rendering pediatric care clinical report—health ... · patients with fragile x syndrome....

Clinical Report—Health Supervision for Children WithFragile X Syndrome

abstractFragile X syndrome (an FMR1–related disorder) is the most commonlyinherited form of mental retardation. Early physical recognition is dif-ficult, so boys with developmental delay should be strongly consideredfor molecular testing. The characteristic adult phenotype usually doesnot develop until the second decade of life. Girls can also be affectedwith developmental delay. Because multiple family members can beaffected with mental retardation and other conditions (prematureovarian failure and tremor/ataxia), family history information is ofcritical importance for the diagnosis and management of affected pa-tients and their families. This report summarizes issues for fragile Xsyndrome regarding clinical diagnosis, laboratory diagnosis, geneticcounseling, related health problems, behavior management, and age-related health supervision guidelines. The diagnosis of fragile X syn-drome not only involves the affected children but also potentially hassignificant health consequences for multiple generations in each fam-ily. Pediatrics 2011;127:994–1006

INTRODUCTIONThis set of guidelines was designed to assist pediatricians in caring forchildren with fragile X syndrome after a diagnosis has been confirmedby DNA analysis. Fragile X syndrome (secondary to an abnormality inthe fragile X mental retardation 1 [FMR1] gene) is the most commonlyinherited formofmental retardation. The disorder affects the child andpotentially the mother and other family members. These guidelines,therefore, discuss issues pertinent to the clinical manifestations ofthis disorder in younger and older people. The multiple manifestationsin different age groups have led to fragile X syndrome being designatedas one in the spectrum of FMR1-related disorders.1

Awareness that mental retardation has a sex-linked component, withan excess of males affected, has existed for more than a century.2 Thisobservation led to the suggestion that genes affecting cognition werelocated on the X chromosome. In 1943, Martin and Bell3 reported thatmental retardation segregated as an X-linked gene in a family in whichboth males and females were affected. Twenty-six years later, in 1969,Lubs4 reported a distinctive fragile site on the X chromosome, whichrequired culture media deficient in folic acid to be induced on a chro-mosome analysis, that segregated with mental retardation in 3 gener-ations of a family. This is now known as the fragile X chromosome. In1977, the relationship of this fragile site at band q27.3 on the long armof the X chromosome (Xq27.3) to X-linked mental retardation was con-firmed, and fragile X syndrome, as a clinical entity, was defined. Since

Joseph H. Hersh, MD, Robert A. Saul, MD, and COMMITTEEON GENETICS

KEY WORDSfragile X syndrome, FMR1–related conditions, mentalretardation, health guidelines

ABBREVIATIONSFMR1—fragile X mental retardation 1 geneCGG—cytosine-guanine-guanineFMRP—fragile X mental retardation 1 proteinmGluR—metabotropic glutamate receptorPOI—primary ovarian insufficiencyFXTAS—fragile X–associated tremor/ataxia syndrome

This document is copyrighted and is property of the AmericanAcademy of Pediatrics and its Board of Directors. All authorshave filed conflict of interest statements with the AmericanAcademy of Pediatrics. Any conflicts have been resolved througha process approved by the Board of Directors. The AmericanAcademy of Pediatrics has neither solicited nor accepted anycommercial involvement in the development of the content ofthis publication.

The guidance in this report does not indicate an exclusivecourse of treatment or serve as a standard of medical care.Variations, taking into account individual circumstances, may beappropriate.

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that time, the clinical and molecularfeatures of the condition have beenmore clearly delineated. Several liter-ature sources are available for addi-tional information.1,5–7 New informa-tion regarding the role of the proteinproduct in synaptic plasticity in thebrain is under investigation.8

The clinical phenotype of fragile X syn-drome, including cognitive abilities, isvariable, and physical features oftenare nonspecific in nature, especially inyoung children. The disorder has beendescribed in every ethnic group andhas an estimated prevalence of 1 in3700 white males and 1 in 2500 blackmales.1 Clinical manifestations of frag-ile X syndrome also may occur inheterozygous females, in whom theprevalence is estimated to be 1 in 7000.

Molecular Basis of Fragile XSyndrome

Cytogenetic assay for fragile X syn-drome is no longer regarded to be suf-ficiently precise for clinical diagnosticuse. In 1991, the FMR1 gene wasmapped to the fragile site at Xq27.3.5,9

FMR1 harbors a novel, unstable CGG(cytosine-guanine-guanine) trinucle-otide repeat within the 5=-untranslatedregion of the gene, which accountsboth for the fragile site and the geneticpeculiarities associated with the re-gion. The CGG repeat is highly polymor-phic in the general population. The nor-mal range is from 5 to 40, and 30 CGGrepeats represents the most commonnumber foundwithin the gene. Full mu-tations, which cause fragile X syn-drome, are the consequence of unsta-ble expansion of the repeats, whichresults in a CGG number that exceeds200. A full mutation results in hyper-methylation of FMR1, which leads togene-silencing and a decrease in theproduction of the fragile X mental re-tardation 1 protein (FMRP). The mostimportant factor that determines theclinical severity of fragile X syndrome

is the degree of FMR1methylation andgene-silencing rather than the lengthof expansion reflected by the numberof CGG repeats, which explains why 2people with the same number of ex-panded CGG repeats but differentFMRP levels will have different clinicalpresentations, because methylationmay differ. Classically, in a person witha full mutation, the repeat number ismassively expanded. Premutations,which have a CGG repeat number thatranges from 55 to 200, are meioticallyunstable in the female. Premutationsare unmethylated, are transcription-ally active, and produce FMRP, al-though possibly in lower amounts thannormal alleles. Repeats in the range of45 to 54 are considered to be interme-diate or “gray-zone” alleles and are notconsidered to be predisposed to mei-otic instability.1 Molecular clinicalcorrelations have demonstrated thatvariation in the clinical phenotype ofaffected people is related to thepresence of mosaicism of methyl-ation status, which results in preser-vation of some gene function andpartial expression of FMRP. Althoughmost instances of fragile X syndromeresult from CGG expansion into thefull mutation range, a rare point mu-tation within the FMR1 gene or dele-tion in FMR1 can produce the typicalphenotype of fragile X syndrome aswell.

Clinical Phenotype

The clinical phenotype in males withfragile X syndrome can be subtle, andits detection in the prepubertal periodcan be difficult. In fact, it was reportedfrom a parent survey that 24% of fam-ilies with a child in whom fragile X syn-drome was diagnosed had seen ahealth care provider more than 10times before fragile X testing was per-formed.10 Often, it is the presence ofdevelopment delay, mental retarda-tion, or specific behavioral patternsthat leads to suspicion of fragile X syn-

drome; mean age at diagnosis is 32months. The classical facial appear-ance that includes a prominent fore-head, a long, narrow face, a prominentjaw, and protuberant ears becomesmore evident late in childhood or inearly adolescence. The palate fre-quently is highly arched, and cleft pal-ate has been reported. Dental crowd-ing and malocclusion are common.Strabismus may be present, and re-fractive errors, including hyperopiaand astigmatism, are present in 23%to 50% of cases. Nystagmus and ptosisalso are occasional ocular findings.Macro-orchidism is observed in morethan 80% of adolescent and adultmales with fragile X syndrome; meantesticular volume is approximately 50mL (normal mean testicular volume:�25 mL). Macro-orchidism is lesscommon in prepubertal boys. Fragile Xsyndrome also has a connective tissuedysplasia, and findings may includesoft velvet-like skin; joint hypermobil-ity, especially in the fingers; pes pla-nus; congenital hip dislocation; scolio-sis and clubfoot; and, in adults,occasionally mitral valve prolapse.6

Feeding problems are common, andgastroesophageal reflux has been re-ported for one-third of affected in-fants. Chronic otitis media, seen in60% to 80% of cases, has its onsetearly in life, and recurrent otitis me-dia is present in 23% of males withfragile X syndrome. Seizures havebeen reported in approximately 13%to 18% of affected males and 5% offemales with a full mutation, andthere may be relative macrocephaly.Birth weight in affected people typi-cally is normal. Accelerated lineargrowth with tall stature is commonthroughout childhood; however,growth velocity tends to slow in ado-lescence, and 26% of adult men withfragile X syndrome have a height thatis equal to or less than the 5thpercentile.6(p27–28)

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A subgroup of males with the fullmutation has been described in whichthe clinical phenotype is reminiscent ofPrader-Willi syndrome.11 Affectedmales have extreme obesity, shortstature, stubby hands and feet, anddiffuse hyperpigmentation.

Cognitive Profile

Fragile X syndrome should be sus-pected in a boy with developmental de-lay and hypotonia in early childhood.Cognitive deficits frequently result inmoderate-to-severe mental retarda-tion; the average IQ is approximately 40in an adult man with a completelymethylated full mutation. Males whoare less severely affected can have in-complete methylation resulting insome gene product and present withonly mild intellectual deficits or learn-ing problems. In addition, slowing inthe acquisition of cognitive skills canoccur with age.

Language delay also is evident in earlychildhood. A child with fragile X syn-dromemaynot begin to speakuntil 2 to 3years of age. Although vocabulary andsyntax may be less involved, deficits inconversational speech are frequent.

In femaleswith a full mutation, the cog-nitive profile is similar to that of males,but there is wider phenotypic variabil-ity, especially in relation to IQ scores.Intellectual abilities range from nor-mal to significant mental retardation,and the majority of females with a fullmutation have a normal or borderlineIQ. The milder phenotype in affected fe-males correlates with the degree of Xinactivation of the X chromosome thatcontains the CGG expansion during ly-onization. A more severe phenotypewould be anticipated when there isskewed X inactivation (eg, when themajority of X chromosomes randomlyinactivated are those with a normalCGG repeat number), thus preferen-tially activating the X chromosomewith an expanded CGG repeat number.

Neurobiology

Gross abnormalities have not been ob-served in the brains of people withfragile X syndrome on autopsy. Al-though diffuse brain atrophy andwhitematter abnormalities have been notedon MRI, routine neuroimaging of thebrain is not indicated. At the cellularlevel, longer and thinner dendriticspines on which most of the synapsesoccur have been detected, which sug-gests a possible misregulation in theirdevelopment and maturation. FMRPhas an important role in the regulationof protein synthesis at a local level inthe dendrites of neurons. Protein syn-thesis in dendritic spines is importantfor synaptic transmission, synapticplasticity, learning, andmemory. A pro-posed role for FMRP at the synapse isthat it is a negative regulator of proteinsynthesis stimulated by group 1metabo-tropic glutamate receptor (mGluR) acti-vation.8 Therefore, fragile X syndromeis at least partially a result of exagger-ated responses to mGluR stimulation.

Behavioral Phenotype

Behavioral problems occur in morethan 50% of affected patients and aregenerally out of proportion with the af-fected child’s cognitive level, comparedwith children with other developmentaldisorderswhoare functioningat similarintellectual levels.6,7 In general, behav-ioral difficulties can be separated intoa few symptom clusters. Features ofattention-deficit/hyperactivity disor-der, including hyperactivity, inatten-tiveness, distractibility, restlessness,and impulsivity, are present in 80% ofpatients with fragile X syndrome. Af-fected children also can exhibitanxiety-related symptoms includingobsessive-compulsive–like and perse-verative behaviors. Emotional labilityis common. Aggressive and self-injurious behaviors can occur, relatedto a difficult temperament, with irrita-bility and frequent temper tantrums.

Hypersensitivity to sensory stimuli canlead to heightened and prolongedarousal in situations in which there isexcessive auditory, visual, or tactilestimuli. This behavior can lead to anincrease in tantrums, hyperactivity,oppositionality, and restricted verbaloutput. On the other hand, affectedmales often have a good sense of hu-mor, are persistent and hardworking,and have an endearing quality. Fea-tures of autismmay be present in earlychildhood, including stereotypies suchas hand-flapping, biting, perseverativespeech, poor eye contact, and lack ofinterest in social interaction. Autism ispresent in 30% of people with a fullmutation, and pervasive developmen-tal disorder–not otherwise specifiedhas been reported in another 20% to30% of affected children. Fragile X syn-drome also is found in approximately2% to 6% of people with autism. Psychi-atric comorbidity also is frequently ob-served in affected people and includesoppositional defiant disorder, separa-tion anxiety, and obsessive-compulsivedisorder. Females with a full muta-tion tend to have a higher risk ofemotional problems compared withthe general population. In fact, shy-ness, social avoidance, social anxi-ety, mood lability, and depressionmay be presenting features in a fe-male with the full mutation.

Premutation

Both females and males with a CGG re-peat number that ranges from 55 to200 are considered to carry a premu-tation. The prevalence of a premuta-tion has been estimated to be approx-imately 1 in 259 in females and 1 in 813inmales. People carrying the premuta-tion originally were believed to be clin-ically normal, because the FMR1 geneis not methylated with a CGG repeatnumber below 200, which results inFMRP activity. However, it is now rec-ognized that carriers of a premutationcan present with 1 or more distinct


clinical disorders: mild cognitiveand/or behavioral deficits; primaryovarian insufficiency (POI); and aneurodegenerative disorder in olderadult premutation carriers, especiallymales, called fragile X–associatedtremor/ataxia syndrome (FXTAS). Incontrast to decreased messenger RNA(mRNA) in people with a full mutationand absence of FMRP, mRNA levels areelevated and FMRP is present in peoplewith a premutation.

A minority of female carriers of a pre-mutation have mild physical featuresof fragile X syndrome, which can in-clude prominent ears or hypermobilefinger joints. Emotional problems alsomay be present, including anxiety, ob-sessional thinking, schizotypy, and/ordepression. It was observed recentlythat depression and interpersonalsensitivity were more likely to occurin females with a premutation withmore than 100 CGG repeats than inthose with fewer repeats.12 Theseemotional findings are likely to rep-resent a mild form of the anxiety andperseverative thinking that occurs inthose with a full mutation and may bethe result of a mild deficit in FMRPfound in the upper half of the premu-tation range. Males with a premutationare prone to have attentional problems,executive dysfunctions, social deficits,and obsessive-compulsive behavior.13

A disorder unique to female carriers ofa premutation is POI (previously re-ferred to as premature ovarian failure[POF]), in which there is cessation ofmenses before 40 years of age.14–17

This disorder is seen in approximately20% of women who carry a premuta-tion allele, in contrast to approxi-mately 1% in the general population.Subclinical ovarian dysfunction thatleads to elevated follicle-stimulatinghormone levels is seen in another 25%of adult women younger than 40 yearswith a premutation. An increased risk

of twinning also exists for conceptionsin a woman with a premutation.

Recently, a new phenotype that devel-ops in the later years of the majority ofadult men who carry a premutation(rarely reported in female premuta-tion carriers) has emerged, desig-nated FXTAS.18,19 A progressive inten-tion tremor develops after 50 years ofage and is typically followed by ataxia.Associated features include a periph-eral neuropathy; parkinsonian mani-festations; autonomic dysfunctionsuch as incontinence, impotence, andorthostatic hypotension; progressivecognitive impairments that involveloss of memory and deficits in execu-tive function; and psychological fea-tures including disinhibition, anxiety,mood lability, irritability, outbursts,depression, and isolation. Some pa-tients progress to having dementia. Thisneurodegenerative disorder seemspathogenetically distinct from fragileX syndrome and is probably related toFMR1 messenger RNA levels that areelevated in premutation carriers.FXTAS has not been observed in maleswith a full mutation. Maternal grandfa-thers of affected males should be coun-seled and evaluated as appropriate foradult-onset movement disorders.

The expansion of the number of CGGrepeats occurs during reproduction ina female with a premutation. This maybe a small expansion to a slightlylarger CGG repeat number in the pre-mutation range, or it may result in amassive expansion into a full mutation.The risk of expansion to a full mutationis determined by the size of the moth-er’s premutation. As the CGG repeatnumber increases, so does the risk ofexpansion to a full mutation (Table 1).Therefore, the larger the number of re-peats, themore likely it will expand to afull mutation in an offspring. To date,no offspring with a full mutation hasbeen described when the CGG repeatnumber is less than 59. Because the

number of CGG repeats in a femalewith a premutation has the potential toincrease through several generationsof a family, the risk of expansion to afull mutation also increases.

A premutation will be transmitted toall female offspring of a male with apremutation. In these females, the CGGrepeat number is similar to their fa-thers’ repeat number or may expandslightly. However, the CGG repeat num-ber may undergo expansion when a fe-male with a premutation reproduces,which could result in an offspring witha full mutation and fragile X syndrome.A premutation in a male will not betransmitted to his male offspring, be-cause the son inherits his father’s Ychromosome.

Who Should Be Tested for Fragile XSyndrome

Because children with fragile X syn-drome may not have apparent physi-cal features, any child who presentswith developmental delay, border-line intellectual abilities, or mentalretardation or has a diagnosis of au-tism without a specific etiologyshould undergo molecular testingfor fragile X syndrome to determinethe number of CGG repeats (Fig 1).Approximately 2% to 6% of these pa-tient populations will be found to havean FMR1 mutation. The family shouldbe made aware of the implications ofthe testing for other family membersand given the option of genetic coun-seling before testing. Array compara-tive genomic hybridization (or array

TABLE 1 Risk of Expansion to a Full Mutationin Male Offspring Based on the CGGRepeat Number in the Mother1,34

CGG RepeatNumber

Risk for Expansion toa Full Mutation, %

59–69 3770–79 6580–89 7090–99 95�100 100




testing) should also be considered.Phenotypic checklists have also beencreated for use in males with develop-mental delay of undetermined etiologyto help identify candidates for fragile Xmolecular testing. These checklistsslightly increase the diagnostic yield,especially when used in concert withtargeted family fragile X historyquestionnaires. Fragile X testingshould also be considered in pa-tients in whom there is suspected,but not molecularly proven, Sotossyndrome or Prader-Willi syndrome.On the other hand, fragile X testing,is not routinely warranted for chil-

dren with isolated attention-deficit/hyperactivity disorder.

When evaluating a family with fragileX syndrome, questions also shouldaddress whether there are peoplewith mild emotional and/or learningproblems, POI, and/or features of FX-TAS. Because people with a premuta-tion are at risk of having theseconditions, molecular testing is sug-gested for asymptomatic siblings ofa child with fragile X syndrome andfor other family members at risk ofcarrying the mutation. In familymembers found to have a premuta-

tion allele (55–200 CGG repeats),developmental testing may beindicated, and in older people, moni-toring is warranted for POI andFXTAS.

Management of a Child WithFragile X Syndrome

Diagnosing fragile X syndrome is ben-eficial to the family, because it estab-lishes the reason why a child has cog-nitive deficits and/or behavioralproblems. Establishing a diagnosis offragile X syndrome also will allow par-ents and/or caregivers to gain an un-derstanding of the disorder and how itaffects the child’s development and be-havior. Diagnosis also will allow thefamily to focus on appropriate man-agement strategies that will maxi-mize their child’s potential. Formalassessment tools are available toassist with a behavior-managementplan. Current approaches to therapyare supportive and symptom based.Psychopharmacologic interventionto modify behavioral problems in achild with fragile X syndrome mayrepresent an important adjunctivetherapy when combined with othersupportive strategies includingspeech therapy, occupational ther-apy, special educational services,and behavioral interventions. Medi-cation management may be indi-cated to modify attentional deficits,problems with impulse control,and hyperactivity. Anxiety-relatedsymptoms, including obsessive-compulsive tendencies with perse-verative behaviors, also may bepresent and require medical inter-vention. Emotional lability and epi-sodes of aggression and self-injurymay be a danger to the child and oth-ers around him or her; therefore, theuse of medication(s) to modify thesesymptoms also may significantly im-prove an affected child’s ability to par-ticipate more successfully in activitiesin home and school settings.

FIGURE 1Testing algorithm for fragile X syndrome and FMR1-related disorders. a Adults to be considered forFMR1molecular testing. (Adapted with permission from Saul RA, Tarleton JC. FMR1-related disorders.GeneReviews [online]. October 28, 2010. Available at: www.ncbi.nlm.nih.gov/books/NBK1384. Copy-right, University of Washington, Seattle, 1997–2010.)


www.ncbi.nlm.nih.gov/books/NBK1384

Several classes of medications aloneor in combination have proven to bebeneficial in managing behavior prob-lems in fragile X syndrome.7,20 Stimu-lants target hyperactivity, inattention,and impulsivity, and two-thirds tothree-quarters of symptomatic chil-dren with fragile X syndrome benefitfrom the use of methylphenidate. How-ever, in some affected people, stimu-lants may exacerbate anxiety, mood la-bility, or aggressive tendencies. The�-2-adrenergic agonists clonidine andguanfacine have been effective in treat-ing hyperactivity, hyperarousal to sen-sory stimuli, impulsivity, and aggressivebehaviors in approximately 70% ofyoung boys with fragile X syndrome.Theseagentsmaybeespeciallyhelpful ina child who is younger than 5 years anddoes not tolerate or respond to stim-ulants. Clonidine also is effective forthe management of sleep distur-bances,21 and melatonin may bebeneficial for regulating sleeppatterns.22

Selective serotonin-reuptake inhibi-tors can be useful in the managementof mood disorders, anxiety, obsessive-compulsive behaviors, tantrums, andaggression in people with fragile X syn-drome. Atypical antipsychotics gener-ally are reserved for people with frag-ile X syndrome who exhibit moreextreme behaviors, particularly ag-gression, marked mood lability, self-injury, and other undesired behaviors.Parent reports of improvement inmood stabilization, attention, and aca-demic performance have been de-scribed with aripiprazole, whichshould be used at low doses to avoidagitation induced by higher doses.23

However, adverse effects can includeexcessive weight gain, sedation, nau-sea, constipation, diabetes, and tar-dive dyskinesia.24

Current psychopharmacologic ther-apy for fragile X syndrome is support-ive or symptom-based, and no therapy

exists that is specifically directed atimproving cognitive ability in patientswith fragile X syndrome. However, be-cause excessivemGLuR signaling playsa role in the fragile X syndrome pheno-type, drugs that target mGLuR may bean effective treatment in this disorder.As more information regarding spe-cific dendritic functions of FMRP areelucidated, pharmacologic investiga-tions will likely be designed to addressspecific neurochemical and synapticdeficits generated by the absence ofFMRP, targeting cognitive deficitsand also leading to improvements inbehavior.7,25

Factors in the environment also mayinfluence adaptive behaviors, cogni-tive abilities, and behavioral symp-toms of patients with fragile X syn-drome. For instance, in 1 study,behavioral symptoms in childrenwith fragile X syndrome who residedin a nurturing home environmentdisplayed few autistic behaviors, bet-ter adaptive behavior, and higherIQ.26

Genetic Counseling

Fragile X syndrome and FMR1-relateddisorders (ie, POI and FXTAS) are inher-ited in an X-linked dominant mannerwith often complex expression. Geneticcounseling is recommended for all fam-ily members who are affected or at riskof having a premutation or an offspringwith a full mutation. Genetic counselingis critical to provide information regard-ing the inheritance pattern and variabil-ity of the clinical phenotype in people be-ingaffectedwithbotha fullmutationandpremutation and to offer the option ofpursuing molecular testing. Options forreproductive planning can be discussedin anticipation of family planning foradults at risk of having an affected child.In addition to seeking help from profes-sionals who are knowledgeable of thecondition, information to assist familiesalso can be obtained from support orga-

nizations and through contact with par-ents who have a similarly affected child.

Themother of a child with an FMR1mu-tation is almost always a carrier of apremutation or full mutation. Femaleswho are premutation carriers mayhave inherited the premutation fromtheir father or from their mother whoalso carries a premutation. Womenwith a premutation are at risk of pre-mature ovarian insufficiency and atsmall risk of FXTAS. They carry a 50%risk of transmitting an abnormal gene,which either contains a premutationcopy number (55–200) or a full muta-tion (�200) in each pregnancy. Rarely,a decrease in the number of CGG re-peats has been reported when the ab-normal allele is transmitted from awoman with a premutation to herdaughter. The risk of expansion of apremutation in a mother to a full mu-tation in her offspring correlates withthe number of CGG repeats in her mu-tation. Therefore, the higher the num-ber of repeats in the mother, thegreater likelihood of expansion to a fullmutation in her offspring (Table 1).

Males who are premutation carriersare referred to as transmitting males.During reproduction, all of theirdaughters will inherit a premutation,but their sons will not inherit the pre-mutation, because they inherit a Ychromosome. All daughters of trans-mittingmales are unaffected premuta-tion carriers. Transmitting males alsoneed to be aware of the risk of devel-oping FXTAS after the fifth decade oflife.

Males with a full mutation, in most in-stances, have mental retardation anddecreased fertility. The FMRP plays arole in spermatogenesis, and in 1study it was found that in later stagesof spermatogenesis, menwith fragile Xsyndrome had significantly malformedspermatids and a reduction in nor-mally differentiated spermatids, whichmay cause reduced fertility. A full




mutation cannot be maintained dur-ing spermatogenesis; therefore, thesperm contains only expanded FMR1gene CGG repeat sizes in the premuta-tion range.

Both males and females can havemosaicism as a result of either fullmutation/premutation mosaicism ormethylation/unmethylation mosaicism.In men, only a premutation will betransmitted to their female offspring.27

Women with a full mutation are at 50%risk of havingmale or female offspringwith a full mutation.

Genetic counseling is more problem-atic when CGG repeats are in therange of 41 to 58 in the FMR1 allele.This is viewed as a “gray zone,” be-cause unstable alleles of this sizehave been reported, but expansion isunlikely. To date, the smallest repeatnumber to expand to a full mutationin a single generation was 59 CGGrepeats.

Because fragile X syndrome can be dif-ficult to diagnose in a child, variousstudies have documented that 50% offamilies with males with fragile X syn-dromemay have their second child be-fore the diagnosis is established in thefirst child.3,28–30 Families with an af-fected male have indicated that earlydiagnosis would have influenced theirreproductive decision-making. After adiagnosis was made, 73% of familiesreported that the diagnosis of fragile Xsyndrome affected their decision tohave another child, and 43% of thefamilies surveyed had a second childwith a full mutation. Therefore, detec-tion of fragile X syndrome not onlywould enable at-risk families to re-ceive accurate reproductive counsel-ing for the immediate and extendedfamily but also could allow for appro-priate intervention beginning in in-fancy. Recently, a pilot study in SouthCarolina on newborn filter-paperblood screens to perform testing forfragile X syndrome was completed

and established the potential feasi-bility of such a screening process.31

Various policy issues still need to beconsidered.32

THE PRENATAL VISIT

In some instances, pediatricians maybe called on to counsel an expectantcouple whose fetus has been deter-mined to have fragile X syndrome orwhen there is a family history of thecondition. In some settings, the pedi-atrician may be the primary re-source for counseling parents andfamily members. The pediatricianshould:

1. Review thediagnostic studies that ledto establishment of the diagnosis.

2. Explain the cause of fragile X syn-drome in the fetus and the potentialfor a recurrence risk.

3. Review the clinical manifestations,the variability seen in fragile X syn-drome, and the long-term prognosis.

4. Review currently available treat-ments and interventions. This dis-cussion should include the efficacy,potential complications and ad-verse effects, and costs or otherburdens of these treatments.

5. Explore, using a nondirective ap-proach, the options available to thefamily for treatment and rearing ofthe child. In cases of prenatal diag-nosis, this approach may includediscussion of pregnancy continua-tion or termination, rearing thechild at home, foster care place-ment, or adoption.

It is strongly encouraged that thiscounseling be done in conjunction withgenetic counseling or referral to a ge-netic counselor or clinical geneticist toprovide a more in-depth discussion offragile X syndrome, including the asso-ciated medical conditions, prognosis,management strategies, recurrencerisk, future reproductive options, and

recommendations for evaluating at-risk family members.

Health care providers should ensurethat children with fragile X syndromeare afforded the standard care for allchildren as outlined in the AmericanAcademy of Pediatrics “Recommenda-tions for Preventive Pediatric HealthCare”33 and specific fragile X syndromehealth supervision guidelines accord-ing to their age (Table 2).

HEALTH SUPERVISION FROM BIRTHTO 1 MONTH: NEWBORNS (TABLE 2)

Examination

1. Examine the neonate for any ortho-pedic abnormalities, especially con-genital hip dysplasia and clubfoot.

2. Review the molecular testing re-sults with the family. In this agegroup, the diagnosis will only havebeenmade if there was a confirmedfamily history or if it was previouslyestablished in utero. Although thetypical phenotype of fragile X syn-drome generally will not be presentin the neonate, review the clinicalmanifestations and characteristicpatterns of growth and develop-ment and problems associatedwiththis condition, which may becomemore apparent with time. Evaluatethe neonate’s occipitofrontal cir-cumference, which may be in-creased, and begin to monitorhead-growth velocity.

3. Monitor for feeding difficulties andsymptoms of gastroesophagealreflux.

Anticipatory Guidance

1. Review the support groups and ser-vices that are available to the childand family. Supply written materi-als on fragile X syndrome and pro-vide the address and telephonenumber of organizations involvedin fragile X syndrome (eg, Na-tional Fragile X Foundation [www.


www.FragileX.org

FragileX.org], FRAXA ResearchFoundation [www.FRAXA.org]).

2. Discuss resources available forsupport, such as family clergy,men-tal health professionals, familieswho have an affected child residingin the area, and friends.

3. Discuss how and what to tell familymembers and friends about the ne-onate’s condition.

4. Review the recurrence risk for subse-quent pregnancies; discuss optionsfor family planning, including prena-tal and preimplantation genetic diag-nosis; or refer for formal geneticcounseling to address these issues.

5. Review the family history regardingevaluation of other family membersat risk of having a premutation or

full mutation, or refer for formal ge-netic counseling to address theseissues.

HEALTH SUPERVISION FROM 1MONTH TO 1 YEAR: INFANCY(TABLE 2)

Examination

Early growth and development maybe normal, although neurologic ab-normalities and delayed develop-ment may be present. Monitor the in-fant for the following problems:

1. Hypotonia that frequently results inmild motor delay.

2. Irritability, which is usually second-ary to sensory problems, includingtactile hypersensitivity.

3. Feeding problems, which are com-mon in infancy, and the presence ofvomiting secondary to gastro-esophageal reflux.


1. Monitor growth parametersclosely.

2. If feeding problems are severe, pur-sue diagnostic evaluations to deter-mine if they are the result of oralmotor problems and/or gastro-esophageal reflux. If gastroesopha-geal reflux is identified, initiate ap-propriate management strategiesor refer the infant for further eval-uation by a pediatric gastroenterol-ogist. If oral motor problems exist,refer the infant to an appropriate

TABLE 2 Fragile X Syndrome: Guidelines for Health Supervision

Infancy to 1 y Early Childhood,1–5 y

Late Childhood,5–12 y

Adolescence to EarlyAdulthood,�13 y

Newborn 1–6 mo 6–12 mo

ExaminationOcular �

a�a

�a

�a

� �

Ear, nose, throat — �b

�b

�b

� �

Skeleton �c — — — � �

Cardiac — — — — �d

�d

Measure testes — — — � � �

Development � � �e

� � �

Neurologic — — �f

� �g

�

Behavior �h

�h

�h

�h

�i

�i

Anticipatory guidanceGenetics �

j� � � �

k�k

Psychosocial �l

�l

�l

�l

�l —

Support groups � � � � � �

Early intervention, physicaland other therapies

— � � � � �

Behavior � � � � �m,n

�m,n

Education — — — �o

�p

�p

Health care providers should ensure that, in addition to the specific guidelines provided here, patients with fragile X syndrome are afforded the standard care for all children as outlinedin the American Academy of Pediatrics “Recommendations for Preventive Pediatric Health Care.”33 � indicates to be performed; —, not applicable.a Strabismus may occur anytime between birth and 4 years of age.b Serous otitis can occur throughout childhood, and the resulting hearing loss can further impair speech development. Pressure-equalizing tubes may be needed.c Joint laxity, hip dislocation, or clubfoot may be seen.d Mitral valve prolapse is possible.e Irritability, hypotonia, and tantrums may begin to be seen.f Seizures more commonly occur in this age group.g Assess for atypical seizures, especially when any neurologic symptoms exist or if intellectual function decreases.h Infants with fragile X syndrome are often described as stiff and irritable and may feed poorly.i Violent outbursts may appear in this age group.j Review molecular testing and discuss risks within the family; genetic counseling is strongly encouraged.k Review risk to offspring of the affected person.l Family support and issues of what to tell others are important at the time of diagnosis regardless of the child’s age.m Address sexual issues.n Ask parents about violent outbursts.o Review the preschool program with regard to special educational needs and future placement.p Discuss the need for planning for vocational training.



www.FragileX.org

www.FRAXA.org


interventionist to initiate feedingtherapy.

3. Review the available resources toprovide the infant with early-intervention services and assist theindividualized family service planteam in providing the most appro-priate services to maximize the in-fant’s developmental potential. Par-ents should consider applying forSupplemental Security Income(SSI) through the Social SecurityAdministration.

HEALTH SUPERVISION FROM 1 TO 5YEARS: EARLY CHILDHOOD(TABLE 2)

Examination

1. Perform an ophthalmologic evalua-tion or arrange for ophthalmologicreferral to check for strabismusand refractive errors, especially hy-peropia and astigmatism, whichare seen in 25% to 50% of affectedchildren. Also monitor for ptosisand nystagmus, which are seenoccasionally.

2. Evaluate the child for orthopedicproblems related to connective tis-sue dysplasia, such as pes planus(80% of affected children), hyper-mobile joints, and scoliosis. Prona-ted feet require treatment with or-thotics if a gait disturbance existsor there is uneven wearing ofshoes.

3. Examine the child for inguinal her-nias, especially at 1 to 3 years ofage.

4. Assess the child’s history for sei-zures or staring episodes and ob-tain an electroencephalogram ifclinically indicated.

5. Monitor the child for recurrent oti-tis media (60%–80% of affectedchildren), which could be associ-ated with conductive hearing loss,and also for recurrent sinusitis

(23% of affected children). Monitorthe child’s audiologic status yearly.

6. Receptive and expressive communi-cation should be monitored closely,because language delay is usuallyevident by 2 years of age. An occu-pational therapy evaluation alsomay be indicated and should in-clude an assessment of sensory in-tegration abilities. A complete psy-chological evaluation that includesIQ testing is an important part of thedevelopmental evaluation of thepreschool-aged child with fragile Xsyndrome. Affected children re-quire early developmental servicesto facilitate language, motor, andcognitive skills. These services aremandated by federal law andshould be followed by enrollment ina developmental preschool andsupplemented with special educa-tion services. Occupational andspeech-language therapy should beincorporated into the program andshould include continued attentionto language, motor, and cognitiveskills up to and including kindergar-ten. Computer technology with soft-ware programs that enhance lan-guage skills and early academicabilities, including reading andmathematics, can be incorporatedinto special education program-ming. Inclusion in a preschool set-ting is achievable with appropriatesupports.

7. Monitor the child’s emotional andbehavioral status closely. Tantrumsand hyperactivity frequently de-velop in the second year of life, es-pecially related to transitioning andexcessive sensory stimuli. Evidenceof anxiety and depression as well asthe presence of aggression andobsessive-compulsive behaviorsmay develop during this time pe-riod. Manifestations of autism, suchas hand-flapping, self-injury, pooreye contact, lack of social engage-

ment, and absent joint attentionmay be present before 3 years ofage and necessitate further evalua-tion. Excessive sensory stimulationshould be avoided when possible,including exposure to large crowdsand loud noises; earphones can beused in such settings to allow thechild to listen to a favorite tape orcalming music to avoid behavioraloutbursts. Significant behaviorproblems, such as tantrums, oppo-sitional behavior, or severe hyper-activity, usually benefit from inter-vention by a psychologist or otherbehavioral specialist. Behavioral in-tervention techniques that empha-size the importance of decreasingexcessive sensory stimuli and usingpositive behavioral reinforcementand the use of behavioral chartingare beneficial.

8. Psychopharmacologic interven-tions can be helpful. The use ofstimulant medication to treat hy-peractivity, short attention span,and impulsivity decreases symp-toms in approximately 60% to 70%of affected children but may bemore effective for a child who is ofschool age than of preschool age. Ata younger age, antihypertensivemedications, such as clonidine orguanfacine,may have a better calm-ing effect and improve hyperactivityand hyperarousal. For treatment ofanxiety, social phobia, obsessive-compulsive tendencies, depression,and aggression, use of a selectiveserotonin-reuptake inhibitor is safeand can be effective. Monitoring forthe development of akathisia (mo-tor restlessness) is important. Inaddition, in the presence of severemood instability and/or aggressionthat are unresponsive to a selectiveserotonin-reuptake inhibitor orstimulant medication, use of anatypical antipsychotic agent to pro-vide mood stabilization may be indi-


cated. Approximately 10% of peoplewith fragile X syndrome developpsychotic symptoms often associ-ated with severe paranoia, whichalso may lead to aggressivebehavior.

9. Linear growth during this periodshould be monitored closely, and lin-ear growth velocity should be similarto that of unaffected children.

10. Structural changes of the facemay start to become evident inpreschool years and include along face, high forehead, higharched palate, and prominentears. Facial changes can result indental crowding and malocclu-sion, and regular dental evalua-tion is recommended.

11. Occasionally, in affected children,obstructive sleep apnea occurs,which may be related, in part, tofacial changes but also can be theresult of the connective tissue dys-plasia and hypotonia of facial andpharyngeal muscles. Excessivesnoring, restless sleep, or fatigueduring the day should signal theneed for further evaluation ofthe child’s sleep problem withevaluation of adenoidal size andthe child’s sleep pattern by usingpolysomnography.

12. Delayed toilet-training is commonduring this age range and is likelyto reflect the child’s cognitivestatus.


The pediatrician should review thechild’s preschool placement and ancil-lary services that complement the pro-gram. Inclusion with typically develop-ing children should be consideredwhen appropriate and may require su-pervision in that setting. Consider aformal developmental evaluation anddiscuss the role of behavior/psycho-logical intervention when indicated.

1. Determine if behaviors such as hy-peractivity, aggression, self-injury,and tantrums warrant medicationmanagement.

2. Seizures are an important clinicalmanifestation that occurs in ap-proximately 20% of people withfragile X syndrome and usually havetheir onset in early childhood. Ap-propriate evaluation and treatmentis indicated when suspicion of sei-zures is present.

3. Auscultation of the heart should beperformed and blood pressureshould be obtained at all clinic vis-its. The presence of a murmur orclick should indicate the need forfurther evaluation by a pediatriccardiologist, and elevated bloodpressure will require monitoringand a determination of whethermedical treatment is indicated.

4. Delays in toilet-training can behelped by behavioral interven-tions including the use of a musicvideo to facilitate toilet-trainingfor people with developmentaldisabilities.6(p291)

5. Review the future reproductiveplans of the parents and discuss re-currence risk and family-planningoptions when indicated.

HEALTH SUPERVISION FROM 5 TO12 YEARS: LATE CHILDHOOD(TABLE 2)

1. Macro-orchidism usually begins todevelop at approximately 9 years ofage, and the testes will increase insize throughout puberty (mean tes-ticular volume in adulthood: �50mL). Testicular volume should bemeasuredwith an orchidometer, andboys shouldbeassessed for thepres-ence of a hernia, which occurs in ap-proximately 15% of males with a fullmutation. Assure the parents thatmacro-orchidism has no relation tosexual function and that it is not asign of precocious puberty.

2. Girls with the full mutation shouldbe monitored for the developmentof precocious puberty, which hasbeen reported occasionally. Al-though the cause in most instancesis unknown, hypothalamic dysfunc-tion has been describedwith fragileX syndrome and may be the causeof precocious puberty.

3. Continuing to monitor the child’sdevelopmental status is critical formaking certain that cognitive,speech and language, and motorneeds are being addressed. Beingprovided with reports of intervalprogress in school is useful in de-termining the effectiveness of thechild’s programming and whethermodifications or further evaluationare indicated.

4. Hyperactivity frequently will persistthroughout childhood and is pres-ent in approximately 70% to 80% ofaffected boys and 30% to 50% ofgirls with a full mutation. Address-ing this problem behaviorallyand/or in combination with medica-tion management may be indicated.

5. Monitor the child for obsessive-compulsive behaviors, especially be-cause they may blend in with perse-verative or repetitive behaviors andnot be recognized. Anxiety—espe-cially social anxiety—frequently ispresent, particularly in childrenwho do not have hyperactivity or im-pulsivity. Pursuing appropriatemanagement strategies to addressthe child’s emotional needs is im-portant for effective adaptation inthe home and school settings.

6. Cognitive impairments result inmental retardation in most boyswho have a full mutation that is fullymethylated (average IQ: �40). Oc-casionally, males with a full muta-tion are higher functioning becauseof incomplete methylation of FMRPas a result of mosaicism. Approxi-mately 50% of females with a full




mutation have cognitive deficits (IQrange: 70–84). Recognition of cog-nitive impairments and adaptivefunctioning deficits should signalthe need for pursuing appropriatesupport services in the school set-ting to meet the child’s needs.

7. In addition to delayed toilet-training, enuresis is common inboth boys and girls with fragile Xsyndrome. Although affected chil-dren are not considered to be at in-creased risk of recurrent urinarytract infections, the connective tis-sue dysplasia may predispose todilatation of the ureters and vesi-coureteral reflux.6(p27) Furtherevaluation of the urinary tractthrough radiographic and ultra-sonographic studies is indicated inthe presence of a urinary tract in-fection, and referral to a nephrolo-gist or urologist is indicated if uri-nary tract infections are recurrentin nature or a structural abnormal-ity or reflux is identified. Behavioralstrategies should be implementedin the presence of nighttime enure-sis. In addition, treatment of enure-sis may also require the use ofbehavior-modification techniquesand an alarm system. If unsuccess-ful, medication management withagents such as imipramine, oxybu-tynin (an anticholinergic agent), ordesmopressin acetate (an analogantidiuretic hormone) should beconsidered. Only occasionally willchildren require medication forthis problem. Macro-orchidism willbe maintained throughout adult lifeand does not require intervention.

8. Because of the connective tissuedysplasia, children should be moni-tored for scoliosis, which occurs inapproximately 20% of affected chil-dren. However, when present, it isusually mild and does not requiretreatment.

HEALTH SUPERVISION FROM 13 TO21 YEARS OR OLDER:ADOLESCENCE TO EARLYADULTHOOD (TABLE 2)

1. Hyperactivity may decrease duringadolescence, but attentional prob-lems and impulsivity frequentlypersist andmay continue to need tobe addressed behaviorally andmedically.

2. Assess adolescents for seizures, es-pecially atypical seizures, particu-larly if intellectual performance isdecreasing, although seizures tendto decrease during this time period.

3. Reassure parents that macro-orchidism will persist. Males (espe-cially with a premutation or mosa-icism) and females with fragile Xsyndrome can reproduce. Only apremutation will be present in thesperm of a male who has a full mu-tation, in contrast to other tissues,because a full mutation cannot bemaintained in spermatogenesis;therefore, fertility is decreased inmales.

4. The adolescent growth spurt maybe slightly less compared with un-affected children, although thetiming is normal. Psychosocial de-velopment, physical sexual devel-opment,35 and fertility should bediscussed, as well as the need forappropriate supervision and birthcontrol. Counseling should be tai-lored appropriately to cognitivelevel.

5. Genetic mechanisms responsible forfragile X syndrome should be dis-cussed with people with full muta-tions and premutations, and the riskof havinganaffectedoffspringshouldbe reviewed. Males who are of repro-ductive age and have nonmosaic fullmutations are infertile. Females withfull mutations are fertile. Femaleswith premutations are at increasedrisk of premature ovarian insuffi-

ciency, whereas femaleswith fullmu-tations are not. Males who are pre-mutation carriers have no knownfertility problems.

6. Determine if behavioral problemscontinue to represent a concern,and pursue behavioral/psychologi-cal intervention if indicated.

7. Discuss the availability and need forvocational training and group homeplacement if appropriate.

8. Monitor for a cardiac murmur orclick; if either is heard, pursue acardiology evaluation (see recom-mendation 1 in “Health Supervisionin Adulthood”).

9. Facilitate transition to adult medi-cal care as appropriate or desired.

10. Agencies that serve people withdevelopmental disabilities arepresent in most states and mayprovide respite for parents, adultday care programs, and personalassistance and nursing servicesas needed.

HEALTH SUPERVISION INADULTHOOD (TABLE 2)

During the transition from pediatric toadult medical care, the pediatriciancan be a valuable source of informa-tion to the affected person’s newprimary care physician and/orobstetrician/gynecologist. The follow-ing information about fragile X syn-drome can be communicated to facili-tate the care of an affected adult:

1. Mitral valve prolapse occurs in ap-proximately 50% of affected adults.Mild aortic root dilatation also hasbeen reported, although it has notbeen documented to enlarge. In ad-dition, hypertension is common inadulthood.

2. Up to 20% of women with a premu-tation will develop prematuremenopause before 40 years of age.

3. There is a greater risk of emotionalproblems in affected females, espe-


cially at times of hormonalchanges or estrogen deficiency,such as menopause, the postpar-tum period, and during menstrualperiods.

4. Genetic counseling should be pro-vided to review the risk for havingan offspring with either a premuta-tion or full mutation and optionsavailable for family planning. An in-creased risk of twinning alsoshould be discussed with femaleswho have a premutation.

5. Men and, to a lesser degree, womenwith a premutation are at in-creased risk of developing FXTAS af-ter 50 years of age. Awareness ofthis risk, particularly in a man

with a premutation, warrantsclose monitoring for symptoms,especially when approaching 50years of age.

People with fragile X syndrome andFMR1–related disorders face chal-lenges throughout their entire lives.Therefore, coordinating medical, de-velopmental, and behavioral serviceswith available community resourcescanmaximize the potential for affectedpeople and minimize the stressorsfaced by other family members.

LEAD AUTHORSJoseph H. Hersh, MDRobert A. Saul, MD

COMMITTEE ON GENETICS, 2009–2010Howard M. Saal, MD, Chairperson

Stephen R. Braddock, MDGregory M. Enns, MB, ChBJeffrey R. Gruen, MDJames M. Perrin, MDRobert A. Saul, MDBeth Anne Tarini, MD

FORMER COMMITTEE ON GENETICSMEMBERJoseph H. Hersh, MD

LIAISONSJames W. Hanson, MD – American College ofMedical GeneticsMichele Ann Lloyd-Puryear, MD, PhD – HealthResources and Services AdministrationThomas J. Musci, MD – American College ofObstetricians and GynecologistsSonja Ann Rasmussen, MD, MS – Centers forDisease Control and Prevention

STAFFPaul Spire

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