70; however, there is variability. [Sansone: 2014]
  • Behavioral features such as attention-deficit/hyperactivity symptoms, gaze aversion, perseverative speech, anxiety, and aggression.
  • Autism spectrum disorder in 50 – 70% of affected individuals
  • Macrocephaly
  • Characteristic facies, including a long narrow face with prominent chin, tall forehead, depressed nasal bridge, and long and protruding ears (these features may be subtle but become more prominent in adolescence). Severity of the FXS physical phenotype and intellectual impairment is correlated with the magnitude of the FMRP deficit. [Loesch: 2004] [Tassone: 1999] [Kaufmann: 1999]
  • Flexible finger joints and flat feet
  • Post-pubertal macroorchidism
  • Eye and vision problems (strabismus) [Storm: 1987]
  • Scoliosis [Storm: 1987]
  • Seizure disorder (13-18% of boys, 5% of girls) [Storm: 1987]
Females with full mutation fragile X generally have milder manifestations, although they may have:
  • Similar physical features, particularly long and protruding ears, flexible finger joints, and flat feet
  • Learning problems in the majority
  • Short attention span
  • Moodiness, shyness, anxiety
  • 70% have IQ in borderline range (70-84)
The phenotypes of FXS are not always clinically distinct, and the classic facial appearance, even in males with the full mutation, is subtle, especially in early childhood. Testing for the FMR1 gene mutation is recommended in boys and girls with developmental delay/intellectual disability and/or autistic features, especially if they also have any phenotypic features or relatives with FXS or undiagnosed intellectual disability (see Fragile X Testing (GTR)). Also, see Comprehensive Evaluation of the Child with Intellectual Disability or Global Developmental Delays (AAP) [Moeschler: 2014].

Other Names & Coding

FXS
ICD-10 coding

Q99.2, Fragile X chromosome

Further coding details can be found at ICD-10 for Fragile X Chromosome (icd10data.com).

Prevalence

The prevalence of the full FXS mutation in both males and females may be as high as 1:2500. The premutation allele is common in the general population and estimated to occur in 1:130-250 females and 1: 250-810 males. [Carey: 2020]

Genetics

FXS is due to a trinucleotide repeat expansion mutation in the FMR-1 gene on the X chromosome. A large repeat expansion, or full mutation, inactivates the FMR-1 gene, preventing production of the FMR-1 protein (FMRP).
  • The mutation involves an expansion of a CGG sequence repeat in an untranslated region of the FMR-1 gene.
    • Full mutations or large expansions are greater than 200 CGG repeats.
    • Premutations or small expansions contain approximately 55-200 CGG repeats.
  • FMR-1 disorders include adult-onset fragile X-associated tremor/ataxia syndrome (FXTAS) and FMR1-related premature ovarian insufficiency (FXPOI) in premutation carriers. These disorders may result from elevated mRNA levels in premutation carriers. [Hunter: 2019]
  • Prenatal testing – amniocentesis and chorionic villus sampling (CVS) – is available for pregnant women who are confirmed premutation carriers. Determining the methylation pattern of the gene may be impossible in cells obtained by CVS, making the distinction between large premutations and smaller full mutations difficult and limiting the potential for clinical correlation. Follow-up amniocentesis is recommended after positive CVS.
  • Some families may also pursue Preimplantation Genetic Testing or PGT to select embryos without the gene expansion. See Preimplantation Genetic Testing (ASRM).

Prognosis

Life expectancy is normal. Clinical features vary widely in children with FXS, and adult functioning will depend on IQ and the presence or absence of autistic behaviors. [Hartley: 2011]
In a study of adults with FXS, the level of functional skills was the strongest predictor of independence for men; the ability to interact appropriately was the strongest predictor for women. Co-occurring mental health conditions influenced independence in adult life for men and women, in particular, autism spectrum disorders for men and affect problems for women. [Hartley: 2011]

Practice Guidelines

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

Finucane B, Abrams L, Cronister A, Archibald AD, Bennett RL, McConkie-Rosell A.
Genetic counseling and testing for FMR1 gene mutations: practice guidelines of the national society of genetic counselors.
J Genet Couns. 2012;21(6):752-60. PubMed abstract

Carey J. (Editor), Cassidy S.B. (Editor), Battaglia A. (Editor), Viskochil D. (Editor).
Management of Genetic Syndromes.
4th ed. Hoboken, NJ: John Wiley & Sons; 2020. 978-1-119-43267-8 https://www.wiley.com/en-us/Cassidy+and+Allanson's+Management+of+Genet...

Riley C, Bailey D,.
Fragile X Syndrome Supplement Article.
Pediatrics. 2017;139(13953). / Full Text

Roles of the Medical Home

The medical home can:
  • Schedule health-maintenance and chronic-condition visits frequently enough to remain aware of issues as they arise, build a strong partnership with the family, and provide needed supports. [Hersh: 2011]
  • Ensure that the family has access to current, reliable information about FXS. Information about autism and intellectual disability may also be helpful. See the Autism Spectrum Disorder (FAQ) and the Intellectual Disability and Global Developmental Delay (FAQ) FAQs.
  • Refer, facilitate access to, and coordinate the services provided by other professionals, and interpreting the information and advice they offer as needed.
  • Guide and assist the family in working with the preschool/school systems to ensure appropriate accommodations, reasonable goal setting, and optimal support.
  • Facilitate access to physical, occupational, speech, and behavioral therapies through private providers or other systems of care, including early intervention if the child does not qualify through the school system.
  • Support and facilitate the family’s awareness and access to financial and health-related resources, such as Medicaid waivers, state services for persons with disabilities, etc. Financing Your Child's Healthcare provides families more information.
  • Assess parental stress, sibling problems, and social supports. Connecting families with others in similar situations to provide support and alleviate the sense of isolation.

Clinical Assessment

Overview

Consider the diagnosis of fragile X syndrome (FXS) for all male patients with developmental delay/intellectual disability, autistic features, speech and motor delay, and a normal-sized or large head. This diagnosis is even more likely if the child has relatives with intellectual disability, 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. [Bailey: 2002] [CDC: 2002]

Pearls & Alerts for Assessment

Delayed diagnosis

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 and limits opportunities for early services.

Molecular testing may be indicated

Molecular genetic testing is much more accurate than cytogenetic analysis. Individuals with a negative cytogenetic analysis but with suspicious findings should be retested using molecular methodology (see Genetic Testing below).

Autism diagnosis in FXS

Approximately 50% of boys with FXS meet formal criteria for autism spectrum disorder from the DSM 5. Referral for autism testing (ADOS) should be performed early as this may open more services for families. [Kaufmann: 2017]

Prader-Willi syndrome phenotype and FXS

Rarely, children with the Prader-Willi phenotype (hyperphagia and obesity occurring in early childhood) are negative for the 15q11 abnormalities seen in Prader-Willi and have FXS.

Screening

Of Family Members

Consider genetic testing for family members of children with known fragile X syndrome (FXS). Family members in surrounding generations may be at risk for learning problems, autism, premature ovarian failure, and fragile X-associated tremor/ataxia syndrome, depending on gene status.
Women with a family history of fragile X-related disorders, unexplained developmental delay/intellectual disability, autism, or premature ovarian insufficiency should receive genetic counseling and fragile X premutation carrier screening as needed.

Presentations

Common presentations will include developmental delay, speech/language/motor issues, large head, gaze-avoidance, and positive family history.

Diagnostic Criteria

There are no specific clinical criteria.

Differential Diagnosis

Because the facial features of children with FXS may be very nonspecific, a presumptive diagnosis should be avoided.
  • Similar facial features can be seen in Sotos syndrome and other conditions of overgrowth.
  • Early clinical features of FXS may be similar to those seen in children with autism spectrum disorder or Prader-Willi syndrome.
Genetic testing will confirm a presumptive diagnosis of FXS. Diagnosis information can be found at Autism Spectrum Disorder, Intellectual Disability & Global Developmental Delay, and Prader-Willi Syndrome.

Comorbid & Secondary Conditions

As in all syndromes, the features and findings of FXS represent the component manifestations encompassing the syndromic pattern. There is variability of expressivity of the features. The most common physical features seen in a male with full Fragile X syndrome include the following:
  • Strabismus
  • Hyperextensible joints
  • Pectus excavatum
  • Mitral valve prolapse
  • Hypotonia
  • Flat feet
  • Enlarged testicles (macroorchidism) in males after puberty
  • Seizures in about 15%
  • Scoliosis

History & Examination

The features of FXS are subtle in young children, may vary considerably, and often change with puberty. Because none of the features are specific for this syndrome, diagnosis should be confirmed by genetic testing. See Faces of Fragile X (National Fragile X Foundation).

Current & Past Medical History

Ask about chronic ear infections, seizures, feeding problems, stooling pattern, and gastroesophageal reflux. Evidence of hearing or visual deficits should be sought. Ask about gross motor and speech delay, anxiety, and behavioral problems. Sleep is deranged in children with FXS.

Family History

Ask about a family history of intellectual disability (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, frequently missed or absent periods, infertility), or older adults with progressive tremor and balance problems (FXTAS). See Fragile X-associated Primary Ovarian Insufficiency (National Fragile X Foundation) and Fragile X–Associated Tremor/Ataxia Syndrome (National Fragile X Foundation) for more information.

Pregnancy/Perinatal History

Since premature ovarian insufficiency has been observed in premutation carrier females (approximately 20%), ask about frequently missed periods, difficulty getting pregnant, and menopause-like symptoms, including hot flashes and vaginal dryness.

Developmental & Educational Progress

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. Detailed questions about learning, school performance, educational interventions, and planning are important. An individualized education plan (IEP) should be in place for any child not keeping up with school. Toilet training should be assessed often. Most boys will toilet train but often several years later than typical.

Maturationalprogress

Ask about macroorchidism and psychosexual development in adolescents. Behavioral management throughout puberty is essential.

Social & Family Functioning

Both females and males with FXS and commonly exhibit shyness and lack of eye contact. Additionally, female full-mutation carriers may demonstrate anxiety and social and emotional immaturity. Children with FXS may have problems with behavior and aggression that can cause social and family stress. Families of individuals with FXS have the typical challenges of coping with and rearing a child with developmental disabilities and autism. Ongoing support from the primary care practitioner should be incorporated into regular care. Ask about sibling interactions and attitudes/support of extended family.

Physical Exam

General

Before puberty, look for a long face, with a prominent chin and forehead, long ears, and hypotonia. Not all affected boys will demonstrate the characteristic facial features before puberty. After puberty, strabismus, low muscle tone, and macroorchidism (large testicles) may be present.

Growth Parameters

The head circumference will usually be greater than the 50th percentile. Some boys with FXS have increased weight, similar Prader-Will syndrome, due to increased intake. Therefore, weight should be monitored, and appropriate nutritional consultation and intervention initiated if needed.

HEENT/Oral

Look for evidence of chronic or acute ear infections and for strabismus. Ptosis should also be noted. Dental health should be attended to, as children with FXS often have poor oral hygiene and need sedation for dental exams.

Heart

Look for signs of mitral valve prolapse (mitral click or regurgitant murmur) or aortic annular dilatation (regurgitant murmur).

Genitalia

Look for macroorchidism in post-pubertal males with FXS.

Extremities/Musculoskeletal

Look for club feet, flat feet, dislocated hips, and hyperextensible joints (due to connective tissue abnormalities). Scoliosis.

Neurologic Exam

Look for seizures that typically present in early childhood. They may include generalized tonic-clonic, absence, partial motor, and temporal lobe seizures. Look for evidence of ataxia or tremor (in adults).

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 and strabismus are frequent in children with FXS. Children with FXS should have at least 1 early baseline ophthalmology exam. Follow-up exams should be triggered by an abnormal vision screen or suspicion of visual problems.

Imaging

Although neuroradiologic abnormalities may be found in FXS (e.g., periventricular heterotopia [Moro: 2006]), neither brain MRI examination nor other imaging is recommended routinely in the absence of an abnormal neurological examination or seizures.

Genetic Testing

Testing for FXS is widely available and molecular genetic testing is recommended – see Table 1 at Molecular Genetic Testing Used in FMR1 Disorders (GeneReviews). Preauthorization from the patient's insurance company is often required to ensure payment. See Fragile X Testing (GTR) for relevant laboratories and Fragile X Syndrome / High-Resolution Chromosome Analysis - Letter of Medical Necessity / Preauthorization (PDF Document 119 KB) for more information. The American College of Medical Genetics and Genomics recommends FXS testing for individuals of either sex with intellectual disability, developmental delay, or autism, especially if they have any of the following: [Moeschler: 2014]
  • Any physical or behavioral characteristics of fragile X syndrome
  • A family history of fragile X syndrome
  • A male or female relatives with undiagnosed intellectual disability

Other Testing

Unless seizures are clinically present, EEGs are not recommended. Approximately 5% of girls and 15% of boys with FXS have seizures, generally in childhood. [Hagerman: 2009]

Specialty Collaborations & Other Services

Medical Genetics (see UT providers [6])

A medical geneticist may be helpful in sorting out heritable causes of developmental delay, intellectual disability, or characteristic 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 genetic counselor.

Genetic Testing and Counseling (see UT providers [13])

Refer for education and guidance 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 UT providers [5])

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 UT providers [5])

Presence or suspicion of strabismus, visual deficit, ptosis, or nystagmus should trigger referral to a pediatric ophthalmologist.

Pediatric Orthopedics (see UT providers [21])

Periodic screening for joint laxity may be helpful. Children with club feet, scoliosis, or dislocated hips should be followed by a pediatric orthopedic surgeon.

Developmental - Behavioral Pediatrics (see UT providers [9])

For developmental assessment and coordination of related services, such as PT, OT, speech, and behavioral therapy.

Therapy/Counseling > … (see UT providers [674])

Assessments may be helpful in guiding educational placement and approaches. Psychologists may also help manage behavior problems, such as aggression, anxiety, and attentional deficits.

Psychiatry/Medication Management (see UT providers [56])

Some children with fragile X syndrome will benefit from medication for behavior problems. Evaluation by a child psychiatrist should be considered.

Pediatric Neurology (see UT providers [5])

About 15% of boys and 5% of girls have seizures and may benefit from referral to pediatric neurology.

Treatment & Management

Overview

Management of behavioral problems and optimal educational placement constitute the central challenges of care in the older child and adolescent with FXS. The subspecialists listed above can provide the necessary guidance for these issues.

Pearls & Alerts for Treatment & Management

Targeted treatments

Although still under study, treatments targeted at the neurobiological problems in FXS may one day be helpful. The ADHD observed in both boys and girls can be managed effectively by primary care providers. Anxiety and depression may be managed by experienced general pediatricians, but referral to child psychiatrists and developmental pediatricians is suggested if response is wanting. For a comprehensive guide to medications in FXS, see [Tranfaglia: 2019]. Three reviews summarize the current progress in various therapies under investigation. [Bagni: 2013] [Davenport: 2016] [Jalnapurkar: 2019]

How should common problems be managed differently in children with Fragile X Syndrome ?

Other

Common problems in children with fragile X syndrome should be managed much the same as other children, allowing for the developmental, intellectual, and behavioral components of the condition.

Systems

Development (general)

Developmental delay/intellectual disability should be assessed. Optimize the child's developmental outcome by referring to to early intervention, psychology, physical therapy, occupational therapy, and speech therapy.

Specialty Collaborations & Other Services

Early Intervention for Children with Disabilities/Delays (see UT providers [55])

No- or low-cost programs providing assessments and interventions for children with developmental delays.

Developmental - Behavioral Pediatrics (see UT providers [9])

May be helpful in assessment and management of developmental delays, cognitive abilities, behavioral challenges, and psychiatric conditions.

Pediatric Physical Medicine & Rehabilitation (see UT providers [15])

Speech, occupational, and physical therapies may be offered through government or school programs. Private services may be needed for specific problems or if the child doesn't qualify for other programs.

Genetics

Many genetic issues will arise during management of children with FXS, including management of the affected child, identification of other at-risk relatives, and risk for subsequent pregnancies of the parents and siblings. The following subspecialists may be helpful.

Specialty Collaborations & Other Services

Medical Genetics (see UT providers [6])

For periodic visits to follow FXS-specific problems in the child and counseling and support for families. If the family is considering another child and wish to discuss risks to future offspring, a visit to prenatal genetics may be helpful. Siblings of children with FXS may also benefit from a referral to prenatal genetics when considering becoming parents.

Genetic Testing and Counseling (see UT providers [13])

Refer for psychosocial counseling and education for the family regarding prognosis, family planning, and support. Genetic Counselors can also coordinate genetic testing for at-risk family members.

Learning/Education/Schools

Medical home providers can assist the family in working with preschool/school systems to assure appropriate accommodations, reasonable goal setting, and optimal support. All school-age children with FXS should have an Individualized Education Plan (IEP) aiming for the most inclusive, least restrictive environment possible and outlining reasonable goals for the child's education. These goals will vary with the child's IQ level and social abilities. IEPs are best developed with input from all the relevant disciplines – psychology, special education, speech therapy, occupational therapy – as well as from the family, teachers, and physicians. See the Resources section below and the Special Education Laws and Process in the Portal's Education Section.

Specialty Collaborations & Other Services

Educational Testing/Assessment (see UT providers [7])

IQ and achievement testing may be helpful in designing a school program.

Mental Health/Behavior

Behavior problems occur in over 50% of affected individuals and should be addressed with therapy and medications as necessary by the medical home with referrals to psychiatry or psychology if necessary. For information regarding the behavioral and cognitive profile of FXS, see [Reiss: 2007]. Symptoms that may respond well to treatment include ADHD, anxiety, aggression, and mood instability. For more information regarding treatment of mental health symptoms in boys with FXS, see [Hagerman: 2009] [Protic: 2019]
Worsening of behavioral symptoms is usually correlated with environmental characteristics “children with FXS residing in a higher quality home environment displayed fewer autistic behaviors, better adaptive behavior, and higher IQ level. Some of the characteristics of the home environment that may be a factor in these effects are parenting ability, parental expectations of child behavior, organization of the home, emotional climate, and enrichments in the home.” [Garber: 2008]

Specialty Collaborations & Other Services

Developmental - Behavioral Pediatrics (see UT providers [9])

Refer for management of behavior problems and some mood disorders.

Behavioral Therapies (see UT providers [35])

Refer to help design and implement behavioral programs for the home.

Psychiatry/Medication Management (see UT providers [56])

Refer for medical treatment of behavior problems and mood disorders.

General Counseling Services (see UT providers [372])

Refer for assessment and management of behavior, IQ/achievement, and autistic features.

Neurology

Seizures in children with FXS generally respond well to seizure medication, which should be prescribed based on the seizure type. Although complex partial seizures are the most common seizure type, others are also observed. [Hagerman: 2009] See the Seizures/Epilepsy for more information on seizure treatment.

Specialty Collaborations & Other Services

Pediatric Neurology (see UT providers [5])

Referral to a pediatric neurologist if seizures are occurring is recommended. Although seizures in children with FXS generally respond well to treatment, it is particularly important that a seizure medication with the fewest cognitive and behavioral side effects for each particular child is used for management of seizures.

Eyes/Vision

Periodic visits with pediatric ophthalmology are recommended if strabismus is present. Consider early screening for refractive errors in children with FXS.

Specialty Collaborations & Other Services

Pediatric Ophthalmology (see UT providers [5])

When vision problems are suspected or present

Cardiology

Although mitral valve prolapse is the most common cardiac problem in children with FXS, other abnormalities are also seen. Signs and symptoms that may be referable to the heart, such as palpitations, exercise intolerance, breathing problems, murmur, chest pain, etc., and aren't otherwise explained, should lead to a cardiology referral.

Specialty Collaborations & Other Services

Pediatric Cardiology (see UT providers [5])

Refer for evaluation of heart problems, including mitral valve prolapse.

Maturation/Sexual/Reproductive

Macroorchidism can be concerning to families. They can be reassured that it bears no relation to sexual functioning, nor does it signal precocious puberty, although it is more likely to be noticed in boys who are school-aged or older. Adolescents with FXS and intellectual disabilities need education about their sexuality and may need more supervision when with adolescents of the opposite sex.

Specialty Collaborations & Other Services

Medical Genetics (see UT providers [6])

A referral to medical genetics or genetic counseling, even if done previously, may be helpful to remind families and adolescents about risks to the offspring of the affected individuals.

Transitions

As children with FXS become adolescents, planning for transitions to adulthood should begin, including planning for potential guardianship, vocational training, group home placement, and seeking adult medical care. A 2020 study and literature review offered recommendations for transitional and adult care in several domains, including physical and mental health, participation and work, relationships and sexuality, and several environmental factors (financial problems, living circumstances, parental stress, and others). [Van: 2020]
See Resources below and the Transition Issues section of the Portal.
No Related Issues were found for this diagnosis.

Ask the Specialist

Why do some children with fragile X syndrome have more severe features than others, even in the same family?

As in all genetic syndromes, there is variable expressivity of clinical features, and most of the time, the biological reason for this is not fully understood. For FXS, some of the variability in males can be explained by mosaicism for the full mutation. In girls, the typical milder expression is best explained by the process of random inactivation (Lyonization), where the X chromosome with the expanded repeat is inactivated more than the X with the normal repeat size.

Do premutation carriers show any signs of FXS?

Approximately 50% of premutation carriers with 55 – 200 CGG repeats have neuropsychiatric disorders. These disorders may include anxiety (~70%), ADHD, social deficits, or autism spectrum disorder in children. In adults with the premutation, anxiety, and depression (~40%) are the most common problems, although obsessive-compulsive disorder, ADHD, substance abuse, and chronic fatigue are common. Together, these conditions are called Fragile X-associated Neuropsychiatric Disorders or FXAND. Treatment of depression and anxiety disorders usually involve selective serotonin reuptake inhibitors (SSRIs) or norepinephrine reuptake inhibitors (SNRIs) and can be managed by the pediatrician. [Hagerman: 2018]

At what age should carrier testing be offered to at-risk females, e.g., sisters of affected boys?

If a woman has no signs or symptoms of the condition but has a positive family history for FXS, carrier testing (testing for a premutation allele) may be performed at 18 years or older. It is also important to remember that 20% of women who carry a premutation allele may have primary ovarian insufficiency before 40 years. Knowing carrier status may help individuals in reproductive planning.
Careful consideration regarding timing of carrier testing should be discussed with the parents/guardian of a patient. While it is important to preserve autonomy in a young child who may not show typical characteristics of FXS, it is essential to consider that some girls can appear unaffected but may have a full mutation. These individuals may benefit from early diagnosis of some of the features of FXAND (Fragile X Associated Neuropsychiatric Disorders) as well as early intervention and school support.

Resources for Clinicians

On the Web

FMR1-Disorders (GeneReviews)
Detailed information addressing clinical characteristics, diagnosis/testing, management, genetic counseling, and molecular pathogenesis; from the University of Washington and the National Library of Medicine.

Helpful Articles

PubMed search for articles over the last 3 years about fragile X in children and adolescents

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

Protic D, Salcedo-Arellano MJ, Dy JB, Potter LA, Hagerman RJ.
New Targeted Treatments for Fragile X Syndrome.
Curr Pediatr Rev. 2019;15(4):251-258. PubMed abstract / Full Text
Discusses the new era of pharmacotherapeutic approach to patients with FXS and combinations of medications that may be beneficial in those with FXS depending on the individual constellation of comorbid symptoms.

Boyle L, Kaufmann WE.
The behavioral phenotype of FMR1 mutations.
Am J Med Genet C Semin Med Genet. 2010;154C(4):469-76. PubMed abstract

Wheeler A, Raspa M, Bann C, Bishop E, Hessl D, Sacco P, Bailey DB Jr.
Anxiety, attention problems, hyperactivity, and the Aberrant Behavior Checklist in fragile X syndrome.
Am J Med Genet A. 2014;164A(1):141-55. PubMed abstract

Mila M, Alvarez-Mora MI, Madrigal I, Rodriguez-Revenga L.
Fragile X syndrome: An overview and update of the FMR1 gene.
Clin Genet. 2018;93(2):197-205. PubMed abstract

Raspa M, Wheeler AC, Riley C.
Public Health Literature Review of Fragile X Syndrome.
Pediatrics. 2017;139(Suppl 3):S153-S171. PubMed abstract / Full Text

Clinical Tools

Letters of Medical Necessity

Fragile X Syndrome / High-Resolution Chromosome Analysis - Letter of Medical Necessity / Preauthorization (PDF Document 119 KB)
A sample of a letter requesting preauthorization for diagnostic testing.

Toolkits

Health Care for Adults with Intellectual & Developmental Disabilities - Toolkit for Clinicians (Vanderbilt)
Health Watch Tables and checklists for autism, Down syndrome, fragile X, Prader-Willi, Williams syndrome, and 22q11.2 deletion syndrome. Developed for primary care providers of adults with developmental and intellectual disabilities; Kennedy Center for Excellence in Developmental Disabilities.

Health Watch Table – Fragile X Syndrome (Forster-Gibson and Berg)
Considerations and recommendations for the treatment of patients with Fragile X Syndrome.

Resources for Patients & Families

National & Local Support

Fragile X Syndrome (MedlinePlus)
Information for families that includes description, frequency, causes, inheritance, other names, and additional resources; from the National Library of Medicine.

FRAXA Research Foundation
Along with funding research, FRAXA runs scientific meetings, advises pharmaceutical companies, and provides education. Families can reach out to FRAXA for resources, guidance, referrals, and an international community of support.

National Fragile X Foundation
A non-profit organization run by parents of children with fragile X syndrome that supports research and families caring for children with fragile X syndrome.

Our Fragile X World
A research community dedicated to gathering practical information about experiences of individuals with fragile X syndrome and their families. Includes a list of organizations, programs, and groups that provides support, information, and community.

Studies/Registries

Fenobam (FRAXA Research Foundation)
Although in the early stages, fenobam, a selective mGluR5 antagonist, may be helpful in individuals with fragile X syndrome. So far, it has been tested only in adults.

Fragile X (clinicaltrials.gov)
Studies looking at better understanding, diagnosing, and treating this condition; from the National Library of Medicine.

National Fragile X Foundation – FORWARD Registry & Database
A patient and family registry plus a longitudinal database populated by clinician- and parent-reported data from individuals living with FXS.

Fragile X Research Registry
A database of people who want to be notified about fragile X research studies. It is a free, confidential, convenient way for families to connect with studies and move research forward.

Services for Patients & Families in Utah (UT)

For services not listed above, browse our Services categories or search our database.

* number of provider listings may vary by how states categorize services, whether providers are listed by organization or individual, how services are organized in the state, and other factors; Nationwide (NW) providers are generally limited to web-based services, provider locator services, and organizations that serve children from across the nation.

Authors & Reviewers

Initial publication: February 2013; last update/revision: January 2021
Current Authors and Reviewers:
Author: Karin Dent, MS, CGC
Senior Author: John C. Carey, MD
Reviewer: Victoria L. Wilkins, MD
Authoring history
2020: update: Karin Dent, MS, CGCA; John C. Carey, MDSA
2013: first version: Karin Dent, MS, CGCA; Lynne M. Kerr, MD, PhDA
AAuthor; CAContributing Author; SASenior Author; RReviewer

Bibliography

Bagni C, Oostra BA.
Fragile X syndrome: From protein function to therapy.
Am J Med Genet A. 2013;161A(11):2809-21. PubMed abstract

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.

Boyle L, Kaufmann WE.
The behavioral phenotype of FMR1 mutations.
Am J Med Genet C Semin Med Genet. 2010;154C(4):469-76. PubMed abstract

Carey J. (Editor), Cassidy S.B. (Editor), Battaglia A. (Editor), Viskochil D. (Editor).
Management of Genetic Syndromes.
4th ed. Hoboken, NJ: John Wiley & Sons; 2020. 978-1-119-43267-8 https://www.wiley.com/en-us/Cassidy+and+Allanson's+Management+of+Genet...

CDC.
Delayed diagnosis of fragile X syndrome--United States, 1990-1999.
MMWR Morb Mortal Wkly Rep. 2002;51(33):740-2. PubMed abstract

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An AAP Clinical Report that provides guidance for primary care clinicians assisting families in preparing for a genetic evaluation; reaffirmed 2020.

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The supplement includes: The Future of Fragile X, Literature Review, Implications of the FMR1 Premutation, Registry and Longitudinal Clinical Database, Autism and Fragile X, Newborn Screening and Fragile X, and Lessons from a Multisite Screening Study.

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